WO2019104065A1 - Méthodes et compositions anti vieillissement - Google Patents

Méthodes et compositions anti vieillissement Download PDF

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Publication number
WO2019104065A1
WO2019104065A1 PCT/US2018/062067 US2018062067W WO2019104065A1 WO 2019104065 A1 WO2019104065 A1 WO 2019104065A1 US 2018062067 W US2018062067 W US 2018062067W WO 2019104065 A1 WO2019104065 A1 WO 2019104065A1
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Prior art keywords
mtor inhibitor
insulin sensitizer
nad
activator
supplement
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PCT/US2018/062067
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English (en)
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Alex Wah Hin Yeung
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Turrinii Pharmaceutical, Llc
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Publication of WO2019104065A1 publication Critical patent/WO2019104065A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to methods, compositions and kits for treating or preventing aging-related diseases or conditions.
  • the present application provides methods, compositions, and kits comprising an insulin sensitizer, an mTOR inhibitor, or an agent having dual functions as an insulin sensitizer and an mTOR inhibitor; a senolytic p53/pRb activator, and an NAD+ supplement for treating or preventing an aging-related disease or condition in an individual.
  • Some embodiments of the methods combine pharmaceutical agents that are already in common clinical use, including FDA approved drugs, to achieve synergistic anti-aging results.
  • the methods described herein can stabilize, suppress, ameliorate or even reverse signs of aging.“Aging” as used herein refers to organismal aging and/or cellular aging, including diseases or symptoms arising from aging.
  • One aspect of the present application provides a method of treating or preventing an aging-related disease or condition in an individual (e.g, human or pet), comprising
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement is administered systemically.
  • the insulin sensitizer, mTOR inhibitor, the senolytic p53/pRb activator and/or the NAD+ supplement is administered via a combination of local and systemic routes.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement is administered locally.
  • the aging- related disease or condition is selected from the group consisting of cancer (e.g., for prevention or as adjuvant therapy), cardiovascular diseases, central nervous system diseases, Alzheimer's disease, Parkinson's disease, age-related macular degeneration, cataract, retinopathy, skeletal muscular diseases, osteoporosis, arthritis, insulin-resistance and type II diabetes, benign prostatic hyperplasia, systemic lupus erythematosus, auto-imnume diseases, psoriasis, and combinations thereof.
  • cancer e.g., for prevention or as adjuvant therapy
  • cardiovascular diseases e.g., central nervous system diseases, Alzheimer's disease, Parkinson's disease, age-related macular degeneration, cataract, retinopathy, skeletal muscular diseases, osteoporosis, arthritis, insulin-resistance and type II diabetes, benign prostatic hyperplasia, systemic lupus erythematosus, auto-imnume diseases, psoriasis, and combinations thereof.
  • the aging-related disease or condition is selected from the group consisting of obesity, non-alcoholic fatty liver disease, non-alcoholic steatotic hepatitis, pre- diabetic, type II diabetes and other fat or inflammatory induced metabolic imbalances (e.g ⁇ ., hypercholesterolemia).
  • the method is for cosmetic treatment.
  • the individual further receives a fat reduction by lipectomy or modification by a lipolysis procedure (such as the surgical procedure of liposuction and/or application of cold, heat, laser, ultrasound, radiofrequency ablation for lipolysis and fat sculpturing, e.g., using machines used such as but not exclusive limited to,
  • the aging-related disease or condition is selected from the group consisting of primary or metastatic cancer lesions (e.g, for prevention or as adjuvant therapy), cardiovascular diseases, central nervous system diseases, Alzheimer's disease,
  • Parkinson's disease age-related macular degeneration, cataract, retinopathy, skeletal muscular diseases, aging skin pigmentation, seborrheic keratosis, actinic keratosis, hair loss, alopecia, photo-aged skin, wrinkles, skin spots, skin cancer (e.g, for prevention or as adjuvant therapy), psoriasis, eczema, pain, inflammation or strain of muscle, tendon or joint, lipolysis (e.g, by cold, heat, laser, ultrasound, or radiofrequency ablation for fat reduction and modification as a cosmetic procedure or a treatment for obesity), post lipectomy and liposuction, non-alcoholic fatty liver disease, non-alcoholic steatotic hepatitis, and combinations thereof.
  • skin cancer e.g, for prevention or as adjuvant therapy
  • psoriasis eczema
  • pain, inflammation or strain of muscle, tendon or joint e.g, by cold, heat, laser, ultrasound, or radiofrequency ablation
  • the insulin sensitizer, the mTGR inhibitor, the senolytic p53/pRb activator, and/or the NL1) ⁇ supplement is administered via an implanted device.
  • the implanted device is selected from the group consisting of an intravesical or other urogenital tract gel, an intra-cranial or intra-thecal device, intra-ocular device, a drug-eluting stent, and CT, MRI or X-ray guided and inserted devices.
  • the aging-related disease or condition is an allergic or auto-immune skin disease, and wherein the method further comprises locally administering an effective amount of a corticosteroid to the individual.
  • the method further comprises administering to the individual an effective amount of vitamin D, vitamin E, vitamin A, resveratrol, pterostilbene, L-carnitine, R-lipoic acid, leptine, a caspase inhibitor, and/or an antioxidant compound (e.g., Chayote (Sechium edii!e) juice or extract).
  • an antioxidant compound e.g., Chayote (Sechium edii!e) juice or extract.
  • Another aspect of the present application provides a method of decelerating, stabilizing, ameliorating, or reversing one or more signs of aging in a mammalian cell, comprising contacting the mammalian cell with: (i) an effective amount of an insulin sensitizer; (ii) an effective amount of an mTOR inhibitor; (iii) an effective amount of a senolytic p53/pRb activator; and (iv) an effective amount of an NAD+ supplement.
  • the method comprises administering an agent having dual functions selected from the group consisting of insulin sensitizer, mTOR inhibitor, senolytic p53/pRb activator, and NAIH supplement.
  • the method comprises administering to the individual: (i) an effective amount of an agent having dual functions as an insulin sensitizer and an mTOR inhibitor; (ii) an effective amount of a senolytic p53/pRb activator; and (iii) an effective amount of an NAD+ supplement.
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor is metformin.
  • the agent is administered systemicaily. In some embodiments, the agent is administered locally.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are nutraceutical agents.
  • the insulin sensitizer comprises a thiazolidinedione and/or a biguanide.
  • the thiazolidinedione is pioglitazone.
  • the biguanide is metformin.
  • the insulin sensitizer is an insulin sensitizing nutraceutical agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapalog, such as everolimus, tacrolimus, CCI-779, ABT-578, AP-23675, AP-23573, AP-23841, 7-epi -rapamycin, 7-thiomethyl -rapamycin, 7-epi -trimethoxyphenyl -rapamycin, 7-epi-thiomethyl-rapamycin, 7- demethoxy-rapamycin, 32-demethox -rapamycin, 2-rapamycin, 7-demethoxy-rapamycin, 32- demethoxy-rapamycin, 2-desmethyl-rapamycin, 42-0-(2-hydroxy)ethyl rapamycin, or any combination thereof.
  • rapamycin or a rapamycin-like nutraceutical agent such as everolimus, tacrolimus, CCI-779, ABT-578, AP-2
  • the effective amount of rapamycin or the rapalog maintains a trough blood level of rapamycin selected from no more than about 8ng/m! for systemic administration, no more than about 2ng/m! for local administration, and no more than about lOng/mi for combined systemic and local administration, or an equivalent trough blood level of the rapalog thereof
  • the mTOR inhibitor comprises a pan-mTQR inhibitor, such as sapanisertib (INK128), AZD2014, torin 1, torin 2, AZD8055, PP242, KU- 006379, 081-027, WAY-600, WAE-687, WYE-354, GSK1059615, or any combination thereof [0017]
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof a COX inhibitor, a CDK4/6 inhibitor, a pan
  • the senolytic p53/pRb activator comprises a nutlin
  • the nutlin is nutlin-3A.
  • the senolytic p53/pRb activator comprises a COX inhibitor
  • the COX inhibitor is selected from the group consisting of aspirin, ibuprofen, naproxen, diclofenac, indomethacin, and combinations thereof
  • the senolytic p53/pRb activator is diclofenac.
  • the senolytic p53/pRb activator comprises a pan CDK inhibitor
  • the pan CDK inhibitor is selected from the group consisting of flavopiridol, o!omoucine II, purvalanol A, SNS-032, dinaciclib, MK-7965, SCH727965, AT7519, R547, AZD5438, and AG024322.
  • the senolytic p53/pRb activator comprises a CDK4/6
  • the CDK4/6 inhibitor is selected from the group consisting of ribocicfib, palbociclib, abemaciclib, and trilaciclib.
  • the senolytic p53/pRb activator comprises any combination of p53 activators, COX inhibitors, pan CDK inhibitors, and CDK4/6 inhibitors.
  • the NAD+ supplement comprises Nicotinic Acid (NA), Nicotinamide Riboside (NR), Nicotinamide Mononucleotide (NMN), and/or Nicotinamide (NAM).
  • the NAD+ supplement comprises: (a) NA and (b) one or more of NR, NMN and NAM.
  • the NAD+ supplement comprises NR and NA.
  • the effective amount of the N AD supplement maintains a blood level of at least about 500mM NAD -
  • the insulin sensitizer, the mTQR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement is formulated in a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
  • the insulin sensitizer and the mTOR inhibitor, or the agent having dual functions as an insulin sensitizer and an mTOR inhibitor; the senolytic p53/pRb activator; and the NAD+ supplement are formulated in a single pharmaceutical composition.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an ni ' TOR inhibitor, the senolytic p53/pRb activator, and the NAD+ supplement are each formulated in a different matrix for immediate or extended release.
  • the pharmaceutically acceptable excipient is a serum, gel, buffer solution, cream, lotion, liniment, ointment or combinations thereof.
  • the insulin sensitizer or the agent having dual functions as an insulin sensitizer and an mTOR inhibitor is in a pharmaceutical composition comprising at least about 0.5% (w/v; e.g., at least about 0.7%) metformin or an insulin sensitizing nutraceutical agent.
  • the insulin sensitizer is in a pharmaceutical composition comprising at least about 0.03% (w/v) pioglitazone.
  • the mTOR inhibitor is in a pharmaceutical composition comprising at least about 0.01% (w/v) rapamycin or a rapamycin-like nutraceutical agent.
  • the senolytic p53/pRb activator is in a pharmaceutical composition comprising at least about 1% (w/v) aspirin. In some embodiments, the senolytic p53/pRb activator is in a pharmaceutical composition comprising at least about 0.5% (w/v) diclofenac. In some embodiments, the senolytic p53/pRb activator is in a pharmaceutical composition comprising at least about 0.3% (w/v) nutlin-3. In some embodiments, the NAD+ supplement is in a pharmaceutical composition comprising: (a) at least about 0.5% (w/v) Nicotinic Acid, and (b) at least about 1% (w/v)
  • Nicotinamide Riboside NR
  • Nicotinamide Mononucleotide MN
  • Nicotinamide NAM
  • the NAD+ supplement is in a pharmaceutical composition comprising at least 0.5 % (w/v) NR.
  • the method comprises administering to the individual an effective amount of a pharmaceutical composition comprising: about 0.5-10% (w/v) metformin, about 0.5-4% (w/v) diclofenac, about 0.5-6% (w/v) nicotinamide riboside, about 0.5-6% (w/v) nicotinic acid, about 0.5-10% (w/v) pterosti!bene, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising: about 0.5-10% (w/v) metformin, about 0.5-4% (w/v) diclofenac, about 0.5-6% (w/v) nicotinamide riboside, about 0.5-6% (w/v) nicotinic acid, about 0.5-10% (w/v) pterosti!bene, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises about 1 -10% (w/v) urea, about 1-10% (w/v) sodium acetate, about 1-30% (w/v) ethanol, about 5-40% (w/v) PEG200, and about 5-40% (w/v) PEG400.
