EP4735120A2 - Chemically induced reprogramming to reverse aging - Google Patents

Abstract

Provided herein are methods of rejuvenating, restoring cellular function to, decreasing the biological age of, decreasing the apparent chronological age of, and reprogramming cells, organs, and tissues, using chemical cocktails comprising two or more compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. Also provided herein are methods of treating a disease, methods of monitoring cellular aging, and pharmaceutical compositions and kits using two or more compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

Description

CHEMICALLY INDUCED REPROGRAMMING TO REVERSE AGING R^ELATED A^PPLICATIONS [0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N.63/511,601, filed June 30, 2023, which is incorporated herein by reference. GOVERNMENT SUPPORT [0002] This invention was made with government support under AG019719 and AG058605 and AG028730 and HG011850 awarded by National Institutes of Health (NIH). The government has certain rights in this invention. BACKGROUND OF THE INVENTION [0003] In many animals, including vertebrates, vital organs have a limited intrinsic capacity for regeneration and repair. Acute injury and chronic disorders can damage vital organs and tissues, including the brain. Mature somatic cells, however, often cannot survive these insults, and even if they do, they are unable to self-renew and transdifferentiate to replace damaged cells. Furthermore, cells that are capable of self-renewal can be limited in quantity, have limited capacity and are susceptible to damage, especially with age. In contrast to somatic cells from adults, cells from individuals that are chronologically closer to fertilization, such as those from embryos and infants, display cellular youthfulness and have a greater capacity to resist injury and stress, heal, renew, and regenerate organs and tissues. Thus, compositions and methods directed at rejuvenating cells, thereby restoring them from an aged, mature state to a younger, more vital state, have long been sought to treat certain injuries and diseases, as well as generally reverse and prevent aging in entire organisms. [0004] There are two types of information in the body: digital and analog. DNA is digital information and the epigenome is analog information. Analog information typically does not last as long as digital, nor can analog information generally be copied with high fidelity compared to digital information. This has consequences for how long organisms live and thrive. [0005] Several “hallmarks of aging” are cited as key contributors to the systemic deterioration of tissue function over time [1,2]. Of the aging hallmarks, there is strong evidence that a loss of epigenetic information and a smoothening of the epigenetic landscape, leading to changes in gene expression and a loss of cell identity, are among the main causes of aging [3–7]. The Information Theory of Aging states that a loss of information, particularly epigenetic information, causes a cascade of events that instigate the emergence of additional aging hallmarks, including mitochondrial dysfunction, inflammation, and cellular senescence [5,7,8]. The breakdown of these processes leads to a progressive decline in cell and tissue function, which manifests as aging and age-related diseases. It has previously been shown that DNA double-strand breaks and cellular injury are a major cause of

1/240 12591029. H0824.70430WO00 epigenetic information loss, leading to a decline in health of the organism, with increased frailty and vulnerability to disease [5]. [0006] Cellular senescence is a state of permanent cell cycle arrest that facilitates wound repair, tissue remodeling, and avoidance of cancer by halting proliferation in aged and damaged cells [9]. Senescence is associated with alterations in cell morphology, chromatin architecture, and the release of inflammatory factors in a process referred to as the senescence associated secretory phenotype (SASP). The transition to cellular senescence can be initiated by telomere shortening, DNA damage, cytoplasmic DNA, or a loss of epigenetic information [7,10]. The accumulation of senescent cells with age increases inflammation and reactive oxygen species both locally and across the organism, contributing to a broad range of age-related diseases, from macular degeneration to increased blood pressure [11]. [0007] Starting in 1962, Gurdon and others demonstrated that the nuclei of adult cells, such as those from intestinal cells, contain the necessary information to generate new individuals with normal lifespans [12]. Then in 2006, Takahashi and Yamanaka showed that by expressing four transcription factors – OCT3/4, SOX2, KLF4 and c-MYC(OSKM) – it is possible to epigenetically reset adult cells in vitro to erase cellular identity then coax them into myriad cell types [12–15]. These findings began the field of stem cell reprogramming, with a string of publications in the 2000s showing that, through transient expression or varying the cocktail of Yamanaka factors in vitro, the identities of adult cells could be erased back to a pluripotent stem cell stage [8,16–18]. [0008] The remarkable potency of the Yamanaka factors raised a significant question: is it possible to reverse cellular aging safely without compromising cellular identity, as the latter is known to lead to uncontrolled cell growth and tumorigenesis, which can swiftly endanger the life of the individual [16]. It has been confirmed that it is possible to improve the function of tissues in vivo by pulsing the expression of OSKM, or expressing only OSK continuously [8,16,17]. In the optic nerve, the expression of Yamanaka factors has been shown to reset youthful DNA methylomes and gene expression patterns, restoring vision in old and glaucomatous mice [8]. Numerous tissues, including brain tissue, kidney, and muscle, have now been safely reprogrammed, and the expression of OSK throughout the entire body of mice is known to extend their lifespan [19]. Together, these results suggest the existence of a “back-up copy” of a youthful epigenome, one that can be reset via partial reprogramming to regain tissue function without erasing cellular identity or causing tumorigenesis [7,8,16]. [0009] Despite the promise of partial reprogramming to reverse aging and treat age-related diseases in humans, translational applications heavily rely on the delivery of genetic material via either adeno- associated viruses (AAV) or lipid nanoparticles [8,20]. These approaches, however, face barriers, especially for whole-body rejuvenation, including high-cost, regulatory stipulations, and unanswered questions about safety and long-term effectiveness.

2/240 12591029. H0824.70430WO00 [0010] Aging was once thought of as a process driven by mutations in the genetic material of a cell. This has largely been abandoned as an explanation. A major cause of aging is now thought to be due to epigenetic changes that cause cells to transcribe the wrong genes at the wrong time, a process that becomes more dysfunctional over time, leading to diseases, an inability to heal and eventually to death. The Yamanaka factors (OCT4, SOX2, c-Myc, and KLF4) have previously been shown to induce pluripotency in vitro (Takahashi et al., Cell.2006 Aug 25;126(4):663-76) and reverse the DNA methlylation clock of aging (Horvath, Genome Biol.2013). Nanog and Lin28 can help induce pluripotency together with Yamanaka factors. And Tet1, NR5A-2, Sall4, and NKX3-1 can replace Oct4 (Gao et al., Cell Stem Cell 12, 1–17, April 4, 2013; and Mai et al., Nature Cell Biology 20, 900–908, 2018). Expression of the original four transcription factors in transgenic mice, however, induces teratomas in vivo, along with other acute toxicities like dysplasia in the intestinal epithelium, that can kill an animal in a few days (Abad et al., Nature.2013 Oct 17;502(7471):340-5). Therefore, non-toxic and efficient methods of cellular reprogramming are needed. S^{UMMARY OF THE} I^NVENTION [0011] The inventors have unexpectedly discovered that it is possible to reverse aspects of aging using chemicals, such as small molecules, rather than genetic means. In connection with this discovery, disclosed herein are a variety of novel chemical cocktails capable of rejuvenating cells and reversing transcriptomic age to a similar extent as OSK overexpression, and methods and uses of the same, as well as novel screening methods, including a quantitative nucleocytoplasmic compartmentalization assay (NCC) that can readily distinguish between young, old, and senescent cells [24]. An advantage of the present disclosure is that the compositions, methods, uses allow for the safe mimicking of OSK’s rejuvenating effects, which can allow for reduction of the cost and timelines for the development of regenerative medicines. [21–23]. [0012] The cellular aging process has been postulated to be caused by the loss of both genetic and epigenetic information. While previous studies have hypothesized that aging is caused primarily by the loss of genetic information (most commonly in the form of genetic mutations such as substitutions and deletions in an organism’s genome), the systems, compositions, uses, kits, and methods of the present disclosure are informed by the unexpected finding that aging in the central nervous system is primarily driven by a loss in the particular epigenetic information that is established closer to fertilization and final differentiation of particular cells. Epigenetic information, which commonly takes the form of covalent modifications to DNA, such as 5-methylcytosine(5mC), hydroxymethylcytosine (5hmeC), 5-formylcytosine (fC), 5-carboxylcytosine (caC), and adenine methylation, and to certain proteins, such as lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation of histone proteins, is sometimes referred to as the “analog” information of the cell. The loss of this analog information can

3/240 12591029. H0824.70430WO00 result in dysregulation of vital cellular processes, such as the processes that maintain cell identity, causing cells to exhibit traits that are typically associated with aging, such as senescence. [0013] The present disclosure stems from the unexpected discovery that, in some embodiments, chemical cocktails comprising two or more compounds can reverse the age of human fibroblasts and restore genome-wide transcript profiles. Surprisingly, in some embodiments, as described herein, this rejuvenation can occur in less than a week and without erasing cellular identity, a crucial aspect of partial epigenetic reprogramming. Thus, reversal of cellular aging by partial reprogramming and the restoration of youth, similar to the effect of the Yamanaka factors, Oct4, Sox2, and Klf4 (OSK), can be achieved by chemical means. See, e.g., International Publication No. WO 2020/069373, the contents of which are incorporated herein by reference. [0014] Aspects of the present disclosure provide several methods, compositions, uses, and kits, that may be useful for efficient rejuvenation of a cell, tissue, and/or organ. In some embodiments, the cell, tissue, and/or organ is the skin. In some embodiments, the cell, tissue, and/or organ is in the central nervous system. In some embodiments, the organ is the eye. In some embodiments, the organ is the ear. In some embodiments, the central nervous system does not include the retina. In some embodiments, the cell, tissue, and/or organ in the central nervous system is a brain cell, brain tissue, and/or the brain. In come embodiments, the cell, tissue, and/or organ is in a human subject. In some embodiments, the cell, tissue, and/or organ is in a non-human subject. In some embodiments, the use is for a nutraceutical. In some embodiments, the use is for improvement of cosmetic beauty. [0015] In one aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

4/240 12591029. H0824.70430WO00 basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [0016] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

5/240 12591029. H0824.70430WO00 Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [0017] In another aspect, the present disclosure provides methods of decreasing the biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

6/240 12591029. H0824.70430WO00 linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [0018] In another aspect, the present disclosure provides methods of decreasing the apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and

7/240 12591029. H0824.70430WO00 lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [0019] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

8/240 12591029. H0824.70430WO00 [0020] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0021] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

9/240 12591029. H0824.70430WO00 ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0022] In another aspect, the present disclosure provides methods of decreasing the biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

10/240 12591029. H0824.70430WO00 butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0023] In another aspect, the present disclosure provides methods of decreasing the apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

11/240 12591029. H0824.70430WO00 smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0024] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

12/240 12591029. H0824.70430WO00 [0025] In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium ascorbate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium chloride. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium orotate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium carbonate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium citrate. [0026] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [0027] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [0028] In another aspect, the present disclosure provides methods of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [0029] In another aspect, the present disclosure provides methods of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [0030] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [0031] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. [0032] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. [0033] In another aspect, the present disclosure provides methods of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

13/240 12591029. H0824.70430WO00 [0034] In another aspect, the present disclosure provides methods of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. [0035] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with lithium ascorbate. [0036] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

14/240 12591029. H0824.70430WO00 [0037] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0038] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [0039] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof lithium ascorbate. [0040] In another aspect, the present disclosure provides a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and

15/240 12591029. H0824.70430WO00 a second reporter gene linked to nuclear export signal. [0041] In another aspect, the present disclosure provides a method of monitoring cellular aging, the method comprising: (a) providing a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal; (b) contacting the cell with at least one test agent; (c) measuring a first signal from a first protein produced by the first reporter gene; (d) measuring a second signal from a second protein produced by the second reporter gene; (e) comparing the first signal and the second signal to assess the distribution of the first protein and the second protein in the cell. [0042] In another aspect, the present disclosure provides a pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

16/240 12591029. H0824.70430WO00 linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [0043] In another aspect, the present disclosure provides a pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0044] In another aspect, the present disclosure provides a kit comprising (a) a container housing a pharmaceutical composition comprising two or more compounds described herein (e.g., laduviglusib,

17/240 12591029. H0824.70430WO00 RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof); and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof. [0045] In another aspect, the present disclosure provides a pharmaceutical composition for use in rejuvenating a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and

18/240 12591029. H0824.70430WO00 lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [0046] In another aspect, the present disclosure provides a pharmaceutical composition for use in rejuvenating a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0047] The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, Examples, Figures, and Claims. [0048]

19/240 12591029. H0824.70430WO00 DEFINITIONS [0049] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987. [0050] Compounds described herein may comprise one or more asymmetric centers, and thus may exist as stereoisomers, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Compounds may exist as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0051] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,

20/240 12591029. H0824.70430WO00 glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N⁺(C_1–4 alkyl)₄- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [0052] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates. [0053] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R⋅x H₂O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R⋅0.5 H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H2O) and hexahydrates (R⋅6 H2O)). [0054] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions. [0055] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain

21/240 12591029. H0824.70430WO00 embodiments, at least one of the components is a solvent. A co-crystal of a compound and an acid is different from a salt formed from a compound and the acid. In the salt, a compound is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound easily occurs at room temperature. In the co-crystal, however, a compound is complexed with the acid in a way that proton transfer from the acid to a herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is substantially no proton transfer from the acid to a compound. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound. [0056] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations. [0057] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” [0058] Stereoisomers that are not mirror images of one another are termed “diastereomers,” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.” [0059] The term “isotopically labeled compound” refers to a derivative of a compound that only structurally differs from the compound in that at least one atom of the derivative includes at least one isotope enriched above (e.g., enriched 3-, 10-, 30-, 100-, 300-, 1,000-, 3,000- or 10,000-fold above) its natural abundance, whereas each atom of the compound includes isotopes at their natural abundances. In certain embodiments, the isotope enriched above its natural abundance is ²H. In certain embodiments, the isotope enriched above its natural abundance is ¹³C, ¹⁵N, or ¹⁸O. [0060] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include choline ester derivatives and the like, N-

22/240 12591029. H0824.70430WO00 alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. [0061] The term “small molecule” refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (e.g.., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and/or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present disclosure. [0062] The terms “pharmaceutical composition,” “composition,” and “formulation” are used interchangeably. [0063] The terms “administer,” “administering,” or “administration,” as used herein, refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described

23/240 12591029. H0824.70430WO00 herein, or a composition thereof, alone, or in combination to any cell, tissue, organ, and/or subject. Any of the compounds described herein, or a composition thereof, alone, or in combination may be administered intravenously, intradermally, intraarterially, intralesionally, intratumorally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, intraperitoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, topically, locally, systemically, injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, in creams, in lipid compositions (e.g., liposomes), or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art (see, for example, Remington’s Pharmaceutical Sciences (1990), incorporated herein by reference). [0064] The term “epigenome” or “epigenetics” refers to the modification and structural changes within a cell that control the expression of nucleic acids (e.g., engineered nucleic acids) or genomic information in a cell. Changes to the epigenome occur during, and drive the processes of embryonic development, disease progression, and aging. [0065] The term “epigenetic clock” may refer to an age estimator or an innate biological process. In some embodiments, rejuvenating or reversing the epigenetic clock refers to reducing the estimated age of a cell, tissue, organ, or a subject. The epigenetic clock may be partially or fully reversed or rejuvenated by any of the methods described herein. In some embodiments, an age estimator is an epigenetic age estimator. For example, an epigenetic age estimator may be sets of CpG dinucleotides that when used in combination with a mathematical algorithm may be used to estimate age of a DNA source, including cells, organs, or tissues. In some embodiments, an age estimator is a DNA methylation-based (DNAm) age estimator. In some embodiments, a DNAm age estimator is calculated as an age correlation using Pearson correlation coefficient r, between DNA methylation- based (DNam) age (also known as estimated age) and chronological age. In some embodiments, the DNA methylation-based (DNAm) age estimator is a single-tissue DNA methylation-based age estimator. In some embodiments, the DNA methylation-based age estimator is a multi-tissue DNA methylation-based age estimator. In some embodiments, the DNAm age estimator is DNAm PhenoAge. See, e.g., Horvath and Raj, Nat Rev Genet.2018 Jun;19(6):371-384 and Levine et al., Aging (Albany NY).2018 Apr 18;10(4):573-591. [0066] “Epigenetic information” as used herein includes covalent modifications to DNA, such as 5- methylcytosine(5mC), hydroxymethylcytosine (5hmeC), 5-formylcytosine (fC), 5-carboxylcytosine (caC), and adenine methylation and to certain proteins, such as lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation of histone proteins, and the 3D architecture of cells, including TADs (topologically associated domains) and compartments. Epigenetic information is sometimes referred to as the “analog” information of the cell.

24/240 12591029. H0824.70430WO00 [0067] “Restoring the expression” of at least one gene to youthful levels is meant to include increasing the expression of a downregulated gene or decreasing the expression of an upregulated gene that changes during aging. In some embodiments, the at least one gene is at least one gene selected from the group consisting of CDKN1A, IL6, CCL2, MMP3, LMNB1, and EZH2. [0068] As used herein, the term “cell” is meant not only to include an individual cell but refers also to the particular tissue or organ from which it originates. [0069] The term “cellular senescence” or “senescent cell” refers to a cell that has exited the cell cycle, displays epigenetic markers consistent with senescence, or expressing senescence cell markers (e.g., senescence-associated beta-galactosidase, or inflammatory cytokines). Cellular senescence may be partial or complete. [0070] The term “gene expression” refers to the degree to which certain genes or all genes in a cell or tissue are transcribed into RNA. In some instances, the RNA is translated by the cell into a protein. The epigenome dictates gene expression patterns. [0071] The term “cellular reprogramming” refers to the process of altering the epigenome of a cell using reprogramming factors (e.g., reversing or preventing epigenetic changes in cells that are causes of dysfunction, deterioration, cell death, senescence, or aging). Cellular reprogramming may be complete reprogramming, such that a differentiated cell (e.g., somatic cell) is reprogrammed to a pluripotent stem cell. Cellular reprogramming may be incomplete, such that a differentiated cell (e.g., somatic cell) retains its cellular identity (e.g., lineage-specific stem cell). Cellular reprogramming may be incomplete, e.g., a stem cell is not created, such that a cell is rejuvenated, or takes on more youthful attributes (e.g., increased survival, reduced inflammation, or ability to divide). Cellular reprogramming may provide additional cellular functions, or prevent cellular aging (e.g., transdifferentiation, or transition into cellular senescence). Cellular reprogramming may induce temporary or permanent gene expression changes. In some embodiments, incomplete cellular reprogramming is shown by the lack of Nanog expression. In some embodiments, cellular reprogramming prevents senescence from occurring. [0072] The term “rejuvenating a cell” as used herein is meant to include preventing or reversing the cellular causes of aging without inducing a pluripotent state. A rejuvenated cell as used herein includes for example a cell that is not a diseased cell. [0073] A “pluripotent state” as used herein is meant to include a state in which the cell expresses at least one stem cell marker, such as, but not limited to, Esrrb, Nanog, Lin28, TRA-1-60/TRA-1- 81/TRA-2-54, SSEA1, or SSEA4. Methods of measuring the expression of stem cell markers on the cell are known in the art and include the methods described herein. [0074] The term “transdifferentiation” refers to a process in which one cell type is changed into another cell type without entering a pluripotent state. Transdifferentiation may also be referred to as lineage reprogramming or lineage conversion. See, e.g., Cieślar-Pobuda et al., Biochim Biophys Acta Mol Cell Res.2017 Jul;1864(7):1359-1369, which is incorporated herein by reference in its entirety.

25/240 12591029. H0824.70430WO00 [0075] The term “central nervous system” refers to the part of the nervous system that includes the brain, cochlea, the spinal cord, the medulla, the pons, the cerebellum, the midbrain, the diencephalon, and the cerebral hemispheres. In some embodiments, the central nervous system includes the cranial nerves. In some embodiments, the central nervous system excludes the eye. In some embodiments, the central nervous system excludes the retina, uvea, pupil, lens, cornea, and/or sclera. In some embodiments, a cell or tissue is derived from the central nervous system. Non-limiting examples of cells from the central nervous system include neurons and glial cells. In some embodiments, a neuron is an excitatory neuron. In some embodiments, a cell from the central nervous system is a brain cell. In some embodiments, a brain cell is a neuron or a glial cell. In some embodiments, a cell from the central nervous system is a neuron, glial cell, or choroid plexus cell. In some embodiments, a glial cell is an astrocyte, oligodendrocyte, ependymal cell, or microglia cell. In some embodiments, a neuron is a sensory neuron, a motor neuron or an interneuron. [0076] The terms “condition,” “disease,” and “disorder” are used interchangeably. Non-limiting examples of conditions, diseases, and disorders include acute injuries, neurodegenerative diseases, chronic diseases, proliferative diseases, cardiovascular diseases, genetic diseases, inflammatory diseases, autoimmune diseases, neurological diseases, hematological diseases, painful conditions, psychiatric disorders, metabolic disorders, chronic diseases, cancers, aging, age-related diseases, and diseases affecting any tissue in a subject. For example, age-related conditions include, heart failure, stroke, heart disease, atherosclerosis, neurodegenerative diseases (e.g., FTO, ALS, Alzheimer’s Disease, Parkinson’s Disease, dementia, Friedreich ataxia, amyotrophic lateral sclerosis, or vascular dementia), cognitive decline, memory loss, diabetes, osteoporosis, arthritis, muscle loss, hearing loss (partial or total), eye-related conditions (e.g., poor eye sight or retinal disease), glaucoma, a progeroid syndrome (e.g., Hutchinson-Gilford progeria syndrome), and cancer. In some embodiments, an age- related condition is senescence. As a non-limiting example, senescence of glial cells may be a cause of Alzheimer’s disease. See e.g., Bussian, et al., Nature.2018 Oct;562(7728):578-582. In some instances, the disease is nerve damage. [0077] In some instances, a condition increases the DNA methylation-based age of a cell, a tissue, an organ, and/or a subject relative to a control. In some embodiments, the cell is a cell of the central nervous system. In some instances, a condition increases the DNA methylation-based age of a cell, a tissue, an organ, and/or a subject by at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1,000% relative to a control. In some instances, the control is a cell, a tissue, an organ, and/or a subject that does not have the condition. In some instances, the control is the same cell, tissue, organ, and/or subject prior to having the condition. Without being bound by a particular theory, any of the methods described herein may be useful in decreasing the DNA methylation-based age of a diseased cell, a diseased tissue, a diseased organ, and/or a subject who has, is at risk for, or is

26/240 12591029. H0824.70430WO00 suspected of having a disease. In some instances, the disease increases the DNA-methylation-based age of the cell, tissue, organ, and/or subject. In some instances, the disease is an injury. [0078] In some instances, the condition is aging. In some instances, aging is driven by epigenetic noise. See, e.g., Oberdoerffer and Sinclair. Nat Rev Mol Cell Biol 8, 692-702, doi:10.1038/nrm2238 (2007); Oberdoerffer et al. Cell 135, 907-918, doi:10.1016/j.cell.2008.10.025 (2008). Without being bound by a particular theory, mammalian cells may retain a faithful copy of epigenetic information from earlier in life, analogous to Shannon’s “observer” system in Information Theory, essentially a back-up copy of the original signal to allow for its reconstitution at the receiving end if information is lost or noise is introduced during transmission. See, e.g., Shannon, The Bell System Technical Journal 27, 379-423 (1948) for a description of the observer system. [0079] As used herein, an “ocular disease” or “eye disease” is a disease or condition of the eye. Non- limiting examples of conditions that affect the eye include Ectropion, Lagophthalmos, Blepharochalasis, Ptosis, Stye, Xanthelasma, Dermatitis, Demodex, leishmaniasis, loiasis, onchocerciasis, phthiriasis, (herpes simplex), leprosy, molluscum contagiosum, tuberculosis, yaws, zoster, impetigo, Dacryoadenitis, Epiphora, exophthalmos, Conjunctivitis, Scleritis, Keratitis, Corneal ulcer / Corneal abrasion, Snow blindness/Arc eye, Thygeson's superficial punctate keratopathy, Corneal neovascularization, Fuchs’ dystrophy, Keratoconus, Keratoconjunctivitis sicca, Iritis, iris, Uveitis, Sympathetic ophthalmia, Cataract, lens, Chorioretinal inflammation, Focal chorioretinal inflammation, chorioretinitis, choroiditis, retinitis, retinochoroiditis, Disseminated chorioretinal inflammation, exudative retinopathy, Posterior cyclitis, Pars planitis, chorioretinal inflammations, Harada’s disease, Chorioretinal inflammation, choroid, Chorioretinal scars, Macula scars, posterior pole (postinflammatory) (post-traumatic), Solar retinopathy, Choroidal degeneration, Atrophy, Sclerosis, angioid streaks, choroidal dystrophy, Choroideremia, choroidal, areolar, (peripapillary), Gyrate atrophy, choroid, ornithinaemia, Choroidal haemorrhage, Choroidal detachment, Chorioretinal, Chorioretinal inflammation, infectious and parasitic diseases, Chorioretinitis, syphilitic, toxoplasma, tuberculosis, chorioretinal, Retinal detachment, retina, choroid, distorted vision, Retinoschisis, Hypertensive retinopathy, Diabetic retinopathy, Retinopathy, Retinopathy of prematurity, Age-related macular degeneration, macula, Macular degeneration, Bull's Eye Maculopathy, Epiretinal membrane, Peripheral retinal degeneration, Hereditary retinal dystrophy, Retinitis pigmentosa, Retinal haemorrhage, retinal layers, Central serous retinopathy, Retinal detachment, retinal disorders, Macular edema, macula, Retinal disorder, Diabetic retinopathy, Glaucoma, optic neuropathy, ocular hypertension, open-angle glaucoma, angle-closure glaucoma, Normal Tension glaucoma, open-angle glaucoma, angle-closure glaucoma, Floaters, Leber’s hereditary optic neuropathy, Optic disc drusen, Strabismus, Ophthalmoparesis, eye muscles, Progressive external ophthaloplegia, Esotropia, Exotropia, Disorders of refraction, accommodation, Hypermetropia, Myopia, Astigmatism, Anisometropia, Presbyopia, ophthalmoplegia, Amblyopia, Leber's congenital amaurosis, Scotoma, Anopsia, Color blindness, Achromatopsia / Maskun, cone

27/240 12591029. H0824.70430WO00 cells, Nyctalopia, Blindness, River blindness, Micropthalmia/coloboma, optic nerve, brain, spinal cord, Red eye, Argyll Robertson pupil, pupils, Keratomycosis, Xerophthalmia, and Aniridia. In some embodiments, the ocular disease is acute or chronic eye injury. [0080] In some embodiments, the ocular disease is a scratched cornea. [0081] In some embodiments, the ocular disease is glaucoma. [0082] In some embodiments, an ocular disease is a corneal disease (e.g., a disease affecting the cornea or corneal cells). In some embodiments, an ocular disease is acanthamoeba keratitis, ectropion, lagoph amblyopia, anisocoria, astigmatism, Bell’s Palsy, blepharitis, blurry vision, burning eyes, cataracts, macular degeneration, age-related macular degeneration, diabetic eye disease, glaucoma, dry eye, poor vision (e.g., low vision), astigmatism, blepharitis, cataract, chalazion, conjunctivitis, diabetic retinopathy, dry eye, glaucoma, keratitis, keratonconus, macular degeneration, ocular hypertension, pinquecula, pterygium, retinitis pigmentosa, or ocular cancer (e.g., retinoblastoma, melanoma of the eye, lymphoma of the eye, medulloepithelioma, squamous cell cancer of the conjunctiva). Examples of corneal diseases include, but are not limited to, corneal neovascularization (NV), corneal dystrophy, corneal inflammation, corneal abrasion, and corneal fibrosis. In some embodiments, the ocular disease is Keritaconus. In some embodiments, an ocular disease is macular degeneration. Additional non-limiting examples of eye diseases may be found in the International Statistical Classification of Diseases and Related Health Problems (e.g., VII Diseases of the eye and adnexa). [0083] An ocular disease may affect any part of the eye and/or adnexa. In some embodiments, the ocular disease is a disorder of the eyelid, lacrimal system and/or orbit. In some embodiments, the ocular disease is a disorders of conjunctiva. In some embodiments, the ocular disease is a disorder of sclera, cornea, iris, and/or ciliary body. In some embodiments, the ocular disease is a disorder of the lens. In some embodiments, the ocular disease is a disorder of choroid and/or retina. In some embodiments, the ocular disease is glaucoma. In some embodiments, the ocular disease is a disorder of vitreous body and/or globe. In some embodiments, the ocular disease is a disorder of optic nerve and/or visual pathways. In some embodiments, the ocular disease is a disorder of ocular muscles, binocular movement, accommodation, and/or refraction. In some embodiments, the ocular disease is a visual disturbance and/or blindness. In some embodiments, the ocular disease is associated with aging, for example, vision loss associated with aging, decline in visual acuity associated with aging, and/or decline in retinal function. [0084] Any suitable method may be used to measure ocular function. Non-limiting examples include visual acuity tests, pattern electroretinograms, and pathology. [0085] The term “genetic disease” refers to a disease caused by one or more abnormalities in the genome of a subject, such as a disease that is present from birth of the subject. Genetic diseases may be heritable and may be passed down from the parents’ genes. A genetic disease may also be caused by mutations or changes of the DNAs and/or RNAs of the subject. In such cases, the genetic disease

28/240 12591029. H0824.70430WO00 will be heritable if it occurs in the germline. Exemplary genetic diseases include, but are not limited to, Aarskog-Scott syndrome, Aase syndrome, achondroplasia, acrodysostosis, addiction, adreno- leukodystrophy, albinism, ablepharon-macrostomia syndrome, alagille syndrome, alkaptonuria, alpha- 1 antitrypsin deficiency, Alport’s syndrome, Alzheimer’s disease, asthma, autoimmune polyglandular syndrome, androgen insensitivity syndrome, Angelman syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention deficit hyperactivity disorder (ADHD), autism, baldness, Batten disease, Beckwith-Wiedemann syndrome, Best disease, bipolar disorder, brachydactyl), breast cancer, Burkitt lymphoma, chronic myeloid leukemia, Charcot-Marie-Tooth disease, Crohn’s disease, cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer, congenital adrenal hyperplasia, Cornelia de Lange syndrome, Costello syndrome, Cowden syndrome, craniofrontonasal dysplasia, Crigler- Najjar syndrome, Creutzfeldt-Jakob disease, cystic fibrosis, deafness, depression, diabetes, diastrophic dysplasia, DiGeorge syndrome, Down’s syndrome, dyslexia, Duchenne muscular dystrophy, Dubowitz syndrome, ectodermal dysplasia Ellis-van Creveld syndrome, Ehlers-Danlos, epidermolysis bullosa, epilepsy, essential tremor, familial hypercholesterolemia, familial Mediterranean fever, fragile X syndrome, Friedreich’s ataxia, Gaucher disease, glaucoma, glucose galactose malabsorption, glutaricaciduria, gyrate atrophy, Goldberg Shprintzen syndrome (velocardiofacial syndrome), Gorlin syndrome, Hailey-Hailey disease, hemihypertrophy, hemochromatosis, hemophilia, hereditary motor and sensory neuropathy (HMSN), hereditary non polyposis colorectal cancer (HNPCC), Huntington’s disease, immunodeficiency with hyper-IgM, juvenile onset diabetes, Klinefelter’s syndrome, Kabuki syndrome, Leigh’s disease, long QT syndrome, lung cancer, malignant melanoma, manic depression, Marfan syndrome, Menkes syndrome, miscarriage, mucopolysaccharide disease, multiple endocrine neoplasia, multiple sclerosis, muscular dystrophy, myotrophic lateral sclerosis, myotonic dystrophy, neurofibromatosis, Niemann-Pick disease, Noonan syndrome, obesity, ovarian cancer, pancreatic cancer, Parkinson’s disease, paroxysmal nocturnal hemoglobinuria, Pendred syndrome, peroneal muscular atrophy, phenylketonuria (PKU), polycystic kidney disease, Prader-Willi syndrome, primary biliary cirrhosis, prostate cancer, REAR syndrome, Refsum disease, retinitis pigmentosa, retinoblastoma, Rett syndrome, Sanfilippo syndrome, schizophrenia, severe combined immunodeficiency, sickle cell anemia, spina bifida, spinal muscular atrophy, spinocerebellar atrophy, sudden adult death syndrome, Tangier disease, Tay-Sachs disease, thrombocytopenia absent radius syndrome, Townes-Brocks syndrome, tuberous sclerosis, Turner syndrome, Usher syndrome, von Hippel-Lindau syndrome, Waardenburg syndrome, Weaver syndrome, Werner syndrome, Williams syndrome, Wilson’s disease, xeroderma piginentosum, a progeroid syndrome (e.g., Hutchinson- Gilford progeria syndrome), and Zellweger syndrome. [0086] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal

29/240 12591029. H0824.70430WO00 location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases. [0087] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue. [0088] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal

30/240 12591029. H0824.70430WO00 adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non- Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T- cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian

31/240 12591029. H0824.70430WO00 embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva). [0089] The term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,