  • the pharmaceutical composition is administered to the individual topically.
  • the pharmaceutical composition comprises about 2% (w/v) diclofenac, about 2% (w/v) metformin, about 3% (w/v) NR and about 1.5% (w/v) pterostilbene.
  • the pharmaceutical composition further comprises about 0 5-6% (w/v) NA, such as about 1.5% (w/v) NA.
  • One aspect of the present application provides a pharmaceutical composition
  • an insulin sensitizer e.g. , metformin or an insulin sensitizing nutraceutical agent
  • an mTOR inhibitor e.g., rapamycin or a rapamycin-like nutraceutical agent, or torin 2
  • a senolytic p53/pRb activator e.g., ibuprofen
  • an NAD+ supplement e.g, NA and NR
  • a pharmaceutical composition comprising: (i) an agent having dual functions as an insulin sensitizer and an mTOR inhibitor (e.g., metformin), (ii) a senolytic p53/pRb activator (e.g., diclofenac); (iii) an NAD+ supplement (e.g., NR); and a pharmaceutically acceptable excipient.
  • an agent having dual functions as an insulin sensitizer and an mTOR inhibitor e.g., metformin
  • a senolytic p53/pRb activator e.g., diclofenac
  • an NAD+ supplement e.g., NR
  • a pharmaceutical composition comprising: about 0.5-10% (w/v) metformin, about 0.5-4% (w/v) diclofenac, about 0.5-6% (w/v) NR, about 0.5-6% (w/v) NA, about 0.5-10% (w/v) pterostilbene, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises about 1-10% (w/v) urea, about 1-10% (w/v) sodium acetate, about 1 -30% (w/v) ethanol, about 5-40% (w/v) PEG200, and about 5-40% (w/v) PEG400.
  • the pharmaceutical composition further comprises about 1-10% (w/v) metformin, about 0.5-4% (w/v) diclofenac, about 0.5-6% (w/v) NR, about 0.5-6% (w/v) NA, about 0.5-10% (w/v) pterostilbene, and a pharmaceutically acceptable excipient.
  • composition is formulated for topical administration.
  • the pharmaceutical composition comprises about 2% (w/v) diclofenac, about 2% (w/v) metformin, about 3% (w/v)
  • the pharmaceutical composition further comprises about 0.5-6% (w/v) NA, such as about 1.5% (w/v) NA.
  • kits for treating or preventing an aging-related disease or condition comprising: (i) an insulin sensitizer (e.g., metformin or an insulin sensitizing nutraceutical agent); (ii) an mTOR inhibitor (e.g, rapamycin or a rapamycin-like nutraceutical agent, or torin 2); (iii) a senolytic p53/pRb activator (e.g, ibuprofen); and (iv) an NAD+ supplement (e.g., NA and NR).
  • an insulin sensitizer e.g., metformin or an insulin sensitizing nutraceutical agent
  • an mTOR inhibitor e.g, rapamycin or a rapamycin-like nutraceutical agent, or torin 2
  • a senolytic p53/pRb activator e.g, ibuprofen
  • an NAD+ supplement e.g., NA and NR
  • kits comprising (i) an agent having dual functions as an insulin sensitizer and an mTOR inhibitor (e.g., metformin), (ii) a senolytic p53/pRb activator (e.g, diclofenac), and (iii) an NAD+ supplement (e.g, NR).
  • an agent having dual functions as an insulin sensitizer and an mTOR inhibitor e.g., metformin
  • a senolytic p53/pRb activator e.g, diclofenac
  • an NAD+ supplement e.g, NR
  • an implantable device for treating or preventing an aging-related disease or condition, comprising: (i) an insulin sensitizer (e.g., metformin or an insulin sensitizing nutraceutical agent): (ii) an mTOR inhibitor (e.g., rapamycin or a rapamycin-like nutraceutical agent, or torin 2); (iii) a senolytic p53/pRb activator (e.g, ibuprofen); and (iv) an NAD+ supplement (e.g, NA and NR).
  • an insulin sensitizer e.g., metformin or an insulin sensitizing nutraceutical agent
  • an mTOR inhibitor e.g., rapamycin or a rapamycin-like nutraceutical agent, or torin 2
  • a senolytic p53/pRb activator e.g, ibuprofen
  • an NAD+ supplement e.g, NA and NR
  • an implantable device comprising: (i) an agent having dual functions as an insulin sensitizer and an mTOR inhibitor (e.g, metformin), (ii) a senolytic p53/pRb activator (e.g, diclofenac), and (iii) an NAD+ supplement (e.g, NR).
  • an agent having dual functions as an insulin sensitizer and an mTOR inhibitor e.g, metformin
  • a senolytic p53/pRb activator e.g, diclofenac
  • an NAD+ supplement e.g, NR
  • FIG. 1 shows results of Patient 1 on the systemic Trial A.
  • FIG. 2 shows results of Patient 2 on the systemic Trial A.
  • FIG. 3 shows results of Patient 1 on the local Trial C.
  • the present invention provides methods, compositions and kits for treating or preventing an aging-related disease or condition in an individual, comprising a combination regimen, including an insulin sensitizer and an mTQR inhibitor, or an agent having dual functions as an insulin sensitizer and an mTQR inhibitor; a seno!ylic p53/pRb activator; and an NAD+ supplement.
  • a combination regimen including an insulin sensitizer and an mTQR inhibitor, or an agent having dual functions as an insulin sensitizer and an mTQR inhibitor; a seno!ylic p53/pRb activator; and an NAD+ supplement.
  • any one or more, or all of the four components can comprise of, or being represented by nutraceutical agents with the same component properties.
  • the insulin sensitizer can maintain or revive insulin sensitivity, which can lead to a metabolic shift critical to basic cellular survival, functions and preservation.
  • the mTQR inhibitor is designed to target one of the most pivotal axes for aging: mTQR is activated by default throughout one’s lifespan, while its activity is accentuated during active growth and feeding.
  • the senolytic p53 inhibitor and the NAD+ supplement can promote DMA repair as well as improve the senescent and inflammatory environment from chronic
  • TQR activation During aging, the senescent and inflammatory environment may be established in the body systemically, or localized in a specific tissue or organ, which may cause age-related diseases or conditions.
  • the combination regimen described herein is applicable for both systemic and/or local treatment.
  • the present invention can be practiced using some of the clinically available pharmaceuticals currently on the market.
  • one aspect of the present application provides a method of treating or preventing an aging-related disease or condition in an individual, comprising administering to the individual : (i) an effective amount of an insulin sensitizer; (ii) an effective amount of an mTGR inhibitor; (iii) an effective amount of a senolytic p53/pRb activator; and (iv) an effective amount of an NAD+ supplement.
  • the present application provides a method of treating or preventing an aging-related disease or condition in an individual, comprising administering to the individual : (i) an effective amount of an agent having dual functions as an insulin sensitizer and an mTOR inhibitor (e.g., metformin); (ii) an effective amount of a senolytic p53/pRb activator (e.g., diclofenac), and (iii) an effective amount of an NAD+ supplement (e.g, NR).
  • an agent having dual functions as an insulin sensitizer and an mTOR inhibitor e.g., metformin
  • an effective amount of a senolytic p53/pRb activator e.g., diclofenac
  • an NAD+ supplement e.g, NR
  • compositions, kits and articles manufacture useful for the methods described herein.
  • the term“combination regimen” is used herein to refer to anti-aging therapies described herein comprising: an insulin sensitizer, an mTOR inhibitor, a senolytic p53/pRb activator, and a NAD+ supplement.
  • Each of components in this combination regimen may comprise a single agent, or two or more agents. Any two of the components in this combination regimen can comprise of, or being represented by, only one agent with dual component properties, thereby reducing the 4-component formulation into a 3-component formulation. Any one or more, or all of the components in this combination regimen can comprise of, or being represented by nutraceutical agents with the same component properties
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from an aging-related disease or condition, diminishing the extent of the aging-related disease or condition, stabilizing the aging-related disease or condition (e.g, preventing or delaying the aging-related disease or condition), preventing or delaying the spread of the aging-related disease or condition, preventing or delaying the recurrence of the aging- related disease or condition, reducing recurrence rate of the aging-related disease or condition, delay or slowing the progression of the aging-related disease or condition, ameliorating the aging-related disease or condition, providing a remission (partial or total) of the aging-related disease or condition, decreasing the dose of one or more other medications required to treat the aging-related disease or condition, delaying the progression of the aging-related disease
  • the treatment reduces the severity of one or more symptoms associated with aging-related disease or condition by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding symptom in the same subject prior to treatment or compared to the corresponding symptom in other subjects not receiving the treatment.
  • treatment is a reduction of pathological consequence of an aging-related disease or condition. The methods of the invention contemplate any one or more of these aspects of treatment.
  • “delaying” the development of an aging-related disease or condition means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a method that“delays” development of an aging-related disease or condition is a method that reduces probability of disease development in a given time frame and/or reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
  • Preventing includes providing prophylaxis with respect to the occurrence or recurrence of an aging-related disease or condition in a subject that may be predisposed to the disease or condition but has not yet been diagnosed with the disease or condition.
  • an“effective amount” of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result, such as ameliorate, palliate, lessen, and/or delay one or more of its symptoms.
  • the effective amount of an agent depends on the route of administration (e.g., systemic and/or local administration) of the agent.
  • an effective agent is chosen by monitoring the trough level, AUC level and/or a pharmacokinetically defined level, e.g., serum or urine level, of the agent and/or its metabolites.
  • A“therapeutically effective amount” of an agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the agent are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount may be delivered in one or more administrations.
  • A“prophyiacticaliy effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophyiacticaliy effective amount will be less than the therapeutically effective amount.
  • an“effective amount” may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents.
  • any component of the combination regimen described herein may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • the components in a combination regimen of the invention may be administered sequentially, simultaneously, or continuously using the same or different routes of administration and the same or different schedule for each component.
  • an effective amount of a combination regimen includes an amount of the insulin sensitizer, an amount of the mTOR inhibitor, or an amount of the agent having dual functions as an insulin sensitizer and an mTOR inhibitor: an amount of the senolytic p53/pRb activator, and an amount of the NAD supplement when administered sequentially, simultaneously, or continuously produces a desired outcome.
  • Administration“in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive or sequential administration in any order.
  • the two or more therapeutic agents are administered with a time separation of no more than about 60 minutes, such as no more than about any of 30, 15, 10, 5, or 1 minute.
  • the term“sequentially” is used herein to refer to administration of two or more therapeutic agents where the administration of one or more agent(s) continues after discontinuing the administration of one or more other agent(s).
  • administration of the two or more therapeutic agents are administered with a time separation of more than about 15 minutes, such as about any of 20, 30, 40, 50, or 60 minutes, 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month, or longer.
  • the term“individual,”“subject,” and“patient” are used interchangeably herein to describe a mammal, including humans.
  • An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate.
  • the individual is human.
  • the individual is in need of treatment.
  • the individual is a sport animal, or a pet animal.
  • composition refers to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • Such formulations may be sterile.
  • A“pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a“pharmaceutical composition” for administration to a subject.
  • a pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
  • the pharmaceutically acceptable carrier is appropriate for the formulation employed.
  • Reference to "about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X” includes description of "X”.
  • the present application provides an anti-aging combination therapy comprising: an insulin sensitizer, an mTOR inhibitor, a senolytic p53/pRb activator, and a NAD+ supplement.
  • an agent having dual functions is used.
  • an agent having dual functions is used. For example, in some embodiments, in some
  • the anti-aging combination therapy comprises an agent having dual functions as an insulin sensitizer and an mTOR inhibitor, a senolytic p53/pRb activator, and an NAD+ supplement.
  • Methods, compositions, and kits of the combination therapy are provided.
  • the combination therapy is also referred herein as“combination regimen.”
  • a method of treating or preventing an aging- related disease or condition in an individual comprising administering to the individual: (a) an effective amount of an insulin sensitizer, (b) an effective amount of an mTOR inhibitor, (c) an effective amount of a senolytic p53/pRb activator, and (d) an effective amount of a NAD+ supplement.
  • the insulin sensitizer comprises a TDZ ⁇ e.g., piog!itazone) and/or a biguanide ⁇ e.g., metformin).
  • the insulin sensitizer is an insulin sensitizing nutraceutical agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapalog ⁇ e.g., everolimus).
  • the mTOR inhibitor comprises a pan-mTQR inhibitor ⁇ e.g., form 2).
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g, ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and/or nicotinamide (NAM).
  • NA nicotinic acid
  • NR nicotinamide riboside
  • NNMN nicotinamide mononucleotide
  • NAM nicotinamide
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the aging-related disease or condition is selected from the group consisting of cancer (e.g., for prevention or as adjuvant therapy), cardiovascular diseases, central nervous system diseases, Alzheimer's disease, Parkinson's disease, age-related macular degeneration, cataract, retinopathy, skeletal muscular diseases, osteoporosis, arthritis, insulin-resistance and type II diabetes, benign prostatic hyperplasia, systemic lupus erythematosus, auto-immune diseases, psoriasis, aging skin pigmentation, seborrheic keratosis, actinic keratosis, hair loss, alopecia, photo-aged skin, wrinkles, skin spots, skin cancer (e.g, for prevention or as adjuvant therapy), eczema, pain, inflammation or strain of muscle, tendon or joint, lipolysis (e.g., by cold, heat, laser, ultrasound, or radiofrequency ablation for fat reduction and modification as a cosmetic procedure or a treatment for obesity), post
  • the insulin sensitizer, the mTOR inhibitor, the senolytie p53/pRb activator and/or the NAD+ supplement are administered systemically. In some embodiments, the insulin sensitizer, the mTOR inhibitor, the senolytie p53/pRb activator and/or the NAD+ supplement are administered locally .
  • a method of treating or preventing an aging- related disease or condition in an individual comprising administering to the individual: (a) an effective amount of an agent having dual functions as an insulin sensitizer and an mTOR inhibitor; (b) an effective amount of a senolytie p53/pRb activator; and (c) an effective amount of a NAD+ supplement.
  • the agent having dual functions as an insulin-sensitizer and an mTOR inhibitor is metformin.
  • the senolytie p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., diclofenac), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and/or nicotinamide (NAM).
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytie p53/pRb activator and/or the NAD+ supplement are nutraceutical agents.
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytie p53/pKb activator and the NAD+ supplement are formulated in a single
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytie p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the aging-related disease or condition is selected from the group consisting of cancer (e.g, for prevention or as adjuvant therapy), cardiovascular diseases, central nervous system diseases, Alzheimer's disease, Parkinson's disease, age-related macular degeneration, cataract, retinopathy, skeletal muscular diseases, osteoporosis, arthritis, insulin-resistance and type II diabetes, benign prostatic hyperplasia, systemic lupus erythematosus, auto-immune diseases, psoriasis, aging skin pigmentation, seborrheic keratosis, actinic keratosis, hair loss, alopecia, photo-aged skin, wrinkles, skin spots, skin cancer (e.g, for prevention or as adjuvant therapy), eczema, pain, inflammation or strain of muscle, tendon or joint, lipolysis (e.g., by cold, heat, laser, ultrasound, or radiofrequency ablation for fat reduction and modification as a cosmetic procedure or a treatment for obesity), post lipolysis (e
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator and/or the NAD+ supplement are administered systemically. In some embodiments, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator and/or the NAD+ supplement are administered locally.
  • a method of treating or preventing an aging- related disease or condition in an individual comprising locally administering to the individual: (a) an effective amount of an insulin sensitizer, (b) an effective amount of an mTOR inhibitor, (c) an effective amount of a senolytic p53/pRb activator, and (d) an effective amount of a NAD+ supplement.
  • the insulin sensitizer comprises a TDZ (e.g., pioglitazone) and/or a biguanide (e.g., metformin).
  • the insulin sensitizer is an insulin sensitizing nulraceutica! agent.
  • the mTOR inhibitor comprises rapamyein or a rapamycin-like nutraceutical agent, and/or a rapalog (e.g., everolimus).
  • the mTOR inhibitor comprises a pan-mTOR inhibitor (e.g., torin 1, torin 2, PP242 or INK! 28).
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • the insulin sensitizer, the mTOR inhibitor, the senolvtic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the aging-related disease or condition is selected from the group consisting of primary ' or metastatic cancer lesions (e.g., for prevention or as adjuvant therapy), cardiovascular diseases, central nervous system diseases, Alzheimer's disease,
  • Parkinson's disease age-related macular degeneration, cataract, retinopathy, skeletal muscular diseases, aging skin pigmentation, seborrheic keratosis, actinic keratosis, hair loss, alopecia, photo-aged skin, wrinkles, skin spots, skin cancer (e.g., for prevention or as adjuvant therapy), psoriasis, eczema, pain, inflammation or strain of muscle, tendon or joint, obesity, cosmetic lipolysis, post lipectomy and liposuction, non-alcoholic fatty liver disease, non-alcoholic steatosis hepatitis, arthritis (such as osteoarthritis and rheumatoid arthritis), auto-immune diseases, and combinations thereof.
  • skin cancer e.g., for prevention or as adjuvant therapy
  • psoriasis eczema
  • pain, inflammation or strain of muscle, tendon or joint e.g., obesity, cosmetic lipolysis, post lipectomy and liposu
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pKb activator, and/or the NAD+ supplement is administered via an implanted device.
  • the implanted device is selected from the group consisting of an intravesical or other urogenital tract gel, an intra-cranial or intra-thecal device, intra-ocular device, a drug-eluting stent, and CT, MRI or X-ray guided and inserted devices.
  • a method of treating or preventing an aging- related disease or condition in an individual comprising administering to the individual: (a) an effective amount of metformin or an insulin sensitizing nutraceutical agent; (b) an effective amount of ibuprofen or a rapamycin-iike nutraceutical agent; (c) an effective amount of rapamycin; and (d) an effective amount of niacin and an effective amount of nicotinamide riboside.
  • the metformin or an insulin sensitizing nutraceutical agent, ibuprofen, rapamycin or a rapamycin-like nutraceutical agent, NA and NR are administered orally.
  • the metformin is administered once, twice or three times daily after rneal(s). In some embodiments, metformin is administered at about 250 mg/dose to about 1000 mg/dose (e.g., about 250 mg/dose, about 500 mg/dose, about 750 mg/dose, or about 1000 mg/dose). In some embodiments, the ibuprofen is administered twice daily for two days per week, or twice daily for 4 weeks out of 6 weeks. In some embodiments, ibuprofen is
  • rapamycin or a rapamycin-like nutraceutical agent is administered weekly or bi-weekly, 6 weeks out of every seven or eight weeks.
  • rapamycin is administered at about 1 g to 10 mg weekly (e.g., about any one of 1 mg, 2mg, 3 mg, 4 mg, 5 mg, 5mg or 10 mg weekly).
  • NA is administered twice daily.
  • NA is administered at about 125 mg/dose to about 2000 mg/dose (e.g, about 125 mg/dose, about 250 mg/dose, or about 2000 mg/dose).
  • NR is administered once twice or four times daily.
  • NR is administered at about 125 mg/dose to about 1000 mg/dose (e.g., about 250 mg/dose, about 500 mg/dose, or about 1000 mg/dose).
  • a method of treating or preventing an aging- related disease or condition in an individual comprising administering to the individual: (a) an effective amount of metformin or an insulin sensitizing nutraceutical agent; (b) an effective amount of ibuprofen; (c) an effective amount of rapamycin or a rapamycin-!ike nutraceutieal agent and/or (d) an effective amount of a pan-mTOR inhibitor; and (e) an effective amount of niacin and an effective amount of nicotinamide riboside.
  • the pan-mTOR inhibitor comprises an agent having a low molecular weight (e.g., no more than about 500 Dalton).
  • the metformin, ibuprofen, rapamycin, NA and NR are examples of the metformin, ibuprofen, rapamycin, NA and NR.
  • metformin or an insulin sensitizing nutraceutieal agent is administered once, twice or three times daily after meal(s).
  • metformin is administered at about 250 mg/dose to about 1000 mg/dose (e.g., about 250 mg/dose, about 500 mg/dose, about 750 mg/dose, or about 1000 mg/dose) hi some
  • the ibuprofen is administered twice daily for two days per week, or twice daily for 4 weeks out of 6 weeks.
  • ibuprofen is administered at about 400 mg/dose to about 600 mg/dose (e.g., about 400 mg/dose or about 600 mg/dose).
  • rapamycin or a rapamycin-like nutraceutieal agent is administered weekly, bi-weekly, once every' three weeks, weekly for 6 weeks out of 7 weeks, or weekly 6 weeks out of 8 weeks.
  • rapamycin is administered at about 1 mg to 10 mg weekly (e.g, about any one of 1 mg, 2mg, 3mg, 4 mg, 5 mg, 5mg or 10 mg weekly).
  • NA is administered twice daily. In some embodiments, NA is administered twice daily. In some embodiments, NA is administered at about 125 mg/dose to about 2000 mg/dose (e.g ⁇ ., about 125 mg/dose, about 250 mg/dose, or about 2000 mg/dose). In some embodiments, NR is
  • NR is administered at about 125 mg/dose to about 1000 mg/dose (e.g ⁇ ., about 250 mg/dose, about 500 mg/dose, or about 1000 mg/dose).
  • the pan-mTOR inhibitor is administered topically.
  • the pan-mTOR inhibitor is torin 1 , torin 2, PP242, or INK 128
  • the aging related disease or condition is a skin disease or condition selected from the group consisting of seborrheic keratosis, actinic keratosis, hair loss and alopecia, photo-aged skin, wrinkles, skin spots, skin cancer (e.g., for prevention or as adjuvant therapy), skeletal muscular diseases, aging skin pigmentation, psoriasis, eczema, pain, inflammation or strain of muscle, tendon or joint, lipolysis (e.g., by cold, heat, laser, ultrasound, or radiofrequency ablation for fat reduction and modification as a cosmetic procedure or a treatment for obesity), post iipectomy and liposuction, non-alcoholic fatty liver disease, non-alcoholic steatotic hepatitis, arthritis (such as osteoarthritis and rheumatoid arthritis), auto-immune diseases and
  • a method of treating a local disease or condition in an individual comprising locally administering to the individual (a) an effective amount of an insulin sensitizer, (b) an effective amount of an mTOR inhibitor, (c) an effective amount of a senolytic p53/pRb activator, and (d) an effective amount of a NAD+ supplement.
  • the insulin sensitizer comprises a TDZ (e.g., pioglitazone) and/or a biguanide (e.g., metformin).
  • the insulin sensitizer is an insulin sensitizing nutraceutical agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapalog (e.g., evero!imus).
  • the mTOR inhibitor comprises a pan-mTQR inhibitor (e.g., torin 1, torin 2, PP242 or INK128).
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition. In some embodiments, the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions. In some embodiments, the local administration is topical administration.
  • the local disease or condition is a skin disease or condition selected from seborrheic keratosis, actinic keratosis, hair loss and alopecia, photo-aged skin, wrinkles, skin spots, skin cancer (e.g., for prevention or as adjuvant therapy), obesity, cosmetic lipolysis, post lipectomy and liposuction, non-alcoholic fatty liver disease, non-alcoholic steatosis hepatitis, and combinations thereof.