32/240 12591029. H0824.70430WO00 epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation. In some embodiments, the inflammatory disease is inflammaging (e.g., inflammation that is a side effect of aging). [0090] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardiomyopathy. [0091] The term “skin” refers to the external tissue layer in humans and animals. Typically, the skin forms a protective barrier against water, UV light, pathogens, physical injury, and chemical agents. Skin comprises the epidermis, dermis, subcutaneous tissue layer, and associated cells, glands, mucous membranes, and connective tissue. The epidermis is the outermost layer of the skin, comprising five sub-layers: stratum corneum, transparent layer, granular layer, visible layer, and an embryonic (base) layer. The dermis is the inner layer between the epidermis and the subcutaneous tissue layer. The dermis comprises the papillary dermis and the reticular dermis and may include connective tissue, blood vessels, oil and sweat glands, nerves, and hair follicles. The subcutaneous tissue layer (hypodermis) is the innermost layer of the skin, comprising fat and a loose meshwork of connective tissue (e.g., collagen and elastic fibers). In certain embodiments, the term “skin” refers to the stratum corneum. In another embodiment, the term “skin” refers to the dermis. Skin is described in detail in Anatomy, Skin (Integument), H. Yousef, M. Alhajj, and S. Sharma, StatPearls, StatPearls Publishing, 2020. [0092] A “skin condition” refers to a disease or condition affecting the skin. Exemplary skin conditions include skin cancer, lupus, seborrheic dermatitis, tinea, psoriasis, acne, rosacea,

33/240 12591029. H0824.70430WO00 hyperseborrhea, xerosis, atopic dermatitis (eczema), sebaceous hyperplasia, sunburn, an open wound, burns, bed sores, skin ulcers, pruritus (itch), dehydration, or wrinkles. [0093] The term “liver disease” or “hepatic disease” refers to damage to or a disease of the liver. Non- limiting examples of liver disease include intrahepatic cholestasis (e.g., alagille syndrome, biliary liver cirrhosis), fatty liver (e.g., alcoholic fatty liver, Reye’s syndrome), hepatic vein thrombosis, hepatolenticular degeneration (i.e., Wilson’s disease), hepatomegaly, liver abscess (e.g., amebic liver abscess), liver cirrhosis (e.g., alcoholic, biliary, and experimental liver cirrhosis), alcoholic liver diseases (e.g., fatty liver, hepatitis, cirrhosis), parasitic liver disease (e.g., hepatic echinococcosis, fascioliasis, amebic liver abscess), jaundice (e.g., hemolytic, hepatocellular, cholestatic jaundice), cholestasis, portal hypertension, liver enlargement, ascites, hepatitis (e.g., alcoholic hepatitis, animal hepatitis, chronic hepatitis (e.g., autoimmune, hepatitis B, hepatitis C, hepatitis D, drug induced chronic hepatitis), toxic hepatitis, viral human hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), granulomatous hepatitis, secondary biliary cirrhosis, hepatic encephalopathy, varices, primary biliary cirrhosis, primary sclerosing cholangitis, hepatocellular adenoma, hemangiomas, bile stones, liver failure (e.g., hepatic encephalopathy, acute liver failure), angiomyolipoma, calcified liver metastases, cystic liver metastases, fibrolamellar hepatocarcinoma, hepatic adenoma, hepatoma, hepatic cysts (e.g., simple cysts, polycystic liver disease, hepatobiliary cystadenoma, choledochal cyst), mesenchymal tumors (mesenchymal hamartoma, infantile hemangioendothelioma, hemangioma, peliosis hepatis, lipomas, inflammatory pseudotumor), epithelial tumors (e.g., bile duct hamartoma, bile duct adenoma), focal nodular hyperplasia, nodular regenerative hyperplasia, hepatoblastoma, hepatocellular carcinoma, cholangiocarcinoma, cystadenocarcinoma, tumors of blood vessels, angiosarcoma, Karposi’s sarcoma, hemangioendothelioma, embryonal sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, carcinosarcoma, teratoma, carcinoid, squamous carcinoma, primary lymphoma, peliosis hepatis, erythrohepatic porphyria, hepatic porphyria (e.g., acute intermittent porphyria, porphyria cutanea tarda), and Zellweger syndrome. [0094] The term “spleen disease” refers to a disease of the spleen. Example of spleen diseases include, but are not limited to, splenomegaly, spleen cancer, asplenia, spleen trauma, idiopathic purpura, Felty’s syndrome, Hodgkin’s disease, and immune-mediated destruction of the spleen. [0095] The term “lung disease” or “pulmonary disease” refers to a disease of the lung. Examples of lung diseases include, but are not limited to, bronchiectasis, bronchitis, bronchopulmonary dysplasia, interstitial lung disease, occupational lung disease, emphysema, cystic fibrosis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), asthma (e.g., intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma), chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, interstitial lung disease, sarcoidosis, asbestosis, aspergilloma, aspergillosis, pneumonia (e.g., lobar pneumonia, multilobar pneumonia, bronchial pneumonia, interstitial pneumonia), pulmonary fibrosis, pulmonary

34/240 12591029. H0824.70430WO00 tuberculosis, rheumatoid lung disease, pulmonary embolism, and lung cancer (e.g., non-small-cell lung carcinoma (e.g., adenocarcinoma, squamous-cell lung carcinoma, large-cell lung carcinoma), small-cell lung carcinoma). [0096] A “hematological disease” includes a disease which affects a hematopoietic cell or tissue. Hematological diseases include diseases associated with aberrant hematological content and/or function. Examples of hematological diseases include diseases resulting from bone marrow irradiation or chemotherapy treatments for cancer, diseases such as pernicious anemia, hemorrhagic anemia, hemolytic anemia, aplastic anemia, sickle cell anemia, sideroblastic anemia, anemia associated with chronic infections such as malaria, trypanosomiasis, HTV, hepatitis virus or other viruses, myelophthisic anemias caused by marrow deficiencies, renal failure resulting from anemia, anemia, polycythemia, infectious mononucleosis (EVI), acute non-lymphocytic leukemia (ANLL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), polycythemia vera, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, Wilm’s tumor, Ewing’s sarcoma, retinoblastoma, hemophilia, disorders associated with an increased risk of thrombosis, herpes, thalassemia, antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red blood cells such as micro-angiopathic hemolytic anemias, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation, infections by parasites such as Plasmodium, chemical injuries from, e.g., lead poisoning, and hypersplenism. [0097] The term “neurological disease” refers to any disease of the nervous system, including diseases and injuries that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, dementia, Friedreich ataxia, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease. Examples of neurological diseases include, but are not limited to, vascular dementias, stroke, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illnesses include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic

35/240 12591029. H0824.70430WO00 dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes- dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg- Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox- Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor

36/240 12591029. H0824.70430WO00 neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig- Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome. In some embodiments, a neurological disorder affects the central nervous system, which includes the brain and the spinal cord. In some embodiments, a neurological disorder affects neurons. In some embodiments, a neurological disorder affects nerves. In some embodiments, a neurological disorder affects the spinal cord. In some embodiments, a neurological disorder is a brain disease (i.e., a disease affecting the brain). [0098] The term “musculoskeletal disease” or “MSD” refers to an injury and/or pain in a subject’s joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck, and back. In

37/240 12591029. H0824.70430WO00 certain embodiments, an MSD is a degenerative disease. In certain embodiments, an MSD includes an inflammatory condition. Body parts of a subject that may be associated with MSDs include upper and lower back, neck, shoulders, and extremities (arms, legs, feet, and hands). In certain embodiments, an MSD is a bone disease, such as achondroplasia, acromegaly, bone callus, bone demineralization, bone fracture, bone marrow disease, bone marrow neoplasm, dyskeratosis congenita, leukemia (e.g., hairy cell leukemia, lymphocytic leukemia, myeloid leukemia, Philadelphia chromosome-positive leukemia, plasma cell leukemia, stem cell leukemia), systemic mastocytosis, myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, myeloid sarcoma, myeloproliferative disorders, multiple myeloma, polycythemia vera, pearson marrow-pancreas syndrome, bone neoplasm, bone marrow neoplasm, Ewing sarcoma, osteochondroma, osteoclastoma, osteosarcoma, brachydactyly, Camurati-Engelmann syndrome, Craniosynostosis, Crouzon craniofacial dysostosis, dwarfism, achondroplasia, bloom syndrome, Cockayne syndrome, Ellis-van Creveld syndrome, Seckel syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, Werner syndrome, hyperostosis, osteophyte, Klippel-Trenaunay-Weber syndrome, Marfan syndrome, McCune-Albright syndrome, osteitis, osteoarthritis, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, Leri- Weill dyschondrosteosis, osteochondrosis, osteodystrophy, osteogenesis imperfecta, osteolysis, Gorham-Stout syndrome, osteomalacia, osteomyelitis, osteonecrosis, osteopenia, osteopetrosis, osteoporosis, osteosclerosis, otospondylomegaepiphyseal dysplasia, pachydermoperiostosis, Paget disease of bone, Polydactyly, Meckel syndrome, rickets, Rothmund-Thomson syndrome, Sotos syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, syndactyly, Apert syndrome, syndactyly type II, or Werner syndrome. In certain embodiments, an MSD is a cartilage disease, such as cartilage neoplasm, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, or Leri-Weill dyschondrosteosis. In certain embodiments, an MSD is hernia, such as intervertebral disk hernia. In certain embodiments, an MSD is a joint disease, such as arthralgia, arthritis (e.g., gout (e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan syndrome), Lyme disease, osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatic fever, rheumatoid arthritis, Felty syndrome, synovitis, Blau syndrome, nail-patella syndrome, spondyloarthropathy, reactive arthritis, Stickler syndrome, synovial membrane disease, synovitis, or Blau syndrome. In certain embodiments, an MSD is Langer-Giedion syndrome. In certain embodiments, an MSD is a muscle disease, such as Barth syndrome, mitochondrial encephalomyopathy, MELAS syndrome, MERRF syndrome, MNGIE syndrome, mitochondrial myopathy, Kearns-Sayre syndrome, myalgia, fibromyalgia, polymyalgia rheumatica, myoma, myositis, dermatomyositis, neuromuscular disease, Kearns-Sayre syndrome, muscular dystrophy, myasthenia, congenital myasthenic syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis, myotonia, myotonia congenita, spinal muscular atrophy, tetany, ophthalmoplegia, or rhabdomyolysis. In certain embodiments, an MSD is Proteus syndrome. In certain embodiments, an MSD is a rheumatic diseases, such as arthritis (e.g., gout (e.g., Kelley-Seegmiller syndrome, Lesch- Nyhan Lyme disease)), osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatic fever, rheumatoid

38/240 12591029. H0824.70430WO00 arthritis, Felty syndrome, synovitis, Blau syndrome, gout (e.g., Kelley-Seegmiller syndrome, Lesch- Nyhan syndrome), polymyalgia rheumatica, rheumatic fever, rheumatic heart disease, or Sjogren syndrome. In certain embodiments, an MSD is Schwartz-Jampel syndrome. In certain embodiments, an MSD is a skeleton disease, such as Leri-Weill dyschondrosteosis, skeleton malformations, Melnick-Needles syndrome, pachydermoperiostosis, Rieger syndrome, spinal column disease, intervertebral disk hernia, scoliosis, spina bifida, spondylitis, ankylosing spondylitis, spondyloarthropathy, reactive arthritis, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, or spondylosis. In some embodiments, the disease is a musculoskeletal disease. [0099] A “painful condition” includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post–operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre–operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and/or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre–term labor, pain associated with withdrawal symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter’s arthritis), lumbosacral pain, musculo–skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental/maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g., nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition. [00100] The term “psychiatric disorder” refers to a disease of the mind and includes diseases and disorders listed in the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM- IV), published by the American Psychiatric Association, Washington D.C. (1994). Psychiatric disorders include, but are not limited to, anxiety disorders (e.g., acute stress disorder agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, and specific phobia), childhood disorders, (e.g., attention-deficit/hyperactivity disorder, conduct disorder, and oppositional defiant disorder), eating disorders (e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g., depression, bipolar disorder, cyclothymic disorder, dysthymic disorder, and major depressive disorder), personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality

39/240 12591029. H0824.70430WO00 disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, and shared psychotic disorder), substance-related disorders (e.g., alcohol dependence, amphetamine dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, and sedative dependence), adjustment disorder, autism, delirium, dementia, multi-infarct dementia, learning and memory disorders (e.g., amnesia and age-related memory loss), and Tourette’s disorder. [00101] The term “metabolic disorder” refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and/or carbohydrates. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity. [00102] In some embodiments, a disease is characterized by cellular dysfunction. For example, a disease may be a mitochondrial disease. Non-limiting mitochondrial diseases include Freidrich’s ataxia, alphers disease, barth syndrome, beta-oxidation defects, carnitine deficiency, CPT I deficiency, and mitochondrial DNA depletion. Cellular dysfunction may include mitochondria dysfunction, RNA replication dysfunction, DNA replication dysfunction, translation dysfunction, and/or protein folding dysfunction. [00103] In some embodiments, the disease or condition is caused by a wound, bleeding out, injuries (e.g., broken bones, gunshot wound, cut, scarring during surgery (e.g., cesarean). In some embodiments, the disease or condition is caused by a spinal cord injury. In some embodiments, the disease or condition is caused by a brain injury. [00104] In some embodiments, the disease is an infectious disease (e.g., a disease caused by a pathogen and/or virus). Non-limiting examples of infectious diseases include tuberculosis, HIV/AIDS, rabies, plague, cholera, dengue fever, measles, malaria, meningitis, whooping cough, Lyme disease, influenza, hepatitis C, typhoid fever, and poliomyelitis. [00105] “Cellular causes of aging” as used herein include loss or modification of epigenetic information. [00106] The term “Nanog” refers to a DNA binding homeobox transcription factor that has been implicated in embryonic stem (ES) cell proliferation, renewal, and pluripotency. Non-limiting examples of amino acid sequences encoding Nanog include the amino acid sequences under UniProtKB Accession Nos. Q9H9S0, Q4JM65, Q80Z64, and A7Y7W3.

40/240 12591029. H0824.70430WO00 [00107] The terms “c-Myc” or “Myc” refer to a nuclear phosphoprotein that has been implicated in cell cycle progression. C-Myc is capable of forming a heterodimer with the transcription factor MAX and the heterodimer is capable of binding to an E box consequence sequence on nucleic acids (e.g., engineered nucleic acids) to regulate transcription of target genes. [00108] The terms “effective amount” and “therapeutically effective amount,” as used herein, refer to the amount or concentration of an agent, small molecule, protein, composition, chemical cocktail, or a composition or chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof), or combination thereof, that, when administered to a cell, tissue, organ, and/or subject, is effective to at least partially treat a condition from which the cell, tissue, organ, and/or subject is suffering. [00109] As used herein, a protein that is “functional” or “active” is one that retains its biological activity (e.g., capable of acting as a transcription factor or as an inducing agent). Conversely, a protein that is not functional or is inactive is one that is not capable of performing one or more of its wild-type functions. [00110] The term “gene” refers to a nucleic acid (e.g., engineered nucleic acid) fragment that expresses a protein, including regulatory sequences preceding (5' non-coding sequences) and following (3' non-coding sequences) the coding sequence. “Native gene” refers to a gene as found in nature with its own regulatory sequences. “Chimeric gene” or “chimeric construct” refers to any gene or a construct, not a native gene, comprising regulatory and coding sequences that are not found together in nature. Accordingly, a chimeric gene or chimeric construct may comprise regulatory sequences and coding sequences that are derived from different sources, or regulatory sequences and coding sequences derived from the same source, but arranged in a manner different than that found in nature. “Endogenous gene” refers to a native gene in its natural location in the genome of an organism. A “foreign” gene refers to a gene not normally found in the host organism, but which is introduced into the host organism by gene transfer. Foreign genes can comprise native genes inserted into a non-native organism, or chimeric genes. A “transgene” is a gene that has been introduced into the genome by a transformation procedure. [00111] “Homolog” or “homologous” refers to sequences (e.g., nucleic acid (e.g., engineered nucleic acid) or amino acid sequences) that share a certain percent identity (e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 71%, at least 72%, at least73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least

41/240 12591029. H0824.70430WO00 97%, at least 98%, at least 99%, or 100% percent identity). Homologous sequences include but are not limited to paralogous or orthologous sequences. Paralogous sequences arise from duplication of a gene within a genome of a species, while orthologous sequences diverge after a speciation event. A functional homolog retains one or more biological activities of a wild-type protein [00112] “KLF4” may also be referred to as Kruppel-like factor 4, EZF, or GKLF and is a zinc-finger transcription factor. KLF4 has been implicated in regulation of differentiation and proliferation and is capable of interacting with co-activators, including members of the p300-CBP coactivator family. A KLF4 transcription factor, homolog (e.g., functional homolog), or variant thereof, as used herein, may be derived from any species, including humans. In certain embodiments, the nucleic acid (e.g., engineered nucleic acid) encoding human KLF4 comprises a sequence that is at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a nucleic acid (e.g., engineered nucleic acid) described in the NCBI RefSeq database under accession number NM_004235.5 or NM_001314052.1. [00113] The terms “nucleic acid,” “polynucleotide”, “nucleotide sequence”, “nucleic acid (e.g., engineered nucleic acid) molecule”, “nucleic acid (e.g., engineered nucleic acid) sequence”, and “oligonucleotide” refer to a series of nucleotide bases (also called “nucleotides”) in DNA and RNA, and mean any chain of two or more nucleotides. The terms “nucleic acid” or “nucleic acid (e.g., engineered nucleic acid) sequence”, “nucleic acid (e.g., engineered nucleic acid) molecule”, “nucleic acid (e.g., engineered nucleic acid) fragment” or “polynucleotide” may be used interchangeably with “gene,” “mRNA encoded by a gene,” and “cDNA”. [00114] “OCT4” may also be referred to as Octamer-binding transcription factor 4, OCT3, OCT3/4, POU5F1, or POU class 5 homeobox 1 and is a transcription factor that has been implicated in embryonic development and determination of cell fate. Similar to other OCT transcription factors, OCT4 is characterized by a bipartite DNA binding domain called a POU domain. An OCT4 transcription factor, homolog, or variant thereof, as used herein, may be derived from any species, including humans. In certain embodiments, the nucleic acid (e.g., engineered nucleic acid) encoding human OCT4 is at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a nucleic acid (e.g., engineered nucleic acid) described in the NCBI RefSeq under accession number NM_002701, NM_203289, NM_001173531, NM_001285986, or NM_001285987. [00115] “SRY-box 2” or “SOX2” is a member of the SRY-related HMG-box (SOX) family of transcription factors. SOX2 has been implicated in promoting embryonic development. Members of the SOX (SRY-related HMG-box) family of transcription factors are characterized by a high mobility group 5 (HMG)-box DNA sequence. This HMG box is a DNA binding domain that is highly conserved throughout eukaryotic species. A SOX2 transcription factor, homolog or variant thereof, as used herein, may be derived from any species, including humans. In certain embodiments, the nucleic acid (e.g., engineered nucleic acid) encoding SOX2 comprises a sequence that is at least 70% (e.g., at

42/240 12591029. H0824.70430WO00 least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a nucleic acid (e.g., engineered nucleic acid) described in the NCBI RefSeq under accession number NM_011443.4. [00116] “Reversing aging” or “reversing ageing” as used herein refers to modifying the physical characteristics associated with aging. All animals typically go through a period of growth and maturation followed by a period of progressive and irreversible physiological decline ending in death. The length of time from birth to death is known as the life span of an organism, and each organism has a characteristic average life span. Aging is a physical manifestation of the changes underlying the passage of time as measured by percent of average life span. [00117] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult, or senior adult)) and/or other non–human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals, such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds, such as chickens, ducks, geese, and/or turkeys). In certain embodiments, the animal is a mammal. The animal may be a male or female and at any stage of development. A non–human animal may be a transgenic animal. [00118] One of ordinary skill in the art would recognize that the biological age of a pediatric subject or adult subject may vary depending on the type of animal. As a non-limiting example, an adult mouse may be 1 year of age, while an adult human may be more than 21 years of age. In some embodiments, a pediatric subject is less than 21 years of age, less than 20 years of age, less than 15 years of age, less than 10 years of age, less than 9 years of age, less than 8 years of age, less than 7 years of age, less than 6 years of age, less than 5 years of age, less than 4 years of age, less than 3 years of age, less than 2 years of age, less than 1 year of age, less than 10 months of age, less than 9 months of age, less than 8 months of age, less than 7 months of age, less than 6 months of age, less than 5 months of age, less than 4 months of age, less than 2 months of age, or less than 1 month of age. In some embodiments, an adult subject is at least 3 weeks of age, 1 month of age, at least 2 months of age, at least 3 months of age, at least 4 months of age, at least 5 months of age, at least 6 months of age, at least 7 months of age, at least 8 months of age, at least 9 months of age, at least 10 months of age, at least 11 months of age, at least 1 year of age, at least 2 years of age, at least 3 years of age, at least 5 years of age, at least 10 years of age, at least 15 years of age, at least 20 years of age, at least 25 years of age, at least 30 years of age, at least 40 years of age, at least 50 years of age, at least 55 years of age, at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 90 years of age, or at least 100 years of age. In some embodiments, an adult subject is at least 10 years of age, at least 15 years of age, at least 20 years of age, at least 25 years of age, at least 30 years of age, at least 40 years of age, at least 50 years of age, at least 55 years of age, at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 90 years of age, or at least 100 years of age. In

43/240 12591029. H0824.70430WO00 some embodiments, a middle-aged adult subject is between 1 and 6 months of age, between 6 and 12 months of age, between 1 year and 5 years of age, between 5 years and 10 years of age, between 10 and 20 years of age, between 20 and 30 years of age, between 30 and 50 years of age, between 50 and 60 years of age, between 40 and 60 years of age, between 40 and 50 years of age, or between 45 and 65 years of age. In some embodiments, a middle-aged adult subject is between 30 and 50 years of age, between 50 and 60 years of age, between 40 and 60 years of age, between 40 and 50 years of age, or between 45 and 65 years of age. In some embodiments, a senior adult subject is at least 1 month of age, at least 2 months of age, at least 3 months of age, at least 4 months of age, at least 5 months of age, at least 6 months of age, at least 7 months of age, at least 8 months of age, at least 9 months of age, at least 10 months of age, at least 11 months of age, at least 1 year of age, at least 2 years of age, at least 3 years of age, at least 5 years of age, at least 10 years of age, at least 15 years of age, at least 20 years of age, at least 25 years of age, at least 30 years of age, at least 40 years of age, at least 50 years of age, at least 55 years of age, at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 90 years of age, or at least 100 years of age. In some embodiments, a senior adult subject is at least 50 years of age, at least 55 years of age, at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 90 years of age, or at least 100 years of age. [00119] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is the object to which a compound, particle, and/or composition of the invention is delivered. A tissue may be an abnormal, damaged, or unhealthy tissue, which may need to be treated. A tissue may also be a normal or healthy tissue that is under a higher-than-normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the tissue is considered healthy but suboptimal for performance or survival in current or future conditions. For example, in agricultural practice, environmental conditions including weather and growing conditions (e.g., nutrition) may benefit from any of the methods described herein. In certain embodiments, the tissue is the central nervous system, e.g., the brain. In some embodiments, the cell or tissue is a neuronal cell or nervous tissue. In some embodiments, the cell is a neuron. In some embodiments, the neuron is an excitatory neuron. In some embodiments, the tissue is not eye tissue. [00120] The term “tissue repair” in the context of damaged tissue refers to restoration of tissue architecture, function following tissue damage, or a combination thereof. Tissue repair includes tissue regeneration, cell growth, tissue replacement, and/or rewiring of existing tissue (reprogramming). [00121] The term “tissue regeneration” refers to production of new tissue or cells within a tissue that are the same type as the tissue of interest (e.g., same type as the damaged tissue or cell). In some embodiments, the methods provided herein promote organ regeneration. [00122] The term “tissue replacement” refers to production of a different type of tissue compared to the tissue of interest (e.g., connective tissue to replace damaged tissue).

44/240 12591029. H0824.70430WO00 [00123] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In certain embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms or may be treated with another damaging agent (e.g., in light of a history of symptoms, in light of genetic or other susceptibility factors, a disease therapy, or any combination thereof). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence. [00124] The term “variant” refers to a sequence that comprises a modification relative to a wild-type sequence. Non-limiting modifications in an amino acid sequence include insertions, deletions, and point mutations. Non-limiting modifications to nucleic acid (e.g., engineered nucleic acid) sequences include frameshift mutations, nucleotide insertions, and nucleotide deletions. [00125] The terms “laduviglusib,” “CHIR-99021,” and “CHIR99021” refer to 6-[2-[[4-(2,4- dichlorophenyl)-5-(5-methyl-1H-imidazol-2-yl)pyrimidin-2-yl]amino]ethylamino]pyridine-3- carbonitrile, of the structure: , and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “C” refers to laduviglusib. [00126] The terms “RepSox,” “Repsox,” and “E-616452” refer to 2-(3-(6-methylpyridin-2-yl)-1H- pyrazol-4-yl)-1,5-naphthyridine, of the structure: ,

45/240 12591029. H0824.70430WO00 and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the numeral “6” refers to RepSox. [00127] The term “ascorbic acid” refers to L-ascorbic acid, or vitamin C, of the structure: , and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. [00128] The term “valproic acid” refers to 2-propylvaleric acid, of the structure: , and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “V” refers to valproic acid. [00129] The term “tranylcypromine” refers to trans-2-phenylcyclopropylamine, with either or both of the structures: , and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “T” refers to tranylcypromine. [00130] The term “forskolin” refers to (3R,4aR,5S,6S,6aS,10S,10aR,10bS)-3-Ethenyl-6,10,10b- trihydroxy-3,4a,7,7,10a-pentamethyl-1-oxododecahydro-1H-naphtho[2,1-b]pyran-5-yl acetate, of the structure:

46/240 12591029. H0824.70430WO00

, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “F” refers to forskolin. [00131] The term “butyric acid” refers to butanoic acid, with structure: , and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. [00132] The terms “basic fibroblast growth factor” and “bFGF” refer to the amino acid sequence under UniProtKB Accession No. Q07659, or any other suitable form of basic fibroblast growth factor. In certain embodiments, the terms “basic fibroblast growth factor” and “bFGF” refer to the amino acid sequence under UniProtKB Accession No. Q07659. [00133] The terms “arotinoid acid” and “TTNPB” refer to 4-[(E)-2-(5,5,8,8-tetramethyl-6,7- dihydronaphthalen-2-yl)prop-1-enyl]benzoic acid, with structure: , and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “N” refers to arotinoid acid. [00134] The term “Y-27632” refers to 4-[(1R)-1-aminoethyl]-N-pyridin-4-ylcyclohexane-1- carboxamide, with structure:

47/240 12591029. H0824.70430WO00 , and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “Y” refers to Y-27632. [00135] The terms “smoothened agonist” and “SAG” refer to 3-chloro-N-[4- (methylamino)cyclohexyl]-N-[(3-pyridin-4-ylphenyl)methyl]-1-benzothiophene-2-carboxamide, with structure: , and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “S” refers to smoothened agonist. [00136] The terms “linifanib” and “ABT-869” refer to 1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2- fluoro-5-methylphenyl)urea, with structure: , and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “A” refers to linifanib. [00137] The terms “alpha-ketoglutaric acid” and “α-KG” refer to 2-oxopentanedioic acid, with structure:

48/240 12591029. H0824.70430WO00 , and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. [00138] The terms “chemical reprogramming cocktail,” “chemical reprogramming cocktails,” “chemical cocktail” or “chemical cocktails” refer to a combination of two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In some embodiments, “chemical cocktail” refers to a combination of two or more small molecules. [00139] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. BRIEF DESCRIPTION OF THE DRAWINGS [00140] FIGs.1A-1H show the NCC reporter system to monitor cellular senescence. FIG.1A shows schematics of the NCC reporter system integrated in human fibroblasts. FIG.1B shows NCC signals in quiescent fibroblasts. FIG.1C shows fluorescence intensity profiles corresponding to the arrow in FIG.1B. FIG.1D shows the colocalization of mCherry and eGFP signals in quiescent fibroblasts by Pearson correlation. FIG.1E shows NCC signals in senescent fibroblasts. FIG.1F shows fluorescence intensity profiles corresponding to the arrow in FIG.1E. FIG.1G shows the colocalization of mCherry and eGFP signals in senescent fibroblasts by Pearson correlation. FIG.1H shows Pearson correlation of quiescent and senescent fibroblasts. Data are mean ± SD. ****p < 0.0001. [00141] FIGs.2A-2J show OSK-mediated partial reprogramming ameliorates features of cellular senescence. FIG.2A shows heatmaps for mRNA levels of genes upregulated by senescence (padj > 0.01, FC > 2). FIG.2B shows the percentage of genes changed by OSK (padj > 0.05) among those upregulated by senescence. FIG.2C shows heatmaps for mRNA levels of genes downregulated by senescence (padj>0.01, FC>2). FIG.2D shows the percentage of genes changed by OSK (padj>0.05) among those downregulated by senescence. FIG.2E shows Top 20 GO processes of genes upregulated by senescence. The red and blue bars indicate upregulation or downregulation by OSK, respectively. FIG.2F shows Top 20 GO processes of genes downregulated by senescence. The red and blue bars indicate upregulation or downregulation by OSK, respectively. FIG.2G shows

49/240 12591029. H0824.70430WO00 schematics of the Tet-On OSK system integrated in NCC reporter system fibroblasts. FIG.2H shows NCC signals and track of the arrows in quiescent, senescent or senescent+OSK fibroblasts. Scale bar, 50 µm. FIG.2I shows fluorescence intensity profiles corresponding to the arrow in FIG.2H. FIG.2J shows EGFP intensities in the cytoplasm. Data are mean ± SD. *p < 0.05; ***p < 0.001. [00142] FIGs.3A-3D show chemical reprogramming cocktails restore NCC alterations in senescent cells. FIG.3A shows chemical structures of compounds of basal cocktails used to generate induced pluripotent stem cells (iPSCs) from mouse (left) or human (right) somatic cells. FIG.3B shows Correlation heatmaps showing eGFP and mCherry colocalization in human senescent fibroblasts demonstrate the effects of 80 different compounds. FIGs.3C-3D show validation of six selected cocktails through independent experiments, showing colocalization (FIG.3C) and representative images (FIG.3D) of eGFP and mCherry signals. Scale bar, 50 µm. [00143] FIGs.4A-4F show transcriptomic rejuvenation by chemical reprogramming cocktails. FIGs. 4A-4B show Delta ages measured by a biological transcriptomic clock built on rodents and humans (FIG.4A), or rodents alone (FIG.4B). FIG.4C shows Delta ages measured by a chronological transcriptomic clock built on humans. n.s.: p > 0.05; *p < 0.05; **p < 0.01; ***p < 0.001. FIG.4D shows correlation matrix of transcriptomic differences by cocktail treatment, iPSC reprogramming or aging. FIG.4E shows enrichment of pathways by cocktail treatment, iPSC reprogramming or aging. Normalized Enrichment Score (NES) FIG.4F shows summary of observations showing that both induction of OSK and treatment with C1-6 are capable of restoring NCC integrity and reversing biomarkers of health. It was created using Biorenderer. [00144] FIG.5 shows NCC signals in fibroblasts from young, old, and HGPG individuals. mCherry (Red) and eGFP (Green) signals in 22y, 94y or HGPS fibroblasts. The cell nuclei were counterstained with Hoechst33342 to define the nuclear compartment. [00145] FIGs.6A-6C show mRNA levels of senescence-associated genes. FIGs.6A-6C show the levels of OSK in quiescent, senescent cells as well as senescent cells treated with OSK. FIG.6B shows expression of senescence associated genes in all three cell types. FIG.6C shows expression of P16 in all three cell types. P-values shown, adjusted significance threshold of 5x10-2. [00146] FIGs.7A-7D indicate transcriptome analysis shows cocktail treatments affect mostly similar gene groups and do not promote pluripotency. FIG.7A shows Venn diagrams of gene groups affected mouse chemical cocktails (C1-3), human chemical cocktails (C4-6) or the transition from quiescence to senescence. FIG.7B shows a Heat-map depicting relative scores of each RNA-seq library condition for each of the gene expression modules as described by SEQUIN for cocktail (C1-6) and DMSO treated senescent cells with quiescent cells (None). FIG.7C shows principal component analysis of modules for pluripotency, cocktail treatments. FIG.7D shows pluripotency module scores for each RNA-seq library condition based on iPSC Profiler (SEQUIN) comparing cocktail and DMSO control treatments in senescent cells with quiescent cells.

50/240 12591029. H0824.70430WO00 [00147] FIG.8 shows the effect of inhibition of key heterochromatin regulators on reprogramming. IF of either control cells or senescent cells treated with cocktail 1 or 4, markers of pluripotency (NANOG, EPCM, & SSEA1) or marker of fibroblast identity THY1. [00148] FIG.9 shows AGi Reverses nuclear leakage in human cells comparable to 5+ factor chemical cocktails. Human dermal fibroblasts integrated with the nuclear cytoplasmic compartmentalization (NCC) reporter were passaged until they were at or near replicative senescence to the point where a striking NCC defect was observable. Cells were then treated with either cocktail 1 (VPA, 250 µM; CHIR99021, 1 µM; Repsox-616452, 10 µM; Forskolin, 50 µM; and Tranylcypromine, 5 µM) or AGi (50 µg/mL Ascorbic acid + 1 µM CHIR99021) for four days followed by confocal microscopy analysis of the NCC signal. Representative images are shown on the left with blue indicating DAPI (Nucleus), red indicating RFP-NLS (should be nuclear) and green indicating eGFP-NES (should be cytoplasmic). AGi significantly restored nuclear integrity measured by the NCC assay to the same extent as cocktail 1. [00149] FIG.10 shows AGi Reverses senescence growth arrest. Mouse ear fibroblasts (n=5) were treated with doxorubicin to produce DNA damage-induced senescence or DMSO as a vehicle control for 24 hrs followed by 9 days to allow the cells to reach full senescence. The cells were then treated with AGi (50 µg/mL Ascorbic acid + 3 µM CHIR99021) or DMSO as a control for an additional five days. EdU was added 24 hrs prior to isolation to label newly synthesized DNA in actively dividing cells. EdU was detected using the Invitrogen Click-IT detection system which covalently attaches a green fluorophore to the EdU. Representative images are shown on the left with blue indicating DAPI (Nucleus) and green indicating EdU (growth). Treatment with AGi significantly reversed senescence associated growth arrest up to ~20% compared to <1% growing in the untreated senescent controls. [00150] FIG.11 shows AGi Reverses senescence-associated reduction in LaminB1. LaminB1 plays a significant role in regulating heterochromatin and its dysregulation is causal in senescence-associated epigenetic and transcriptomic changes. To determine if AGi reduces senescence associated LaminB1 defects, mouse ear fibroblasts (n=5) were treated with the chemotherapeutic doxorubicin (DXR) to induce senescence, followed by incubation with AGi as described in in Figure 2. Immunofluorescence staining was performed on cells following treatment to detect LaminB1. Treatment with AGi entirely reversed levels of LaminB1 in senescent cells back to the levels of healthy cells (p<0.05). This indicates a striking recovery of nuclear health. Based on these findings, it is likely that the recovery of LaminB1 will cause (or at least reflect) epigenomic and transcriptomic rejuvenation in these AGi- treated senescent cells. [00151] FIGs.12A-12B show that treatment of senescent cells with chemical cocktail 1 (C1) (VC6FT) reduced standard inflammatory cytokine levels and increased anti-inflammatory Il-10. FIG. 12A shows that senescence associated inflammatory cytokines are decreased upon treatment of senescent cells with C1 and C4. Treatment with either C1 or C4 produced a statistically significant difference compared to the untreated senescent cells. FIG.12B shows that anti-inflammatory factor

51/240 12591029. H0824.70430WO00 IL-10, repressed in senescent cells, is increased upon treatment of senescent cells with C1 (>4 fold increase) and C4 (>100 fold increase). [00152] FIG.13 shows an NCC based assay of chemical combinations show that valproic acid (VPA), laduviglusib (CIHR), tranylcypromine (TCP), and forskolin (FSK) produced significant effects on NCC integrity. [00153] FIGs.14A and 14B show a DNA-Cytoplasmic based assay of chemical combinations. FIG. 14A shows that valproic acid (VPA), laduviglusib (CIHR), tranylcypromine (TCP), and forskolin (FSK) have the cleanest separation of Nuclear and Cytoplasmic domains. FIG.14B shows combinations of small molecule chemicals used in FIG.14A. [00154] FIG.15 shows results of a stress test assay for varied chemical concentrations. Boxplots show cell survival of human retinal cells (ARPE19 cells) treated with dilutions of the chemical cocktails. Differences in cell numbers arise from variability in plating. Chemicals were tested at various concentration either alone, or in combination with the other components of chemical cocktail 1 (C1, see Table 3). Relative doses are based on dilution factors and shown in Table 6 for specific doses. [00155] FIG.16 shows the results of a stress test assay for varied chemical concentrations. Boxplots show human fibroblasts (HF8) survival following treatments with the chemicals. Differences in cell numbers arise from variability in plating. Chemicals were tested at various concentration either alone, or in combination with the other components of chemical cocktail 1 (C1). Relative doses are based on dilution factors and shown in Table 6 for specific doses. [00156] FIGs.17A-17C show that characterization of combinations of reprogramming small molecules identifies the specific combination of three compounds C6F (laduviglusib, Repsox, and forskolin) as a potent rejuvenative combination from the five compounds of VC6FT (Cocktail 1, see Table 3). FIG.17A shows the Pearson correlation of nucleocytoplasmic compartmentalization (NCC) signal of quiescent fibroblasts or senescent fibroblasts treated with combinations of 250 µM valproic acid (V), 1 µM CHIR-99021 (C), 10 µM E-616452/RepSox (6), 50 µM forskolin (F), and 5 µM tranylcypromine (n=3). Activation of the OSK cassette with 2 µg/mL doxycycline or treatment with AGi (1 µM CHIR-99021 + 50 µg/mL ascorbic acid) in senescent cells was also performed for benchmarking purposes. FIG.17B shows representative images of NCC signal in senescent cells treated with a minimal reprogramming cocktail C6F in an independent validation experiment (n=4). FIG.17C shows the Pearson correlation of NCC signal in FIG.17B. Data are mean ± SD. One-way ANOVA-Bonferroni. [00157] FIGs.18A-18B show that formulations of lithium and ascorbic acid potently restore nuclear integrity assayed by NCC. FIG.18A shows the Pearson correlation of NCC signal of senescent fibroblasts treated with lithium chloride (LiCl) and ascorbic acid (AA) either at a 1:1 stoichiometry or with ascorbic acid held constant at 50 µg/mL (to mimic AGi).10 mM lithium chloride with 50 µg/mL ascorbic acid, but no other combination, significantly reset NCC. These data evidence that the

52/240 12591029. H0824.70430WO00 rejuvenative effects of the two-factor AGi can be achieved even when CHIR-99021 is replaced by other GSK3B inhibitors, such as lithium salts.1:1 LiCl + AA was attempted at 10 µM, but this dose exceeded the solubility limit of the media. FIG.18B shows the Pearson correlation of NCC signal of senescent fibroblasts treated with LiCl, lithium ascorbate (LiAA), or LiCl + LiCl + AA at a 1:1 stoichiometry to mimic lithium ascorbate. LiAA but not equivalent doses of LiCl or LiCl + AA was capable of significantly resetting NCC. This finding indicates that a single compound mimicking the activity of AGi is sufficient for substantial amelioration of nuclear health of human senescent cells. Data are mean ± SD. One-way ANOVA-Bonferroni. * p < 0.05; ** p < 0.01. [00158] FIG.19 shows levels of reactive oxygen species (ROS) in cells treated with chemical cocktails containing different doses of the constituent chemicals. Reduced CHIR (64nM) concentration in combination with V6TF (valproic acid, Repsox, tranylcypromine, and forskolin) leads to decreased levels of ROS in cells following treatments (left arrow). Reduced Repsox concentration from 10 µM to 0.64 µM in combination with V6TF leads to decreased levels of ROS in cells, though not in combination with other drugs (middle two arrows). Reduced Forskolin to 8 µM concentration alone and in combination with VC6T leads to decreased levels of ROS in cells following treatments, and the lowest relative level is reached (right two arrows). All chemical treatments were performed in senescent cells, quiescent cells were included in column 12 as a control. [00159] FIGs.20A-20H show the viability of SY5Y human cell line treated with single reprogramming chemicals. Cell viability of undifferentiated SY5Y human neuroblastoma cell line after four days of treatment with doses of single chemicals was assessed via calcein-AM staining followed by live cell-microscopy for valproic acid (VPA) (FIG.20A), CHIR-99021 (FIG.20B), forskolin (FIG.20C), tranylcypromine (TCP) (FIG.20D), RepSox (FIG.20E), ascorbic acid (AA) (FIG.20F), lithium ascorbate (LiAA)( FIG.20G), and lithium chloride (LiCl) (FIG.20H). Cell viability is represented as a value relative to the untreated control cells. n=3 error bares are mean +/- STD. [00160] FIGs.21A-21C show the viability of SY5Y human cell line treated with reprogramming chemical cocktails. Cell viability of undifferentiated SY5Y human neuroblastoma cell line after four days of treatment with doses of chemical cocktails was assessed via calcein-AM staining followed by live cell-microscopy for C1 (VC6FT) (FIG.21A), CHIR-99021, RepSox, and Forskolin (C6F) (FIG. 21B), or AGi (FIG.21C) with variable doses of CHIR-99021. All other chemical components were kept at constant dose typically used for their respective cocktails: 250 µM VPA, 50 µM forskolin, 10 µM RepSox, 5 µM TCP, and 50 µg/ml ascorbic acid. Cell viability is represented as a value relative to the untreated control cells. n=3 error bares are mean +/- STD. [00161] FIGs.22A-22L show the viability of primary mouse fibroblasts treated with single reprogramming chemicals. Cell viability of primary mouse ear fibroblasts after five days of treatment with doses of single small molecule chemicals was assessed via calcein-AM staining followed by live cell-microscopy for valproic acid (VPA) (FIG.22A), CHIR-99021 (FIG.22B), forskolin (FIG.22C),

53/240 12591029. H0824.70430WO00 tranylcypromine (TCP) (FIG.22D), RepSox (FIG.22E), ABT869 (FIG.22F), smoothend agonist (SAG) (FIG.22G), basic fibroblast growth factor (b-FGF) (FIG.22H), sodium butyrate (FIG.22I), TTNBP (FIG.22J), Y-27632 (FIG.22K), and alpha-ketoglutarate (FIG.22L).Cell viability is represented as a value relative to the untreated control cells. Cell viability is represented as a value relative to the untreated control cells. n=3 error bares are mean +/- STD. [00162] FIG.23 shows the viability of primary mouse fibroblasts treated with AGi cocktail. Cell viability of primary mouse ear fibroblasts after five days of treatment with AGi Cocktail (CHIR- 99021 with ascorbic acid) was assessed via calcein-AM staining followed by live cell-microscopy for AGi with variable doses of CHIR-99021 and 50 µg/ml ascorbic acid. Cell viability is represented as a value relative to the untreated control cells. n=3 error bares are mean +/- STD. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION [00163] The present disclosure is based, at least in part, on the unexpected results demonstrating that chemical cocktails comprising two or more compounds can reverse the age of human fibroblasts and restore genome-wide transcript profiles. Surprisingly, in some embodiments, as described herein, this rejuvenation can occur in less than a week and without erasing cellular identity, a crucial aspect of partial epigenetic reprogramming. Thus, reversal of cellular aging by partial reprogramming and the restoration of youth, similar to the effect of the Yamanaka factors, Oct4, Sox2, and Klf4 (OSK), can be achieved by chemical means. [00164] The methods, compositions, uses, and kits of the present disclosure are in part informed by the surprising and unexpected discovery that chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), lithium salts, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) can rejuvenate a cell in the absence of OSK without reprogramming the cell to a pluripotent state. [00165] Aspects of the present disclosure provide several systems, compositions, uses, kits, and methods that may be useful for efficient rejuvenation of a cell, tissue, and/or organ. [00166] In some embodiments, the results disclosed herein suggest that treatment with chemical cocktails can reprogram cells and reverse the age of the transcriptome. Without being bound by a particular theory, the results disclosed herein suggest that cells maintain a backup epigenome that can be restored using the methods described herein. [00167] Thus, in various embodiments the methods and uses of the invention rejuvenate a cell by restoring the cellular identity of the cell by reversing the effects of or by preventing the effects of age, or of one or more dysregulated developmental pathways. For example, in certain embodiments, the methods may:

54/240 12591029. H0824.70430WO00 (i) increase the abundance of at least one of histone H2A, histone H2B, histone H3, histone H4, or any combination thereof in the cell; (ii) increase the abundance of at least one of CHAF1a, CHAF1b, HP1α, NuRD, or any combination thereof in the cell; (iii) increase at least one heterochromatin mark in the cell, such as, for example, H3K9me3, H3K27me3, or any combination thereof; or decrease one heterochromatin mark, such as H4K20me3 or euchromatin mark H3K4me3; (iv) increase/decrease DNA methylation of at least one age-related CpG site in the cell towards a younger level; (v) increase the abundance of lamin B1 in the cell; (vi) increase acetylation of histone H3 at lysine 27 (H3K27ac), increase acetylation of histone H3 at lysine 56 (H3K56ac), or any combination thereof in the cell; (vii) decrease acetylation of histone H3 at lysine 122 (H3K122Ac) or histone H4 at lysine 16 (H4K16ac), or any combination thereof in the cell (viii) decrease the abundance of IL6, Ccl2, Ccl20, Apob, p16, LINE-1 repeats, Sat III repeats, Alu elements, IAP, or any combination thereof; (ix) restore the balance between euchromatin epigenetic marks, such as H3K4me3, and heterochromatin epigenetic marks, such as H3K9me3 or H3K27me3; (x) induce the formation of euchromatin; (xi) restore youthful levels of at least one repressive heterochromatin epigenetic mark; (xii) restore the expression of at least one gene to youthful levels. In some embodiments, a youthful level is the level of expression of the gene in a subject who is between 1-5, 1-10, 1-20, 1-30, or 1-40 years old; (xiii) decrease the abundance of senescence-associated inflammatory cytokines, such as, for example, IFNγ, IL-1B, IL-6, IL-8, MCP-1, or TNFα, or any combination thereof; and/or (xiv) increase the abundance of cytokines repressed in senescent cells, such as, for example, IL-10. [00168] In some embodiments, the at least one gene that is restored to youthful levels is at least one gene selected from the group consisting of CDKN1A, IL6, CCL2, MMP3, LMNB1, and EZH2. [00169] In some embodiments, the methods disclosed herein alleviate one or more hallmarks of aging, including deterioration of nucleocytoplasmic compartmentalization (NCC), genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. See, e.g., Kennedy et al., Cell.2013 Jun 6; 153(6): 1194–1217. [00170] In some embodiments, methods disclosed herein increase the expression of one or more of the following gene sets: KEGG PPAR signaling pathway, REACTOME Activation of gene expression by SREBF/SREBP, REACTOME Mitochondrial translation, REACTOME Respiratory

55/240 12591029. H0824.70430WO00 electron transport, HALLMARK Oxidative phosphorylation, HALLMARK MYC targets v1, REACTOME Base excision repair, REACTOME DNA repair, REACTOME Extension of telomeres, KEGG Ribosome, or REACTOME Metabolism of amino acids and derivatives. See, e.g., Molecular Signatures Database (MSigDB) for gene sets. In some embodiments, a gene set is determined using the Biological Process terms of the Gene Ontology (GOBP). In some embodiments, the methods disclosed herein increase expression of one or more of these gene sets by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% relative to a control. In some embodiments, a control is the level of expression of one or more gene sets in the absence of treatment with a chemical cocktail comprising two or more compounds. In some embodiments, gene expression is measured at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 20 weeks, at least 30 weeks, at least 40 weeks, or at least 50 weeks after treatment with the chemical cocktail has stopped. [00171] Without being bound by a particular theory, more specifically, the methods, compositions, uses, and kits of the present disclosure rejuvenate cells by restoring epigenetic information that has been lost due to the aging process, injury, or disease. The methods, compositions, uses, and kits of the present disclosure comprise chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT- 869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). The Yamanaka factors have traditionally been used to reprogram cells to a pluripotent state. However, the induction of expression of the four transcription factors in transgenic mice resulted in the formation of teratomas in vivo, along with other acute toxicities like dysplasia in the intestinal epithelium, which can kill the animal in a few days. Moreover, the fact that the four Yamanaka factors are typically used to reprogram cells to a completely pluripotent state, wherein the cell loses its pre-established cellular identity, can be dangerous for in vivo applications where the cellular identity of target cells must be maintained for tissue and/or organ integrity. In contrast, in some embodiments, the methods described herein, allow controlled reprogramming and do not result in global changes in demethylation. In some embodiments, the methods described herein do not require complete de- differentiation of cells. [00172] Cellular reprograming allows for the production of numerous cell types from existing somatic cells. Although the Yamanaka factors (OCT4, SOX2, KLF4 and c-Myc, also known collectively as OSKM) have been shown to induce pluripotency in differentiated cells, administration of these factors may induce teratomas or other cancers in vivo (Takahashi et al., Cell 2006 Aug 25;126(4):663-76; Abad et al., Nature 2013 Oct 17;502(7471):340-5). As a result of these safety concerns, use of the

56/240 12591029. H0824.70430WO00 Yamanaka factors has largely been limited to in vitro applications. Furthermore, existing methods of gene therapy are plagued by inefficient and inconsistent gene transduction of target cells. The compounds, pharmaceutical compositions thereof, methods, uses, and kits provided herein overcome many of these limitations. Methods of Rejuvenating, Restoring Cellular Function, Decreasing Biological Age, Decreasing Apparent Chronological Age, and Reprogramming [00173] In one aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and

57/240 12591029. H0824.70430WO00 lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00174] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00175] In another aspect, the present disclosure provides methods of decreasing the biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of:

58/240 12591029. H0824.70430WO00 laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00176] In another aspect, the present disclosure provides methods of decreasing the apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

59/240 12591029. H0824.70430WO00 ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00177] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

60/240 12591029. H0824.70430WO00 tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00178] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

61/240 12591029. H0824.70430WO00 butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00179] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

62/240 12591029. H0824.70430WO00 smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00180] In another aspect, the present disclosure provides methods of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

63/240 12591029. H0824.70430WO00 [00181] In another aspect, the present disclosure provides methods of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00182] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

64/240 12591029. H0824.70430WO00 ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00183] In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. For example, in certain embodiments, the terms “laduviglusib” and “CHIR99021” refer to laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, or stereoisomer thereof. In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt thereof. In certain embodiments, the name of a chemical compound may refer to the compound. [00184] In certain embodiments, the method comprises treating the cell, tissue, or organ with 3 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632,

65/240 12591029. H0824.70430WO00 smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 4 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 5 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 6 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 7 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 8 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 9 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 10 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid,

66/240 12591029. H0824.70430WO00 tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 11 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 12 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 13 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). [00185] In certain embodiments, the method comprises treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and

67/240 12591029. H0824.70430WO00 basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00186] In certain embodiments, the method comprises treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00187] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and RepSox (E-616452). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and ascorbic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and valproic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021)

68/240 12591029. H0824.70430WO00 and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and ascorbic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E- 616452) and valproic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E- 616452) and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and Y- 27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and valproic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with

69/240 12591029. H0824.70430WO00 valproic acid and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and alpha-ketoglutaric acid (α- KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and linifanib (ABT-869). In certain embodiments, the method comprises treating the

70/240 12591029. H0824.70430WO00 cell, tissue, or organ with basic fibroblast growth factor (bFGF) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and linifanib (ABT- 869). In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with Y-27632 and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with Y-27632 and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with Y- 27632 and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with smoothened agonist (SAG) and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with smoothened agonist (SAG) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with linifanib (ABT-869) and alpha-ketoglutaric acid (α-KG). [00188] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and ascorbic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), and valproic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and basic fibroblast growth factor (bFGF). [00189] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and valproic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-

71/240 12591029. H0824.70430WO00 616452), ascorbic acid, valproic acid, and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, and forskolin. [00190] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), tranylcypromine, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, tranylcypromine, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, forskolin, and butyric acid. [00191] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with

72/240 12591029. H0824.70430WO00 laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, valproic acid, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), butyric acid, and basic fibroblast growth factor (bFGF). [00192] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and linifanib (ABT-869). In certain

73/240 12591029. H0824.70430WO00 embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and alpha-ketoglutaric acid (α-KG). [00193] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), arotinoid acid (TTNPB), and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), arotinoid acid (TTNPB), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y- 27632, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), linifanib (ABT-869), and butyric acid. In certain

74/240 12591029. H0824.70430WO00 embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), butyric acid, and alpha-ketoglutaric acid (α-KG). [00194] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and Y- 27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), and linifanib (ABT- 869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT- 869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y- 27632, and smoothened agonist (SAG). In certain embodiments, the method comprises treating the

75/240 12591029. H0824.70430WO00 cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y- 27632, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), linifanib (ABT-869), and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, linifanib (ABT-869), and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, butyric acid, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method

76/240 12591029. H0824.70430WO00 comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). [00195] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452),

77/240 12591029. H0824.70430WO00 ascorbic acid, Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y- 27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y- 27632, linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating

78/240 12591029. H0824.70430WO00 the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, linifanib (ABT- 869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), Y-27632, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, linifanib (ABT-869), butyric acid, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). [00196] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened

79/240 12591029. H0824.70430WO00 agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), butyric acid, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG),

80/240 12591029. H0824.70430WO00 butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y- 27632, smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α- KG). [00197] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). [00198] In certain embodiments, the pharmaceutically acceptable salt of butyric acid is sodium butyrate. In certain embodiments, the pharmaceutically acceptable salt of butyric acid is lithium butyrate. In certain embodiments, the pharmaceutically acceptable salt of butyric acid is potassium butyrate. [00199] In certain embodiments, the pharmaceutically acceptable salt of valproic acid is lithium valproate. In certain embodiments, the pharmaceutically acceptable salt of ascorbic acid is lithium ascorbate. In certain embodiments, the pharmaceutically acceptable salt of forskolin is a lithium salt of forskolin. In certain embodiments, the pharmaceutically acceptable salt of TTNPB is a lithium salt of TTNPB. In certain embodiments, the pharmaceutically acceptable salt of α-KG is a lithium salt of α-KG. [00200] In certain embodiments, the group further comprises a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the group further comprises lithium ascorbate. In certain embodiments, the group further comprises lithium chloride. In certain embodiments, the

81/240 12591029. H0824.70430WO00 group further comprises lithium orotate. In certain embodiments, the group further comprises lithium carbonate. In certain embodiments, the group further comprises lithium citrate. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co– crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with Y-27632 and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with smoothened agonist (SAG) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with linifanib (ABT-869) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with alpha-ketoglutaric acid (α-KG) and a lithium salt, or a solvate, hydrate,

82/240 12591029. H0824.70430WO00 polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00201] In certain embodiments, one or more of the compounds in the group are replaced with a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, one or more of the compounds in the group are replaced with lithium ascorbate. In certain embodiments, one or more of the compounds in the group are replaced with lithium chloride. In certain embodiments, one or more of the compounds in the group are replaced with lithium orotate. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with Y-27632 and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with smoothened agonist (SAG) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate,

83/240 12591029. H0824.70430WO00 lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with linifanib (ABT-869) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with alpha-ketoglutaric acid (α-KG) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00202] In certain embodiments, CHIR99021 is replaced with a GSK3 ^ inhibitor. In certain embodiments, the GSK3 ^ inhibitor is a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate), SB216763, SB415286, SB203580, TDZD-8, AR-A014418, CHIR99021, BIO, Kenpaullone, Indirubin-3′-monoxime, AZD1080, Tideglusib, LY2090314, LY2095496, LY2097409, LY2097634, FRAX597, Y-27632, DMAT, TWS119, or Berberine. In certain embodiments, the GSK3 ^ inhibitor is a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate), SB216763, SB415286, SB203580, TDZD-8, AR-A014418, CHIR99021, BIO, Kenpaullone, Indirubin-3′-monoxime, AZD1080, Tideglusib, LY2090314, LY2095496, LY2097409, LY2097634, FRAX597, Y-27632, DMAT, or TWS119. [00203] In certain embodiments, the ascorbic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is ascorbic acid, lithium ascorbate, Ester-C (form of calcium ascorbate), ascorbyl palmitate, liposomal vitamin C, sodium ascorbate, magnesium ascorbyl phosphate (MAP), tetrahexyldecyl ascorbate, ascorbyl glucoside, calcium ascorbate, or sodium erythorbate. [00204] In certain embodiments, ascorbic acid is replaced with a Tet activator. In certain embodiments, the Tet activator is lithium ascorbate, Ester-C, ascorbyl palmitate, liposomal vitamin C, sodium ascorbate, magnesium ascorbyl phosphate (MAP), tetrahexyldecyl ascorbate, ascorbyl glucoside, calcium ascorbate, or sodium erythorbate. [00205] The following compounds may offer benefits compared to ascorbic acid: Ester-C (enhanced absorption and retention, providing similar antioxidant effects), ascorbyl palmitate (increased stability and solubility in lipid environments, with antioxidant properties), liposomal vitamin C (improved bioavailability and cellular uptake, maintaining antioxidant activity), sodium ascorbate (provides similar antioxidant effects with reduced acidity), magnesium ascorbyl phosphate (MAP) (water- soluble, with enhanced stability and similar antioxidant effects), tetrahexyldecyl ascorbate (increased stability and ability to penetrate lipid membranes, providing antioxidant benefits), ascorbyl glucoside (enhanced stability and sustained release of ascorbic acid, maintaining antioxidant properties), calcium ascorbate (buffered form, reducing gastrointestinal discomfort while providing antioxidant effects), and sodium erythorbate (similar antioxidant properties with enhanced stability).

84/240 12591029. H0824.70430WO00 [00206] In certain embodiments, RepSox is replaced with a TGF-β inhibitor. In certain embodiments, the TGF-β inhibitor is SB431542, A-83-01, LY2109761, Galunisertib (LY2157299), Epigallocatechin gallate (EGCG), or Resveratrol. The TGF-β inhibitors may have the following mechanisms of action: SB431542 (inhibition of TGF-β signaling, facilitating mesenchymal-to-epithelial transition (MET)), A-83-01 (potent inhibition of ALK4, ALK5, and ALK7 receptors, effectively blocking TGF-β signaling), LY2109761 (blocking of both TGF-βRI and TGF-βRII, inhibiting TGF-β signaling pathways), Galunisertib (LY2157299) (selective inhibition of TGF-β receptor I, facilitating reprogramming), Epigallocatechin gallate (EGCG) (inhibition of TGF-β signaling pathways), and Resveratrol (inhibition of TGF-β signaling). [00207] In certain embodiments, RepSox is replaced with a CDK8 inhibitor. In certain embodiments, the CDK8 inhibitor is BI-1347 or MSC2530818. The CDK8 inhibitors may have the following mechanisms of action: BI-1347 (selective inhibition of CDK8 and CDK19) and MSC2530818 (selective inhibition of CDK8 and CDK19). [00208] In certain embodiments, forskolin is replaced with a cAMP agonist. In certain embodiments, the cAMP agonist is IBM-X (3-isobutyl-1-methylxanthine), 8-bromo-cAMP, or dibutyryl cAMP (db- cAMP). The cAMP agonists may have the following mechanisms of action: IBM-X (3-isobutyl-1- methylxanthine) (increases cAMP levels by inhibiting its breakdown, enhancing cellular reprogramming), 8-Bromo-cAMP (directly activates cAMP-dependent pathways, mimicking forskolin’s effects), and Dibutyryl cAMP (db-cAMP) (more stable and cell-permeable form of cAMP, effectively increasing intracellular cAMP levels). [00209] In certain embodiments, forskolin is replaced with a cAMP activator. In certain embodiments, the cAMP activator is caffeine or theobromine. The cAMP activators may have the following mechanisms of action: caffeine (inhibits phosphodiesterase, increasing cAMP levels) and theobromine (mild phosphodiesterase inhibitor, increasing cAMP levels). [00210] In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium ascorbate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium chloride. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium orotate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium carbonate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium citrate. [00211] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

85/240 12591029. H0824.70430WO00 [00212] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [00213] In another aspect, the present disclosure provides methods of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [00214] In another aspect, the present disclosure provides methods of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [00215] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [00216] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. [00217] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. [00218] In another aspect, the present disclosure provides methods of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. [00219] In another aspect, the present disclosure provides methods of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. [00220] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with lithium ascorbate. [00221] In certain embodiments, two or more of the compounds in the group are associated through a noncovalent interaction. [00222] In certain embodiments, the cell is a senescent cell. In certain embodiments, the senescent cell is within the tissue or organ. In certain embodiments, the cell, tissue, or organ is within a subject. In certain embodiments, the subject is a human. In certain embodiments, the subject is a pediatric

86/240 12591029. H0824.70430WO00 subject. In certain embodiments, the subject is an adult subject. In certain embodiments, the adult subject is a senior adult subject. In certain embodiments, the subject is healthy. In certain embodiments, the subject has a disease. In certain embodiments, the subject has, is suspected of having, or is at risk for an age-related disease. In certain embodiments, the age-related disease is a neurological disorder. In certain embodiments, the neurological disorder is a neurodegenerative disorder. In certain embodiments, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). [00223] In certain embodiments, the method further comprises: increasing cellular respiration, reducing cellular inflammatory pathways, improving integrity of nucleocytoplasmic compartmentalization, or a combination thereof, ex vivo or in vitro. In certain embodiments, the method further comprises increasing cellular respiration, ex vivo or in vitro. In certain embodiments, the method further comprises reducing cellular inflammatory pathways, improving integrity of nucleocytoplasmic compartmentalization, ex vivo or in vitro. In certain embodiments, the method further comprises improving integrity of nucleocytoplasmic compartmentalization, ex vivo or in vitro. [00224] In certain embodiments, the cell or tissue is from eye, ear, nose, mouth including gum and roots of teeth, bone, lung, breast, udder, pancreas, stomach, esophagus, muscle including cardiac muscle, liver, blood vessel, skin including hair, heart, brain, nerve tissue, kidney, testis, prostate, penis, cloaca, fin, ovary, or intestine. In certain embodiments, the tissue is damaged or the tissue may be considered healthy but suboptimal for performance or survival in current or future conditions. [00225] In certain embodiments, the method alters expression of at least one gene associated with aging. In certain embodiments, the method reduces expression of at least one gene associated with aging. In certain embodiments, the method increases expression of at least one gene associated with aging. [00226] In certain embodiments, at least one gene associated with aging is associated with: inflammation, mitochondrial metabolism, lysosomal function, apoptosis, p53, growth signaling, or a combination thereof, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with inflammation, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with mitochondrial metabolism, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with lysosomal function, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with apoptosis, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with p53, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with growth signaling, ex vivo or in vitro. [00227] In certain embodiments, at least one gene associated with aging is a central nervous system gene. In certain embodiments, at least one gene associated with aging is a brain gene.