  • the skin disease or condition is an allergic or auto-immune skin disease, such as eczema or psoriasis.
  • the local disease or condition is a disease of the muscular skeletal system, including but not limited to ail forms of arthritis such as
  • the method further comprises locally administering an effective amount of a corticosteroid.
  • the method further comprises locally administering an anti-oxidant, such as Chayote (Sechium edule) juice and/or extract.
  • the local administration is a guided intra-lesion or intra- regional visceral treatment.
  • the local disease or condition is a visceral disease or condition such as primary or metastatic cancer lesions (e.g., for prevention or as adjuvant therapy), post cancer resection area as an adjuvant for the prevention of future relapse, cardiovascular diseases, central nervous system diseases, Alzheimer’s disease, Parkinson's disease, age-related macular degeneration, cataract, or retinopathy.
  • a visceral disease or condition such as primary or metastatic cancer lesions (e.g., for prevention or as adjuvant therapy), post cancer resection area as an adjuvant for the prevention of future relapse, cardiovascular diseases, central nervous system diseases, Alzheimer’s disease, Parkinson's disease, age-related macular degeneration, cataract, or retinopathy.
  • a method of treating or preventing an aging- related disease or condition in an individual comprising administering to the individual: (a) an effective amount of metformin; (b) an effective amount of diclofenac; and (c) an effective amount of NR.
  • metformin, diclofenac and NR are formulated in a single pharmaceutical composition.
  • metformin, diclofenac and NR are formulated in two or more pharmaceutical compositions.
  • the aging-related disease or condition is selected from the group consisting of cancer (e.g., for prevention or as adjuvant therapy), cardiovascular diseases, central nervous system diseases, Alzheimer's disease, Parkinson's disease, age-related macular degeneration, cataract, retinopathy, skeletal muscular diseases, osteoporosis, arthritis, insulin-resistance and type II diabetes, benign prostatic hyperplasia, systemic lupus erythematosus, auto-immune diseases, psoriasis, aging skin pigmentation, seborrheic keratosis, actinic keratosis, hair loss, alopecia, photo-aged skin, wrinkles, skin spots, skin cancer (e.g., for prevention or as adjuvant therapy), eczema, pain, inflammation or strain of muscle, tendon or joint, lipolysis (e.g., by cold, heat, laser, ultrasound, or radiofrequency ablation for fat reduction and modification as a cosmetic procedure or a treatment for obesity),
  • cancer
  • metformin, diclofenac and NR are administered systemieally. In some embodiments, metformin, diclofenac and NR are administered locally. In some embodiments, the method further comprises administering to the individual an effective amount of vitamin D, vitamin E, vitamin A, resveratrol, pterostilbene, 1,- carnitine, R-lipoic acid, ieptine, a caspase inhibitor, and/or Chayote (Sechinm edule) juice or extract.
  • the method comprises administering to the individual a pharmaceutical composition comprising about 0.5-10% (w/v) metformin, about 0.5-4% (w/v) diclofenac, about 0.5-6% (w/v) NR, about 0.5-6% (w/v) NA, and about 0.5-10% (w/v) pterostilbene.
  • the pharmaceutical composition further comprises about 1- 10% (w/v) urea, about 1-10% (w/v) sodium acetate, about 1-30% (w/v) ethanol, about 5-40% (w/v) PEG200, and about 5-40% (w/v) PEG400.
  • the pharmaceutical composition is administered to the individual topically.
  • the pharmaceutical composition comprises about 2% (w/v) diclofenac, about 2% (w/v) metformin, about 3% (w/v) NR, about 1.5% (w/v) NA, and about 1.5% (w/v) pterostilbene.
  • a method of providing cosmetic treatment of skin in an individual comprising topically administering to the skin of the individual: (a) an effective amount of an insulin sensitizer, (b) an effective amount of an mTQR inhibitor, (c) an effective amount of a senolytic p53/pRb activator, and (d) an effective amount of a NAD+ supplement.
  • the insulin sensitizer comprises a TDZ (e.g, piogiitazone) and/or a higuanide (e.g., metformin).
  • the insulin sensitizer is an insulin sensitizing nutraceutical agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapa!og (e.g., everolimus).
  • the mTOR inhibitor comprises a pan-mTOR inhibitor (e.g., torin 1, torin 2, PP242 or INK 128).
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g, ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the method is used for treating aging skin pigmentation and/or wrinkles.
  • the method further comprises locally administering an anti-oxidant, such as Chayote (Sechium edule) juice and/or extract.
  • a method of providing cosmetic treatment of skin in an individual comprising topically administering to the skin of the individual: (a) an effective amount of an agent having dual functions as an insulin sensitizer and an mTOR inhibitor; (b) an effective amount of a senolytic p53/pRb activator; and (c) an effective amount of a NAD+ supplement.
  • a method of providing cosmetic treatment of skin in an individual comprising topically administering to the skin of the individual: (a) an effective amount of metformin; (b) an effective amount of diclofenac; and (c) an effective amount of NR.
  • metformin, diclofenac and NR are formulated in a single pharmaceutical composition.
  • the method further comprises administering to the individual an effective amount of vitamin D, vitamin E, vitamin A, resveratrol, pterostilbene, L-camitine, R-lipoic acid, leptine, a caspase inhibitor, and/or Chayote ( Sechium edule) juice or extract.
  • the method comprises administering to the individual a pharmaceutical composition comprising about 0.5-10% (w/v) metformin, about 0.5-4% (w/v) diclofenac, about 0.5-6% (w/v) NR, about 0.5-6% (w/v) NA, and about 0.5-10% (w/v) pterostilbene.
  • the pharmaceutical composition further comprises about 1-10% (w/v) urea, about 1-10% (w/v) sodium acetate, about 1-30% (w/v) ethanol, about 5- 40% (w/v) PEG200, and about 5-40% (w/v) PEG400.
  • the pharmaceutical composition comprises about 2% (w/v) diclofenac, about 2% (w/v) metformin, about 3% (w/v) NR, about 1.5% (w/v) NA, and about 1.5% (w/v) pterostilbene.
  • a method of preventing, inhibiting, or reversing one or more signs of aging in a cell comprises contacting the cel! with (a) an effective amount of an insulin sensitizer, (b) an effective amount of an mTOR inhibitor, (c) an effective amount of a senolytic p53/pRb activator, and (d) an effective amount of a N AD+ supplement.
  • the insulin sensitizer comprises a TDZ (e.g., pioglitazone) and/or a biguanide (e.g., metformin).
  • the insulin sensitizer is an insulin sensitizing nutraceutical agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapalog (e.g., everolimus).
  • the mTOR inhibitor comprises a pan-mTOR inhibitor (e.g., torin 2).
  • the senolytic p53/pRb activator is selected from a nutiin or analog thereof, a COX inhibitor (e.g., ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • a method of preventing, inhibiting, or reversing one or more signs of aging in a cel! comprises contacting the cel! with: (a) an effective amount of an agent having dual functions as an insulin sensitizer and an mTOR inhibitor; (b) an effective amount of a senolytic p53/pRb activator; and (c) an effective amount of a NAD+ supplement.
  • the agent having dual functions as an insulin- sensitizer and an mTOR inhibitor is metformin.
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., diclofenac), a
  • the NAD- ⁇ - supplement comprises nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and/or nicotinamide (NAM).
  • NA nicotinic acid
  • NR nicotinamide riboside
  • NNMN nicotinamide mononucleotide
  • NAM nicotinamide
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator and/or the NAD+ supplement are nutraceutical agents.
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition.
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD supplement are formulated in two or more pharmaceutical compositions.
  • the method further comprises contacting the cell with an effective amount of vitamin D, vitamin E, vitamin A, resveratroi, pterostilbene, L-carnitine, R-lipoic acid, leptine, a caspase inhibitor, and/or Chayote ( Sechium edule) juice or extract.
  • a method of stabilizing, decelerating and/or ameliorating one or more signs of aging in a plurality of mammalian cells by contacting the plurality of mammalian cells with (a) an effective amount of an insulin sensitizer, (b) an effective amount of an mTOR inhibitor, (c) an effective amount of a senolytic p53/pRb activator, and (d) an effective amount of a NAD+ supplement.
  • the insulin sensitizer comprises a TDZ (e.g, pioglitazone) and/or a biguanide (e.g, metformin) hi some embodiments, the insulin sensitizer is an insulin sensitizing nutraceutical agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapalog (e.g., everolimus).
  • the mTOR inhibitor comprises a pan-mTOR inhibitor (e.g, torin 2).
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g ⁇ ., ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition. In some embodiments, the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions. In some embodiments, the plurality of mammalian cells is present in a human. In some embodiments, the human has not previously been administered with the composition.
  • the human has previously been administered one, two or three regimen selected from the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and the NAD- ⁇ - supplement in some embodiments, the plurality of mammalian cells becomes free of quiescent or senescent phenotypes after the contacting.
  • the plurality of mammalian cells prior to the contacting, is quiescent.
  • the plurality of mammalian cells is senescent.
  • the plurality of mammalian cells comprises both quiescent and senescent cells.
  • a method of stabilizing, decelerating and/or ameliorating one or more signs of aging in a plurality of mammalian cells by contacting the plurality of mammalian cells with: (a) an effective amount of an agent having dual functions as an insulin sensitizer and an mTOR inhibitor; (b) an effective amount of a senolytic p53/pRb activator; and (c) an effective amount of a NAD+ supplement.
  • the agent having dual functions as an insulin-sensitizer and an mTOR inhibitor is metformin.
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g, diclofenac), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and/or nicotinamide (NAM).
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator and/or the NAD+ supplement are nutraceutical agents.
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the plurality of mammalian cells is present in a human.
  • the human has not previously been administered with the composition.
  • the human has previously been administered one, two or three regimen selected from the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement.
  • the method further comprises contacting the plurality of mammalian cells with an effective amount of vitamin D, vitamin E, vitamin A, resveratrol, pterostilbene, L-carnitine, R ⁇ lipoic acid, leptine, a caspase inhibitor, and/or Chayote ( Sec ium edule) juice or extract.
  • the plurality of mammalian cells becomes tree of quiescent or senescent phenotypes after the contacting.
  • the plurality of mammalian cells prior to the contacting, is quiescent.
  • the plurality of mammalian cells is senescent.
  • the plurality of mammalian cells comprises both quiescent and senescent cells.
  • Signs of aging in cells include, but are not limited to, shortening of telomeres, cell cycle arrest, senescence, mitochondrial dysfunction, deregulated cellular signaling (e.g., rnTOR, p53 and insulin signaling), change in metabolic state (e.g, to RIG state, i.e., Reproduction, Immune-aetivati on/Inflammation and Growth), altered level of protein synthesis, accumulation of DNA damage, and genome instability.
  • Signs of cellular aging can be assessed using known methods in the art, including, but not limited to, ELISA, Western blot, RT-PCR, microscopy, in situ hybridization, DNA sequencing, etc. Such methods can be used to measure, for example, telomere length, expression levels of cytokines ⁇ e.g, 1L6, IL17), cell aging hypertrophy, protein and fat accumulation, etc.
  • a method of converting a mammalian cell from senescent state to quiescent state or normal state comprising contacting the mammalian cell with (a) an effective amount of an insulin sensitizer, (b) an effective amount of an rnTOR inhibitor, (c) an effective amount of a senolytic p53/pRb activator, and (cl) an effective amount of a NAD+ supplement.
  • the insulin sensitizer comprises a TDZ (e.g ⁇ ., piogiitazone) and/or a biguanide ⁇ e.g, metformin).
  • the insulin sensitizer is an insulin sensitizing nutraceuticai agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceuticai agent, and/or a rapalog ⁇ e.g., everolimus).
  • the mTOR inhibitor comprises a pan-mTOR inhibitor ⁇ e.g, torin 2).
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g ⁇ ., ihuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition. In some embodiments, the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • a method of converting a mammalian cell from senescent state to quiescent state or normal state comprising contacting the mammalian ceil with (a) an effective amount of an agent having dual functions as an insulin sensitizer and an rnTOR inhibitor; (b) an effective amount of a senolytic p53/pRb activator; and (c) an effective amount of a NAD+ supplement.
  • the agent having dual functions as an insulin-sensitizer and an niTOR inhibitor is metformin in some embodiments, the senoiytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., diclofenac), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and/or nicotinamide (NAM).
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senoiytic p53/pRb activator and/or the NAD+ supplement are nutraceutical agents.
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senoiytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition.
  • the agent having dual functions as an insulin sensitizer and an mTO inhibitor, the senoiytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the method further comprises contacting the cell with an effective amount of vitamin D, vitamin E, vitamin A, resveratrol, pterostilbene, L-carnitine, R-lipoic acid, lepline, a caspase inhibitor, and/or Chayote ( Sechium edule) juice or extract.
  • the method is applicable for prophylactic and/or therapeutic treatment of symptoms and functional abnormalities of aging ceils having the senescence associated secretory phenotype (SASP).
  • SASP cells contributes to aging-related diseases such as Alzheimer’s disease, cardiovascular system atherosclerosis which can lead to stroke, heart attack and heart failure, prostate enlargement, cardiac hypertrophy, arterial wall thickening, osteoarthritis, age-related macular degeneration, etc.
  • SASP cells also secrete IL6
  • the combination regimen described herein can decrease the number of SASP ceils, and convert them to a quiescence or normal phenotype, as well as reducing the IL6 level in an individual.
  • a method of inhibiting or reducing SASP cells in an individual in need thereof comprising administering to the individual: (a) an effective amount of an insulin sensitizer, (b) an effective amount of an mTOR inhibitor, (c) an effective amount of a senoiytic p53/pRb activator, and (d) an effective amount of a NAD+ supplement.
  • the insulin sensitizer comprises a TDZ (e.g., pioglitazone) and/or a biguanide (e.g., metformin).
  • the insulin sensitizer is an insulin sensitizing nutraceutical agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapalog (e.g., everolimus).
  • the mTOR inhibitor comprises a pan -mTOR inhibitor (e.g., torin 2).
  • the seno!ytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g, ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and the NAD-- supplement are formulated in a single phar aceutical composition.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and/or the NAIH supplement are administered systemically.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and/or the NAD+ supplement are administered locally.
  • a method of inhibiting or reducing SASP cells in an individual in need thereof comprising administering to the individual: (a) an effective amount of an agent having dual functions as an insulin sensitizer and an mTOR inhibitor; (b) an effective amount of a senolytic p53/pRb activator; and (c) an effective amount of a NAD supplement.
  • the agent having dual functions as an insulin-sensitizer and an mTOR inhibitor is metformin.
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g , diclofenac), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and/or nicotinamide (NAM).
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator and/or the NAD+ supplement are nutraceutical agents.
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition. In some embodiments, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the method further comprises administering to the individual an effective amount of vitamin D, vitamin E, vitamin A, resveratroi, pterostilbene, L- camitine, R-lipoic acid, leptine, a caspase inhibitor, and/or Chayote (Sechium edule) juice or extract.
  • a method of reducing IL-6 level in an individual in need thereof comprising administering to the individual: (a) an effective amount of an insulin sensitizer, (b) an effective amount of an mTOR inhibitor, (c) an effective amount of a senolytic p53/pKb activator, and (d) an effective amount of a NAD+ supplement.
  • the insulin sensitizer comprises a TDZ (e.g., pioglitazone) and/or a biguanide (e.g., metformin).
  • the insulin sensitizer is an insulin sensitizing nutraceutical agent.
  • the rnTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapalog (e.g., everolimus).
  • the mTOR inhibitor comprises a pan-mTGR inhibitor (e.g., torin 2).
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g, ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and the NAD supplement are formulated in a single pharmaceutical composition.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and/or the NAD+ supplement are administered systemically.
  • the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pRb activator and/or the NAD supplement are administered locally.
  • a method of reducing IL-6 level in an individual in need thereof comprising administering to the individual : (a) an effective amount of an agent having dual functions as an insulin sensitizer and an mTOR inhibitor; (b) an effective amount of a senolytic p53/pRb activator, and (c) an effective amount of a NAD ⁇ supplement.
  • the agent having dual functions as an insulin-sensitizer and an mTOR inhibitor is metformin hi some embodiments, the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., diclofenac), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and/or nicotinamide (NAM).
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator and/or the NAD+ supplement are nutraceutical agents.
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition.
  • the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions in some embodiments, the method further comprises administering to the individual an effective amount of vitamin D, vitamin E, vitamin A, resveratrol, pterostilbene, L-camitine, R-lipoic acid, leptine, a caspase inhibitor, and/or Chayote ( Sechium edule) juice or extract.
  • the insulin sensitizer is any one or more agents listed in the section“A. Insulin sensitizer” below, including any combinations thereof
  • the various agents can be administered via the same or different routes of administration, and in any suitable order.
  • the insulin sensitizer comprises an agent of the thiazolidinedione (TZD) family, such as pioglitazone, or rosiglitazone.
  • the insulin sensitizer comprises a biguanide, such as metformin.
  • the insulin sensitizer comprises an insulin sensitizing nutraeeutical agent.
  • the insulin sensitizer comprises a thiazolidinedione (TZD) and/or a biguanide.
  • the insulin sensitizer is metformin.
  • the insulin sensitizer comprises an insulin sensitizing nutraeeutical agent.
  • the insulin sensitizer is a combination of TZD (e.g, pioglitazone) and metformin.
  • the insulin sensitizer is administered orally. In some embodiments, the insulin sensitizer is administered once daily, twice daily, or three times daily in some embodiments, the insulin sensitizer is administered after meals.
  • metformin is administered at a dose of no more than about 3000 mg per day, such as no more than about any one of 750 mg, 1000 mg, 1250mg, ISOOmg, 2Q00mg, 2500mg or 3,000 mg per day. In some embodiments, metformin is administered at a dose of about 250 mg/dose to about 1000 mg/dose, such as about any one of 250 mg/dose, 500 mg/dose, 750 mg/dose, or 1000 mg/dose.
  • the mTOR inhibitor is any one or more agents listed in the section“B. mTOR inhibitor” below, including any combinations thereof.
  • the various agents can be administered via the same or different routes of administration, and in any suitable order.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraeeutical agent, and/or a rapalog.
  • the rapalog is selected from the group consisting of everolimus, tacrolimus, CCI-779, ABT-578, AP -23675, AP-23573, AP -23841, 7-epi- rapamycin, 7-thiomethyl -rapamycin, 7-epi-trimethoxyphenyl -rapamycin, 7-epi-thiomethyl- rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-rapamycin, 7-demethoxy- rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, 42-0-(2-hydroxy)ethyi rapamycin, and combinations thereof.
  • the mTOR inhibitor comprises a pan-mTOR inhibitor, also known as“dual mTORCl/TORC2 inhibitor” (i.e., an inhibitor that inhibits both TORC1 and TORC2).
  • the pan-mTOR inhibitor is selected from the group consisting of sapanisertib (GNK128), AZD2014, torin 1, torin 2, AZD8055,
  • the mTOR inhibitor comprises an indirect AMPK activator. In some embodiments, the mTOR inhibitor comprises a direct AMPK activator. In some embodiments, the AMPK activator is metformin or an insulin sensitizing nutraceutical agent or any agents in the biguanide group. In some embodiments, the mTOR inhibitor comprises an agent that inhibits PI3K and/or AKT. In some embodiments, the mTOR inhibitor comprises any combination of: (a) a
  • rapamycin or a rapamycin-like nutraceutical agent and/or a rapalog (b) a pan-mTOR inhibitor;
  • the mTOR inhibitor is rapamycin or a rapamycin-like
  • the mTOR inhibitor is everolimus. In some embodiments, the mTOR inhibitor is administered orally. In some embodiments, the mTOR inhibitor is administered weekly. In some embodiments, the mTOR inhibitor is administered bi weekly. In some embodiments, the mTOR inhibitor is administered in cycles of 6 weeks on and 1 week off. In some embodiments, the mTOR inhibitor is administered in cycles of 6 weeks on and 2 weeks off.
  • the effective amount of rapamycin or the rapalog maintains a trough blood level of rapamycin selected from no more than about 8ng/ml for systemic administration, no more than about 2ng/ml for local administration, and no more than about lOng/mi for combined systemic and local administration, or an equivalent trough blood level of the rapalog thereof
  • rapamycin is administered at a dose of no more than about 10 mg/week, such as no more than about any one of 8mg/week, 6 mg/week, 3 mg/week, 2 mg/week, or 1 mg/week.
  • the senolytic p53/pRb activator is any one or more agents listed in the section“C. senolytic p53/pRb activator” below, including any combinations thereof.
  • the various agents can be administered via the same or different routes of administration, and in any suitable order.
  • the senolytic p53/pRb activator comprises an agent that activates or stabilizes p53, such as nutlin or analog thereof (e.g., nutlin-3A).
  • the senolytic p53/pRb activator comprises an agent that inhibits a Sirtuin, such as SirTI and SirT2.
  • the senolytic p53/pRb activator comprises a COX inhibitor, such as a COX2 inhibitor.
  • the COX inhibitor is selected from the group consisting of voltaren, aspirin, ibuprofen, naproxen, diclofenac, indometbacin, and combinations thereof.
  • the senolytic p53/pRb activator comprises an agent that activates or dephosphorylates pRb, such as a pan CDK inhibitor, or a CDK4/6 inhibitor (/. ⁇ ?., an inhibitor that specifically inhibits CDK 4/C ⁇
  • the pan CDK inhibitor is selected from the group consisting of tlavopiridol, olomoucine II, purvalanol A, SNS-032, dinaciclib, MK-7965, SCH727965, AT7519, R547, AZD5438, and AG024322.
  • the CDK4/6 inhibitor is selected from the group consisting of ribociclib, paiboeiclib, abemaciclib, and trilaciclib
  • the senolytic p53/pKb activator is selected from a nutlin or analog thereof, a COX inhibitor, a CDK4/6 inhibitor, a pan-CD K inhibitor, and combinations thereof. In some embodiments, the senolytic p53/pKb activator is ibuprofen. In some embodiments, the senolytic p53/pKb activator is ibuprofen. In some
  • the senolytic p53/pRb activator is administered orally.
  • ibuprofen is administered twice daily for two days per week, or twice daily for 4 weeks out of 6 weeks.
  • ibuprofen is administered at a dose of about 400 mg/dose to about 600 mg/dose, such as about any one of 400 mg, 450 mg, 50Qmg or 600 mg per dose.
  • the NAD+ supplement is any one or more agents listed in the section“D. NAD+ supplement” below, including any combinations thereof.
  • the various agents can be administered via the same or different routes of administration, and in any suitable order.
  • the NAD+ supplement comprises an agent from the de novo crossover pathway, such as Nicotinic Acid or Niacin (NA).
  • the NAD+ supplement comprises an agent from the salvage pathway, such as Nicotinamide Riboside (NR),
  • the NAD+ supplement comprises NA, NR, NMN, and/or NANI. In some embodiments, the NAD+ supplement comprises: (a) NA and (b) one or more of NR, NMN and NAM. In some
  • the NAD+ supplement comprises NR and NA.
  • the NAD+ supplement comprises NA and NR
  • the NAD+ supplement is administered orally.
  • the NAD+ supplement is administered twice daily.
  • the NA is administered at a dose of at. least about 125 mg per day, such as at least about any one of 150 mg, 200 mg, 250mg, 300 mg, 400 g, 500 mg, 1000 mg, 2000 mg, or 3000 mg per day.