87/240 12591029. H0824.70430WO00 [00228] In certain embodiments, the method further comprises activating an enhancer of reprogramming in the cell, tissue, or organ. In certain embodiments, the enhancer of reprogramming is a class I histone deacetylase (HDAC1-3). [00229] In certain embodiments, the method comprises restoring epigenetic information in the cell, tissue, or organ. In certain embodiments, the epigenetic information is lost due to aging, injury, disease, or a combination thereof in the cell, tissue, or organ. [00230] In certain embodiments, the method comprises reestablishing an epigenetic status of the cell, tissue, or organ that is similar to the status formed soon after final differentiation. [00231] In certain embodiments, the cell, tissue, or organ is not reprogrammed to a pluripotent state. [00232] In certain embodiments, the method rejuvenates an epigenetic clock of a cell, tissue, organ, subject, or a combination thereof. [00233] In some embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by a period of time. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by at least about 1 hour, at least about 6 hours, at least about 12 hours, at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 18 months, at least about 2 years, at least about 30 months, at least about 3 years, at least about 42 months, at least about 4 years, at least about 54 months, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, at least about 60 years, at least about 70 years, at least about 80 years, at least about 90 years, or at least about 100 years. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by about 1 year. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by about 2 years. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by about 3 years. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by about 4 years. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by about 5 years. [00234] In some embodiments, the cell, tissue, or organ is treated for a time period that is sufficient to rejuvenate the cell, tissue, or organ. In certain embodiments, the cell, tissue, or organ is treated for at least about 1 hour, at least about 6 hours, at least about 12 hours, at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6

88/240 12591029. H0824.70430WO00 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 18 months, at least about 2 years, at least about 30 months, at least about 3 years, at least about 42 months, at least about 4 years, at least about 54 months, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, at least about 60 years, at least about 70 years, at least about 80 years, at least about 90 years, or at least about 100 years. In certain embodiments, the cell, tissue, or organ is treated for about 1 day. In certain embodiments, the cell, tissue, or organ is treated for about 2 days. In certain embodiments, the cell, tissue, or organ is treated for about 3 days. In certain embodiments, the cell, tissue, or organ is treated for about 4 days. In certain embodiments, the cell, tissue, or organ is treated for about 5 days. In certain embodiments, the cell, tissue, or organ is treated for about 6 days. In certain embodiments, the cell, tissue, or organ is treated for about 1 week. In certain embodiments, the cell, tissue, or organ is treated for about 2 weeks. In certain embodiments, the cell, tissue, or organ is treated for about 3 weeks. In certain embodiments, the cell, tissue, or organ is treated for about 1 month. In certain embodiments, the cell, tissue, or organ is treated for about 2 months. [00235] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 1 µM to about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 2 µM to about 40 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 3 µM to about 30 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 4 µM to about 20 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 7.5 µM to about 12.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 10 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 10 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.5 µM to about 5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.75 µM to about 2.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a

89/240 12591029. H0824.70430WO00 concentration of about 1 µM to about 10 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM. [00236] In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 50 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 10 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 1 µM to about 50 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 2 µM to about 40 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 3 µM to about 30 µM. In certain embodiments, the RepSox (E- 616452) is used at a concentration of about 4 µM to about 20 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 7.5 µM to about 12.5 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 10 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM. [00237] In certain embodiments, the ascorbic acid is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 2.5 µg/mL to about 400 µg/mL, about 5 µg/mL to about 300 µg/mL, about 7.5 µg/mL to about 200 µg/mL, about 5 µg/mL to about 100 µg/mL, about 10 µg/mL to about 100 µg/mL, about 20 µg/mL to about 90 µg/mL, about 25 µg/mL to about 75 µg/mL, about 35 µg/mL to about 65 µg/mL, about 40 µg/mL to about 60 µg/mL, about 50 µg/mL, or about 10 µg/mL to about 60 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 1 µg/mL to about 500 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 2.5 µg/mL to about 400 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 5 µg/mL to about 300 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 7.5 µg/mL to about 200 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 5 µg/mL to about 100 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 10 µg/mL to about 100 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 20 µg/mL to about 90 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 25 µg/mL to about 75 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 35 µg/mL to about 65 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 40 µg/mL to about 60 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 50

90/240 12591029. H0824.70430WO00 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 10 µg/mL to about 60 µg/mL. In certain embodiments, the ascorbic acid is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 10 µg/mL to about 100 µg/mL, about 25 µg/mL to about 75 µg/mL, or about 50 µg/mL. [00238] In certain embodiments, the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM. In certain embodiments, the valproic acid is used at a concentration of about 1 µM to about 1000 µM. In certain embodiments, the valproic acid is used at a concentration of about 10 µM to about 800 µM. In certain embodiments, the valproic acid is used at a concentration of about 50 µM to about 600 µM. In certain embodiments, the valproic acid is used at a concentration of about 100 µM to about 400 µM. In certain embodiments, the valproic acid is used at a concentration of about 150 µM to about 350 µM. In certain embodiments, the valproic acid is used at a concentration of about 250 µM. In certain embodiments, the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM. [00239] In certain embodiments, the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 1 µM to about 50 µM, about 1 µM to about 10 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 1 µM to about 50 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 1 µM to about 10 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 2.5 µM to about 7.5 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 5 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. [00240] In certain embodiments, the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 1 µM to about 400 µM, about 5 µM to about 250 µM, about 10 µM to about 100 µM, about 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the forskolin is used at a concentration of about 0.1 µM to about 500 µM. In certain embodiments, the forskolin is used at a concentration of about 1 µM to about 400 µM. In certain embodiments, the forskolin is used at a concentration of about 5 µM to about 250 µM. In certain embodiments, the forskolin is used at a concentration of about 10 µM to about 100 µM. In certain embodiments, the forskolin is used at a concentration of about 25 µM to about 75 µM. In certain embodiments, the forskolin is used at a concentration of about 50 µM. In certain embodiments, the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 100 µM, 25 µM to about 75 µM, or about 50 µM. [00241] In certain embodiments, the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 100 µM to about 300 µM, or about 200 µM. In certain

91/240 12591029. H0824.70430WO00 embodiments, the butyric acid is used at a concentration of about 1 µM to about 1000 µM. In certain embodiments, the butyric acid is used at a concentration of about 10 µM to about 800 µM. In certain embodiments, the butyric acid is used at a concentration of about 50 µM to about 600 µM. In certain embodiments, the butyric acid is used at a concentration of about 100 µM to about 400 µM. In certain embodiments, the butyric acid is used at a concentration of about 100 µM to about 300 µM. In certain embodiments, the butyric acid is used at a concentration of about 200 µM. In certain embodiments, the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 100 µM to about 300 µM, or about 200 µM. [00242] In certain embodiments, the basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 10 µg/mL to about 400 µg/mL, about 25 µg/mL to about 250 µg/mL, about 50 µg/mL to about 150 µg/mL, or about 100 µg/mL. In certain embodiments, the basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL. In certain embodiments, the basic fibroblast growth factor (bFGF) is used at a concentration of about 10 µg/mL to about 400 µg/mL. In certain embodiments, the basic fibroblast growth factor (bFGF) is used at a concentration of about 25 µg/mL to about 250 µg/mL. In certain embodiments, the basic fibroblast growth factor (bFGF) is used at a concentration of about 50 µg/mL to about 150 µg/mL. In certain embodiments, the basic fibroblast growth factor (bFGF) is used at a concentration of about 100 µg/mL. In certain embodiments, the basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 50 µg/mL to about 150 µg/mL, or about 100 µg/mL. [00243] In certain embodiments, the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM. In certain embodiments, the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 25 µM. In certain embodiments, the arotinoid acid (TTNPB) is used at a concentration of about 0.25 µM to about 10 µM. In certain embodiments, the arotinoid acid (TTNPB) is used at a concentration of about 0.5 µM to about 7.5 µM. In certain embodiments, the arotinoid acid (TTNPB) is used at a concentration of about 0.75 µM to about 5 µM. In certain embodiments, the arotinoid acid (TTNPB) is used at a concentration of about 1 µM to about 3 µM. In certain embodiments, the arotinoid acid (TTNPB) is used at a concentration of about 2 µM. In certain embodiments, the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM. [00244] In certain embodiments, the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM. In certain embodiments, the

92/240 12591029. H0824.70430WO00 Y-27632 is used at a concentration of about 0.1 µM to about 25 µM. In certain embodiments, the Y- 27632 is used at a concentration of about 0.25 µM to about 10 µM. In certain embodiments, the Y- 27632 is used at a concentration of about 0.5 µM to about 7.5 µM. In certain embodiments, the Y- 27632 is used at a concentration of about 0.75 µM to about 5 µM. In certain embodiments, the Y- 27632 is used at a concentration of about 1 µM to about 3 µM. In certain embodiments, the Y-27632 is used at a concentration of about 2 µM. In certain embodiments, the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM. [00245] In certain embodiments, the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM. In certain embodiments, the smoothened agonist (SAG) is used at a concentration of about 0.05 µM to about 2.5 µM. In certain embodiments, the smoothened agonist (SAG) is used at a concentration of about 0.1 µM to about 1.5 µM. In certain embodiments, the smoothened agonist (SAG) is used at a concentration of about 0.25 µM to about 0.75 µM. In certain embodiments, the smoothened agonist (SAG) is used at a concentration of about 0.5 µM. In certain embodiments, the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. [00246] In certain embodiments, the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.25 µM to about 5 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM. In certain embodiments, the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 25 µM. In certain embodiments, the linifanib (ABT-869) is used at a concentration of about 0.25 µM to about 10 µM. In certain embodiments, the linifanib (ABT-869) is used at a concentration of about 0.25 µM to about 5 µM. In certain embodiments, the linifanib (ABT-869) is used at a concentration of about 0.5 µM to about 3 µM. In certain embodiments, the linifanib (ABT-869) is used at a concentration of about 0.5 µM to about 1.5 µM. In certain embodiments, the linifanib (ABT-869) is used at a concentration of about 1 µM. In certain embodiments, the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. [00247] In certain embodiments, the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM, about 50 µM to about 1500 µM, about 100 µM to about 1000 µM, about 250 µM to about 750 µM, or about 500 µM. In certain embodiments, the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM. In certain embodiments, the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 50 µM to about 1500 µM. In certain embodiments, the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 100 µM to about 1000 µM. In certain embodiments, the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 250 µM to about 750 µM. In certain embodiments, the alpha-ketoglutaric acid

93/240 12591029. H0824.70430WO00 (α-KG) is used at a concentration of about 500 µM. In certain embodiments, the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM, 250 µM to about 750 µM, or about 500 µM. [00248] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM. [00249] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM.

94/240 12591029. H0824.70430WO00 [00250] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 1 µM to about 50 µM, about 1 µM to about 10 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. In certain embodiments, the RepSox (E- 616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 1 µM to about 50 µM, about 1 µM to about 10 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E- 616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 1 µM to about 50 µM, about 1 µM to about 10 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E- 616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM; and the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 1 µM to about 50 µM, about 1 µM to about 10 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. [00251] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to

95/240 12591029. H0824.70430WO00 about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 1 µM to about 400 µM, about 5 µM to about 250 µM, about 10 µM to about 100 µM, about 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 1 µM to about 400 µM, about 5 µM to about 250 µM, about 10 µM to about 100 µM, about 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 1 µM to about 400 µM, about 5 µM to about 250 µM, about 10 µM to about 100 µM, about 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 1 µM to about 50 µM, about 1 µM to about 10 µM, about 2.5 µM to about 7.5 µM, or about 5 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 1 µM to about 400 µM, about 5 µM to about 250 µM, about 10 µM to about 100 µM, about 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM

96/240 12591029. H0824.70430WO00 to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 1 µM to about 400 µM, about 5 µM to about 250 µM, about 10 µM to about 100 µM, about 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM; the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 1 µM to about 50 µM, about 1 µM to about 10 µM, about 2.5 µM to about 7.5 µM, or about 5 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 1 µM to about 400 µM, about 5 µM to about 250 µM, about 10 µM to about 100 µM, about 25 µM to about 75 µM, or about 50 µM. [00252] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 100 µM to about 300 µM, or about 200 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 100 µM to about 300 µM, or about 200 µM. In certain embodiments, the laduviglusib

97/240 12591029. H0824.70430WO00 (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 100 µM to about 300 µM, or about 200 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM; the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 1 µM to about 50 µM, about 1 µM to about 10 µM, about 2.5 µM to about 7.5 µM, or about 5 µM; the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 1 µM to about 400 µM, about 5 µM to about 250 µM, about 10 µM to about 100 µM, about 25 µM to about 75 µM, or about 50 µM; and the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 100 µM to about 300 µM, or about 200 µM. [00253] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 10 µg/mL to about 400 µg/mL, about 25 µg/mL to about 250 µg/mL, about 50 µg/mL to about 150 µg/mL, or about 100 µg/mL. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1

98/240 12591029. H0824.70430WO00 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 10 µg/mL to about 400 µg/mL, about 25 µg/mL to about 250 µg/mL, about 50 µg/mL to about 150 µg/mL, or about 100 µg/mL. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 10 µg/mL to about 400 µg/mL, about 25 µg/mL to about 250 µg/mL, about 50 µg/mL to about 150 µg/mL, or about 100 µg/mL. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM; the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 1 µM to about 50 µM, about 1 µM to about 10 µM, about 2.5 µM to about 7.5 µM, or about 5 µM; the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 1 µM to about 400 µM, about 5 µM to about 250 µM, about 10 µM to about 100 µM, about 25 µM to about 75 µM, or about 50 µM; and the basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 10 µg/mL to about 400 µg/mL, about 25 µg/mL to about 250 µg/mL, about 50 µg/mL to about 150 µg/mL, or about 100 µg/mL. [00254] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the arotinoid acid

99/240 12591029. H0824.70430WO00 (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. [00255] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM

100/240 12591029. H0824.70430WO00 to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; and the Y-27632 is used at a concentration of

101/240 12591029. H0824.70430WO00 about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM. [00256] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the

102/240 12591029. H0824.70430WO00 RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM

103/240 12591029. H0824.70430WO00 to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. [00257] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.25 µM to about 5 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.25 µM to about 5 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.25 µM to about 5 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5

104/240 12591029. H0824.70430WO00 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E- 616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.25 µM to about 5 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.25 µM to about 5 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid

105/240 12591029. H0824.70430WO00 acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.25 µM to about 5 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E- 616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.25 µM to about 5 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. [00258] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5

106/240 12591029. H0824.70430WO00 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM; the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.25 µM to about 5 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 1.5 µM, or about 1 µM; and the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 100 µM to about 300 µM, or about 200 µM. [00259] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM, about 50 µM to about 1500 µM, about 100 µM to about 1000 µM, about 250 µM to about 750 µM, or about 500 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM, about 50 µM to about 1500 µM, about 100 µM to about 1000 µM, about 250 µM to about 750 µM, or about 500 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the alpha- ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM, about 50 µM to about 1500 µM, about 100 µM to about 1000 µM, about 250 µM to about 750 µM, or about 500 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about

107/240 12591029. H0824.70430WO00 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.5 µM to about 7.5 µM, about 0.75 µM to about 5 µM, about 1 µM to about 3 µM, or about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.05 µM to about 2.5 µM, about 0.1 µM to about 1.5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM; the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.1 µM to about 25 µM, about 0.25 µM to about 10 µM, about 0.25 µM to about 5 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 1.5 µM, or about 1 µM; and the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM, about 50 µM to about 1500 µM, about 100 µM to about 1000 µM, about 250 µM to about 750 µM, or about 500 µM. [00260] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM; and the ascorbic acid is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 2.5 µg/mL to about 400 µg/mL, about 5 µg/mL to about 300 µg/mL, about 7.5 µg/mL to about 200 µg/mL, about 5 µg/mL to about 100 µg/mL, about 10 µg/mL to about 100 µg/mL, about 20 µg/mL to about 90 µg/mL, about 25 µg/mL to about 75 µg/mL, about 35 µg/mL to about 65 µg/mL, about 40 µg/mL to about 60 µg/mL, about 50 µg/mL, or about 10 µg/mL to about 60 µg/mL. [00261] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM. [00262] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM

108/240 12591029. H0824.70430WO00 to about 12.5 µM, or about 10 µM; and the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM. [00263] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM; and the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. [00264] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 100 µM, 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 100 µM, 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 100 µM, 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 2.5 µM to about 7.5 µM, or about 5 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 100 µM, 25 µM to about 75 µM, or

109/240 12591029. H0824.70430WO00 about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 100 µM, 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM; the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 2.5 µM to about 7.5 µM, or about 5 µM; and the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 100 µM, 25 µM to about 75 µM, or about 50 µM. [00265] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 100 µM to about 300 µM, or about 200 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 100 µM to about 300 µM, or about 200 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 100 µM to about 300 µM, or about 200 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM; the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 2.5 µM to about 7.5 µM, or about 5 µM; the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 100 µM, 25 µM to about 75 µM, or about 50 µM; and the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 100 µM to about 300 µM, or about 200 µM.

110/240 12591029. H0824.70430WO00 [00266] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 50 µg/mL to about 150 µg/mL, or about 100 µg/mL. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 50 µg/mL to about 150 µg/mL, or about 100 µg/mL. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 50 µg/mL to about 150 µg/mL, or about 100 µg/mL. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM; the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 2.5 µM to about 7.5 µM, or about 5 µM; the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 100 µM, 25 µM to about 75 µM, or about 50 µM; and basic fibroblast growth factor (bFGF) is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 50 µg/mL to about 150 µg/mL, or about 100 µg/mL. [00267] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM. [00268] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM

111/240 12591029. H0824.70430WO00 to about 3 µM, or about 2 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; and the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM. [00269] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the RepSox (E- 616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to

112/240 12591029. H0824.70430WO00 about 3 µM, or about 2 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; and the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM. [00270] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the linifanib

113/240 12591029. H0824.70430WO00 (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; the Y- 27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; and the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.5 µM to about 1.5 µM, or about 1 µM. [00271] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; the Y-27632 is used at a

114/240 12591029. H0824.70430WO00 concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM; the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.5 µM to about 1.5 µM, or about 1 µM; and the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 100 µM to about 300 µM, or about 200 µM. [00272] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM, 250 µM to about 750 µM, or about 500 µM. In certain embodiments, the RepSox (E- 616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM, 250 µM to about 750 µM, or about 500 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; and the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM, 250 µM to about 750 µM, or about 500 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; the Y-27632 is used at a concentration of about 0.1 µM to about 50 µM, about 1 µM to about 3 µM, or about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.01 µM to about 5 µM, about 0.25 µM to about 0.75 µM, or about 0.5 µM; the linifanib (ABT-869) is used at a concentration of about 0.1 µM to about 50 µM, about 0.5 µM to about 1.5 µM, or about 1 µM; and the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 1 µM to about 2000 µM, 250 µM to about 750 µM, or about 500 µM. [00273] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM; and the ascorbic acid is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 10 µg/mL to about 100 µg/mL, about 25 µg/mL to about 75 µg/mL, or about 50 µg/mL. [00274] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 10 µM; the RepSox (E-616452) is used at a concentration of about 10 µM; the valproic acid is used at a concentration of about 250 µM; the tranylcypromine is used at a concentration of about 5 µM; and the forskolin is used at a concentration of about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 1 µM; the RepSox (E-616452) is used at a

115/240 12591029. H0824.70430WO00 concentration of about 10 µM; the valproic acid is used at a concentration of about 250 µM; the tranylcypromine is used at a concentration of about 5 µM; and the forskolin is used at a concentration of about 50 µM. [00275] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 1 µM; the RepSox (E-616452) is used at a concentration of about 10 µM; and the forskolin is used at a concentration of about 50 µM. [00276] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 10 µM; the RepSox (E-616452) is used at a concentration of about 10 µM; the valproic acid is used at a concentration of about 250 µM; the tranylcypromine is used at a concentration of about 5 µM; the forskolin is used at a concentration of about 50 µM; and the butyric acid is used at a concentration of about 200 µM. [00277] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 10 µM; the RepSox (E-616452) is used at a concentration of about 10 µM; the valproic acid is used at a concentration of about 250 µM; the tranylcypromine is used at a concentration of about 5 µM; the forskolin is used at a concentration of about 50 µM; and basic fibroblast growth factor (bFGF) is used at a concentration of about 100 µg/mL [00278] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 10 µM; the RepSox (E-616452) is used at a concentration of about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 2 µM; the Y-27632 is used at a concentration of about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.5 µM; and the linifanib (ABT-869) is used at a concentration of about 1 µM. [00279] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 10 µM; the RepSox (E-616452) is used at a concentration of about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 2 µM; the Y-27632 is used at a concentration of about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.5 µM; the linifanib (ABT-869) is used at a concentration of about 1 µM; and the butyric acid is used at a concentration of about 200 µM. [00280] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 10 µM; the RepSox (E-616452) is used at a concentration of about 10 µM; the arotinoid acid (TTNPB) is used at a concentration of about 2 µM; the Y-27632 is used at a concentration of about 2 µM; the smoothened agonist (SAG) is used at a concentration of about 0.5 µM; the linifanib (ABT-869) is used at a concentration of about 1 µM; and the alpha-ketoglutaric acid (α-KG) is used at a concentration of about 500 µM. [00281] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 10 µM; and the ascorbic acid is used at a concentration of about 50 µg/mL. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 1 µM; and the ascorbic acid is used at a concentration of about 50 µg/mL.

116/240 12591029. H0824.70430WO00 [00282] In certain embodiments, the ascorbic acid is used at a concentration of about 1 µg/mL to about 500 µg/mL, about 10 µg/mL to about 100 µg/mL, about 25 µg/mL to about 75 µg/mL, or about 50 µg/mL, and the lithium salt is used at a concentration of about 0.01 mM to about 100 mM, about 0.1 mM to about 50 mM, about 0.1 mM to about 25 mM, about 0.1 mM to about 10 mM, about 1 mM to about 50 mM, about 1 mM to about 25 mM, about 1 mM to about 10 mM, or about 10 mM. In certain embodiments, the ascorbic acid is used at a concentration of about 10 µg/mL to about 100 µg/mL, about 25 µg/mL to about 75 µg/mL, or about 50 µg/mL, and the lithium salt is used at a concentration of about 0.1 mM to about 25 mM, about 0.1 mM to about 10 mM, about 1 mM to about 25 mM, about 1 mM to about 10 mM, or about 10 mM. In certain embodiments, the ascorbic acid is used at a concentration of about 25 µg/mL to about 75 µg/mL, or about 50 µg/mL, and the lithium salt is used at a concentration of about 1 mM to about 25 mM, about 1 mM to about 10 mM, or about 10 mM. In certain embodiments, the ascorbic acid is used at a concentration of about 25 µg/mL to about 75 µg/mL, and the lithium salt is used at a concentration of about 1 mM to about 25 mM. In certain embodiments, the ascorbic acid is used at a concentration of about 50 µg/mL, and the lithium salt is used at a concentration of about 10 mM. [00283] In certain embodiments, the lithium ascorbate is used at a concentration of about 0.01 mM to about 100 mM, about 0.1 mM to about 50 mM, about 0.1 mM to about 25 mM, about 0.1 mM to about 10 mM, about 0.1 mM to about 5 mM, about 0.1 mM to about 2.5 mM, about 0.1 mM to about 1 mM, about 1 mM to about 25 mM, about 1 mM to about 10 mM, about 1 mM to about 5 mM, about 1 mM to about 2.5 mM, or about 1 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 0.01 mM to about 100 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 0.1 mM to about 50 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 0.1 mM to about 25 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 0.1 mM to about 10 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 0.1 mM to about 5 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 0.1 mM to about 2.5 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 0.1 mM to about 1 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 1 mM to about 25 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 1 mM to about 10 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 1 mM to about 5 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 1 mM to about 2.5 mM. In certain embodiments, the lithium ascorbate is used at a concentration of about 1 mM. [00284] In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is between about 1:100 and about 100:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is between about 1:50 and about 50:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is between about 1:25 and about 25:1.

117/240 12591029. H0824.70430WO00 In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is between about 1:10 and about 10:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is between about 1:5 and about 5:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is about 1:1. [00285] In certain embodiments, the ratio of laduviglusib (CHIR99021) to valproic acid is between about 1:10,000 and about 1:5. In certain embodiments, the ratio of laduviglusib (CHIR99021) to valproic acid is between about 1:5,000 and about 1:7.5. In certain embodiments, the ratio of laduviglusib (CHIR99021) to valproic acid is between about 1:1,000 and about 1:10. In certain embodiments, the ratio of laduviglusib (CHIR99021) to valproic acid is between about 1:100 and about 1:15. In certain embodiments, the ratio of laduviglusib (CHIR99021) to valproic acid is between about 1:50 and about 1:15. In certain embodiments, the ratio of laduviglusib (CHIR99021) to valproic acid is about 1:25. [00286] In certain embodiments, the ratio of laduviglusib (CHIR99021) to tranylcypromine is between about 1:200 and about 50:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to tranylcypromine is between about 1:100 and about 25:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to tranylcypromine is between about 1:50 and about 12.5:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to tranylcypromine is between about 1:10 and about 10:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to tranylcypromine is between about 1:5 and about 5:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to tranylcypromine is about 2:1. [00287] In certain embodiments, the ratio of laduviglusib (CHIR99021) to forskolin is between about 1:1000 and about 10:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to forskolin is between about 1:500 and about 7.5:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to forskolin is between about 1:100 and about 5:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to forskolin is between about 1:25 and about 2.5:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to forskolin is between about 1:10 and about 1:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to forskolin is about 1:5. [00288] In certain embodiments, the ratio of laduviglusib (CHIR99021) to butyric acid is between about 1:50,000 and about 1:5. In certain embodiments, the ratio of laduviglusib (CHIR99021) to butyric acid is between about 1:10,000 and about 1:7.5. In certain embodiments, the ratio of laduviglusib (CHIR99021) to butyric acid is between about 1:1,000 and about 1:10. In certain embodiments, the ratio of laduviglusib (CHIR99021) to butyric acid is between about 1:100 and about 1:12.5. In certain embodiments, the ratio of laduviglusib (CHIR99021) to butyric acid is between about 1:25 and about 1:15. In certain embodiments, the ratio of laduviglusib (CHIR99021) to butyric acid is about 1:20. [00289] In certain embodiments, the ratio of laduviglusib (CHIR99021) to basic fibroblast growth factor (bFGF) is between about 1:1 and about 10,000:1. In certain embodiments, the ratio of

118/240 12591029. H0824.70430WO00 laduviglusib (CHIR99021) to basic fibroblast growth factor (bFGF) is between about 100:1 and about 5,000:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to basic fibroblast growth factor (bFGF) is between about 500:1 and about 2,500:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to basic fibroblast growth factor (bFGF) is between about 1,000:1 and about 2,000:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to basic fibroblast growth factor (bFGF) is about 1,667:1. [00290] In certain embodiments, the ratio of laduviglusib (CHIR99021) to arotinoid acid (TTNPB) is between about 1:100 and about 100:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to arotinoid acid (TTNPB) is between about 1:50 and about 50:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to arotinoid acid (TTNPB) is between about 1:25 and about 25:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to arotinoid acid (TTNPB) is between about 1:10 and about 15:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to arotinoid acid (TTNPB) is between about 1:5 and about 10:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to arotinoid acid (TTNPB) is about 1:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to arotinoid acid (TTNPB) is about 5:1. [00291] In certain embodiments, the ratio of laduviglusib (CHIR99021) to Y-27632 is between about 1:100 and about 100:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to Y-27632 is between about 1:50 and about 50:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to Y-27632 is between about 1:25 and about 25:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to Y-27632 is between about 1:10 and about 15:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to Y-27632 is between about 1:5 and about 10:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to Y-27632 is about 1:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to Y-27632 is about 5:1. [00292] In certain embodiments, the ratio of laduviglusib (CHIR99021) to linifanib (ABT-869) is between about 1:20 and about 100:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to linifanib (ABT-869) is between about 1:10 and about 50:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to linifanib (ABT-869) is between about 1:1 and about 25:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to linifanib (ABT-869) is between about 5:1 and about 15:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to linifanib (ABT-869) is about 10:1. [00293] In certain embodiments, the ratio of laduviglusib (CHIR99021) to smoothened agonist (SAG) is between about 1:10 and about 50:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to smoothened agonist (SAG) is between about 1:5 and about 40:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to smoothened agonist (SAG) is between about 1:1 and about 30:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to smoothened agonist (SAG) is between about 5:1 and about 25:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to smoothened agonist (SAG) is about 20:1.

119/240 12591029. H0824.70430WO00 [00294] In certain embodiments, the ratio of laduviglusib (CHIR99021) to alpha-ketoglutaric acid (α- KG) is between about 1:10,000 and about 1:5. In certain embodiments, the ratio of laduviglusib (CHIR99021) to alpha-ketoglutaric acid (α-KG) is between about 1:5,000 and about 1:10. In certain embodiments, the ratio of laduviglusib (CHIR99021) to alpha-ketoglutaric acid (α-KG) is between about 1:1,000 and about 1:25. In certain embodiments, the ratio of laduviglusib (CHIR99021) to alpha-ketoglutaric acid (α-KG) is between about 1:100 and about 1:35. In certain embodiments, the ratio of laduviglusib (CHIR99021) to alpha-ketoglutaric acid (α-KG) is about 1:50. [00295] In certain embodiments, the ratio of RepSox (E-616452) to valproic acid is between about 1:10,000 and about 1:5. In certain embodiments, the ratio of RepSox (E-616452) to valproic acid is between about 1:5,000 and about 1:7.5. In certain embodiments, the ratio of RepSox (E-616452) to valproic acid is between about 1:1,000 and about 1:10. In certain embodiments, the ratio of RepSox (E-616452) to valproic acid is between about 1:100 and about 1:15. In certain embodiments, the ratio of RepSox (E-616452) to valproic acid is between about 1:50 and about 1:15. In certain embodiments, the ratio of RepSox (E-616452) to valproic acid is about 1:25. [00296] In certain embodiments, the ratio of RepSox (E-616452) to tranylcypromine is between about 1:200 and about 50:1. In certain embodiments, the ratio of RepSox (E-616452) to tranylcypromine is between about 1:100 and about 25:1. In certain embodiments, the ratio of RepSox (E-616452) to tranylcypromine is between about 1:50 and about 12.5:1. In certain embodiments, the ratio of RepSox (E-616452) to tranylcypromine is between about 1:10 and about 10:1. In certain embodiments, the ratio of RepSox (E-616452) to tranylcypromine is between about 1:5 and about 5:1. In certain embodiments, the ratio of RepSox (E-616452) to tranylcypromine is about 2:1. [00297] In certain embodiments, the ratio of RepSox (E-616452) to forskolin is between about 1:1000 and about 10:1. In certain embodiments, the ratio of RepSox (E-616452) to forskolin is between about 1:500 and about 7.5:1. In certain embodiments, the ratio of RepSox (E-616452) to forskolin is between about 1:100 and about 5:1. In certain embodiments, the ratio of RepSox (E-616452) to forskolin is between about 1:25 and about 2.5:1. In certain embodiments, the ratio of RepSox (E- 616452) to forskolin is between about 1:10 and about 1:1. In certain embodiments, the ratio of RepSox (E-616452) to forskolin is about 1:5. [00298] In certain embodiments, the ratio of RepSox (E-616452) to butyric acid is between about 1:50,000 and about 1:5. In certain embodiments, the ratio of RepSox (E-616452) to butyric acid is between about 1:10,000 and about 1:7.5. In certain embodiments, the ratio of RepSox (E-616452) to butyric acid is between about 1:1,000 and about 1:10. In certain embodiments, the ratio of RepSox (E-616452) to butyric acid is between about 1:100 and about 1:12.5. In certain embodiments, the ratio of RepSox (E-616452) to butyric acid is between about 1:25 and about 1:15. In certain embodiments, the ratio of RepSox (E-616452) to butyric acid is about 1:20. [00299] In certain embodiments, the ratio of RepSox (E-616452) to basic fibroblast growth factor (bFGF) is between about 1:1 and about 10,000:1. In certain embodiments, the ratio of RepSox (E-

120/240 12591029. H0824.70430WO00 616452) to basic fibroblast growth factor (bFGF) is between about 100:1 and about 5,000:1. In certain embodiments, the ratio of RepSox (E-616452) to basic fibroblast growth factor (bFGF) is between about 500:1 and about 2,500:1. In certain embodiments, the ratio of RepSox (E-616452) to basic fibroblast growth factor (bFGF) is between about 1,000:1 and about 2,000:1. In certain embodiments, the ratio of RepSox (E-616452) to basic fibroblast growth factor (bFGF) is about 1,667:1. [00300] In certain embodiments, the ratio of RepSox (E-616452) to arotinoid acid (TTNPB) is between about 1:100 and about 100:1. In certain embodiments, the ratio of RepSox (E-616452) to arotinoid acid (TTNPB) is between about 1:50 and about 50:1. In certain embodiments, the ratio of RepSox (E-616452) to arotinoid acid (TTNPB) is between about 1:25 and about 25:1. In certain embodiments, the ratio of RepSox (E-616452) to arotinoid acid (TTNPB) is between about 1:10 and about 15:1. In certain embodiments, the ratio of RepSox (E-616452) to arotinoid acid (TTNPB) is between about 1:5 and about 10:1. In certain embodiments, the ratio of RepSox (E-616452) to arotinoid acid (TTNPB) is about 1:1. In certain embodiments, the ratio of RepSox (E-616452) to arotinoid acid (TTNPB) is about 5:1. [00301] In certain embodiments, the ratio of RepSox (E-616452) to Y-27632 is between about 1:100 and about 100:1. In certain embodiments, the ratio of RepSox (E-616452) to Y-27632 is between about 1:50 and about 50:1. In certain embodiments, the ratio of RepSox (E-616452) to Y-27632 is between about 1:25 and about 25:1. In certain embodiments, the ratio of RepSox (E-616452) to Y- 27632 is between about 1:10 and about 15:1. In certain embodiments, the ratio of RepSox (E- 616452) to Y-27632 is between about 1:5 and about 10:1. In certain embodiments, the ratio of RepSox (E-616452) to Y-27632 is about 1:1. In certain embodiments, the ratio of RepSox (E- 616452) to Y-27632 is about 5:1. [00302] In certain embodiments, the ratio of RepSox (E-616452) to smoothened agonist (SAG) is between about 1:10 and about 50:1. In certain embodiments, the ratio of RepSox (E-616452) to smoothened agonist (SAG) is between about 1:5 and about 40:1. In certain embodiments, the ratio of RepSox (E-616452) to smoothened agonist (SAG) is between about 1:1 and about 30:1. In certain embodiments, the ratio of RepSox (E-616452) to smoothened agonist (SAG) is between about 5:1 and about 25:1. In certain embodiments, the ratio of RepSox (E-616452) to smoothened agonist (SAG) is about 20:1. [00303] In certain embodiments, the ratio of RepSox (E-616452) to linifanib (ABT-869) is between about 1:20 and about 100:1. In certain embodiments, the ratio of RepSox (E-616452) to linifanib (ABT-869) is between about 1:10 and about 50:1. In certain embodiments, the ratio of RepSox (E- 616452) to linifanib (ABT-869) is between about 1:1 and about 25:1. In certain embodiments, the ratio of RepSox (E-616452) to linifanib (ABT-869) is between about 5:1 and about 15:1. In certain embodiments, the ratio of RepSox (E-616452) to linifanib (ABT-869) is about 10:1.

121/240 12591029. H0824.70430WO00 [00304] In certain embodiments, the ratio of RepSox (E-616452) to alpha-ketoglutaric acid (α-KG) is between about 1:10,000 and about 1:5. In certain embodiments, the ratio of RepSox (E-616452) to alpha-ketoglutaric acid (α-KG) is between about 1:5,000 and about 1:10. In certain embodiments, the ratio of RepSox (E-616452) to alpha-ketoglutaric acid (α-KG) is between about 1:1,000 and about 1:25. In certain embodiments, the ratio of RepSox (E-616452) to alpha-ketoglutaric acid (α-KG) is between about 1:100 and about 1:35. In certain embodiments, the ratio of RepSox (E-616452) to alpha-ketoglutaric acid (α-KG) is about 1:50. [00305] In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is about 1:1, the ratio of laduviglusib (CHIR99021) to valproic acid is about 1:25, and the ratio of laduviglusib (CHIR99021) to forskolin is about 1:5. In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is about 1:1, the ratio of laduviglusib (CHIR99021) to valproic acid is about 1:25, the ratio of laduviglusib (CHIR99021) to forskolin is about 1:5, and the ratio of laduviglusib (CHIR99021) to butyric acid is about 1:20. In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is about 1:1, the ratio of laduviglusib (CHIR99021) to valproic acid is about 1:25, the ratio of laduviglusib (CHIR99021) to forskolin is about 1:5, and the ratio of laduviglusib (CHIR99021) to basic fibroblast growth factor (bFGF) is about 1,667:1. [00306] In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is about 1:1, the ratio of laduviglusib (CHIR99021) to arotinoid acid (TTNPB) is about 5:1, the ratio of laduviglusib (CHIR99021) to Y-27632 is about 5:1, the ratio of laduviglusib (CHIR99021) to smoothened agonist (SAG) is about 20:1, and the ratio of laduviglusib (CHIR99021) to linifanib (ABT-869) is about 10:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is about 1:1, the ratio of laduviglusib (CHIR99021) to arotinoid acid (TTNPB) is about 5:1, the ratio of laduviglusib (CHIR99021) to Y-27632 is about 5:1, the ratio of laduviglusib (CHIR99021) to smoothened agonist (SAG) is about 20:1, the ratio of laduviglusib (CHIR99021) to linifanib (ABT-869) is about 10:1, and the ratio of laduviglusib (CHIR99021) to butyric acid is about 1:20. In certain embodiments, the ratio of laduviglusib (CHIR99021) to RepSox (E-616452) is about 1:1, the ratio of laduviglusib (CHIR99021) to arotinoid acid (TTNPB) is about 5:1, the ratio of laduviglusib (CHIR99021) to Y-27632 is about 5:1, the ratio of laduviglusib (CHIR99021) to smoothened agonist (SAG) is about 20:1, the ratio of laduviglusib (CHIR99021) to linifanib (ABT- 869) is about 10:1, and the ratio of laduviglusib (CHIR99021) to alpha-ketoglutaric acid (α-KG) is about 1:50. [00307] In certain embodiments, the ratio of laduviglusib (CHIR99021) to ascorbic acid is between about 1:3,000 and about 1:1. In certain embodiments, the ratio of laduviglusib (CHIR99021) to ascorbic acid is between about 1:2,000 and about 1:25. In certain embodiments, the ratio of laduviglusib (CHIR99021) to ascorbic acid is between about 1:1,000 and about 1:75. In certain embodiments, the ratio of laduviglusib (CHIR99021) to ascorbic acid is between about 1:750 and about 1:50. In certain embodiments, the ratio of laduviglusib (CHIR99021) to ascorbic acid is

122/240 12591029. H0824.70430WO00 between about 1:500 and about 1:100. In certain embodiments, the ratio of laduviglusib (CHIR99021) to ascorbic acid is between about 1:300 and about 1:250. In certain embodiments, the ratio of laduviglusib (CHIR99021) to ascorbic acid is about 1:284. [00308] In certain embodiments, the cell, tissue, or organ is ex vivo. In certain embodiments, the cell, tissue, or organ is in vivo. [00309] Cellular reprogramming may be determined by measuring gene expression (e.g., expression of embryonic markers and/or pluripotency markers). In some embodiments, pluripotency markers include AP, SSEA1, and/or Nanog. [00310] Chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) can be administered to a cell, tissue, or organ in combination with activating an enhancer of reprogramming and/or inhibiting a barrier of reprogramming. An enhancer of reprogramming may be activated using any suitable method known in the art, including overexpression of the enhancer, increasing expression of an endogenous gene encoding the enhancer (e.g., using CRISPR technology), use of a chemical agent and/or antibody to increase the biological activity of the enhancer, and use a chemical agent and/or antibody to promote expression of the enhancer. A barrier of reprogramming may be inhibited using any suitable method known in the art, including knocking down expression of the inhibitor (e.g., with siRNAs, miRNAs, shRNAs), knocking out an endogenous copy of the inhibitor (e.g., using CRISPR technology, TALENs, zinc finger nucleases, etc.), using a chemical agent and/or antibody to decrease the biological activity of the inhibitor, and using a chemical agent and/or antibody to decrease expression of the inhibitor. [00311] Non-limiting examples of enhancers and barriers of reprogramming are provided in Table 1. See also, e.g., Ebrahimi, Cell Regen (Lond).2015 Nov 11;4:10, which is herein incorporated by reference in its entirety. Table 1. Non-limiting examples of strategies to enhance reprogramming.

123/240 12591029. H0824.70430WO00 [00312] Additional reprogramming enhancers that may be activated in combination with treatment of a cell, tissue, or organ with chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT- 869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) include histone lysine demethylases (e.g., KDM2, KDM3, and KDM4). Histone lysine demethylases may be activated by being overexpressed in a cell, tissue, organ, and/or a subject. Chemical activators of histone lysine demethylases are also encompassed by the present disclosure. For example, vitamin C may be used to activate KDM3 and/or KDM4. [00313] In some embodiments, a cell, tissue, or organ may be treated with chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) in combination with a cytokine that facilitates reprogramming. IL6 is a non-limiting example of a cytokine. See, e.g., Mosteiro et al, Science.2016 Nov 25;354(6315), which is herein incorporated by reference in its entirety. [00314] In some embodiments, a cell, tissue, or organ may be treated with chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) in combination with activation of

124/240 12591029. H0824.70430WO00 a miRNA (e.g., administration of a miRNA and/or expression of a miRNA). For example, a miRNA that promotes cell cycle progression may be introduced to a cell, tissue, organ, and/or subject. Non- limiting examples of miRNAs that promote cell cycle progression include miR 302-367, miR 371- 373, miR-200b, miR-200c, miR-205, miR 290-295, miR-93, miR-106, and miR 135b. [00315] As a non-limiting example, a reprogramming barrier may be a DNA methyltransferase (DNMT) may be and a DNMT may be inhibited to promote reprogramming of a tissue, cell, and/or organ. Most DNA methyltransferases use S-adenosyl-L-methionine as a methyl donor. DNMT may be from any species. There are at least three different types of methyltransferases. M6A methyltransferases are capable of methylating the amino group at the c-6 position of adenines in DNA (e.g., Enzyme Commission (EC) No.2.1.1.72). m4C methyltransferases are capable of generating N4-methylcytosine (e.g., Enzyme Commission (EC) No.2.1.1.113). M5C methyltransferases are capable of generating C5-methylcytosine (e.g., Enzyme Commission (EC) No. 2.1.1.37). [00316] Non-limiting examples of mammalian DNA methyltransferases (DNMTs) include DNMT1 and its isoforms DNMT1b and DNMT1o (oocytes-specific), DNMT3a, DNMT3b, DNMT3L. GenBank Accession Nos. NM_001130823.3 (isoform a), NM_001318730.1 (isoform c), NM_001318731.1 (isoform d), and NM_001379.3 (isoform b) are non-limiting examples of nucleotide sequences encoding human DNMT1. A nucleic acid encoding a DNMT1 may comprise a sequence that is at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a sequence set forth in GenBank Accession Nos. NM_001130823.3 (isoform a), NM_001318730.1 (isoform c), NM_001318731.1 (isoform d), and/or NM_001379.3 (isoform b). GenBank Accession Nos. NP_001124295.1 (isoform a), NP_001305659.1 (isoform c), NP_001305660.1 (isoform d), and NP_001370.1 (isoform b) are non-limiting examples of amino acid sequences encoding human DNMT1. An amino acid sequence encoding a DNMT1 may comprise a sequence that is at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a sequence set forth in GenBank Accession Nos. NP_001124295.1 (isoform a), NP_001305659.1 (isoform c), NP_001305660.1 (isoform d), and/or NP_001370.1 (isoform b). A nucleic acid encoding human DNMT3A includes GenBank Accession No. NM_001320892.1, NM_001320893.1, NM_022552.4, NM_153759.3, NM_175629.2, and NM_175630.1. A nucleic acid encoding a DNMT3A may be at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a sequence set forth in GenBank Accession Nos. NM_001320892.1, NM_001320893.1, NM_022552.4, NM_153759.3, NM_175629.2, and/or NM_175630.1. An amino acid sequence encoding human DNMT3A includes GenBank Accession Nos. NP_001307821.1, NP_001307822.1, NP_072046.2, NP_715640.2, NP_783328.1, and NP_783329.1. An amino acid sequence encoding a DNMT3A may be at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a sequence set forth in GenBank Accession Nos. NP_001307821.1, NP_001307822.1, NP_072046.2, NP_715640.2, NP_783328.1, and/or NP_783329.1. A nucleic acid encoding human DNMT3B includes GenBank Accession No. NM_001207055.1, NM_001207056.1, NM_006892.3,

125/240 12591029. H0824.70430WO00 NM_175848.1, NM_175849.1, and NM_175850.2. A nucleic acid encoding a DNMT3B may be at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a sequence set forth in GenBank Accession Nos. NM_001207055.1, NM_001207056.1, NM_006892.3, NM_175848.1, NM_175849.1, and/or NM_175850.2. An amino acid sequence encoding human DNMT3B includes GenBank Accession Nos. NP_001193984.1, NP_001193985.1, NP_008823.1, NP_787044.1, NP_787045.1, and NP_787046.1. An amino acid sequence encoding a DNMT3B may be at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a sequence set forth in GenBank Accession Nos. NP_001193984.1, NP_001193985.1, NP_008823.1, NP_787044.1, NP_787045.1, and/or NP_787046.1. A nucleic acid encoding human DNMT3L includes GenBank Accession No. NM_013369.3 and NM_175867.2. A nucleic acid encoding a DNMT3L may be at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a sequence set forth in GenBank Accession Nos. NM_013369.3 and/or NM_175867.2. An amino acid sequence encoding human DNMT3L includes GenBank Accession Nos. NP_037501.2 and NP_787063.1. An amino acid sequence encoding a DNMT3L may be at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a sequence set forth in GenBank Accession Nos. NP_037501.2 and/or NP_787063.1. [00317] A DNMT may be inhibited using any suitable method known in the art. Suitable methods include knockdown of a DNMT mRNA, genetically knocking out a DNMT, and use of a DNMT inhibitor (e.g., chemical inhibitors). DNMT inhibitors are being investigated in clinical trials (e.g., phase III clinical trials) in the United States of America and beyond. Non-limiting examples of DNMT inhibitors include VIDAZA^TM (azacitidine) (e.g., for the treatment of Myelodysplastic Syndromes and treatment of acute myeloid leukemia (AML)), DACOGEN^TM (decitabine) (e.g., for treatment of AML and treatment of Chronic myeloid leukemia (CML)), and Guadecitabine (SGI-110) (e.g., for treatment of AML). In 2012, the European Union approved DACOGEN^TM (decitabine) for use in patients with AML. [00318] A DNMT may be inhibited by inhibiting a DNMT stabilizer. Suitable methods of inhibiting a DNMT stabilizer include knockdown of the mRNA encoding the stabilizer, genetically knocking out the gene that encodes the stabilizer and use of an inhibitor (e.g., chemical inhibitors). As a non- limiting example, KDM1a, which is also referred to as Lsd1 or Aof2, is a stabilizer of DNMT1. See, e.g., Wang et al., Nat Genet.2009 Jan;41(1):125-9. In some embodiments, KDM1a expression is knocked down using a shRNA disclosed herein or known in the art. In some embodiments, KDM1a is inhibited to prevent injury induced by hypermethylation from DNMTs, which could be useful in promoting reprogramming. [00319] In some embodiments, a histone methyltransferase is a reprogramming barrier and is inhibited to facilitate reprogramming of a cell, tissue and/or organ. Histone methyltransferases may be inhibited by any suitable method, including use of chemical inhibitors. For example, 3-

126/240 12591029. H0824.70430WO00 deazaneplanocin A (Dznep), epz004777, and BIX-01294 are examples of histone methyltransferase inhibitors. [00320] In some embodiments, a reprogramming barrier is a histone deacetylase (HDAC) and a HDAC is inhibited to facilitate reprogramming of a cell, tissue, and/or organ. Non-limiting examples of HDAC inhibitors include valproic acid (VPA), trichostatin A (TSA), suberoylanilide hydroxamic Acid (SAHA), sodium butyrate (SB), Belinostat (PXD101), Panobinostat (LBH589), Quisinostat (JNJ-26481585), Abexinostat (PCI-24781), Givinostat (ITF2357), Resminostat (4SC-201), Phenylbutyrate (PBA), Depsipeptide (romidepsin), Entinostat (MS-275), Mocetinostat (MGCD0103), and Tubastatin A (TBA). [00321] In some embodiments, a reprogramming barrier is a NF-κB, and it is inhibited to facilitate reprogramming of a cell, tissue, and/or organ. Non-limiting examples of NF-κB inhibitor includes BAY 11-7082, TPCA 1, and p65 siRNA. See, e.g., the NF-κB small molecule guide compiled by Abcam, which is available on the Abcam website (www.abcam.com/reagents/nf-kb-small-molecule- guide). [00322] In some embodiments, a reprogramming barrier is a cytokine secreted from senescent cells in which a cytokine is inhibited to facilitate reprogramming of a cell, tissue, and/or organ. Non-limiting examples of cytokines inhibitors include Anti-TNFα (Mahmoudi et al, Biorxiv, 2018) and drugs, including Navitoclax, that kill senescence cells. [00323] In some embodiments, a reprogramming barrier is a microRNA (miRNA) and a microRNA is inhibited to facilitate reprogramming of a cell, tissue, and/or organ. Non-limiting examples of microRNAs that are reprogramming barriers include miR Let-7 and miR-34. Without being bound by a particular theory, inhibition of miR Let-7 may increase the efficiency of reprogramming because miR Let-7 inhibits the cell cycle and inhibition of miR-34 may facilitate reprogramming because miR-34 inhibits the translation of p53. [00324] In some embodiments, a cell, tissue, or organ may be treated with chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) in combination with inhibition of PTEN, SOCS3, RhoA, and/or ROCK to enhance nerve regeneration. In some embodiments, PTEN is deleted, SOCS3 is deleted, RhoA is knocked down, and/or ROCK is knocked down in a cell, tissue, organ and/or subject. See, e.g., Park et al., Science.2008 Nov 7;322(5903):963-6; Smith et al., Neuron.2009 Dec 10;64(5):617-23; Koch et al., Front Cell Neurosci.2014 Sep 5;8:273; Koch et al., Cell Death Dis.2014 May 15;5:e1225 for descriptions of inhibition of PTEN, SOCS3, RhoA, and/or ROCK. Each reference is incorporated herein by reference in its entirety.

127/240 12591029. H0824.70430WO00 Methods of Treatment [00325] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00326] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and

128/240 12591029. H0824.70430WO00 RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00327] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [00328] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof lithium ascorbate. [00329] In certain embodiments, the subject is a human. In certain embodiments, the subject is a pediatric subject. In certain embodiments, the subject is an adult subject. In certain embodiments, the adult subject is a senior adult subject. In some embodiments, the subject is a non-human mammal. In certain embodiments, the subject is healthy. In certain embodiments, the subject has a disease. In certain embodiments, the subject has, is suspected of having, or is at risk for an age-related disease. In certain embodiments, the age-related disease is a neurological disease. In certain embodiments, the neurological disease is a neurodegenerative disease. In certain embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). In some

129/240 12591029. H0824.70430WO00 embodiments, the neurodegenerative disease is Alzheimer’s Disease, Parkinson’s Disease, dementia, Friedreich ataxia, amyotrophic lateral sclerosis, or vascular dementia. In some embodiments, the method improves cognitive function of the subject. In some embodiments, the method improves the memory of the subject. [00330] In certain embodiments, the administration comprises direct administration to the cell, tissue, or organ. In certain embodiments, the administration comprises systemic administration to the subject. In certain embodiments, the systemic administration comprises intravenous injection. In some embodiments, the administration comprises intrathecal administration. [00331] In some embodiments, the compounds are administered for a time period that is sufficient to treat the disease in the subject in need thereof. In some embodiments, the compounds are administered for at least about 1 hour, at least about 6 hours, at least about 12 hours, at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 18 months, at least about 2 years, at least about 30 months, at least about 3 years, at least about 42 months, at least about 4 years, at least about 54 months, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, at least about 60 years, at least about 70 years, at least about 80 years, at least about 90 years, or at least about 100 years. In certain embodiments, the compounds are administered for about 1 day. In certain embodiments, the compounds are administered for about 2 days. In certain embodiments, the compounds are administered for about 3 days. In certain embodiments, the compounds are administered for about 4 days. In certain embodiments, the compounds are administered for about 5 days. In certain embodiments, the compounds are administered for about 6 days. In certain embodiments, the compounds are administered for about 1 week. In certain embodiments, the compounds are administered for about 2 weeks. In certain embodiments, the compounds are administered for about 3 weeks. In certain embodiments, the compounds are administered for about 1 month. In certain embodiments, the compounds are administered for about 2 months. [00332] A chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may be used for regulating (e.g., inducing or inducing and stopping) cellular reprogramming, tissue repair, tissue

130/240 12591029. H0824.70430WO00 regeneration, organ regeneration, reversing aging, treating a disease, or any combination thereof. In some embodiments, the disease is a neurological disease. In some embodiments, a composition described herein is used to improve the cognitive ability of a subject. In some embodiments, a composition described herein is used to improve memory of a subject. In some embodiments, a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may be useful in regulating cellular reprogramming, tissue repair, tissue survival, tissue regeneration, tissue growth, tissue function, organ regeneration, organ survival, organ function, or any combination thereof, optionally wherein regulating comprises inducing cellular reprogramming, reversing aging, improving tissue function, improving organ function, tissue repair, tissue survival, tissue regeneration, tissue growth, angiogenesis, scar formation, the appearance of aging, organ regeneration, organ survival, altering the taste and quality of agricultural products derived from animals, treating a disease, or any combination thereof, in vivo or in vitro may be administered to a cell, tissue, or organ that is in vivo (e.g., part of a subject), or may be administered to a cell, tissue, or organ ex vivo. As used herein, regulating may refer to any type of modulation, including inducing or promoting, inhibiting, and/or stopping. Angiogenesis refers to growth of new blood vessels, including capillaries. [00333] Aspects of the present disclosure also provide methods of regulating cellular reprogramming, promoting tissue repair, promoting tissue survival, promoting tissue regeneration, promoting tissue growth, regulating tissue function, promoting organ regeneration, promoting organ survival, regulating organ function, treating and/or preventing disease, or any combination thereof. Regulating may comprise inducing cellular reprogramming, reversing aging, improving tissue function, improving organ function, tissue repair, tissue survival, tissue regeneration, tissue growth, promoting angiogenesis, reducing scar formation, promoting organ regeneration, promoting organ survival, treating a disease, or any combination thereof, in vivo or in vitro. The methods may comprise administering a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). [00334] In some embodiments, the method does not induce expression of stem cell markers (e.g., Nanog). Without being bound by any particular theory, Nanog activation may induce teratomas and cause death of the host. In some embodiments, the method does not induce teratoma formation. In some embodiments, the method does not induce unwanted cell proliferation. In some embodiments,

131/240 12591029. H0824.70430WO00 the method does not induce malignant cell growth. In some embodiments, the method does not induce cancer. [00335] As used herein, partial or incomplete reprogramming of a cell refers to a cell that are not stem cells, but have youthful characteristics. In some embodiments, a youthful characteristic is an epigenome that is similar to a young cell. In some embodiments, a stem cell shows higher levels of Nanog expression compared to a cell that is not a stem cell. In some embodiments, youthful characteristics refers to rejuvenation of a cell without changing cell identity. [00336] To practice this embodiment, an effective amount of a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may be used. [00337] In some embodiments, a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof), may be introduced to a tissue, cell, or organ ex vivo (e.g., not in a subject) and the tissue, cell, and/or organ may be further cultured ex vivo. In some embodiments, engineered cells are cultured to produce an engineered tissue. In some embodiments, engineered cells are cultured to produce an engineered organ. In some embodiments, an engineered tissue is cultured to produce an engineered organ. These methods may be useful in producing an engineered cell, engineered tissue or organ for transplantation into a subject. In some embodiments, the engineered cell, tissue, and/or organ is transplanted into a subject. [00338] In some embodiments, cells, tissues, organs, or any combination thereof are autologous to the subject, e.g., obtained from a subject in need thereof. Administration of autologous cells, autologous tissues, autologous organs, or any combination thereof may result in reduced rejection of the cells, tissues, organs, or any combination thereof compared to administration of non-autologous cells, non-autologous tissue and/or non-autologous organs. Alternatively, the cells, tissues, or organs to be engineered may be allogenic cells, allogenic tissues, or allogenic organs. For example, allogenic cells, allogenic tissue, allogenic organs, or any combination thereof may be derived from a donor (e.g., from a particular species) and administered to a recipient (e.g., from the same species) who is different from the donor. In some embodiments, allogenic cells, allogenic tissue, allogenic organs, or any combination thereof may be derived from a donor subject from a particular species and administered to a recipient subject from a different species from the donor.

132/240 12591029. H0824.70430WO00 [00339] In some embodiments, engineered cells comprise more than one cell type (e.g., more than one type of nerve cell). [00340] As a non-limiting example, the methods described herein may be used to produce engineered cell, tissue, or organ of the central nervous system. The engineered organ, engineered tissue, engineered organ, or any combination thereof may be administered to a subject. In some embodiments, administration of an engineered cell, engineered tissue, engineered organ, or a combination thereof improves survival of a subject (e.g., increases the lifespan of a subject relative to not receiving the engineered cell, tissue, or organ). [00341] A pharmaceutical composition described herein may be administered to a subject in need thereof. Non-limiting examples of subjects include any animal (e.g., mammals, including humans). A subject may be suspected of having, be at risk for or have a condition. For example, the condition may be an injury or a disease and the condition may affect any tissue (e.g., nerve tissue). Non- limiting examples of conditions, diseases, and disorders include acute injuries, neurodegenerative disease, chronic diseases, proliferative diseases, cardiovascular diseases, genetic diseases, inflammatory diseases, autoimmune diseases, neurological diseases, hematological diseases, painful conditions, psychiatric disorders, metabolic disorders, cancers, aging, age-related diseases, and diseases affecting any tissue in a subject. In some embodiments, the disease is an ocular disease. [00342] In certain embodiments, a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof), may be introduced to a subject prior to the onset of a disease (e.g., to prevent a disease or to prevent damage to a cell, tissue, or organ). In some embodiments, the subject may be a healthy subject. In certain embodiments, a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof), may be introduced to a subject following the onset of disease (e.g., to alleviate the damage or symptoms associated with a disease). In some embodiments, cell rejuvenation induced prior to the onset of a disease. In some embodiments, cell rejuvenation is induced after the onset of a disease. In some embodiments, cell rejuvenation is induced in a young subject, young cell, young tissue, and/or young organ. In some embodiments, cell rejuvenation is induced in an aged subject, aged cell, aged tissue, and/or aged organ.

133/240 12591029. H0824.70430WO00 [00343] In certain embodiments, the tissue may be considered healthy but suboptimal for performance or survival in current or future conditions (e.g., in agriculture, or adverse conditions including disease treatments, toxic therapies, sun exposure, or space travel outside the earth’s atmosphere). [00344] In certain embodiments, the condition is aging. All animals typically go through a period of growth and maturation followed by a period of progressive and irreversible physiological decline ending in death. The length of time from birth to death is known as the life span of an organism, and each organism has a characteristic average life span. Aging is a physical manifestation of the changes underlying the passage of time as measured by percent of average life span. [00345] In some cases, characteristics of aging can be quite obvious. For example, characteristics of older humans include skin wrinkling, graying of the hair, baldness, and cataracts, as well as hypermelanosis, osteoporosis, cerebral cortical atrophy, lymphoid depletion, thymic atrophy, increased incidence of diabetes type II, atherosclerosis, cancer, and heart disease. Nehlin et al. (2000), Annals NY Acad Sci 980:176-79. Other aspects of mammalian aging include weight loss, lordokyphosis (hunchback spine), absence of vigor, lymphoid atrophy, decreased bone density, dermal thickening and subcutaneous adipose tissue, decreased ability to tolerate stress (including heat or cold, wounding, anesthesia, and hematopoietic precursor cell ablation), liver pathology, atrophy of intestinal villi, skin ulceration, amyloid deposits, and joint diseases. Tyner et al. (2002), Nature 415:45-53. In some embodiments, aging is determined by a decrease in cognitive ability. [00346] Those skilled in the art will recognize that the aging process is also manifested at the cellular level, as well as in mitochondria. Cellular aging is manifested in deterioration of nucleocytoplasmic compartmentalization (NCC), loss of doubling capacity, increased levels of apoptosis, changes in differentiated phenotype, and changes in metabolism, e.g., decreased levels of protein synthesis and turnover. [00347] Given the programmed nature of cellular and organismal aging, it is possible to evaluate the “biological age” of a cell or organism by means of phenotypic characteristics that are correlated with aging. For example, biological age can be deduced from patterns of gene expression, resistance to stress (e.g., oxidative or genotoxic stress), rate of cellular proliferation, and the metabolic characteristics of cells (e.g., rates of protein synthesis and turnover, mitochondrial function, ubiquinone biosynthesis, cholesterol biosynthesis, ATP levels within the cell, levels of a Krebs cycle intermediate in the cell, glucose metabolism, nucleic acid (e.g., engineered nucleic acid) metabolism, ribosomal translation rates, etc.). As used herein, “biological age” is a measure of the age of a cell or organism based upon the molecular characteristics of the cell or organism. Biological age is distinct from “temporal age,” which refers to the age of a cell or organism as measured by days, months, and years, and “apparent chronological age,” which refers to refers to the age that a cell, organ, or tissue matches based on biomarkers or other metrics from individuals of such chronological age. [00348] The rate of aging of an organism, e.g., an invertebrate (e.g., a worm or a fly) or a vertebrate (e.g., a rodent, e.g., a mouse) can be determined by a variety of methods, e.g., by one or more of: a)

134/240 12591029. H0824.70430WO00 assessing the life span of the cell or the organism; (b) assessing the presence or abundance of a gene transcript or gene product in the cell or organism that has a biological age-dependent expression pattern; (c) evaluating resistance of the cell or organism to stress, e.g., genotoxic stress (e.g., etoposide, UV irradiation, exposure to a mutagen, and so forth) or oxidative stress; (d) evaluating one or more metabolic parameters of the cell or organism; (e) evaluating the proliferative capacity of the cell or a set of cells present in the organism; and (f) evaluating physical appearance or behavior of the cell or organism. In one example, evaluating the rate of aging includes directly measuring the average life span of a group of animals (e.g., a group of genetically matched animals) and comparing the resulting average to the average life span of a control group of animals (e.g., a group of animals that did not receive the test compound but are genetically matched to the group of animals that did receive the test compound). Alternatively, the rate of aging of an organism can be determined by measuring an age-related parameter. Examples of age-related parameters include: appearance, e.g., visible signs of age; the expression of one or more genes or proteins (e.g., genes or proteins that have an age- related expression pattern); resistance to oxidative stress; metabolic parameters (e.g., protein synthesis or degradation, ubiquinone biosynthesis, cholesterol biosynthesis, ATP levels, glucose metabolism, nucleic acid (e.g., engineered nucleic acid) metabolism, ribosomal translation rates, etc.); and cellular proliferation (e.g., of retinal cells, bone cells, white blood cells, etc.). [00349] Aging can also be determined by the rate of change of biomarkers (e.g., epigenetic marks including DNA methylation level of CpG island in the genome (known as the “Horvath Clock”) beta- galactosidase-positive cells in cells, gene expression changes, or certain changes to the abundance of molecules in the bloodstream). An example is an algorithm from Segterra Inc. that determines “InnerAge” based on blood biomarkers (see InsideTracker.com). [00350] In some embodiments, a method described herein increases cognitive function of a subject by at least 1.5 fold, by at least 2 fold, by at least 3 fold, by at least 5 fold, by at least 6 fold, by at least 7 fold, by at least 8 fold, by at least 9 fold, by at least 10 fold, by at least 20 fold, by at least 30 fold, by at least 40 fold, by at least 50 fold, by at least 60 fold, by at least 70 fold, by at least 80 fold, by at least 90 fold, or by at least 100 fold relative to a control. In some embodiments, the control is the cognitive function of the subject prior to cell rejuvenation. In some embodiments, cognitive function is measured by memory of a subject. In some embodiments, memory refers to long-term memory, short-term memory, or a combination thereof. In some embodiments, cognitive function is measured using one or more of the following tests: Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), Mini-Cog, and/or a test described herein. See, e.g., Arevalo‐Rodriguez et al., Cochrane Database Syst Rev.2015 Mar; 2015(3): CD010783, Breton et al., Int J Geriatr Psychiatry. 2019 Feb;34(2):233-242 and Example 1 below. [00351] In some embodiments, a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG),

135/240 12591029. H0824.70430WO00 linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may be used to treat and/or prevent any of the diseases described herein. [00352] Non-limiting uses of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) include wound healing, bleed out, injuries, broken bones, gunshot wounds, cuts, scarring during surgery (e.g., cesarean). In some embodiments, an inducing agent and/or a chemical agent capable of modulating activity of the inducing agent is also used. [00353] In some embodiments, a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) are used to slow aging, boost vitality, or treat disease that affects a non-human subject (e.g., a disease affecting livestock, domesticated pets, and/or other non-human animals). For example, the disease may be a cattle disease, a primate (e.g., cynomolgus monkeys, rhesus monkeys) disease, a disease affecting a commercially relevant animal, such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and/or a disease affecting birds (e.g., commercially relevant birds, such as chickens, ducks, geese, and/or turkeys). As a non-limiting example, a non-human animal may be treated using a method disclosed herein for veterinary or research purposes. [00354] In some embodiments, any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) are used to promote wound healing (e.g., for a cut), treat an injury (e.g., broken bones, bleeding out, gun shot injury, and/or reduce scarring during surgery). In some embodiments, surgery includes cesarean. In some embodiments, an inducing agent and/or a chemical agent capable of modulating activity of the inducing agent is also used. [00355] In some embodiments, any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or

136/240 12591029. H0824.70430WO00 prodrugs thereof) are useful in healing an injury and/or inflammation. In some embodiments, an inducing agent and/or a chemical agent capable of modulating activity of the inducing agent is also used. In some embodiments, the inflammation is hyperinflammation, which may be a side effect of aging. In some embodiments, the hyperinflammation is inflammaging. [00356] In some embodiments, any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) provide a healing capacity. [00357] In some embodiments, any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) are useful in enhancing or rejuvenating optimal or sub-optimal organs. As a non- limiting example, a chemical cocktail comprising two or more compounds described herein may be useful in enhancing or rejuvenating suboptimal organs (e.g., from older individuals) that are used for transplantation or to promote organ survival during transport or to promote organ survival after reimplantation of the organ into a subject. [00358] A chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may be used to rejuvenate or increase the survival and longevity of cells (e.g., hematopoietic stem cells, T-cells, etc.) that are used for transplantation. [00359] In some embodiments, any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) are used to prevent or relieve the side effects of a toxin and/or a drug (e.g., a chemotherapy) in a subject. Non-limiting examples of side effects include hair loss and peripheral neuropathy. Chemotherapies include vincristine (VCS). [00360] In some embodiments, a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic

137/240 12591029. H0824.70430WO00 fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) is administered to a subject to prevent or relieve the side effects of a toxin and/or a drug (e.g., a chemotherapy). [00361] In some embodiments, a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) is administered to a subject to protect a tissue, organ, and/or entire body of the subject from radiation (e.g., prevent or reverse the damaging effects of radiation). In certain embodiments, the compounds are administered to a subject to protect a tissue, organ, and/or entire body of the subject from radiation (e.g., prevent or reverse the damaging effects of radiation). In certain embodiments, the compounds are administered to a subject to prevent the damaging effects of radiation. In certain embodiments, the compounds are administered to a subject to reverse the damaging effects of radiation. [00362] Methods for identifying subjects suspected of having a condition may include physical examination, subject’s family medical history, subject’s medical history, biopsy, genetic testing, DNA sequencing of pathogens or the microbiome, proteomics, or a number of imaging technologies such as ultrasonography, computed tomography, magnetic resonance imaging, magnetic resonance spectroscopy, or positron emission tomography. [00363] Effective amounts of the compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α- KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and co-usage with other active agents. The quantity to be administered depends on the subject to be treated, including, for example, the age of the subject, the gravity of the condition, the weight of the subject, the genetics of the subject, the cells, tissue, or organ to be targeted, or any combination thereof. [00364] Treatment with a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT- 869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may result in reprogramming of a cell, tissue repair, tissue regeneration, increase blood flow,

138/240 12591029. H0824.70430WO00 organ regeneration, improved immunity, reversal of aging, counter senescence, or any combination thereof. Cellular reprogramming may be determined by determining the extent of differentiation of a cell (e.g., by determining the expression of one or more lineage markers or pluripotency markers, including OCT4, KLF4, SOX2, NANOG, ESRRB, NR4A2, and C/EBPα). The differentiation potential of a cell may also be determined using routine differentiation assays or gene expression patterns. Tissue repair may be determined by tissue replacement and tissue regeneration assays. For example, tissue replacement assays include wound healing assays in cell culture or in mice. Tissue regeneration may be determined by quantifying a particular cell type following treatment with compounds disclosed herein compared to before treatment. Tissue regeneration may be determined by quantifying a particular cell type following treatment with compounds disclosed herein compared to before treatment. In some instances, the methods described herein promote organ regeneration (e.g. liver regeneration or reversal of liver fibrosis and regrowth). In some instances, the methods described herein promote tissue and cell survival. Cell survival in the face of adversity and damage may be determined using assays for cell viability that are standard in the art (e.g., testing neuronal survival with the nano-glo live cell assay from Promega corp.). [00365] In some embodiments, the methods described herein do not induce teratoma formation. In some embodiments, the methods described herein do not induce unwanted cell proliferation. In some embodiments, the methods described herein do not induce tumor formation or tumor growth. [00366] In yet another aspect, the present disclosure provides methods of regulating (e.g., inducing) cellular reprogramming, tissue repair, tissue regeneration, organ regeneration, reversing aging, or any combination thereof comprising administering to a cell a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the compound is administered to a subject. The subject may be human or non-human. Non-human subjects include, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals, such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds, such as chickens, ducks, geese, and/or turkeys). [00367] Further aspects of the disclosure relate to methods of reprogramming comprising rejuvenating the epigenetic clock of a cell, tissue, organ, subject, or any combination thereof. In some embodiments, the cell, tissue, or organ is from the central nervous system. In some embodiments, the subject has a neurological disease. [00368] Further aspects of the disclosure relate to methods of reprogramming comprising altering the expression of one or more genes associated with aging.