  • the NR is administered at a. dose of at least about 250 mg per day, such as at least about any one of 400 mg, 500 mg, 600 mg, 800 mg, lOQOmg, or 2000 mg per day.
  • the effective amount of the NAD+ supplement maintains a blood level of at least about 500mM NAD+.
  • any two of the insulin sensitizer, the mTOR inhibitor, the senolytic p53/pKb activator and the NAD+ supplement can comprise of, or being represented by, only one agent with dual component properties.
  • any one or more, or ail of the components in the combination regimen can comprise of, or being represented by
  • nutraceutical agents with the same component properties.
  • the insulin sensitizer and the mTOR inhibitor, or the agent having dual functions as an insulin sensitizer and an mTOR inhibitor; the senolytic p53/pRb activator; and the NAD+ supplement are administered simultaneously or sequentially in any suitable order.
  • each component of the combination regimen i.e., the insulin sensitizer, the mTOR inhibitor, or the agent having dual functions as an insulin sensitizer and an mTOR inhibitor; the senolytic p53/pKb activator; and the NAD+ supplement etc., is formulated as separate pharmaceutical compositions.
  • two or more components of the combination regimen are formulated as a. single pharmaceutical composition.
  • the insulin sensitizer, the mTOR inhibitor, or the agent having dual functions as an insulin sensitizer and an mTOR inhibitor; the senolytic p53/pRb activator; and the NAIH supplement are formulated as a single pharmaceutical composition.
  • each component of the combination regimen comprises two or more agents, the two or more agents are formulated as a single pharmaceutical composition or separate pharmaceutical compositions.
  • a pharmaceutical composition comprising two or more of: (i) an insulin sensitizer; (ii) an mTOR inhibitor; (iii) a senolytic p53/pRb activator; (iv) an NAD+ supplement, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is a pill, a tablet, a mixture, a solution, a cream, a liniment, an eye drop, or a nanoparticle composition.
  • a pharmaceutical composition comprising two or more of: (i) an agent having dual functions as an insulin sensitizer and an mTOR inhibitor; (ii) a senolytic p53/pRb activator; (iii) an NAD+ supplement, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is a pill, a tablet, a mixture, a solution, a cream, a liniment, an eye drop, or a nanoparticle composition.
  • a pharmaceutical composition comprising metformin, diclofenac, NR and/or NA, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises pterostilbene.
  • the pharmaceutical composition further comprises urea, sodium acetate, ethanol, PEG200, and/or PEG400.
  • the pharmaceutical composition is formulated for topical administration.
  • the pharmaceutical composition is a solution or a cream.
  • the pharmaceutical composition comprises about 0.5-10% (w/v) metformin, such as at least about any one of 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10%, or no more than about any one of 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5%, or about any one of 0.5-1%, 1-2%, 2- 5%, 5-10%, 0.5-2.5%, 2,5-5%, 5-5.75%, or 7.5-10% (w/v) metformin.
  • the pharmaceutical composition comprises about 0.5-4% (w/v) diclofenac, such as at least about any one of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4%, or no more than about any one of 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5%, or about any one of 0.5-1%, 1 -2%, 2-3%, 3-4%, 0.5-2%, 2-4%, or 1-3% (w/v) diclofenac.
  • the pharmaceutical composition comprises about 2% (w/v) diclofenac.
  • the pharmaceutical composition comprises about 0.5-6%
  • (w/v) NR such as at least about any one of 0.5, I, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6%, or no more than about any one of 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5%, or about any one of 0.5-1, 1-2, 2-4, 4-6, 0.5-2, 1-4, 2-5, or 3-6% (w/v) NR.
  • the pharmaceutical composition comprises about 3% > (w/v) NR.
  • the pharmaceutical composition comprises about 0.5-6% (w/v) NA, such as at least about any one of 0.5, 1 , 1 5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6%, or no more than about any one of 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5%, or about any one of 0.5-1, 1-2, 2-4, 4-6, 0.5-2, 1-4, 2-5, or 3-6% (w/v) NA.
  • the pharmaceutical composition comprises about 1.5% (w/v) NA.
  • the pharmaceutical composition comprises about 1 -10% (w/v) urea, such as at least about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%, or no more than about any one of 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%, or about any one of 1-2.5, 2.5-5, 5-7.5, 7.5-10, 1-5, 5-10, 2-4, 4-6, 6-8, or 8-10% (w/v) urea.
  • the pharmaceutical composition comprises about 1-10% (w/v) sodium acetate, such as at least about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% , or no more than about any one of 10, 9, 8, 7, 6, 5, 4, 3, 2, or l%o, or about any one of 1-2.5, 2.5-5, 5-7.5, 7.5-10, 1-5, 5-10, 2-4, 4-6, 6-8, or 8-10% (w/v) sodium acetate.
  • the pharmaceutical composition comprises about 1-30% (w/v) ethanol, such as at least about any one of 1, 2, 5, 10, 15, 20, 25, or 30%, or no more than about any one of 30, 25,
  • the pharmaceutical composition comprises about 5-40% (w/v) PEG200, such as at least about any one of 5, 10, 15, 20, 25, 30, 35, or 40%, or no more than about any one of 40, 35, 30, 25, 20, 15, 10 or 5%, or about any one of 5-10, 10- 15, 15-20, 20-30, 30-40, 5-20, 20-40, or 10-30% (w/v) PEG200.
  • the pharmaceutical composition comprises about 5-40% (w/v) PEG400, such as at least about any one of 5, 10, 15, 20, 25, 30, 35, or 40%, or no more than about any one of 40, 35, 30, 25, 20, 15,
  • the pharmaceutical composition further comprises about 0.5-10% (w/v) pterostilbene, such as at least about any one of 0.5, I, 2, 3, 4, 5, 6, 7, 8, 9, or 10%, or no more than about any one of 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5%, or about any one of 0.5-1%, 1 - 2%, 2-3%, 3-5%, 5-10%, 0.5-5%, 2.5%-7.5%, 1-3%, 3-6% or 6-9% (w/v) pterostilbene.
  • the pharmaceutical composition comprises about 1.5% (w/v) pterostilbene.
  • the pharmaceutical composition further comprises water.
  • a pharmaceutical composition comprising about 0.5-10% (w/v) metformin, about 0.5-4% (w/v) diclofenac, about 0.5-6% (w/v) NR, about 0.5-6% (w/v) NA, about 0.5-10% (w/v) pterostilbene, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises urea, sodium acetate, ethanol, PEG200, and/or PEG400.
  • the pharmaceutical composition comprises about 2% (w/v) diclofenac, about 2% (w/v) metformin, about 3% (w/v)
  • the NR about 1.5% NA, and about 1.5% (w/v) pterostilbene.
  • the pterostilbene is about 1.5% (w/v) pterostilbene.
  • the pharmaceutical composition is formulated for topical administration.
  • the pharmaceutical composition is a solution or a cream.
  • a pharmaceutical composition comprising about 0.5-10% (w/v) metformin, about 0.5-4% (w/v) diclofenac, about 0.5-6% (w/v) NR, about 0.5-6% (w/v) NA, about 0.5-10% (w/v) pterostilbene, about 1-10% (w/v) urea, about 1-10%
  • (w/v) sodium acetate about 1-30% (w/v) ethanol, about 5-40% (w/v) PEG20Q, and about 5-40% (w/v) PEG400.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and the NAD+ supplement can be administered to the individual via any suitable route of administration.
  • the methods described herein further contemplates in vitro or ex vivo use of the combination regimen.
  • One of skill in the art. will recognize that the form and character of the particular dosing regimen employed in the methods of the present invention depend on the route of administration and other well-known variables, such as rate of clearance, the size of the individual, the stage of the particular disease being treated, toxicities, rate and total penetration enhancement of the medium and excipient, etc. Based on such criteria, one skilled in the art can determine an effective amount of any of the particular compositions described herein that will be effective for prophylaxis and/or therapy of aging-related diseases and/or for cellular aging in an individual.
  • the individual is a human individual.
  • the human individual is at least about 50 years old, such as at least about any one of 55, 60, 65, 70, 75, 80 years old or higher.
  • the individual is non-diabetic.
  • the individual has impaired glucose regulation (IGR) or pre-diabetic.
  • IGR impaired glucose regulation
  • the individual has diabetes, such as type diabetes.
  • the individual has an HbAlC level of no more than 42 mmol/mol or no more than 6.0%.
  • the individual has an HbAl C level of about 42 to about 47 mmol/mol, or about 6.0-6.4%. in some embodiments, the individual has an HbAlC level of higher than 48
  • HbAlC levels in a blood sample from the individual can be measured using commercially available kits. Together with the fasting plasma glucose test, the HbAlC test can be used to assess insulin resistance/sensitivity and status of diabetes in an individual.
  • the individual is a pet animal or a sport animal, such as a cat, a dog, or a horse.
  • the dosages of the insulin sensitizer, the rnTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytie p53/pRb activator, and the NAD+ supplement are adjusted according to the average body weight, body surface area and pharmacological parameters (e.g, clearance and metabolism) specific to the individual’s species.
  • the effective amount of an agent for a pet is no less than about 20% (such as about any one of 10%, 5%, 2%, or 1%) of the effective amount of the agent for a human individual.
  • the effective amount of metformin for a pet animal is about 5 mg twice daily, or about 7.5 mg twice daily.
  • the effective amount of ibuprofen for a pet animal is about 4 mg twice daily for 2 days/week, or 6 mg daily for 2 days/week.
  • the effective amount of rapamycin for a pet animal is about IQpg weekly.
  • the effective amount of the NA for a pet animal is about 1.25 mg twice daily or about 2.5 mg twice daily.
  • the effective amount of the NR for a pet animal is about 2.5 mg twice daily or about 5 mg twice daily.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the sen y tic p53/pRb activator, and the NAD+ supplement can be administered via any suitable routes of administration, and/or via any suitable device.
  • the agents of the combination regimen can be administered via the same routes or different routes, depending on the nature of the aging-related disease or condition being treated or prevented.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are administered via routes that are most amenable for long-term administration, e.g, by gastrointestinal routes or topical route in some embodiments, the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are administered via routes that reduce or minimize toxicity of the agents to the individual.
  • agents with narrow therapeutic window such as highly potent mTOR inhibitors and senolytic p53 activators, may be administered locally.
  • Suitable routes, formulations, and devices for administration of the combination regimen are described in the sections“E. Administration” and“F. Indications.”
  • one or more of the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and the NAD+ supplement is administered locally.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are administered topically.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are administered via an implanted device in a tissue or organ.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are administered systemieally. In some embodiments, the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are administered orally.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are administered via a combination of systemic and local routes.
  • a first combination regimen or component thereof is administered to the individual locally, and a second combination regimen or component thereof is administered systemieally prior to, concurrently with, or subsequent to the first combination regimen or component thereof.
  • any of the methods and compositions described herein may be administered in conjunction with another conventional therapy for treating or preventing an aging-related disease or condition, and/or cellular aging.
  • conventional therapies include, but are not limited to, chemotherapies, radiation therapy and surgical interventions.
  • corticosteroid is an exemplary conventional therapy.
  • Additional anti- aging compounds or agents that augment, supplement, or synergize with the combination regimen can be administered in conjunction to the combination regimen to the individual.
  • Suitable anti-aging compounds include, but are not limited to, vitamins and over-the-counter supplements such as vitamin D, vitamin E, vitamin A, resveratrol, pterostilbene, L-earnitine, R- lipoic acid, leptine, caspase inhibitors, and/or antioxidant compounds ⁇ e.g., Chayote (Sechium edule) juice or extract) and combinations thereof.