139/240 12591029. H0824.70430WO00 [00369] Further aspects of the disclosure relate to methods comprising resetting the transcriptional profile of an old cell, an old organ, an old tissue, and/or any combination thereof in vitro. [00370] Further aspects of the disclosure relate to methods comprising resetting the transcriptional profile of an old cell, an old organ, an old tissue, an old subject and/or any combination thereof in vivo. [00371] Methods of reprogramming are also provided herein. In some embodiments, a method of reprogramming described herein comprises reversing or rejuvenating the epigenetic clock of a cell, tissue, organ, or a subject. In some embodiments, the epigenetic clock may be partially or fully reversed. In some embodiments, the epigenetic clock of a cell, tissue, organ, or a subject is measured using DNA methylation-based age (DNAmAGE or DNAm age). In some embodiments, a method described herein reduces the DNAmAge age of a cell by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. [00372] In some embodiments, a method of reprogramming described herein comprises altering the expression of one or more genes associated with aging. In some embodiments, expression of a gene is increased by at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In some embodiments, expression of a gene is reduced by at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In some embodiments, expression of one or more genes following performance of a method is determined relative to expression of the one or more genes prior to performance of the method. In some embodiments, expression of one or more genes is determined relative to expression of the one or more genes in a young cell, a young subject, a young tissue, a young organ, or any combination thereof. In some embodiments, expression of one or more genes is determined relative to expression of the one or more genes in an old cell, an old subject, an old tissue, an old organ, or any combination thereof. [00373] A gene associated with aging may be a gene whose expression is altered in an old, an old tissue, an old organ, an old subject, or any combination thereof as compared to a young counterpart. Non-limiting examples of genes include RE1 Silencing Transcription Factor (REST), (Tumor Protein P73) TP73, Glial Fibrillary Acidic Protein (GFAP), Intercellular Adhesion Molecule 2 (ICAM2), and Thioredoxin Interacting Protein (TXNIP). [00374] Aspects of the present disclosure relate to methods comprising resetting the transcriptional profile of an old cell, an old organ, an old tissue, and/or any combination thereof in vitro. Aspects of the present disclosure relate to methods comprising resetting the transcriptional profile of an old cell, an old organ, an old tissue, an old subject and/or any combination thereof in vivo. In some embodiments, resetting the transcriptional profile an old cell, an old organ, an old tissue, an old subject and/or any combination thereof comprises altering the gene expression of one or more genes associated with aging. In some embodiments, resetting the transcriptional profile an old cell, an old

140/240 12591029. H0824.70430WO00 organ, an old tissue, an old subject and/or any combination thereof comprises reversing the epigenetic clock. In some embodiments, the transcription profile of an old cell is reset. In some embodiments, the transcriptional profile of an old cell, an old organ, an old tissue, an old subject, or any combination thereof is reset to that of a young cell, a young tissue, a young organ, a young subject, or any combination thereof. In some embodiments, a method described herein reverses one or more changes in gene expression that are detected between an old cell, an old organ, an old tissue, an old subject, or any combination thereof and a control. In some embodiments, the control is a young cell, a young organ, a young tissue, a young subject, or any combination thereof. In some embodiments, the transcriptional profile of an old cell, an old organ, an old tissue, an old subject, or any combination thereof is changed from a young counterpart. In some embodiments, a method described herein resets at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the gene expression change in an old cell, an old organ, an old tissue, an old subject, or any combination thereof to a young level. In some embodiments, the method alters the expression of one or more genes associated with aging. [00375] In some embodiments, the method does not induce malignant cell growth. In some embodiments, the method does not induce tumor growth or tumor formation. [00376] In some embodiments, the method comprises one or more of enhancing physical activity, enhancing physical performance, enhancing energy, enhancing energy expenditure, improving metabolic health, improving energy metabolism, enhancing food intake, enhancing oxygen consumption, and improving VO2 (maximum oxygenation threshold). In some embodiments, the method comprises one or more of increasing NAD+ biosynthesis, increasing insulin signaling (e.g., skeletal muscle insulin signaling), improving insulin sensitivity (e.g., insulin action, insulin secretion), supporting glucose metabolism, suppressing age-associated weight gain, suppressing age-related adipose tissue inflammation, suppressing inflammaging (e.g., the increase in inflammation associated with aging), improving inflammation response, reducing triglyceride levels, and improving plasma lipid profile. In some embodiments, the method comprises one or more of improving mitochondrial function, improving mitochondrial metabolism, improving mitochondrial respiratory capability (e.g., in skeletal muscle), improving eye function, improving bone density, improving myeloid-lymphoid composition, increasing collagen formation, and restoring skeletal muscle. In some embodiments, the method comprises one or more of lengthening telomeres, facilitating DNA repair, supporting DNA health, maintaining DNA health, maintaining epigenetic function, reducing age-associated gene expression changes, reducing age-associated gene expression changes in a tissue-dependent manner, and reducing reactive oxygen species. In some embodiments, the method comprises one or more of improving circadian rhythms, improving neuronal function (e.g., neuronal function in the brain), improving neuronal survival (e.g., neuronal survival in the brain), inducing neuroprotection, improving focus, improving sleep quality, improving sleep duration, and maintaining the integrity of the blood brain barrier. In some embodiments, the method comprises preventing one or more of

141/240 12591029. H0824.70430WO00 neurodegenerative diseases, cancer, heart disease, age-related metabolic disorders, and mental disorders. In some embodiments, the method comprises preventing one or more of obesity, type 2 diabetes, depression, anxiety, Alzheimer’s disease, Parkinson’s disease, ischemia, and reperfusion injury. Cells and Methods of Monitoring Cellular Aging [00377] In another aspect, the present disclosure provides a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal. [00378] In another aspect, the present disclosure provides a method of monitoring cellular aging, the method comprising: (a) providing a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal; (b) contacting the cell with at least one test agent; (c) measuring a first signal from a first protein produced by the first reporter gene; (d) measuring a second signal from a second protein produced by the second reporter gene; (e) comparing the first signal and the second signal to assess the distribution of the first protein and the second protein in the cell. [00379] In certain embodiments, the first reporter gene encodes a first fluorescent protein. In certain embodiments, the first fluorescent protein is mCherry or mScarlet. In certain embodiments, the first fluorescent protein is mCherry. In certain embodiments, the first fluorescent protein is mScarlet. In certain embodiments, the second reporter gene encodes a second fluorescent protein. In certain embodiments, the second fluorescent protein is eGFP or mNeon. In certain embodiments, the second fluorescent protein is eGFP. In certain embodiments, the second fluorescent protein is mNeon. In certain embodiments, the cell is a fibroblast. In certain embodiments, the cell is a human cell. In certain embodiments, the cell is a non-human cell. [00380] In certain embodiments, the at least one test agent is a compound capable of rejuvenating a cell, tissue, or organ. In certain embodiments, the at least one test agent is a compound capable of restoring cellular function in a cell, tissue, or organ. In certain embodiments, the at least one test agent is a compound capable of decreasing a biological age of a cell, tissue, or organ. In certain embodiments, the at least one test agent is a compound capable of decreasing an apparent chronological age of a cell, tissue, or organ. In certain embodiments, the at least one test agent is a

142/240 12591029. H0824.70430WO00 compound capable of reprogramming a cell, tissue, or organ, wherein reprogramming comprises altering the expression of at least one gene associated with aging. [00381] In certain embodiments, the first signal is measured using fluorescence spectroscopy. In certain embodiments, the second signal is measured using fluorescence spectroscopy. In certain embodiments, the first signal and second signal are compared by measuring the colocalization between the first protein and the second protein. In certain embodiments, the first signal and second signal are compared by measuring the colocalization between mCherry and eGFP. In certain embodiments, the cellular location of the first signal and/or second signal are determined. [00382] One of the most well-conserved physiological hallmarks of aging is deterioration of nucleocytoplasmic compartmentalization (NCC), which causes leakage of nuclear proteins into the cytoplasm and a failure of proteins to be imported into the nucleus. Without being bound by a particular theory, a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system can monitor aging both forward and backward at the cellular level based on differences in nucleocytoplasmic trafficking between senescent and non-senescent cells (e.g., quiescent cells). [00383] In some embodiments, deterioration of nucleocytoplasmic compartmentalization is monitored using a cell permeable DNA dye. As a non-limiting example, a cell may be contacted with a DNA dye and the amount of the DNA dye in the nucleus and/or cytoplasm is determined before and after contacting the cell with any of the test agents disclosed herein. In some embodiments, contacting the cell with a test agent decreases the amount of the DNA dye in the cytoplasm. Pharmaceutical Compositions and Kits [00384] In another aspect, the present disclosure provides a pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

143/240 12591029. H0824.70430WO00 basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00385] In another aspect, the present disclosure provides a pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

144/240 12591029. H0824.70430WO00 smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00386] In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Suitable carriers may be readily selected by one of skill in the art in view of the indication for which any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) is directed. Suitable carriers may be readily selected by one of skill in the art in view of the indication for which the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) is directed. Suitable carriers may also be readily selected by one of skill in the art in view of the indication for which the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) is directed. For example, one suitable carrier includes saline, which may be formulated with a variety of buffering solutions (e.g., phosphate buffered saline). Other exemplary carriers include sterile saline, lactose, sucrose, calcium phosphate, gelatin, dextran, agar, pectin, peanut oil, sesame oil, and water. The selection of the carrier is not a limitation of the present disclosure. [00387] Formulation of pharmaceutically-acceptable excipients and carrier solutions is well-known to those of skill in the art, as is the development of suitable dosing and treatment regimens for using the particular compositions described herein in a variety of treatment regimens. Typically, these formulations may contain at least about 0.1% of the active compound or more, although the percentage of the active ingredient(s) may, of course, be varied and may conveniently be between about 1 or 2% and about 70% or 80% or more of the weight or volume of the total formulation. Naturally, the amount of active compound in each therapeutically-useful composition may be

145/240 12591029. H0824.70430WO00 prepared is such a way that a suitable dosage will be obtained in any given unit dose of the compound. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable. [00388] In certain embodiments, the pharmaceutical composition is for use in rejuvenating a cell, tissue, or organ. In certain embodiments, the pharmaceutical composition is for use in restoring cellular function in a cell, tissue, or organ. In certain embodiments, the pharmaceutical composition is for use in decreasing a biological age of a cell, tissue, or organ. In certain embodiments, the pharmaceutical composition is for use in decreasing an apparent chronological age of a cell, tissue, or organ. In certain embodiments, the pharmaceutical composition is for use in reprogramming a cell, tissue, or organ, wherein reprogramming comprises altering the expression of at least one gene associated with aging. [00389] In another aspect, the present disclosure provides a pharmaceutical composition for use in rejuvenating a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

146/240 12591029. H0824.70430WO00 smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00390] In another aspect, the present disclosure provides a pharmaceutical composition for use in restoring cellular function in a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

147/240 12591029. H0824.70430WO00 alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00391] In another aspect, the present disclosure provides a pharmaceutical composition for use in decreasing a biological age of a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

148/240 12591029. H0824.70430WO00 [00392] In another aspect, the present disclosure provides a pharmaceutical composition for use in decreasing an apparent chronological age of a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00393] In another aspect, the present disclosure provides a pharmaceutical composition for use in reprogramming a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

149/240 12591029. H0824.70430WO00 RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate); thereby altering the expression of at least one gene associated with aging. [00394] In another aspect, the present disclosure provides a pharmaceutical composition for use in rejuvenating a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

150/240 12591029. H0824.70430WO00 valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00395] In another aspect, the present disclosure provides a pharmaceutical composition for use in restoring cellular function in a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

151/240 12591029. H0824.70430WO00 basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00396] In another aspect, the present disclosure provides a pharmaceutical composition for use in decreasing a biological age of a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

152/240 12591029. H0824.70430WO00 linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00397] In another aspect, the present disclosure provides a pharmaceutical composition for use in decreasing an apparent chronological age of a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00398] In another aspect, the present disclosure provides a pharmaceutical composition for use in reprogramming a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of:

153/240 12591029. H0824.70430WO00 laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; thereby altering the expression of at least one gene associated with aging. [00399] In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. For example, in certain embodiments, the terms “laduviglusib” and “CHIR99021” refer to laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, or stereoisomer thereof. In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, the name of a chemical compound may refer to the compound, or a

154/240 12591029. H0824.70430WO00 pharmaceutically acceptable salt thereof. In certain embodiments, the name of a chemical compound may refer to the compound. [00400] In certain embodiments, the pharmaceutical composition comprises 3 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the pharmaceutical composition comprises 4 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the pharmaceutical composition comprises 5 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α- KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the pharmaceutical composition comprises 6 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the pharmaceutical composition comprises 7 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the pharmaceutical composition comprises 8 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the pharmaceutical composition comprises 9 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-

155/240 12591029. H0824.70430WO00 KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the pharmaceutical composition comprises 10 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the pharmaceutical composition comprises 11 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the pharmaceutical composition comprises 12 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the pharmaceutical composition comprises 13 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α- KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). [00401] In certain embodiments, the pharmaceutical composition comprises two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

156/240 12591029. H0824.70430WO00 butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00402] In certain embodiments, the pharmaceutical composition comprises two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [00403] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and RepSox (E-616452). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and ascorbic acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and valproic acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and tranylcypromine. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and forskolin. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and arotinoid acid (TTNPB). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and Y-27632. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises

157/240 12591029. H0824.70430WO00 laduviglusib (CHIR99021) and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and ascorbic acid. In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and valproic acid. In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and tranylcypromine. In certain embodiments, the pharmaceutical composition comprises RepSox (E- 616452) and forskolin. In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and butyric acid. In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and arotinoid acid (TTNPB). In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and Y-27632. In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises RepSox (E- 616452) and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises ascorbic acid and valproic acid. In certain embodiments, the pharmaceutical composition comprises ascorbic acid and tranylcypromine. In certain embodiments, the pharmaceutical composition comprises ascorbic acid and forskolin. In certain embodiments, the pharmaceutical composition comprises ascorbic acid and butyric acid. In certain embodiments, the pharmaceutical composition comprises ascorbic acid and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises ascorbic acid and arotinoid acid (TTNPB). In certain embodiments, the pharmaceutical composition comprises ascorbic acid and Y- 27632. In certain embodiments, the pharmaceutical composition comprises ascorbic acid and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises ascorbic acid and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises ascorbic acid and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises valproic acid and tranylcypromine. In certain embodiments, the pharmaceutical composition comprises valproic acid and forskolin. In certain embodiments, the pharmaceutical composition comprises valproic acid and butyric acid. In certain embodiments, the pharmaceutical composition comprises valproic acid and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises valproic acid and arotinoid acid (TTNPB). In certain embodiments, the pharmaceutical composition comprises valproic acid and Y- 27632. In certain embodiments, the pharmaceutical composition comprises valproic acid and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises valproic acid and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises valproic acid and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises tranylcypromine and forskolin. In certain embodiments, the

158/240 12591029. H0824.70430WO00 pharmaceutical composition comprises tranylcypromine and butyric acid. In certain embodiments, the pharmaceutical composition comprises tranylcypromine and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises tranylcypromine and arotinoid acid (TTNPB). In certain embodiments, the pharmaceutical composition comprises tranylcypromine and Y-27632. In certain embodiments, the pharmaceutical composition comprises tranylcypromine and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises tranylcypromine and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises tranylcypromine and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises forskolin and butyric acid. In certain embodiments, the pharmaceutical composition comprises forskolin and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises forskolin and arotinoid acid (TTNPB). In certain embodiments, the pharmaceutical composition comprises forskolin and Y-27632. In certain embodiments, the pharmaceutical composition comprises forskolin and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises forskolin and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises forskolin and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises butyric acid and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises butyric acid and arotinoid acid (TTNPB). In certain embodiments, the pharmaceutical composition comprises butyric acid and Y-27632. In certain embodiments, the pharmaceutical composition comprises butyric acid and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises butyric acid and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises butyric acid and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises basic fibroblast growth factor (bFGF) and arotinoid acid (TTNPB). In certain embodiments, the pharmaceutical composition comprises basic fibroblast growth factor (bFGF) and Y-27632. In certain embodiments, the pharmaceutical composition comprises basic fibroblast growth factor (bFGF) and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises basic fibroblast growth factor (bFGF) and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises basic fibroblast growth factor (bFGF) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises arotinoid acid (TTNPB) and Y- 27632. In certain embodiments, the pharmaceutical composition comprises arotinoid acid (TTNPB) and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises arotinoid acid (TTNPB) and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises arotinoid acid (TTNPB) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises Y-27632 and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises Y-27632 and linifanib (ABT- 869). In certain embodiments, the pharmaceutical composition comprises Y-27632 and alpha-

159/240 12591029. H0824.70430WO00 ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises smoothened agonist (SAG) and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises smoothened agonist (SAG) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises linifanib (ABT-869) and alpha-ketoglutaric acid (α-KG). [00404] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), and ascorbic acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), and valproic acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), and tranylcypromine. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), and forskolin. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), and basic fibroblast growth factor (bFGF). [00405] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and valproic acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and tranylcypromine. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and forskolin. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), valproic acid, and tranylcypromine. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and forskolin. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, and forskolin. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, and tranylcypromine. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, and forskolin. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, and forskolin. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, and forskolin. [00406] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-

160/240 12591029. H0824.70430WO00 616452), forskolin, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, forskolin, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, forskolin, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, forskolin, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, tranylcypromine, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, forskolin, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, forskolin, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, forskolin, and butyric acid. [00407] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, forskolin, and basic fibroblast growth factor

161/240 12591029. H0824.70430WO00 (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), butyric acid, and basic fibroblast growth factor (bFGF). [00408] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), and arotinoid acid (TTNPB). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), and Y- 27632. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), and alpha-ketoglutaric acid (α-KG). [00409] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and arotinoid acid (TTNPB). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, and Y-27632. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), and Y-27632. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-

162/240 12591029. H0824.70430WO00 616452), arotinoid acid (TTNPB), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), Y-27632, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, and alpha-ketoglutaric acid (α- KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), butyric acid, and alpha-ketoglutaric acid (α-KG). [00410] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and Y-27632. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises

163/240 12591029. H0824.70430WO00 laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y- 27632, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), and alpha- ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), linifanib (ABT-869), and alpha- ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), butyric acid, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632,

164/240 12591029. H0824.70430WO00 linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), linifanib (ABT-869), and alpha- ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), butyric acid, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), linifanib (ABT-869), butyric acid, and alpha- ketoglutaric acid (α-KG). [00411] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and smoothened agonist (SAG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and alpha-ketoglutaric acid (α- KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-

165/240 12591029. H0824.70430WO00 616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α- KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α- KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and linifanib

166/240 12591029. H0824.70430WO00 (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y- 27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), butyric acid, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), Y-27632, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). [00412] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y- 27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid

167/240 12591029. H0824.70430WO00 (TTNPB), Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), and alpha- ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), linifanib (ABT-869), butyric acid, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y- 27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-

168/240 12591029. H0824.70430WO00 27632, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). [00413] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α- KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). [00414] In certain embodiments, the pharmaceutically acceptable salt of butyric acid is sodium butyrate. In certain embodiments, the pharmaceutically acceptable salt of butyric acid is lithium butyrate. In certain embodiments, the pharmaceutically acceptable salt of butyric acid is potassium butyrate. [00415] In certain embodiments, the pharmaceutically acceptable salt of valproic acid is lithium valproate. In certain embodiments, the pharmaceutically acceptable salt of ascorbic acid is lithium ascorbate. In certain embodiments, the pharmaceutically acceptable salt of forskolin is a lithium salt of forskolin. In certain embodiments, the pharmaceutically acceptable salt of TTNPB is a lithium salt of TTNPB. In certain embodiments, the pharmaceutically acceptable salt of α-KG is a lithium salt of α-KG. [00416] In certain embodiments, the group further comprises a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the group further comprises lithium ascorbate. In certain embodiments, the group further comprises lithium chloride. In certain embodiments, the group further comprises lithium orotate. In certain embodiments, the group further comprises lithium orotate. In certain embodiments, the group further comprises lithium carbonate. In certain embodiments, the group further comprises lithium citrate. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and a lithium salt, or a solvate,

169/240 12591029. H0824.70430WO00 hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises valproic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises tranylcypromine and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises forskolin and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises butyric acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises basic fibroblast growth factor (bFGF) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises arotinoid acid (TTNPB) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises Y-27632 and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises smoothened agonist (SAG) and a lithium salt, or a solvate, hydrate, polymorph, or co– crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises linifanib (ABT-869) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises alpha-ketoglutaric acid (α-KG) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). [00417] In certain embodiments, one or more of the compounds in the group are replaced with a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, one or more of the compounds in the group are replaced with lithium ascorbate. In certain embodiments, one or more

170/240 12591029. H0824.70430WO00 of the compounds in the group are replaced with lithium chloride. In certain embodiments, one or more of the compounds in the group are replaced with lithium orotate. In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises RepSox (E-616452) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises valproic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises tranylcypromine and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises forskolin and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises butyric acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises basic fibroblast growth factor (bFGF) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises arotinoid acid (TTNPB) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises Y-27632 and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises smoothened agonist (SAG) and a lithium salt, or a solvate, hydrate, polymorph, or co– crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises linifanib (ABT-869) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the pharmaceutical composition comprises alpha-ketoglutaric acid (α-KG) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

171/240 12591029. H0824.70430WO00 [00418] In certain embodiments, CHIR99021 is replaced with a GSK3 ^ inhibitor. In certain embodiments, the GSK3 ^ inhibitor is a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate), SB216763, SB415286, SB203580, TDZD-8, AR-A014418, CHIR99021, BIO, Kenpaullone, Indirubin-3′-monoxime, AZD1080, Tideglusib, LY2090314, LY2095496, LY2097409, LY2097634, FRAX597, Y-27632, DMAT, or TWS119. [00419] In certain embodiments, the pharmaceutical composition comprises ascorbic acid and lithium ascorbate. In certain embodiments, the pharmaceutical composition comprises ascorbic acid and lithium chloride. In certain embodiments, the pharmaceutical composition comprises ascorbic acid and lithium orotate. In certain embodiments, the pharmaceutical composition comprises ascorbic acid and lithium carbonate. In certain embodiments, the pharmaceutical composition comprises ascorbic acid and lithium citrate. [00420] In another aspect, the present disclosure provides a pharmaceutical composition for use in rejuvenating a cell, tissue, or organ, the pharmaceutical composition comprising ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [00421] In another aspect, the present disclosure provides a pharmaceutical composition for use in restoring cellular function in a cell, tissue, or organ, the pharmaceutical composition comprising ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [00422] In another aspect, the present disclosure provides a pharmaceutical composition for use in decreasing a biological age of a cell, tissue, or organ, the pharmaceutical composition comprising ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [00423] In another aspect, the present disclosure provides a pharmaceutical composition for use in decreasing an apparent chronological age of a cell, tissue, or organ, the pharmaceutical composition comprising ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride. [00424] In another aspect, the present disclosure provides a pharmaceutical composition for use in reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the pharmaceutical composition comprising ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

172/240 12591029. H0824.70430WO00 [00425] In another aspect, the present disclosure provides a pharmaceutical composition for use in rejuvenating a cell, tissue, or organ, the pharmaceutical composition comprising lithium ascorbate. [00426] In another aspect, the present disclosure provides a pharmaceutical composition for use in restoring cellular function in a cell, tissue, or organ, the pharmaceutical composition comprising lithium ascorbate. [00427] In another aspect, the present disclosure provides a pharmaceutical composition for use in decreasing a biological age of a cell, tissue, or organ, the pharmaceutical composition comprising lithium ascorbate. [00428] In another aspect, the present disclosure provides a pharmaceutical composition for use in decreasing an apparent chronological age of a cell, tissue, or organ, the pharmaceutical composition comprising lithium ascorbate. [00429] In another aspect, the present disclosure provides a pharmaceutical composition for use in reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the pharmaceutical composition comprising lithium ascorbate. [00430] In certain embodiments, two or more of the compounds in the group are associated through a noncovalent interaction. [00431] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) at a concentration of about 10 µM; RepSox (E-616452) at a concentration of about 10 µM; the valproic acid at a concentration of about 250 µM; the tranylcypromine at a concentration of about 5 µM; and the forskolin at a concentration of about 50 µM. [00432] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) at a concentration of about 10 µM; the RepSox (E-616452) at a concentration of about 10 µM; the valproic acid at a concentration of about 250 µM; the tranylcypromine at a concentration of about 5 µM; the forskolin at a concentration of about 50 µM; and the butyric acid at a concentration of about 200 µM. [00433] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) at a concentration of about 10 µM; the RepSox (E-616452) at a concentration of about 10 µM; the valproic acid at a concentration of about 250 µM; the tranylcypromine at a concentration of about 5 µM; the forskolin at a concentration of about 50 µM; and basic fibroblast growth factor (bFGF) at a concentration of about 100 µg/mL [00434] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) at a concentration of about 10 µM; the RepSox (E-616452) at a concentration of about 10 µM; the arotinoid acid (TTNPB) at a concentration of about 2 µM; the Y-27632 at a concentration of about 2 µM; the smoothened agonist (SAG) at a concentration of about 0.5 µM; and the linifanib (ABT-869) at a concentration of about 1 µM. [00435] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) at a concentration of about 10 µM; the RepSox (E-616452) at a concentration of about

173/240 12591029. H0824.70430WO00 10 µM; the arotinoid acid (TTNPB) at a concentration of about 2 µM; the Y-27632 at a concentration of about 2 µM; the smoothened agonist (SAG) at a concentration of about 0.5 µM; the linifanib (ABT-869) at a concentration of about 1 µM; and the butyric acid at a concentration of about 200 µM. [00436] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) at a concentration of about 10 µM; the RepSox (E-616452) at a concentration of about 10 µM; the arotinoid acid (TTNPB) at a concentration of about 2 µM; the Y-27632 at a concentration of about 2 µM; the smoothened agonist (SAG) at a concentration of about 0.5 µM; the linifanib (ABT-869) at a concentration of about 1 µM; and the alpha-ketoglutaric acid (α-KG) at a concentration of about 500 µM. [00437] In certain embodiments, the pharmaceutical composition comprises laduviglusib (CHIR99021) at a concentration of about 10 µM; and the ascorbic acid at a concentration of about 50 µg/mL. In certain embodiments, the laduviglusib (CHIR99021) at a concentration of about 1 µM; and the ascorbic acid at a concentration of about 50 µg/mL. [00438] In certain embodiments, the pharmaceutical composition comprises ascorbic acid at a concentration of about 50 µg/mL, and the lithium salt at a concentration of about 10 mM. [00439] In certain embodiments, the pharmaceutical composition comprises lithium ascorbate at a concentration of about 1 mM. [00440] In certain embodiments, the cell, tissue, or organ is a central nervous system cell, central nervous system tissue, or central nervous system organ. In certain embodiments, the central nervous system does not include the eye. In certain embodiments, the central nervous system does not include the retina, uvea, pupil, lens, cornea, and/or sclera. In certain embodiments, the cell, tissue, or organ is a brain cell, brain tissue, or brain. In some embodiments, the brain cell is a neuron. In some embodiments, the neuron is an excitatory neuron. In some embodiments, the brain tissue is nervous tissue. [00441] In some embodiments, the cell, tissue, or organ is in a subject, optionally wherein the composition is administered to a subject in need thereof. In certain embodiments, the subject has a neurological disease. [00442] In some embodiments, the subject is a human or non-human mammal. [00443] Optionally, the compositions of the disclosure may comprise, in addition to any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) and carrier(s), other pharmaceutical ingredients, such as preservatives, or chemical stabilizers. Suitable exemplary preservatives include chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, the

174/240 12591029. H0824.70430WO00 parabens, ethyl vanillin, glycerin, phenol, and parachlorophenol. Suitable chemical stabilizers include gelatin and albumin. [00444] Examples of pharmaceutically acceptable routes of administration include, but are not limited to, direct delivery to the selected organ (e.g., direct delivery to the central nervous system, e.g., including the brain). Any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may be delivered intravenously, intradermally, intraarterially, intralesionally, intratumorally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, intraperitoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, topically, locally, systemically, injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, in creams, in lipid compositions (e.g., liposomes), or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art. In some embodiments, any of the compositions described herein is administered to the central nervous system. In some embodiments, any of the compositions described herein is not administered to the eye (e.g., not administered to the retina). In some embodiments, any of the compositions described herein is administered to the brain. Routes of administration may be combined, if desired. [00445] In some embodiments, a pharmaceutical composition comprising a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) is administered to a cell, tissue, organ or a subject. For example, the cell, tissue, or organ may be in the central nervous system. The subject may have a neurological disease. In some embodiments, the pharmaceutical composition is administered systemically. In some embodiments, pharmaceutical composition is administered locally (e.g., directly to a tissue or organ of interest, including, e.g., a tissue or organ from the central nervous system). In some embodiments, the tissue or organ is brain tissue or is the brain. In some embodiments, a pharmaceutical composition is administered through retro-orbital venous injection. In some embodiments, a pharmaceutical composition is administered by Intrathecal administration. [00446] As an example, the dose of pharmaceutical composition comprising a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid

175/240 12591029. H0824.70430WO00 (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) will vary based on the specific disease being treated. [00447] An effective amount of pharmaceutical composition comprising a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) is an amount sufficient to target infect an animal, target a desired tissue. In some embodiments, an effective amount of pharmaceutical composition comprising a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) is an amount sufficient to produce a stable somatic transgenic animal model. The effective amount will depend primarily on factors such as the species, age, weight, health of the subject, and the tissue to be targeted, and may thus vary among animal and tissue. [00448] In some embodiments, chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) in suitably formulated pharmaceutical compositions disclosed herein are delivered directly to target tissue, e.g., direct to a tissue of interest (e.g., nerve tissue). [00449] In some embodiments, the mode of administration does not comprise administration to the eye (e.g., retina, uvea, pupil, lens, cornea, and/or sclera) of the subject. In some embodiments, the mode of administration does not comprise administration to the retina of the subject. [00450] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. In many cases the form is sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol,

176/240 12591029. H0824.70430WO00 polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils. Proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. [00451] For administration of an injectable aqueous solution, for example, the solution may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, a suitable sterile aqueous medium may be employed. For example, one dosage may be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, Remington’s Pharmaceutical Science”" 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the host. The person responsible for administration will, in any event, determine the appropriate dose for the individual host. [00452] Sterile injectable solutions are prepared by incorporating chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) in the required amount in the appropriate solvent with various of the other ingredients enumerated herein, as required, followed by filtered sterilization. In certain embodiments, the sterile injectable solutions are prepared by incorporating a chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) in the required amount in the appropriate solvent with various of the other ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying

177/240 12591029. H0824.70430WO00 techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [00453] The pharmaceutical compositions comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may also be formulated in a neutral or salt form. Pharmaceutically-acceptable salts, include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms such as injectable solutions, drug-release capsules, and the like. [00454] A carrier includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Supplementary active ingredients can also be incorporated into the compositions. [00455] Delivery vehicles such as liposomes, nanocapsules, microparticles, microspheres, lipid particles, vesicles, and the like, may be used for the introduction of the compositions of the present disclosure into suitable host cells. In particular, any of the chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may be encapsulated in a lipid particle, a liposome, a vesicle, a nanosphere, or a nanoparticle or the like. [00456] In some embodiments, the delivery vehicle targets the cargo. For example, any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may be delivered via a nanoparticle that delivers the cargo to a certain tissue or cell type. Nanoparticles

178/240 12591029. H0824.70430WO00 coated in galactose polymers, for example, are known to release their cargo within senescent cells as a result of their endogenous beta-galactosidase activity. See, e.g., Lozano-Torres et al., J Am Chem Soc.2017 Jul 5;139(26):8808-8811. [00457] In some embodiments, any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) is formulated in a poly(glycoamidoamine) brush nanoparticles. See, e.g., Dong et al., Nano Lett.2016 Feb 10;16(2):842-8. [00458] Any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) may, in some embodiments, be assembled into pharmaceutical or diagnostic or research kits to facilitate their use in therapeutic, diagnostic or research applications. For example, a kit may be used in treating a neurological disease. In some embodiments, a kit may be used to rejuvenate a cell, tissue, or organ from the central nervous system. A kit may include one or more containers housing one or more components of the disclosure and instructions for use. Specifically, such kits may include one or more agents described herein, along with instructions describing the intended application and the proper use of these agents. In certain embodiments agents in a kit may be in a pharmaceutical formulation and dosage suitable for a particular application and for a method of administration of the agents. Kits for research purposes may contain the components in appropriate concentrations or quantities for running various experiments. [00459] In some embodiments, a kit comprises instructions for instructions for rejuvenating a cell, tissue, or organ (e.g., instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof). In some embodiments, a kit comprises instructions for instructions for restoring cellular function in a cell, tissue, or organ (e.g., instructions for restoring cellular function in the cell, tissue, or organ of a subject in need thereof). In some embodiments, a kit comprises instructions for decreasing a biological age of a cell, tissue, or organ (e.g., instructions for decreasing a biological age of the cell, tissue, or organ of a subject in need thereof). In some embodiments, a kit comprises instructions for decreasing an apparent chronological age of a cell, tissue, or organ (e.g., instructions for decreasing an apparent chronological age of the cell, tissue, or organ of a subject in need thereof). In some embodiments, a kit comprises instructions for reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging (e.g., instructions for reprogramming a cell, tissue, or organ of a subject in need thereof, thereby altering the expression of at least one gene

179/240 12591029. H0824.70430WO00 associated with aging). In some embodiments, the cell, tissue, or organ is from the central nervous system. In some embodiments, the subject has or is suspected of having a neurological disease. In some embodiments the cell, tissue, or organ from the central nervous system is a brain cell, brain tissue, or brain. In some embodiments, the kit comprises instructions for treating a neurological disease. [00460] In some embodiments, the kit comprises (a) a container housing a pharmaceutical composition comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof); and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof. [00461] In some embodiments, the kit comprises (a) a container housing a pharmaceutical composition comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof); and (b) instructions for restoring cellular function in a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof. [00462] In some embodiments, the kit comprises (a) a container housing a pharmaceutical composition comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof); and (b) instructions for decreasing a biological age of a cell, tissue, or organ, optionally instructions for decreasing the biological age the cell, tissue, or organ of a subject in need thereof. [00463] In some embodiments, the kit comprises (a) a container housing a pharmaceutical composition comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof); and (b) instructions for decreasing an apparent chronological age of a cell, tissue, or organ, optionally

180/240 12591029. H0824.70430WO00 instructions for decreasing the apparent chronological age the cell, tissue, or organ of a subject in need thereof. [00464] In some embodiments, the kit comprises (a) a container housing a pharmaceutical composition comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof); and (b) instructions for reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, optionally instructions for reprogramming the cell, tissue, or organ of a subject in need thereof. [00465] In some embodiments, the kit comprises (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

181/240 12591029. H0824.70430WO00 smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof. [00466] In some embodiments, the kit comprises: (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

182/240 12591029. H0824.70430WO00 linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and (b) instructions for restoring cellular function in a cell, tissue, or organ, optionally instructions for restoring cellular function in the cell, tissue, or organ of a subject in need thereof. [00467] In some embodiments, the kit comprises: (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

183/240 12591029. H0824.70430WO00 linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and (b) instructions for decreasing a biological age of a cell, tissue, or organ, optionally instructions for decreasing the biological age of the cell, tissue, or organ of a subject in need thereof. [00468] In some embodiments, the kit comprises: (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

184/240 12591029. H0824.70430WO00 linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and (b) instructions for decreasing an apparent chronological age of a cell, tissue, or organ, optionally instructions for decreasing the apparent chronological age of the cell, tissue, or organ of a subject in need thereof. [00469] In some embodiments, the kit comprises: (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

185/240 12591029. H0824.70430WO00 linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and (b) instructions for reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, optionally instructions for reprogramming the cell, tissue, or organ of a subject in need thereof. [00470] In yet another aspect, the present disclosure provides kits comprising any of the chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). [00471] In another aspect, the present disclosure provides a kit comprising (a) a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal; and (b) instructions for: contacting the cell with at least one test agent; measuring a first signal from a first protein produced by the first reporter gene; measuring a second signal from a second protein produced by the second reporter gene; and comparing the first signal and the second signal to assess the distribution of the first protein and the second protein in the cell. [00472] The kit may be designed to facilitate use of the methods described herein by researchers and can take many forms. Each of the compositions of the kit, where applicable, may be provided in liquid form (e.g., in solution), or in solid form, (e.g., a dry powder). In certain cases, some of the compositions may be constitutable or otherwise processable (e.g., to an active form), for example, by the addition of a suitable solvent or other species (for example, water or a cell culture medium), which may or may not be provided with the kit. As used herein, “instructions” can define a component of instruction and/or promotion, and typically involve written instructions on or associated with packaging of the disclosure. Instructions also can include any oral or electronic instructions provided in any manner such that a user will clearly recognize that the instructions are to be associated with the kit, for example, audiovisual (e.g., videotape, DVD, etc.), Internet, and/or web-based communications, etc. The written instructions may be in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflect approval by the agency of manufacture, use or sale for animal administration.