  • vitamins and over-the-counter supplements such as vitamin D, vitamin E, vitamin A, resveratrol, pterostilbene, L-earnitine, R- lipoic acid, leptine, caspase inhibitors, and/or antioxidant compounds ⁇ e.g., Chayote (Sechium edule) juice or extract) and combinations thereof.
  • one or more antioxidant compounds are administered to the individual in conjunction to the combination regimen.
  • the antioxidant compounds can be natural or man-made, and they can be derived from plants, vegetables, fruits and their juices and/or extracts and combinations thereof.
  • the antioxidant compound is
  • the antioxidant compound is a polyphenol, a lycopene, a xanthine, a flavonoid, a derivative or an analog thereof.
  • one or more anti-inflammatory agents are administered in conjunction to the combination regimen to the individual.
  • Suitable anti-inflammatory' agents include, but are not limited to, !eukotrienes inhibitors, HMCo-A reductase inhibitors such as statins, antibodies against pro-inflammatory cytokines, chemokines and combinations thereof.
  • a cell therapy is administered in conjunction to the combination regimen to the individual.
  • Exemplary ' cell therapies include, but are not limited to,
  • the stem cells can be non- induced, or induced by genetic manipulation (e.g., iPS by KOSM, Klf4, Oct3/4, Sox2 and cMyc), by chemical or small molecule manipulation such as HDAC inhibitors, or by a chemical cocktail VCRFSGY (HDAC inhibitors such as valproic acid; CHIR99021; Repsox; SP600125 (INK inhibitor), G06983 (PKC inhibitor) and Y-27632 (ROCK inhibitor)).
  • HDAC inhibitors such as valproic acid; CHIR99021; Repsox; SP600125 (INK inhibitor), G06983 (PKC inhibitor) and Y-27632 (ROCK inhibitor)
  • Neurons can be obtained by inducing stem cells with LDN193189, SB431542, TTNPB, Thiazovivin, CHIR99021, VP A,
  • a hormone is administered in conjugation to the combination regimen to the individual.
  • Suitable hormones include, but are not limited to, hGH, testosterone, estrogens, progesterone, GnRH, gonadal stimulating hormones, corticosteroid, and combination thereof.
  • the methods described herein comprise administering an effective amount of an insulin sensitizer, which may comprise one or more insulin sensitizing agents.
  • the insulin sensitizer comprises a biguanide such as Metformin, or an insulin sensitizing nutraceutical agent.
  • Metformin is a well-known anti-diabetic drug used clinically for over fifty years, and its main mechanism of action is insulin sensitization.
  • the insulin sensitizer comprises a direct PPARy agonist.
  • PPARy agonists include, but are not limited to, thiazolidinediones (TZDs) and structurally diversified TZDs, PPARcc/y dual agonists, and PPAR pan agonist.
  • Many PPARy agonists are chemical derivatives of the parent compound thiazolidinedione.
  • Several PPARy agonists have been approved for clinical use for various indications. For example, pioglitazone (e.g., ACTOS ⁇ has been approved but with a warning on a possible bladder cancer risk. Rosiglitazone (e.g., ACTOS ⁇ has been approved but with a warning on a possible bladder cancer risk. Rosiglitazone (e.g., ACTOS ⁇ has been approved but with a warning on a possible bladder cancer risk. Rosiglitazone (e.g., ACTOS ⁇ has been approved but with a warning on
  • AVANDIA * which was put under selling restrictions in the US and withdrawn from the market in Europe due to an increased risk of cardiovascular events suggested by some studies. Upon re- evaluation of new data in 2013, the FDA lifted the restrictions.
  • Lobeglitazone e.g ⁇ ., DUVIE 5 '
  • the insulin sensitizer comprises a selective PPARy modulator, for example, a PPARy modulator that hinds to PPARy with no agonism and inhibits pSer273PPARy.
  • the insulin sensitizer comprises an angiotensin inhibitor, or a related agent thereof, such as an angiotensin converting enzyme (ACE) inhibitor, and an angiotensin receptor blocker (ARB).
  • ACE angiotensin converting enzyme
  • ARB angiotensin receptor blocker
  • angiotensin inhibitors include, but are not limited to, benazepril (e.g., LOTENSIN ® ), captopril (e.g, CAPOTEN' ® ), enalapril (e.g., VASOTEC ® , EPANED ® , or LEXXEL ® ), fosinopril (MONOPRIL ® ), lisinopril (e.g., PRINIVIL ® , ZESTRIL ® , or QBRELIS ® ), moexipril (e.g., UNIVA8C ® ), perindopril (e.g ⁇ ., ACEQN ® ), quinapril (e.g., ACCUPRIL ® ), ramipril (e.g, ALT ACE ® ), trandolapril (e.g.,
  • MAV1K ® azilsartan (e.g, ED ARBI ® ), candesartan (e.g, AT AC AND 4 '), eprosartan, irbesartan (e.g, AVAPRO ® ), losartan (e.g, COZAAR ® ), olmesartan (e.g, BENICAR ® ), telmisartan (e.g, M1CARDIS ® ), and valsartan (e.g, DIO VAN ® ).
  • azilsartan e.g, ED ARBI ®
  • candesartan e.g, AT AC AND 4 '
  • eprosartan e.g, irbesartan
  • losartan e.g, COZAAR ®
  • olmesartan e.g, BENICAR ®
  • telmisartan e.g, M1CARDIS ®
  • valsartan
  • the insulin sensitizer comprises a PPARy sparing compound.
  • the PPARy sparing compound is a ligand or modulator of mTQT such as a ligand of mito-NEET (i.e., TT01001), or a ligand/modulator of m ’ TOT (i.e., MSDC -0602/0160).
  • the PPARy sparing compound is an agent that targets one or more PPARy downstream effectors, such as adiponectin activator, FGF receptor targeted ligand and a derivative of FGF21 and/or FGF1
  • the PPARy sparing compound is an agent that stimulates HSP and/or NOS, such as RGP-15.
  • the PPARy sparing compound is a biguanide such as metformin.
  • the insulin sensitizer also functions as an mTOR inhibitor.
  • the insulin sensitizer is metformin, or an insulin sensitizing nutraceutical agent.
  • exemplary insulin sensitizing nutraceutical agent can be an agent or an extract of a mixture of agents from Galega officinalis, commonly known also as galega, goat’s- rue, French lilac or professor-weed and with ingredients such as guanidine, galegine, hydroxvgalegine, guanidine derivatives such as 4-hydroxygaIegine flavones, flavone glycosides, kaemferol, and quercetin.
  • Flavonoids Luteolin, Kaempferol, -Catechin, 2’-Hydroxychalcone, Biochanin A, Genistein, 6-Hydroxydaidzein, 6 -Hydroxyl-0-desmethylangolensin
  • Neolignans Honokiol, Magnolol, Resveratrol, Pterostilbene, Amorphastilbol
  • Amorfrutins Amorfrutins 1, 2, B
  • Falcarindiol Deoxyelephantopin
  • Sargaquinoic acid and Sargahydroquinoic acid.
  • the insulin sensitizer can be one of the pde5 inhibitors such as iOS (sildenafil), or cialis (tadalafil) etc.
  • pde5 inhibitors such as Skype (sildenafil), or cialis (tadalafil) etc.
  • the methods described herein comprise administering an effective amount of an mTOR inhibitor, which may comprise one or more mTOR inhibiting agents.
  • the mTOR inhibitor can reset the metabolic state in the body at rest or fasting to the default state, i.e., changing the metabolic state from RIG (i.e , Reproduction, Immune-activation/lnflammation and Growth) to RCH (i.e.,
  • RIG to RCH default reset refers to reset of body metabolism at rest or fasting from a default of reproduction, immune-activation/inflamrnation and growth to a default consisting of repair/regeneration, conservation and homeostasis.
  • mTOR inhibition which via RIG to RCH reset, can promote regeneration, homeostasis, natural cell death, and tissue replenishment.
  • mTOR inhibiting agents are known in the art.
  • Exemplary mTOR inhibiting agents include, but are not limited to, rapamycin or a rapamycin-like nutraceuticaf agent, and rapalogs, pan-mTOR inhibitor, and direct or indirect AMPK activators.
  • the AMPK activator is metformin, an insulin sensitizing nutraceutical agent, or an agent in the biguanide group.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapalog.
  • Suitable rapalogs include, but are not limited to, rapamycin (sirolimus), evero!imus, temsirolimus, ridaforolimus, tacrolimus, CCI-779, ABT-578, AT -23675, AP-23573, AP -23841, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi- trimethoxyphenyl -rapamycin, 7-epi-thiomethy!
  • the mTOR inhibitor comprises a pan-mTOR inhibitor, also known as a dual mTORC I/TO C2 inhibitor.
  • exemplary pan-mTOR inhibitors include, but are not limited to, sapanisertib (INK 128), AZD2014, torin 1, torin 2, AZD8055, PP242, KU-006379, QSI-027, WAY-600, WAE-687, WYE-354 and GSK 1059615
  • the pan- mTOR inhibitors have a small molecular weight. For example, torin 1 , torin 2, PP242 and INK 128 are about 500 Dalton, and thus are suitable for topical delivery.
  • pan-mTOR inhibitors may have better pharmacological profile in certain applications (e.g., topical administration) than rapamycin or a rapamycin-like nutraceuticai agent for promoting re- proliferation of senescent cells, cell hypertrophy and/or oil retention
  • the mTOR inhibitor comprises a direct AMPK activator, or an indirect AMPK activator.
  • Suitable indirect AMPK activators include, but are not limited to, pterostilbene, quercetin, genistein, epigailocatechin gallate, berberine, curcurmin, ginsenoside Rbl, alpha-lipoic acid, and cryptotanshinone.
  • Suitable direct AMPK activators include, but are not limited to, 5-aminoimidazo!e-4-carboxamide riboside (i.e., AICAR), thienopyridone (e.g., A- 7.69662), benzimidazole (e.g..
  • Compound 911 salicylate or pro-drug of aspirin, Compound- 13 (i.e., Pro-drug C2), PT-1, and MT63-78 (i.e., Debio0930).
  • Compound- 13 i.e., Pro-drug C2
  • PT-1 i.e., PT-1
  • MT63-78 i.e., Debio0930.
  • Other AMPK activators have been described, for example, see WO2009124636, W02009100130, WO2011029855,
  • the mTOR inhibitor comprises an agent that inhibits PI3K and/or AKT.
  • the PI3K/AKT pathway is upstream of mTOR.
  • Agents that can inhibit PI3K, or AKT, or combination inhibition of PBK and AKT, with or without directly inhibiting mTOR, are effective mTOR inhibitors.
  • the mTOR inhibitor comprises a PI3K inhibitor, such as an inhibitor of PI3K alpha, delta, and/or gamma.
  • Exemplary PI3K inhibitors include, but are not limited to, taselisib, perifosine, idelalisib, buparlisib (BKM120), duvelisib (IPI-145), alpelisib (BYL719), umbralisib, (TGR 1202), copanlisib (BAY 80-6946), PX-866, dactolisib, CUDC-907, ME-401 (a PI3K-Delta inhibitor), IPI-549 (a PI3K-gamma inhibitor),
  • SF1126, RP6530 (a Dual PI3K delta/gamma inhibitor), INK! 117 (a PI3K-alpha inhibitor in phase I trial), pictilisib (GDC-0941), XL147 (SAR245408), XI.765 (SAR245409), palomid 529, GSKIQ596I5, ZSTK474, PWT33597 (a dual PBK-alpha/mTOR inhibitor), NVP-BEZ235 (a dual P13K/AKT inhibitor), IC87114, TGI 00-1 15, CAL263, RP6503, PI-103 (a dual P13K- mTOR inhibitor), GNE-477 (PI3K-a!pha and mTOR inhibitor), and AEZS-136 (Erkl/2 inhibitor).
  • the mTOR inhibitor comprises an AKT inhibitor.