186/240 12591029. H0824.70430WO00 [00473] The kit may contain any one or more of the components described herein in one or more containers. As an example, in one embodiment, the kit may include instructions for mixing one or more components of the kit and/or isolating and mixing a sample and applying to a subject. The kit may include a container housing agents described herein. The agents may be in the form of a liquid, gel or solid (powder). The agents may be prepared sterilely, packaged in syringe and shipped refrigerated. Alternatively it may be housed in a vial or other container for storage. A second container may have other agents prepared sterilely. Alternatively the kit may include the active agents premixed and shipped in a syringe, vial, tube, or other container. The kit may have one or more or all of the components required to administer the agents to an animal, such as a syringe, topical application devices, or iv needle tubing and bag, particularly in the case of the kits for producing specific somatic animal models. [00474] The kit may have a variety of forms, such as a blister pouch, a shrink-wrapped pouch, a vacuum sealable pouch, a sealable thermoformed tray, or a similar pouch or tray form, with the accessories loosely packed within the pouch, one or more tubes, containers, a box or a bag. The kit may be sterilized after the accessories are added, thereby allowing the individual accessories in the container to be otherwise unwrapped. The kits can be sterilized using any appropriate sterilization techniques, such as radiation sterilization, heat sterilization, or other sterilization methods known in the art. The kit may also include other components, depending on the specific application, for example, containers, cell media, salts, buffers, reagents, syringes, needles, a fabric, such as gauze, for applying or removing a disinfecting agent, disposable gloves, a support for the agents prior to administration etc. [0001] These and other aspects of the present invention will be further appreciated upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the invention but are not intended to limit its scope, as defined by the claims. EXAMPLES [00475] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Example 1: Disruption of nucleocytoplasmic compartmentalization (NCC) by senescence [00476] To identify chemical reprogramming cocktails that mimic OSK treatment, an efficient high- throughput system was developed with the following criteria. To ensure reliability and applicability across various contexts, an age-dependent assay that examines cellular physiology was developed, rather than solely relying on the activities of a limited set of genes that exhibit age-related changes. To

187/240 12591029. H0824.70430WO00 facilitate scalability and ease of use, a fluorescence-based system was employed that enables the assessment of alterations in millions of cells through automated microscopy. One of the most well- conserved physiological hallmarks of aging is deterioration of nucleocytoplasmic compartmentalization (NCC), which can be visualized as a the leakage of nuclear proteins into the cytoplasm and failure of proteins to be imported into the nucleus [24,25]. In neurons and astrocytes directly converted from fibroblasts of old humans, as well as old nematodes and rat brain tissue, the nuclear pore complex deteriorates, leading to increased nuclear permeability and cytosolic protein aggregation [24,26,27]. [00477] To monitor age-associated alterations in nuclear permeability, the NCC reporter system was introduced into human fibroblasts from a 22 year-old donor (FIG.1A). mCherry and eGFP were linked to nuclear localization signal (NLS) and nuclear export signal (NES), respectively. In healthy young fibroblasts, the cellular localization of these proteins distinctly separated whereas in old fibroblasts from normal individuals or from Hutchinson-Gilford progeria syndrome patients, the number and the intensity of cytoplasmic mCherry puncta were higher (FIG.5). Despite the visible difference, Z-factor analysis indicated that the system was not sufficiently robust when the groups were compared, leading to the pursuit of an alternative model for this large scale screening process [28]. [00478] As the endpoint of cellular aging, senescence is accompanied by substantial reorganization of the nuclear envelope and a breakdown in nucleocytoplasmic trafficking, including altered expression and degradation of Lamin B1, and the formation of cytoplasmic chromatin fragments (CCFs) [25,29– 35]. It was reasoned that the use of the NCC system in senescent fibroblasts would produce a more distinct signal than in naturally aged or prematurely aged cells. In primary cells, such as telomerase- expressing cells and oncogene-expressing cells of the same genetic background, the induction of replicative senescence (RS) and oncogene-induced senescence (OIS) is accompanied by an increase in DNA methylation age, whereas senescence induced by DNA damage is not [36]. Because epigenetic clocks advance during replicative senescence and not after DNA damage-induced senescence [37], it was hypothesized that replicative senescence would be a more relevant model of aging in vivo. [00479] To avoid unintended false-rejuvenation effects caused by the expansion of a small percentage of replication-capable cells in the senescent population, all experiments were performed in low serum conditions that completely suppressed cell division [38]. In quiescent control fibroblasts, the mCherry and eGFP signals were clearly distinguishable (FIGs.1B-1D), whereas in the senescent fibroblasts, mCherry was aggregated in the cytoplasm, colocalizing with eGFP (FIGs.1E-1G). This is consistent with a previous report on replicative senescence disrupting nucleocytoplasmic trafficking [25]. Colocalization measured by Pearson correlation was significantly higher in replicative senescent cells, indicating that the NCC system effectively monitors replicative senescence in real time (FIG.1H).

188/240 12591029. H0824.70430WO00 Example 2: Reversal of characteristics of cellular senescence by epigenetic reprogramming [00480] To assess the applicability of the NCC system for detecting interventions, whether it could detect the effects of epigenetic reprogramming on age reversal was evaluated. Ectopic expression of Yamanaka factors OCT4, SOX2 and KLF4 (OSK) is known to safely restore youthful gene expression, epigenetic age, and youthful functions to old cells and tissues [7,8]. Previously published reverse tetracycline-controlled transactivator (rtTA) module and the polycistronic OSK cistron under the control of a tetracycline-inducible promoter (Tet-on OSK) were transduced using lentivirus to create stable cell lines from the human fibroblasts and passaged until they reached replicative senescence around passage 40. Treatment with doxycycline was sufficient to activate the OSK cassette in these fibroblasts (FIG.6A). [00481] Transcriptomic changes are involved in driving an aging-related decline in function and provide effective biomarkers for predicting biological and chronological age [39]. To verify if these phenotypic changes reflected a more youthful epigenetic signature, their transcriptional profile was analyzed by genome-wide RNAseq. A comparison of quiescent young to quiescent old cells identified 190 genes that were significantly upregulated, and 326 genes that were significantly downregulated. Induction of OSK for four days led to 43.2% (82) reduction of age-upregulated genes and 63.5% (213) increase in age-downregulated genes (FIGs.2A-2D and FIG.6B). In all, 57.2% of the genes changed by senescence were restored by OSK expression. This finding is consistent with previous findings that expressing OSK in a variety of cell types and tissues, including human and mouse fibroblasts, can substantially restore the epigenetic landscape and gene expression patterns of old cells [7, 8, 19].This process is dubbed the EPOCH method, for epigenetic programming of old cell health. [00482] Gene ontology (GO) analysis indicated that the top 20 GO biological processes of upregulated genes encompassed key features of aging, including dysregulation of development, localization, and transport, eleven of which were reversed by OSK (Figure 2E) [7]. Despite the absence of cell division in all conditions, senescence caused subtle but significant changes in cell cycle gene mRNA levels, including the cell-cycle regulator and aging associated gene CDKN1A (FIG.6C) [40]. Numerous cell cycle related processes were enriched with downregulated genes by senescence, and 19 of the top 20 were reversed by OSK expression (FIG.2F). The net outcome of this was to demonstrate that the induction of OSK partially counteracted the aging related changes resulting from senescence. [00483] Using the NCC system the deterioration of nucleocytoplasmic integrity was examined as cells transition from quiescence to senescence, and the regenerative effects of OSK treatment on those senescent cells were examined (FIGs.2G-2H). Cross sectional intensity profiles of the cells were used to assess the correlation between distributions of fluorescent molecules (FIG.2I). Compared to quiescent cells, senescent cells had a significant increase in the aggregation of mCherry and eGFP in senescent cells compared to quiescent cells, indicating disruption of nucleocytoplasmic integrity (FIG. 2J). The integrity was significantly restored after four days of OSK treatment in the senescent cells,

189/240 12591029. H0824.70430WO00 with compartmentalization integrity comparable to the quiescent, non-senescent cell population (FIG. 2J). Taken together, these data show that OSK-mediated epigenetic reprogramming substantially reverses senescence-associated pathology and transcriptomic changes, and that the NCC reporter system can detect rejuvenation of senescent cells by OSK. Example 3: Reversal of senescence associated NCC changes by chemical reprogramming cocktails [00484] To identify chemical reprogramming cocktails that rejuvenate old and senescent cells, a list of molecules that have successfully reprogrammed human and mouse somatic cells into chemically induced pluripotent stem cells (CiPSCs) was curated [41,42], and the compounds were tested using the NCC assay. Chemical reprogramming cocktails were tested in fully senescent cells to avoid detecting potential confounding effects on the cell cycle or during the transition to senescence. Age reversal is known to occur within a week of OSK(M)-mediated reprogramming, while the epigenetic age continuously decreases until pluripotency and reaches an approximate age of zero [43,44]. To ensure consistency, compound combinations were initially tested on cells within the same four-day period required for OSK to rejuvenate cells safely and consistently. [00485] To achieve age reduction without altering cell identity, combinations of compounds that were likely to work in the early stages of CiPSC formation were investigated, including valproic acid (V), CHIR-99021 (C), E-616452 (6), tranylcypromine (T) and forskolin (F). Previous studies of reprogramming efficiency with small molecules demonstrated that either OCT4 alone or SKM, when combined with VC6T or F, respectively, can generate iPSCs, and VC6TF facilitates a mesenchymal- to-epithelial transition, an early stage of reprogramming in mouse cells [43,45]. Because of the known differences in differentiation between mice and humans, molecules that have been reported for the initiation states of generating human CiPSCs were also studied, including CHIR-99021 (C), E- 616452 (6), TTNPB (N), Y-27632 (Y), Smoothened Agonist (S), and ABT-869 (A) [43]. The molecules VC6TF (Cocktail 1: C1) and C6NYSA (Cocktail 4: C4) were used as basal reprogramming cocktails and supplemented with other boosters known to increase iPSC efficiency, including sodium butyrate and alpha ketoglutarate (α-KG) (FIGs.3A-3B, Tables 2-3)[46]. [00486] Based on the fact that iPSCs can also be generated using SKM or O alone [47,48], the effect of the boosters on VC6T (SKM alternative) and F (O alternative) was evaluated. The effect of combinations including C6N was also assessed, because it has been reported that the removal of Y, S or A from Cocktail 1 (C6NYSA) did not reduce the CiPSC efficiency [42]. Among 80 cocktails tested in the NCC assay, the VC6TF basal cocktail was the most effective at restoring the integrity of nucleocytoplasmic compartmentalization, a key sign of age-reversal (FIG.3B). No benefit was observed with F alone or the VC6T cocktail on reversing senescence phenotypes in this system (FIG. 3B). [00487] Next, six cocktails of compounds were selected for further investigation, three of which were based on Cocktail 1 as well as two additives (referred to as Cocktail 2 and 3) and the other three based

190/240 12591029. H0824.70430WO00 on Cocktail 4 plus additional additives (referred to as Cocktail 5 and 6) (Table 3). Sodium butyrate, a histone deacetylase inhibitor, was one of the most effective additives in both human and mouse cocktails (C2 and C5) [47]. Basic fibroblast growth factor (bFGF) was used for Cocktail 3, while α- KG was included in Cocktail 6. To better gauge the effect of these compounds on NCC integrity, Pearson’s correlation was used to assess the distribution of fluorescent compounds (FIGs.3C-3D). The six cocktails statistically improved compartmentalization in senescent cells, both in terms of correlation analysis (FIG.3C) and imaging of NCC signaling (FIG.3D). [00488] Despite previous reports that the G9a inhibitor BIX-01294 and the TGFβ/SMAD inhibitor enhance reprogramming and can each replace both Sox2 and c-Myc, addition of both abolished the ability of all cocktails to rejuvenate cells (as measured by NCC assay). Likewise, Mirametanib is a MEK/MAPK inhibitor that, together with CHIR99021, promotes cells to enter a fully I “ground state” of pluripotency. Despite this synergy in the context of establishing and maintaining pluripotency, this compound was deleterious to rejuvenation, highlighting that there are unexpected differences between pluripotency and rejuvenation pathways. It was also hypothesized that folate would boost reprogramming by feeding into one-carbon metabolism to enhance methylation dynamics in a way that is known to support pluripotency. Unexpectedly, folate was deleterious to chemical- reprogramming, indicating that not all boosters or cofactors of epigenetic remodeling that enhance Yamanaka factor reprogramming function similarly in chemical reprogramming-mediated rejuvenation. [00489] To explore how the mechanism by which the cocktails were facilitating rejuvenation, the requirement of candidate mediators was tested, including specific chromatin modifiers. For nearly two decades, the writing and maintenance of chromatin marks have been known to be critical for reprogramming [49]. For this reason, it was examined whether the chemical cocktails relied on common chromatin modifying enzymes to achieve rejuvenation. The rejuvenation pathway(s) initiated by C1 and C4 were both blocked by the inhibition of H3K9 methyltransferase G9a (BIX01294: 0.5uM) and TGF-β (SB431542, 10uM), however they were not disrupted when the H3K27 methyltransferase component of PRC2, EZH2, was inhibited (DZNep 20 nM) (FIG.3B). Without being bound by a particular theory, the H3K9 methyltransferase G9a and TGF-β may be involved in the mechanism of rejuvenation. Example 4: Chemical reprogramming cocktails reverse the age of the transcriptome [00490] Based on the improvement in NCC integrity, the effect of these six cocktails on the transcriptomic age of the cells was tested using clocks trained on mouse, human, and a combined training data set. After treatments with the chemicals, there were no iPSC-like changes in cell morphology, or stem cell markers by immunofluorescence, nor was the expression of iPSC specific genes or gene modules observed in the RNA datasets (FIG.7A). The two groups of cocktails generally affected the same groups of genes (FIG.7A). iPSC-like changes in cell morphology were

191/240 12591029. H0824.70430WO00 not observed, and neither was the expression of iPSC specific genes or gene modules in the RNA datasets (FIGs.7B-7C). IF was performed looking for signs of expression of pluripotency related genes such as Nanog, EPCM and SSEA1 following all cocktail treatments, no expression was observed (FIG.8). This shows that chemical-mediated treatments are only partially reprogrammed and not fully reset to pluripotency. Relative biological age was assessed using a mouse transcriptome clock as well as a combined human and mouse transcriptomic clock (FIGs.4A-4B). The change in years of age was determined using a human-specific clock (FIG.4C). All data were normalized to the measured age of the quiescent cell populations. [00491] The transition of primary replicating NCC cells from quiescence to senescence led to a significant increase in biological age, based on the transcriptomics clocks, consistent with previous findings assessing DNA methylation age [36,50]. Treatment of NCC cells with each of the six chemical cocktails (C1-6) resulted in statistically significant decreases in the biological age of senescent cells, with those originating from mouse studies (C1-3) generally producing a greater decrease in biological age relative to the human derived cocktails (FIGs.4A-4B). The reported magnitude of the effect of all six cocktails differed between the hybrid and mouse biological clocks, with the hybrid clock indicating a greater decrease in age by all six cocktails, with the mouse clock showing less variability between treatments. [00492] All six reprogramming cocktails also significantly decreased the estimated chronological age of NCC senescent cells, several years below that of the quiescent cells (FIG.4C). As observed with clock based biological age estimates, C1,2, and C3 produced the greatest effect, reducing the measured age by more than three years after only four days of treatment. For reference, the effect of this 4 day treatment is comparable to the total change seen after a year of treatment with epigenetic described in the landmark study from 2019 [51]. [00493] To understand the effect of the chemical cocktails on cell identity and function, overall gene expression patterns of chemically treated cells were assessed and compared to old human cells and genetically-induced rejuvenated cells, with the correlation in gene expression between groups expressed as a heatmap of the Spearman’s ranked correlation. Despite having different chemical components, the transcriptomic profile of all six cocktails grouped most closely together, with human C4-6 and mouse C1-3 derived cocktails grouping more closely within their groups (FIG.4D). All six of the chemical treatments were positively correlated with the induced pluripotent stem cell (iPSC) populations, while most negatively correlated with the aged cell populations. To determine which pathways were responsible for the differences observed between these cell populations, GO enrichment analysis was performed using the KEGG genes database, HALLMARK gene set collection (gene sets defining specific biological states processes), and Reactome pathways database (FIG.4E). Compared to aged cells, the cocktail-treated cells had higher signals for respiration and lower signals for several different inflammatory pathways, supporting the idea that these cocktails reversed key aspects of cellular senescence.

192/240 12591029. H0824.70430WO00 Example 5: Discussion [00494] In the present disclosure, it is demonstrated that compositions and compounds disclosed herein can reverse the biological age of senescent human cells and promote gene expression patterns consistent with an earlier age, without loss of cell identity. Even in senescent cells, the expression of OSK resulted in a noticeable improvement in the integrity of nucleocytoplasmic compartmentalization. Disruption of NCC is a well-established effect of aging across species and is directly associated with other diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). [00495] Transcriptomic analysis of epigenetic reprogramming with OSK and the chemical reprogramming cocktails identified in this study indicate that these interventions broadly ameliorate senescence features. This was illustrated by the striking changes in senescence-associated gene expression patterns involving inflammation, mitochondrial metabolism, lysosomal function, apoptosis, p53 and growth signaling. Furthermore, the observation from the transcriptomic clocks that all six chemical cocktails, C1-C6, decreased both biological and chronological age below that of even the non-senescent progenitor cell populations, indicated that the cocktails are potent and capable of reversing senescence-associated cellular dysfunction. Despite the differences in the composition of mouse and human based chemical cocktails, both affected mostly the same grouping of genes, suggesting that the effects may be operating through shared pathways. [00496] CHIR99021 is a known GSK3ɑ/ ^ inhibitor shown to be an effective inducer of CiPSCs and promoter of certain stem cell characteristics [56,57]. E-616452, also known as RepSox, is a TGF- ^ inhibitor which has been used in experiments that replace SOX2 during epigenetic reprogramming [58,59]. Independent studies have found associations with individual chemicals and reprogramming in various contexts, indicating that each component likely contributes to rejuvenation through a broad range of mechanisms. Valproic acid is a well-known broad spectrum histone deacetylase inhibitor that leads to a rapid and dramatic spread of histone acetylation marks across the genome [62]. Sodium Butyrate is another histone deacetylase inhibitor that was found to be effective in both human and mouse cocktails. It has been associated with improving the expression of genes associated with reprogramming, supporting the model that the regulation of histone acetylation marks is important for reprogramming [46]. Forskolin is an activator of adenylyl cyclase that has been shown to drive reprogramming and transdifferentiation, depending upon the combination of other compounds present [63,64]. While the mechanism of action of forskolin in the context of rejuvenation remains to be identified, increasing cellular levels of cAMP and the triggering of signal cascades that are critical for adaptations in cell identity may be significant. [00497] Although the combination of VPA, CHIR99021, Repsox-616452, Forskolin, and TCP has been used to successfully produce iPSCs in mouse cells, to the inventors’ knowledge, this cocktail is incapable of producing iPSCs in human cells. Consequently, despite its prior use in the field for reprogramming, it is unexpected that this combination of chemicals can induce cellular rejuvenation

193/240 12591029. H0824.70430WO00 despite its inability to induce stem cell-like reprogramming trajectories in human cells. Given that chemical reprogramming cocktails have not been reported to be capable of fully reprogramming human cells to CiPSCs, the findings of this study substantiate the notion that the rejuvenation is inherent to early phases of reprogramming and is at least partially separable from pluripotency programs [7,8]. [00498] The observation that cellular rejuvenation is possible, restoring earlier gene expression patterns, while retaining cellular identity, indicates that old cells possess information to reset their epigenetic age. Identifying how this putative information is encoded and where it resides will greatly speed the development of increasingly effective approaches to rejuvenate cells, organs and tissues. The assays developed in the present disclosure, and the EPOCH cocktails that mimic OSK, may facilitate further advances as well as larger screens for genes, biologics, and chemical compounds that can reverse human aging. Example 6: Materials and Methods [00499] Cell culture. Human fibroblasts derived from a healthy 22-year-old, 94-year-old, or a 14- year old with HGPS were obtained from the Coriell Institute (GM23976, AG08433 and AG11498). These cells were cultured in DMEM supplemented with 20% Fetal Bovine Serum (FBS), 1% Penicillin-Streptomycin (P/S), and 0.1 mM β-Mercaptoethanol (β-ME). For Tet-On cells, the medium composition was adjusted to include 15% Tet-free FBS instead of the usual 20% FBS. To induce replicative senescence, fibroblasts were passaged until their growth ceased completely for at least two weeks. Senescence was confirmed through various assessments, including analysis of cell morphology, cell size, and immunostaining for gold-standard senescence markers. [00500] When analyzing the NCC signal of cells during the time point analysis, cells were imaged in a Cytation 10 every 24 hours by live-cell imaging in a heated and CO2/O2 controlled chamber (5% CO2 and 3%O2). [00501] Generation of stable cells. To generate NCC-stable cells, FugeneHD (Promega, E2311) was used for transfection of pLVX-EF1alpha-2xGFP:NES-IRES-2xRFP:NLS (addgene, #71396), psPAX2 (addgene, #12260), and pMD2.G (addgene, #12259) into 293FT cells following the provided instructions. The 293FT cell medium was collected at 2 and 4 days post-transfection and filtered through a 0.45-micron filter. To facilitate transduction, the collected medium was combined in a tube, concentrated using the Lenti-X™ Concentrator (Takara Bio, #631231), and added to human fibroblast medium with Polybrene at a concentration of 5 µg/ml. After 24 hours, the medium was replaced with fresh medium. Following approximately one week, a subset of fibroblasts showing stable expression of mCherry and GFP were observed, and NCC-positive cells were sorted using the BD FACSAria system. [00502] For cloning of the pLVX-UbC-rtTA-hOSK-Neo vector, the Ngn2:2A:EGFP and PuroR cassettes on pLVX-UbC-rtTA-Ngn2:2A:EGFP (addgene, #127288) were swapped with the

194/240 12591029. H0824.70430WO00 hOCT4:2A:hSOX2:2A:hKLF4 and NeoR cassettes, respectively. NCC fibroblasts were transduced with hOSK lentivirus using the same procedure as mentioned earlier to achieve stable hOSK expression. Two days post lentiviral transduction, the cells were cultured in DMEM supplemented with 15% Tet-free FBS, 1% P/S, 0.1mM β-ME, and 200 µg/ml G418. To induce hOSK expression, senescent fibroblasts were treated with 2 µg/ml Doxycycline. [00503] Compound treatment. The compounds disclosed herein were dissolved in suitable solvents and carefully stored according to the recommended conditions. Table 4 shows non-limiting examples of suitable solvents for each component of the cocktails. To prepare for the compound treatment, the growth medium was changed to a low serum medium with 1% FBS, a day prior to the treatment. Fresh low serum medium was used to prepare the compound cocktail solution, which was thoroughly mixed before replacing the old medium in the dish. The medium containing the compounds was completely refreshed every other day until the cells were harvested. To evaluate the alterations in NCC signals resulting from the compound cocktail treatment, NCC images were captured using the Cytation C10 (Agilent) imaging system. NCC correlation was calculated using Cellprofiler colocalization analysis. [00504] Immunofluorescence. Immunofluorescence was performed according to abcam’s immunofluorescence protocol. Briefly, cells were fixed in 3.7% PFA for 15 minutes and washed 3x with 1X PBS. Then cells were permeablized in 0.1% Triton X in PBS followed by 30 minutes of blocking in 1% BSA in PBS + 22.52 mg/mL glycine. Primary antibodies were used at 1:200 and incubated for 1 hr at room temp followed by 3x washes of PBS. Then secondary antibodies were used at 1:1000, followed by 3X washes of PBS. Nuclear counterstaining was performed for 15 minutes using Hoescht (1:2000 in PBS) followed by a final 3x washes with 1X PBS. Staining was assessed by 20X confocal imaging using the cytation imager and analyzed using the Gen5 imaging software. [00505] RNA sequencing and Analysis. RNA was harvested from cells using Omega ENZA Total RNA kit and assessed for quality and integrity using an Agilent Tapestation. Library preparation and150 bp paired-end sequencing was performed on an Illumina Novaseq by Novagene. Fastq read files were processed using FastQC. Illumina adapters were removed using TrimGalore! (Version 0.4.0, Babraham Bioinformatics), and aligned to the mm10 genome using Hisat2 (Version 2.2.1) [65]. Aligned reads were assembled using StringTie (Version 1.3.3b) [66], and expression level and transcripts were estimated. Differential expression was determined using Deseq2 [67], with FDR < 0.05. To assess the transcriptomic age (tAge) of fibroblasts treated with chemical cocktails, multi- tissue chronological human, lifespan-adjusted biological rodent (mouse + rat) and hybrid (mouse + rat + human) transcriptomic clocks were applied based on the identified gene expression signatures of aging [45]. For data preprocessing, filtered RNAseq count data was passed to log transformation and scaling. The missing values corresponding to clock genes not detected in the data were imputed with the precalculated average values. Estimated sample tAges were centered around the median tAge of control quiescent cells. Pairwise differences between average tAges of senescent untreated cells and

195/240 12591029. H0824.70430WO00 either quiescent cells or senescent cells treated with C1-6 cocktails were assessed using independent t- tests. Resulting p-values were adjusted with the Bemjamini-Hochberg method. [00506] iPSC profiler. In order to validate that the cells treated with chemical reprogramming cocktails did not lose their fibroblast cell type identity, transcriptome of all samples were compared against that of human stem cells using SEQUIN iPSC Profiler [68]. [00507] Abbreviations. Amyotrophic lateral sclerosis (ALS), β-mercaptoethanol (β-ME), chemically induced pluripotent stem cells (CiPSCs), cytoplasmic chromatin fragments (CCFs), Epigenetic programming of old cell health (EPOCH), frontotemporal dementia (FTD), Hutchinson-Gilford progeria syndrome (HGPS), induced pluripotent stem cells (iPSCs), Inducible changes in the epigenome (ICE), nuclear export signal (NES), nuclear localization signal (NLS), nucleocytoplasmic compartmentalization (NCC), OCT4, SOX2 and KLF4 (OSK), OCT4, SOX2, KLF4 and cMYC (OSKM), Senescence associated secretory phenotype (SASP), SOX2, KLF4 and cMYC (SKM), tetracycline-inducible promoter (Tet-on) Table 2. Non-limiting compound concentrations Table 3. Non-limiting cocktail combinations

196/240 12591029. H0824.70430WO00 Table 4. Non-limiting suitable solvents for cocktail components

197/240 12591029. H0824.70430WO00 Example 7: Identification of a 2 factor cocktail that resets age comparable to 5+ factor cocktails [00508] Yamanaka factor reprogramming is a stochastic and inefficient process with many cells failing to become stem cells or, in the case of partial reprogramming, becoming rejuvenated [1-2]. As detailed above, compounds known to enhance the initial stages of reprogramming are sufficient to reverse features of cellular aging including nuclear leakage (NCC assay) and transcriptomic clock analysis. Consequently, other combinations of compounds reportedly capable of boosting Yamanaka factor reprogramming, but which do not induce pluripotency, were studied. A combination of ascorbic Acid and CHIR99021 was first reported in 2014 to dramatically boost the ability of OSK(M) to produce induced pluripotent stem cells (iPSCs) [3]. This combination, to the inventors’ knowledge, has not been tested in the context of aging, and has not been used outside of its combination together with Yamanaka factors. In senescent human cells, this combination is hereafter referred to as Agi (the original name given by the 2014 paper which stands for Ascorbic Acid and GSK3B inhibitor, which is the mechanism of CHIR99021). Agi was found to reverse nuclear leakiness at a level comparable to the most effective 5+ chemical cocktail, a.k.a. VC6FT (cocktail 1 (C1)), (FIG.9). Additionally, in mouse cells, this cocktail is capable of fully reversing senescence growth arrest as indicated by positive EdU staining (a marker of newly synthesized cells). This finding is widely accepted in the field to be impossible (FIG.10). Moreover, Agi entirely reversed the senescence-associated decline in LaminB1, a marker of nuclear health that is causal in the pathology of cellular senescence (FIG.11). Altogether, these striking data indicate that the addition of a safe and well-tolerated natural compound (ascorbic acid) unleashes previously unknown synergy with CHIR99021 to produce profound reversal of aging and senescence features. Example 8: Additional compounds, targets, and mechanisms that may facilitate chemical reprogramming rejuvenation [00509] A combination of CHIR99021 and Repsox-616452 is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and Repsox-616452 can induce chemical programming rejuvenation.

198/240 12591029. H0824.70430WO00 [00510] A combination of CHIR99021 and valproic acid is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and valproic acid can induce chemical programming rejuvenation. [00511] A combination of CHIR99021 and Tranylcypromine is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and Tranylcypromine can induce chemical programming rejuvenation. [00512] A combination of CHIR99021 and Forskolin is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and Forskolin can induce chemical programming rejuvenation. [00513] A combination of CHIR99021 and TTNPB is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and TTNPB can induce chemical programming rejuvenation. [00514] A combination of CHIR99021 and Y-27632is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and Y- 27632can induce chemical programming rejuvenation. [00515] A combination of CHIR99021 and SAG is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and SAG can induce chemical programming rejuvenation. [00516] A combination of CHIR99021 and ABT869 is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and ABT869 can induce chemical programming rejuvenation. [00517] A combination of CHIR99021 and Alpha-ketoglutarate is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and Alpha-ketoglutarate can induce chemical programming rejuvenation. [00518] A combination of CHIR99021 and butyric acid is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and butyric acid can induce chemical programming rejuvenation. [00519] A combination of CHIR99021 and b-FGF is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of CHIR99021 and b-FGF can induce chemical programming rejuvenation. [00520] A combination of ascorbic acid and Repsox-616452 is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and Repsox-616452 can induce chemical programming rejuvenation. [00521] A combination of ascorbic acid and valproic acid is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and valproic acid can induce chemical programming rejuvenation.

199/240 12591029. H0824.70430WO00 [00522] A combination of ascorbic acid and Tranylcypromine is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and Tranylcypromine can induce chemical programming rejuvenation. [00523] A combination of ascorbic acid and Forskolin is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and Forskolin can induce chemical programming rejuvenation. [00524] A combination of ascorbic acid and TTNPB is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and TTNPB can induce chemical programming rejuvenation. [00525] A combination of ascorbic acid and Y-27632 is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and Y- 27632 can induce chemical programming rejuvenation. [00526] A combination of ascorbic acid and SAG is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and SAG can induce chemical programming rejuvenation. [00527] A combination of ascorbic acid and ABT869 is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and ABT869 can induce chemical programming rejuvenation. [00528] A combination of ascorbic acid and Alpha-ketoglutarate is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and Alpha-ketoglutarate can induce chemical programming rejuvenation. [00529] A combination of ascorbic acid and butyric acid is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and butyric acid can induce chemical programming rejuvenation. [00530] A combination of ascorbic acid and b-FGF is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of ascorbic acid and b-FGF can induce chemical programming rejuvenation. [00531] A combination of a GSK3β inhibitor and Repsox-616452 is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and Repsox-616452 can induce chemical programming rejuvenation. [00532] A combination of a GSK3β inhibitor and valproic acid is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and valproic acid can induce chemical programming rejuvenation. [00533] A combination of a GSK3β inhibitor and Tranylcypromine is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and Tranylcypromine can induce chemical programming rejuvenation.

200/240 12591029. H0824.70430WO00 [00534] A combination of a GSK3β inhibitor and Forskolin is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and Forskolin can induce chemical programming rejuvenation. [00535] A combination of a GSK3β inhibitor and TTNPB is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and TTNPB can induce chemical programming rejuvenation. [00536] A combination of a GSK3β inhibitor and Y-27632is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and Y-27632can induce chemical programming rejuvenation. [00537] A combination of a GSK3β inhibitor and SAG is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and SAG can induce chemical programming rejuvenation. [00538] A combination of a GSK3β inhibitor and ABT869 is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and ABT869 can induce chemical programming rejuvenation. [00539] A combination of a GSK3β inhibitor and Alpha-ketoglutarate is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and Alpha-ketoglutarate can induce chemical programming rejuvenation. [00540] A combination of a GSK3β inhibitor and butyric acid is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and butyric acid can induce chemical programming rejuvenation. [00541] A combination of a GSK3β inhibitor and b-FGF is prepared in a ratio disclosed herein and is tested as in Example 6. The results are expected to show that the combination of a GSK3β inhibitor and b-FGF can induce chemical programming rejuvenation. Example 9: Further optimization of cocktail concentrations [00542] A preliminary cell survival assay was performed on different concentrations of the chemicals from chemical cocktail 1. The concentrations shown in Table 5 were found to be the highest that could be used without causing a noticeable drop off compared to lower doses. To select the modified C1 doses, the lowest dose that did not cause cell death, either alone or in combination with the other chemical cocktails, was selected. These doses are based on tests in both human retinal cells (ARPE19 cells) and human fibroblasts (HF8). [00543] Characterization of combinations of reprogramming small molecules identified C6F as optimal rejuvenative combination from VC6FT (Cocktail 1) (FIGs.17A-17C). The core activities of GSK3B inhibition, TGF-β inhibition, and cAMP agonism were identified as the most effective combinations of the C1 chemicals. The combinations CF (CHIR-99021 and Forskolin) and C6F (CHIR-99021, Repsox, and Forskolin) represented the best combinations and are minimal

201/240 12591029. H0824.70430WO00 reprogramming cocktails from the combinations of the C1 chemicals. Nevertheless, combinations of two chemicals (Ascorbic acid and CHIR99021 (AGi), and others) or a single chemical (Lithium ascorbate, which mimics AGi) were determined to be potent at eliciting cellular rejuvenation. This identification of minimal sets of reprogramming chemicals indicate that use of one or more of the chemicals with activities matching or similar to those tested here are likely to elicit cellular rejuvenation. [00544] Cells were also treated with chemical cocktails containing different doses of the constituent chemicals, and reactive oxygen species (ROS) measured (FIG.19). Slight decreases to the doses of CHIR and forskolin in particular led to decreases of the basal levels of ROS in the cells toward quiescent levels. This suggests that these chemical cocktails may have additional benefits for cellular metabolic wellbeing. Table 5. Summary of optimal doses of chemicals in cocktail C1 based on survival. Table 6. Chemical concentrations and doses used in FIGs.15-16. Table 7. Layout of plate with concentrations used in FIG.19.

202/240 12591029. H0824.70430WO00 References [00545] 1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. Europe PMC Funders; 2013; 153: 1194. [00546] 2. Hallmarks of aging: An expanding universe. Cell. Cell Press; 2023; 186: 243–78. [00547] 3. Sinclair DA, Mills K, Guarente L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science.1997; 277: 1313–6. [00548] 4. Mills KD, Sinclair DA, Guarente L. MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks. Cell.1999; 97: 609–20. [00549] 5. Oberdoerffer P, Sinclair DA. The role of nuclear architecture in genomic instability and ageing. Nat Rev Mol Cell Biol.2007; 8: 692–702. [00550] 6. Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, Bhimavarapu A, Luikenhuis S, de Cabo R, Fuchs C, Hahn WC, Guarente LP, Sinclair DA. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One.2008; 3: e2020. [00551] 7. Yang J-H, Hayano M, Griffin PT, Amorim JA, Bonkowski MS, Apostolides JK, Salfati EL, Blanchette M, Munding EM, Bhakta M, Chew YC, Guo W, Yang X, et al. Loss of epigenetic information as a cause of mammalian aging. Cell.2023; 186: 305–26.e27. [00552] 8. Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang J-H, Zhou S, Hoffmann EM, et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature.2020; 588: 124–9. [00553] 9. Song S, Tchkonia T, Jiang J, Kirkland JL, Sun Y. Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities. Adv Sci.2020; 7: 2002611. [00554] 10. Miller KN, Dasgupta N, Liu T, Adams PD, Vizioli MG. Cytoplasmic chromatin fragments-from mechanisms to therapeutic potential. Elife [Internet]. Elife; 2021 [cited 2023 Jun 29]; 10. Available from: https://pubmed.ncbi.nlm.nih.gov/33512316/ [00555] 11. Cellular Senescence in Disease [Internet]. Google Books. [cited 2023 Apr 17]. Available from: https://books.google.com/books/about/Cellular_Senescence_in_Disease.html?id=jEsiEAAAQBAJ

203/240 12591029. H0824.70430WO00 [00556] 12. Gurdon JB. The Developmental Capacity of Nuclei taken from Intestinal Epithelium Cells of Feeding Tadpoles. Development. The Company of Biologists; 1962; 10: 622–40. [00557] 13. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell [Internet]. Cell; 2006 [cited 2023 May 21]; 126. Available from: https://pubmed.ncbi.nlm.nih.gov/16904174/ [00558] 14. Wakayama T, Perry ACF, Zuccotti M, Johnson KR, Yanagimachi R. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature. Nature Publishing Group; 1998; 394: 369–74. [00559] 15. Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KHS. Viable offspring derived from fetal and adult mammalian cells. Nature. Nature Publishing Group; 1997; 385: 810–3. [00560] 16. Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, et al. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell. Elsevier; 2016; 167: 1719–33.e12. [00561] 17. Sarkar TJ, Quarta M, Mukherjee S, Colville A, Paine P, Doan L, Tran CM, Chu CR, Horvath S, Qi LS, Bhutani N, Rando TA, Sebastiano V. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun. Nature Publishing Group; 2020; 11: 1–12. [00562] 18. Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N, Leschik J, Pellestor F, Ramirez JM, De Vos J, Lehmann S, Lemaitre JM. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev [Internet]. Genes Dev; 2011 [cited 2023 May 21]; 25. Available from: https://pubmed.ncbi.nlm.nih.gov/22056670/ [00563] 19. Macip CC, Hasan R, Hoznek V, Kim J, Metzger LE IV, Sethna S, Davidsohn N. Gene therapy mediated partial reprogramming extends lifespan and reverses age-related changes in aged mice [Internet]. bioRxiv.2023. Available from: http://biorxiv.org/lookup/doi/10.1101/2023.01.04.522507 [00564] 20. Sung YK, Kim SW. Recent advances in the development of gene delivery systems. Biomaterials Research. BioMed Central; 2019; 23: 1–7. [00565] 21. Liuyang S, Wang G, Wang Y, He H, Lyu Y, Cheng L, Yang Z, Guan J, Fu Y, Zhu J, Zhong X, Sun S, Li C, et al. Highly efficient and rapid generation of human pluripotent stem cells by chemical reprogramming. Cell Stem Cell. Elsevier; 2023; 30: 450–9.e9. [00566] 22. Schoenfeldt L, Paine PT, Kamaludeen M NH, Phelps GB, Mrabti C, Perez K, Ocampo A. Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan [Internet]. bioRxiv.2022 [cited 2023 May 21]. p.2022.08.29.505222. Available from: https://www.biorxiv.org/content/10.1101/2022.08.29.505222v1.abstract

204/240 12591029. H0824.70430WO00 [00567] 23. Hu Y, Yang Y, Tan P, Zhang Y, Han M, Yu J, Zhang X, Jia Z, Wang D, Yao K, Pang H, Hu Z, Li Y, et al. Induction of mouse totipotent stem cells by a defined chemical cocktail. Nature. Nature Publishing Group; 2022; : 1–6. [00568] 24. Mertens J, Paquola ACM, Ku M, Hatch E, Böhnke L, Ladjevardi S, McGrath S, Campbell B, Lee H, Herdy JR, Gonçalves JT, Toda T, Kim Y, et al. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell.2015; 17: 705–18. [00569] 25. Park J-H, Ryu SJ, Kim BJ, Cho H-J, Park CH, Choi HJC, Jang E-J, Yang EJ, Hwang J-A, Woo S-H, Lee JH, Park JH, Choi K-M, et al. Disruption of nucleocytoplasmic trafficking as a cellular senescence driver. Exp Mol Med.2021; 53: 1092–108. [00570] 26. D’Angelo MA, Raices M, Panowski SH, Hetzer MW. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell.2009; 136: 284– 95. [00571] 27. Gatto N, Dos Santos Souza C, Shaw AC, Bell SM, Myszczynska MA, Powers S, Meyer K, Castelli LM, Karyka E, Mortiboys H, Azzouz M, Hautbergue GM, Márkus NM, et al. Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease. Aging Cell.2021; 20: e13281. [00572] 28. Zhang JH, Chung TD, Oldenburg KR. A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. J Biomol Screen.1999; 4: 67–73. [00573] 29. Freund A, Laberge R-M, Demaria M, Campisi J. Lamin B1 loss is a senescence- associated biomarker. Mol Biol Cell.2012; 23: 2066–75. [00574] 30. Shah PP, Donahue G, Otte GL, Capell BC, Nelson DM, Cao K, Aggarwala V, Cruickshanks HA, Rai TS, McBryan T, Gregory BD, Adams PD, Berger SL. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev.2013; 27: 1787–99. [00575] 31. Lenain C, de Graaf CA, Pagie L, Visser NL, de Haas M, de Vries SS, Peric-Hupkes D, van Steensel B, Peeper DS. Massive reshaping of genome-nuclear lamina interactions during oncogene-induced senescence. Genome Res.2017; 27: 1634–44. [00576] 32. Shimi T, Butin-Israeli V, Adam SA, Hamanaka RB, Goldman AE, Lucas CA, Shumaker DK, Kosak ST, Chandel NS, Goldman RD. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev.2011; 25: 2579–93. [00577] 33. Ivanov A, Pawlikowski J, Manoharan I, van Tuyn J, Nelson DM, Rai TS, Shah PP, Hewitt G, Korolchuk VI, Passos JF, Wu H, Berger SL, Adams PD. Lysosome-mediated processing of chromatin in senescence. J Cell Biol.2013; 202: 129–43. [00578] 34. Dou Z, Xu C, Donahue G, Shimi T, Pan J-A, Zhu J, Ivanov A, Capell BC, Drake AM, Shah PP, Catanzaro JM, Ricketts MD, Lamark T, et al. Autophagy mediates degradation of nuclear lamina. Nature.2015; 527: 105–9.

205/240 12591029. H0824.70430WO00 [00579] 35. Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P, Wangensteen KJ, Simithy J, Lan Y, Lin Y, Zhou Z, Capell BC, Xu C, Xu M, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature.2017; 550: 402–6. [00580] 36. Lowe D, Horvath S, Raj K. Epigenetic clock analyses of cellular senescence and ageing. Oncotarget. Impact Journals; 2016; 7: 8524–31. [00581] 37. Kabacik S, Lowe D, Fransen L, Leonard M, Ang S-L, Whiteman C, Corsi S, Cohen H, Felton S, Bali R, Horvath S, Raj K. The relationship between epigenetic age and the hallmarks of aging in human cells. Nat Aging.2022; 2: 484–93. [00582] 38. Kinetics of G1 transit following brief starvation for serum factors. Exp Cell Res. Academic Press; 1984; 152: 459–66. [00583] 39. Anisimova AS, Meerson MB, Gerashchenko MV, Kulakovskiy IV, Dmitriev SE, Gladyshev VN. Multifaceted deregulation of gene expression and protein synthesis with age. Proc Natl Acad Sci U S A.2020; 117: 15581–90. [00584] 40. López-Domínguez JA, Rodríguez-López S, Ahumada-Castro U, Desprez P-Y, Konovalenko M, Laberge R-M, Cárdenas C, Villalba JM, Campisi J. Cdkn1a transcript variant 2 is a marker of aging and cellular senescence. Aging . Impact Journals, LLC; 2021; 13: 13380. [00585] 41. Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K, Ge J, Xu J, Zhang Q, et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science.2013; 341: 651–4. [00586] 42. Guan J, Wang G, Wang J, Zhang Z, Fu Y, Cheng L, Meng G, Lyu Y, Zhu J, Li Y, Wang Y, Liuyang S, Liu B, et al. Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature.2022; 605: 325–31. [00587] 43. Olova N, Simpson DJ, Marioni RE, Chandra T. Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging Cell.2019; 18: e12877. [00588] 44. Gill D, Parry A, Santos F, Okkenhaug H, Todd CD, Hernando-Herraez I, Stubbs TM, Milagre I, Reik W. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. Elife [Internet].2022; 11. Available from: http://dx.doi.org/10.7554/eLife.71624 [00589] 45. Li Y, Zhang Q, Yin X, Yang W, Du Y, Hou P, Ge J, Liu C, Zhang W, Zhang X, Wu Y, Li H, Liu K, et al. Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res.2011; 21: 196–204. [00590] 46. Zhang Z, Xiang D, Wu W-S. Sodium Butyrate Facilitates Reprogramming by Derepressing OCT4 Transactivity at the Promoter of Embryonic Stem Cell–Specific miR-302/367 Cluster. Cell Reprogram. Mary Ann Liebert, Inc.; 2014; 16: 130. [00591] 47. Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hübner K, Bernemann C, et al. Oct4-induced pluripotency in adult neural stem cells. Cell.2009; 136: 411–9.

206/240 12591029. H0824.70430WO00 [00592] 48. Velychko S, Adachi K, Kim K-P, Hou Y, MacCarthy CM, Wu G, Schöler HR. Excluding Oct4 from Yamanaka Cocktail Unleashes the Developmental Potential of iPSCs. Cell Stem Cell.2019; 25: 737–53.e4. [00593] 49. Morgan HD, Santos F, Green K, Dean W, Reik W. Epigenetic reprogramming in mammals. Hum Mol Genet. Oxford Academic; 2005; 14: R47–58. [00594] 50. Liu Z, Leung D, Thrush K, Zhao W, Ratliff S, Tanaka T, Schmitz LL, Smith JA, Ferrucci L, Levine ME. Underlying features of epigenetic aging clocks in vivo and in vitro. Aging Cell.2020; 19: e13229. [00595] 51. Fahy GM, Brooke RT, Watson JP, Good Z, Vasanawala SS, Maecker H, Leipold MD, Lin DTS, Kobor MS, Horvath S. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell.2019; 18: e13028. [00596] 52. Knowles TPJ, Vendruscolo M, Dobson CM. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol.2014; 15: 384–96. [00597] 53. Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature.2015; 525: 56–61. [00598] 54. Huang J, Zhang H, Yao J, Qin G, Wang F, Wang X, Luo A, Zheng Q, Cao C, Zhao J. BIX-01294 increases pig cloning efficiency by improving epigenetic reprogramming of somatic cell nuclei. Reproduction.2016; 151: 39–49. [00599] 55. Papait R, Serio S, Pagiatakis C, Rusconi F, Carullo P, Mazzola M, Salvarani N, Miragoli M, Condorelli G. Histone Methyltransferase G9a Is Required for Cardiomyocyte Homeostasis and Hypertrophy. Circulation.2017; 136: 1233–46. [00600] 56. Singh VK, Kumar N, Kalsan M, Saini A, Chandra R. Mechanism of Induction: Induced Pluripotent Stem Cells (iPSCs). J Stem Cells.2015; 10: 43–62. [00601] 57. Takeda Y, Harada Y, Yoshikawa T, Dai P. Chemical compound-based direct reprogramming for future clinical applications. Biosci Rep [Internet].2018; 38. Available from: http://dx.doi.org/10.1042/BSR20171650 [00602] 58. Ichida JK, Blanchard J, Lam K, Son EY, Chung JE, Egli D, Loh KM, Carter AC, Di Giorgio FP, Koszka K, Huangfu D, Akutsu H, Liu DR, et al. A Small Molecule Inhibitor of Tgf-β Signaling Replaces Sox2 in Reprogramming by Inducing Nanog. Cell Stem Cell. NIH Public Access; 2009; 5: 491. [00603] 59. Maherali N, Hochedlinger K. Tgfβ signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Curr Biol. NIH Public Access; 2009; 19: 1718. [00604] 60. Fu Y, Huang C, Xu X, Gu H, Ye Y, Jiang C, Qiu Z, Xie X. Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails. Cell Res. Nature Publishing Group; 2015; 25: 1013.

207/240 12591029. H0824.70430WO00 [00605] 61. Tu W-Z, Fu Y-B, Xie X. RepSox, a small molecule inhibitor of the TGFβ receptor, induces brown adipogenesis and browning of white adipocytes. Acta Pharmacol Sin. Nature Publishing Group; 2019; 40: 1523. [00606] 62. Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P, Kögler G, Müller F-J, Koch P, Brüstle O. Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods. Nature Publishing Group; 2012; 9: 575–8. [00607] 63. Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, Zhu J, Du X, Xiong L, Du Y, Xu J, Xiao X, Wang J, et al. Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. Cell Stem Cell [Internet]. Cell Stem Cell; 2015 [cited 2023 May 22]; 17. Available from: https://pubmed.ncbi.nlm.nih.gov/26253201/ [00608] 64. Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L, Shen L, Huang Y, Xie G, Zhao H, Jin Y, Tang B, et al. Direct Conversion of Normal and Alzheimer’s Disease Human Fibroblasts into Neuronal Cells by Small Molecules. Cell Stem Cell [Internet]. Cell Stem Cell; 2015 [cited 2023 May 22]; 17. Available from: https://pubmed.ncbi.nlm.nih.gov/26253202/ [00609] 65. Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods [Internet]. Nat Methods; 2015 [cited 2023 May 22]; 12. Available from: https://pubmed.ncbi.nlm.nih.gov/25751142/ [00610] 66. Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol [Internet]. Nat Biotechnol; 2015 [cited 2023 May 22]; 33. Available from: https://pubmed.ncbi.nlm.nih.gov/25690850/ [00611] 67. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. BioMed Central; 2014; 15: 1–21. [00612] 68. SEQUIN is an R/Shiny framework for rapid and reproducible analysis of RNA-seq data. Cell Reports Methods. Cell Press; 2023; 3: 100420. I^{NCORPORATION BY} R^EFERENCE [00613] The present application refers to various issued patent, published patent applications, scientific journal articles, and other publications, all of which are incorporated herein by reference. The details of one or more embodiments of the present disclosure are set forth herein. Other features, objects, and advantages of the present disclosure will be apparent from the Detailed Description, the Figures, the Examples, and the Claims. EQUIVALENTS AND SCOPE [00614] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include

208/240 12591029. H0824.70430WO00 “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. [00615] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects described herein, is/are referred to as comprising particular elements and/or features, certain embodiments described herein or aspects described herein consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments described herein, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [00616] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment described herein can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [00617] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

209/240 12591029. H0824.70430WO00

Claims

CLAIMS What is claimed is: 1. A method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

210/240 12591029. H0824.70430WO00

2. A method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 3. A method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

211/240 12591029. H0824.70430WO00 RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 4. A method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

212/240 12591029. H0824.70430WO00 valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 5. A method of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

213/240 12591029. H0824.70430WO00 forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 6. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

214/240 12591029. H0824.70430WO00 arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 7. A method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

215/240 12591029. H0824.70430WO00 smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 8. A method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

216/240 12591029. H0824.70430WO00

9. A method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 10. A method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

217/240 12591029. H0824.70430WO00 ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 11. A method of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

218/240 12591029. H0824.70430WO00 forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 12. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

219/240 12591029. H0824.70430WO00 Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 13. The method of any one of claims 1-12, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof three or more compounds selected from the group. 14. The method of any one of claims 1-13, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof four or more compounds selected from the group. 15. The method of any one of claims 1-14, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof five or more compounds selected from the group. 16. The method of any one of claims 1-15, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof six or more compounds selected from the group. 17. The method of any one of claims 1-16, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 18. The method of any one of claims 1-17, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

220/240 12591029. H0824.70430WO00 tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 19. The method of any one of claims 1-18, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 20. The method of any one of claims 1-19, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

221/240 12591029. H0824.70430WO00

21. The method of any one of claims 1-20, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 22. The method of any one of claims 1-21, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 23. The method of any one of claims 1-22, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

222/240 12591029. H0824.70430WO00 RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 24. The method of any one of claims 1-23, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 25. The method of any one of claims 1-24, wherein the pharmaceutically acceptable salt of butyric acid is sodium butyrate. 26. The method of any one of claims 1-25, wherein the ascorbic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is ascorbic acid, lithium ascorbate, Ester-C, ascorbyl palmitate, liposomal vitamin C, sodium ascorbate, magnesium ascorbyl phosphate (MAP), tetrahexyldecyl ascorbate, ascorbyl glucoside, calcium ascorbate, or sodium erythorbate. 27. The method of any one of claims 1-6 and 13-16, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof. 28. The method of any one of claims 1-6, 13-16, and 27, wherein the lithium salt is selected from lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, and lithium citrate.

223/240 12591029. H0824.70430WO00

29. The method of any one of claims 1-6, 13-16, 27, and 28, wherein the lithium salt is lithium chloride. 30. A method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. 31. A method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. 32. A method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. 33. A method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. 34. A method of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with lithium ascorbate. 35. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof lithium ascorbate. 36. The method of any one of claims 1-5 and 7-34, wherein the cell is a senescent cell. 37. The method of claim 36, wherein the senescent cell is within the tissue or organ. 38. The method of any one of claims 1-5, 7-34, 36, and 37 , wherein the cell, tissue, or organ is within a subject. 39. The method of any one of claims 1-38, further comprising: increasing cellular respiration, reducing cellular inflammatory pathways, improving integrity of nucleocytoplasmic compartmentalization, or a combination thereof, ex vivo or in vitro. 40. The method of any one of claims 1-5, 7-11, 13-34, and 36-39, wherein the cell or tissue is from eye, ear, nose, mouth including gum and roots of teeth, bone, lung, breast, udder, pancreas, stomach, esophagus, muscle including cardiac muscle, liver, blood vessel, skin including hair, heart, brain, nerve tissue, kidney, testis, prostate, penis, cloaca, fin, ovary, or intestine, optionally wherein

224/240 12591029. H0824.70430WO00 the tissue is damaged or the tissue may be considered healthy but suboptimal for performance or survival in current or future conditions. 41. The method of any one of claims 5, 11, 13-29, 34, and 36-40, wherein the method reduces expression of the at least one gene associated with aging. 42. The method of any one of claims 5, 11, 13-29, 34, and 36-40, wherein the method increases expression of the at least one gene associated with aging. 43. The method of any one of claims 5, 11, 13-29, 34, and 36-42, wherein the at least one gene associated with aging is associated with: inflammation, mitochondrial metabolism, lysosomal function, apoptosis, p53, growth signaling, or a combination thereof, ex vivo or in vitro. 44. The method of any one of claims 1-5, 7-11, 13-34, and 36-43, further comprising activating an enhancer of reprogramming in the cell, tissue, or organ. 45. The method of claim 44, wherein the enhancer of reprogramming is a class I histone deacetylase (HDAC1-3). 46. The method of any one of claims 1-5, 7-11, 13-34, and 36-45, comprising restoring epigenetic information in the cell, tissue, or organ. 47. The method of claim 46, wherein the epigenetic information is lost due to aging, injury, disease, or a combination thereof in the cell, tissue, or organ. 48. The method of any one of claims 1-5, 7-11, 13-34, and 36-47, comprising reestablishing an epigenetic status of the cell, tissue, or organ that is similar to the status formed soon after final differentiation. 49. The method of any one of claims 1-5, 7-11, 13-34, and 36-48, wherein the cell, tissue, or organ is not reprogrammed to a pluripotent state. 50. The method of any one of claims 1-49, wherein the method rejuvenates an epigenetic clock of a cell, tissue, organ, subject, or a combination thereof. 51. The method of any one of claims 4, 10, 13-29, 33, 36-40, and 44-50, wherein the apparent chronological age of the cell, organ, or tissue is reduced by about three years.

225/240 12591029. H0824.70430WO00

52. The method of any one of claims 1-5, 7-11, 13-34, and 36-51, wherein the cell, tissue, or organ is treated for about four days. 53. The method of any one of claims 1-29 and 36-52, wherein the laduviglusib (CHIR99021), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM. 54. The method of any one of claims 1-29 and 36-53, wherein the RepSox (E-616452), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM. 55. The method of any one of claims 1-29 and 36-54, wherein the ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 10 µg/mL to about 100 µg/mL. 56. The method of any one of claims 1-29 and 36-55, wherein the valproic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 400 µM. 57. The method of any one of claims 1-29 and 36-56, wherein the tranylcypromine, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 2.5 µM to about 7.5 µM. 58. The method of any one of claims 1-29 and 36-57, wherein the forskolin, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 25 µM to about 75 µM. 59. The method of any one of claims 1-29 and 36-58, wherein the butyric acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 300 µM.

226/240 12591029. H0824.70430WO00

60. The method of any one of claims 1-29 and 36-59, wherein the basic fibroblast growth factor (bFGF), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 50 µg/mL to about 150 µg/mL. 61. The method of any one of claims 1-29 and 36-60, wherein the arotinoid acid (TTNPB), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM. 62. The method of any one of claims 1-29 and 36-61, wherein the Y-27632, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM. 63. The method of any one of claims 1-29 and 36-62, wherein the smoothened agonist (SAG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.25 µM to about 0.75 µM. 64. The method of any one of claims 1-29 and 36-63, wherein the linifanib (ABT-869), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.5 µM to about 1.5 µM. 65. The method of any one of claims 1-29 and 36-64, wherein the alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 250 µM to about 750 µM. 66. The method of any one of claims 1-6, 13-29, and 36-65, wherein the ascorbic acid is used at a concentration of about 25 µg/mL to about 75 µg/mL, and the lithium salt is used at a concentration of about 1 mM to about 25 mM. 67. The method of any one of claims 30-52, wherein the lithium ascorbate is used at a concentration of about 0.1 mM to about 5 mM.

227/240 12591029. H0824.70430WO00

68. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-67, wherein the subject is a human. 69. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-68, wherein the subject is a pediatric subject. 70. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-68, wherein the subject is an adult subject. 71. The method of claim 70, wherein the adult subject is a senior adult subject. 72. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-71, wherein the subject is healthy. 73. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-71, wherein the subject has, is suspected of having, or is at risk for an age-related disease. 74. The method of claim 73, wherein the age-related disease is a neurological disease. 75. The method of claim 74, wherein the neurological disease is a neurodegenerative disease. 76. The method of claim 75, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). 77. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-76, wherein the administration comprises systemic administration to the subject. 78. A method of monitoring cellular aging, the method comprising: (a) providing a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal; (b) contacting the cell with at least one test agent; (c) measuring a first signal from a first protein produced by the first reporter gene; (d) measuring a second signal from a second protein produced by the second reporter gene; (e) comparing the first signal and the second signal to assess the distribution of the first protein and the second protein in the cell.

228/240 12591029. H0824.70430WO00

79. The method of claim 78, wherein the first reporter gene encodes a first fluorescent protein. 80. The method of claim 79, wherein the first fluorescent protein is mCherry. 81. The method of any one of claims 78-80, wherein the second reporter gene encodes a second fluorescent protein. 82. The method of claim 81, wherein the second fluorescent protein is eGFP. 83. The method of any one of claims 78-82, wherein the cell is a fibroblast. 84. The method of any one of claims 78-83, wherein the cell is a human cell. 85. A cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal. 86. The cell of claim 85, wherein the first reporter gene encodes a first fluorescent protein. 87. The cell of claim 86, wherein the first fluorescent protein is mCherry. 88. The cell of any one of claims 85-87, wherein the second reporter gene encodes a second fluorescent protein. 89. The cell of claim 88, wherein the second fluorescent protein is eGFP. 90. The cell of any one of claims 85-89, wherein the cell is a fibroblast. 91. The cell of any one of claims 85-90, wherein the cell is a human cell. 92. A pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

229/240 12591029. H0824.70430WO00 RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 93. A pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

230/240 12591029. H0824.70430WO00 valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 94. The pharmaceutical composition of claim 92 or claim 93, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. 95. The pharmaceutical composition of any one of claims 92-94, comprising three or more compounds selected from the group. 96. The pharmaceutical composition of any one of claims 92-95, comprising four or more compounds selected from the group. 97. The pharmaceutical composition of any one of claims 92-96, comprising five or more compounds selected from the group. 98. The pharmaceutical composition of any one of claims 92-97, comprising six or more compounds selected from the group.

231/240 12591029. H0824.70430WO00

99. The pharmaceutical composition of any one of claims 92-98, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 100. The pharmaceutical composition of any one of claims 92-99, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 101. The pharmaceutical composition of any one of claims 92-100, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 102. The pharmaceutical composition of any one of claims 92-101, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

232/240 12591029. H0824.70430WO00 RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 103. The pharmaceutical composition of any one of claims 92-102, comprising: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 104. The pharmaceutical composition of any one of claims 92-103, comprising: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

233/240 12591029. H0824.70430WO00 linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 105. The pharmaceutical composition of any one of claims 92-104, comprising: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 106. The pharmaceutical composition of any one of claims 92-105, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 107. The pharmaceutical composition of any one of claims 92-106, wherein the pharmaceutically acceptable salt of butyric acid is sodium butyrate. 108. The pharmaceutical composition of any one of claims 92-107, comprising ascorbic acid and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

234/240 12591029. H0824.70430WO00

109. The pharmaceutical composition of any one of claims 92-108, wherein the lithium salt is selected from lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, and lithium citrate. 110. The pharmaceutical composition of any one of claims 92-109, wherein the lithium salt is lithium chloride. 111. The pharmaceutical composition of any one of claims 92-110, wherein the laduviglusib (CHIR99021), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM. 112. The pharmaceutical composition of any one of claims 92-111, wherein the RepSox (E- 616452), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM. 113. The pharmaceutical composition of any one of claims 92-112, wherein the ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 10 µg/mL to about 100 µg/mL. 114. The pharmaceutical composition of any one of claims 92-113, wherein the valproic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 400 µM. 115. The pharmaceutical composition of any one of claims 92-114, wherein the tranylcypromine, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 2.5 µM to about 7.5 µM. 116. The pharmaceutical composition of any one of claims 92-115, wherein the forskolin, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 25 µM to about 75 µM.

235/240 12591029. H0824.70430WO00

117. The pharmaceutical composition of any one of claims 92-116, wherein the butyric acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 300 µM. 118. The pharmaceutical composition of any one of claims 92-117, wherein the basic fibroblast growth factor (bFGF), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 50 µg/mL to about 150 µg/mL. 119. The pharmaceutical composition of any one of claims 92-118, wherein the arotinoid acid (TTNPB), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM. 120. The pharmaceutical composition of any one of claims 92-119, wherein the Y-27632, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM. 121. The pharmaceutical composition of any one of claims 92-120, wherein the smoothened agonist (SAG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.25 µM to about 0.75 µM. 122. The pharmaceutical composition of any one of claims 92-121, wherein the linifanib (ABT- 869), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.5 µM to about 1.5 µM. 123. The pharmaceutical composition of any one of claims 92-122, wherein the alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 250 µM to about 750 µM.

236/240 12591029. H0824.70430WO00

124. The pharmaceutical composition of any one of claims 92-123, wherein the ascorbic acid is used at a concentration of about 25 µg/mL to about 75 µg/mL, and the lithium salt is used at a concentration of about 1 mM to about 25 mM. 125. A pharmaceutical composition comprising lithium ascorbate. 126. The pharmaceutical composition of claim 125, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. 127. The pharmaceutical composition of claim 125 or claim 126, wherein the lithium ascorbate is used at a concentration of about 0.1 mM to about 5 mM. 128. The pharmaceutical composition of any one of claims 92-127 for use in rejuvenating a cell, tissue, or organ. 129. The pharmaceutical composition of any one of claims 92-127 for use in restoring cellular function in a cell, tissue, or organ. 130. The pharmaceutical composition of any one of claims 92-127 for use in decreasing a biological age of a cell, tissue, or organ. 131. The pharmaceutical composition of any one of claims 92-127 for use in decreasing an apparent chronological age of a cell, tissue, or organ. 132. The pharmaceutical composition of any one of claims 92-127 for use in reprogramming a cell, tissue, or organ, wherein reprogramming comprises altering the expression of at least one gene associated with aging. 133. A kit comprising: (a) a container housing the pharmaceutical composition of any one of claims 92-94; and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof. 134. A kit comprising: (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of:

237/240 12591029. H0824.70430WO00 laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate); and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof. 135. A kit comprising: (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of:

238/240 12591029. H0824.70430WO00 laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof.

239/240 12591029. H0824.70430WO00