  • the AKT inhibitor is an ATP competitive inhibitor selected from isoquinoline-5- sulfonamides (e.g., H-8, H-89, NL-71-101), azepane derivatives, aminofurazans (e.g., GSK 690693), heterocyclic rings (e.g., 7-azaindole, 6-phenylpurine derivatives, pyrrolo[2,3- djpyrimidine derivatives, CCT 128930, 3-aminopyrrolidine, anilinotriazole derivatives, spiroindoline derivatives, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A- 443654), and phenylpyrazole derivatives (e.g ., AT7867, AT13148).
  • the AKT inhibitor is a thiophenecarboxamide derivative (e.g., GSK 2141795).
  • the AKT inhibitor is an allosteric inhibitor, such as a 2,3-diphenylquinoxaline analogue or derivative, triazolo, naphthyridin-3(2/: )-one derivative (e.g., MK-2206); an alkylphospholipid such as ede!fosine (l-0-octadecyl-2-0-methy!-rac-glycero-3-phosphocholine, ET-I8-OCH 3 ), ilmofosine (BM 41.440), miltefosine (hexadecylphosphocholine, HePC), perifosine (D-21266), erucylphosphocholine (ErPC), or erufosine (ErPC3,
  • an allosteric inhibitor such as a 2,3-diphenylquinoxaline analogue or derivative, triazol
  • erucylphosphohomocholine or an indole-3 -carbinal analogue such as indole-3 -earbinol, 3- chloroacetylindole, diindolylrnethane, diethyl 6-methoxy-5,7-dihydroi dolo [2,3 ⁇ />]earbazole ⁇ 2,10-dicarboxylate (SR13668), or OSU-A9; a sulfonamide derivative (e.g, PH-316, PHT-427); a thiourea derivative such as PIT-1, PIT-2, DM -PIT- 1 , or N ⁇ [(l -methyl- Ii/-pyrazol-4 ⁇ yl)carbonyl]-N'-(3-bromophenyl)-thiourea; a purine derivative such as triciribine (TCN, NSC 154020), triciribine mono-phosphate active analogue (TCN-P), 4-a
  • the AKT inhibitor is an irreversible inhibitor, such as a natural product, an antibiotic such as lactoquinomycin, frenolicin B, kalafungin, medermycin, Boc-Phe-vinyl ketone, 4-hydroxynonenal (4-HNE), 1,6-naphthyridinone derivatives, or an i midazo- 1 ,2-pyridine derivative.
  • an antibiotic such as lactoquinomycin, frenolicin B, kalafungin, medermycin, Boc-Phe-vinyl ketone, 4-hydroxynonenal (4-HNE), 1,6-naphthyridinone derivatives, or an i midazo- 1 ,2-pyridine derivative.
  • the mTOR inhibitor is a rapamycin-like nutraceutical agent.
  • a rapamycin-like nutraceutical agent is an agent, or precursor or derivative thereof, which exhibits anti -mTOR pathway effects.
  • Exemplary' rapamycin-like nutraceutical agents include, but are not limited to, agents such as steroids, resveratrol, pterostilbene, aspirin, polyunsaturated fatty acids, curcumin, R-lipoic acid, caffeine, fisetin, apigenin, alcohol, andrographis, pomegranate, Reishi, milk thistle, oieanolic acid, anthocyanins, Astragalus, Rhodiola, Camosine, Plumbagin and Chrysophanic acid
  • the method comprises administration of an effective amount of one or more mTOR inhibiting agents in cycles to achieve a high level of mTOR inhibition.
  • the one or more mTOR inhibiting agents can inhibit mTOR expression or activity by at least about any one of 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, or more.
  • rapamycin or a rapamycin-like nutraceutical agent and rapalogs are known to be potent mTOR inhibitors that can achieve a high level of mTOR inhibition, such as niTORCl inhibition.
  • the percentage of inhibition can be measured by methods such as, but not limited to, the quantity of proteins ofmTORCl suppression from the pS6K/pS6 axis, and also in-vitro cellular re-proliferative potential, senescent cell hypertrophy, morphology, Oil Red O staining and yeast cell chronological life span (CLS) measurement.
  • the one or more mTOR inhibiting agents are administered weekly or bi-weekly.
  • each cycle of administration comprises seven weeks, and the one or more mTOR inhibiting agents are administered for six weeks and off in week 7.
  • administration comprises eight weeks, and the one or more mTOR inhibiting agents are administered for six weeks and off in week 7 and week 8.
  • the cyclic regimen of the one or more mTOR inhibiting agents is combined with administration of an effective amount of one or more mTOR inhibiting agents to maintain a modest baseline threshold of mTOR inhibition.
  • the one or more mTOR inhibiting agents can inhibit mTOR activity by no more than about any one of 40%, 30%, 20%, 10%, 5% or less.
  • direct and indirect AMPK activators are suitable for maintaining a modest baseline threshold of mTOR inhibition.
  • Many known methods and kits can be used to assess mTOR activity. As non-limiting examples, ELISA and western blots can be used to assess the kinase activity of immunoprecipitated mTOR from cell lysates on its substrates
  • Cyclic administration can reduce undesirable toxicities of some highly potent mTOR inhibiting agents that lead to a constantly high level of mTOR inhibition. Such toxicities, including hematological toxicity and mucosal ulcers, etc , have been observed when mTOR inhibitors are used as immune suppressant in kidney transplant and cancer treatments. These toxicities are undesirable for long-term anti-aging interventions.
  • the mTOR inhibitor is administered locally, the toxicity effects may be localized, and cyclic administration of the mTOR inhibitor may not be necessary.
  • the effective amount of the mTOR inhibitor is chosen to reduce undesirable side effects and toxicity of the mTOR inhibitor.
  • the mTOR inhibitor comprises a rapamycin and/or a rapalog
  • the effective amount of rapamycin or the rapalog is sufficient to maintain a systemic plasma or serum trough level of no more than about 8 ng/ml of rapamycin or equivalent amount of the rapalog.
  • the dose and dosing frequency of rapamycin and/or the rapalog are chosen to maintain a systemic plasma or serum trough level of no more than about 8ng/mi of rapamycin or equivalent amount of the rapalog.
  • the dose of rapamycin is about any one of 0.5 mg to 8 mg daily, 1 mg to 15 mg once weekly, or about 2 mg to 40 mg once every 2 or 3 weeks.
  • the trough level of rapamycin or the rapalog in plasma or serum samples can be monitored periodically to guide selection of an appropriate dosage.
  • the effective amount of rapamycin or the rapalog is sufficient to maintain a systemic plasma or serum trough level of no more than about 2 ng/ml of rapamycin or equivalent amount of the rapalog.
  • the mTOR inhibitor comprises a rapamycin and/or a rapalog
  • the effective amount of rapamycin of the rapalog is sufficient to maintain a systemic plasma or serum trough level of no more than about 10 ng/ml.
  • the mTOR inhibitor also functions as an insulin sensitizer.
  • the methods described herein comprise administering an effective amount of a senolytic p53/pRb activator, which may comprise one or more agents that promotes p53 and/or pRb activity.
  • a senolytic p53/pRb activator which may comprise one or more agents that promotes p53 and/or pRb activity.
  • the senolytic p53/pRb activator comprises an agent
  • p53 activator (referred herein as p53 activator”) that activates p53, and/or stabilizes p53.
  • the senolytic p53/pRb activator comprises an agent (referred herein as“pRb activator) that activates pRb, stabilizes pRb, and/or dephosphoryiates pRb.
  • the pRb activators can also activate, and/or stabilize p53.
  • the senolytic p53/pRb activator comprises both a p53 activator and a pRb activator. There is extensive cross talk between downstream effector molecules of the p53 and pRb pathways.
  • the senolytic p53/pRb activator is a single agent that leads to increased p53/pRb activities.
  • the senolytic p53/pRb activator increases p53 activity by at least about any one of 20%, 50%, 75%, 100%, 150%, 200% or more. In some embodiments, the senolytic p53/pRb activator increases pRb activity by at least about any one of 20%, 50%, 75%, 100%, 150%, 200% or more.
  • Many known methods and kits can be used to assess p53 and pRb activity, including, but not limited to, ELISA and western blots that can be used to assess the levels of p53 and pRb.
  • RT-PCR can be used to assess the levels of mRNA transcripts of genes under the control of p53 and pRb to determine the activity of p53 and pRb.
  • the senolytic p53/pKb activator comprises an agent that activates p53. In some embodiments, the senolytic p53/pRb activator comprises an agent that inhibits or suppresses binding of p53 to MDM2 or MDMX.
  • Suitable inhibitors of p53-MDM2 binding or p53-MDMX binding include, but are not limited to, nutlins such as RG7112 (i.e., RO5045337), RO5503781 ; benzodiazedinediones such as TDP665759; spiro-oxindoles such as MI-219 and SAR405838; imidazothiazole such as DS-3032b; dihydroisoquinolinone such as CGM-097; HDM201; piperidines such as MK4828; piperidinone such as AMG232; pyrroidine such as RG7388; peptide MDM2/X inhibitors such as ALRN-6924, ALRNRITA; and other small molecule inhibitors such as JNJ-26854165 (i.e., serdemetan), SJ-172550, RO-2443/RO- 5693, and XI -01 1.
  • nutlins such as RG7112 (i.e.,
  • the senolytic p53/pRb activator comprises an agent that inhibits a sirtuin, such as SirTl and/or SirT2.
  • Suitable sirtuin inhibitors include, but are not limited to, Tenovin 1 and 6
  • the senolytic p53/pRb activator comprises a COX inhibitor.
  • COX inhibitors can promote or stabilize p53 transcription by down-regulating cycloxygenase-2 (COX-2), retrieve p53 from COX-2 association, and/or activate p53 via ataxia telangiectasia mutated-/p38 mitogen-activated protein.
  • COX-2 and p53 Upon genotoxic stress, COX-2 and p53 accumulate in the nucleus, where they physically interact with one another.
  • An amino-terminal region (amino acids 1—126) of COX-2 interacts with the DNA-binding domain of p53.
  • the p53-interacting region is critical for CQX-2- mediated inhibition of p53, including DNA binding, transcriptional activity, and p53- and genotoxic stress-induced apoptosis.
  • an active site mutant of COX-2 S5 I6Q
  • wild-type COX-2 potently inhibits p53 transcriptional activity and genotoxic stress-induced apoptosis.
  • the senolytic p53/pRb activator comprises a nonselective COX inhibitor.
  • non-selective COX inhibitors include, but are not limited to, acetates such as diclofenac, indomethacin, and sulindac; fena ales such as mefenamic acid; oxicams such as piroxicam; propionates such as ibuprofen, ketoprofen, naproxen; pyrazolones such as
  • the senolytic p53/pRb activator comprises a selective COX inhibitor.
  • selective COX inhibitors include, but are not limited to, meloxicam, nimesu!id, and coxibs such as first generation celecoxib, second generation celecoxib, etorcoxib and valdecoxib.
  • the senolytic p53/pRb activator comprises a COX inhibitor having a half-life less than about 6 hours, e.g., aspirin, diclofenac, ibuprofen, indo ethacin, or ketoprofen.
  • the senolytic p53/pRb activator comprises a COX inhibitor having a half-life more than about 10 hours, e.g., diunisal, naproxen, phenylbutazone, piroxicam, or sulindac.
  • the senolytic p53/pRb activator comprises an agent that activates pRb.
  • agents that can activate pRb include, but are not limited to, agents that dephosphorylate pRb; pan CDK inhibitors such as flavopiridol, olomoucine II, purvalanol A, SNS-032 (Le., BMS387032), dinaciclib, MK-7965, SCH727965, AT7519 (Astex), R547, AZD5438, and AG024322; and specific CDK4/6 inhibitors, such as ribociclib, palbociclib (i.e., PD-0332991), abemaciclib (i.e., LY2835219, VERZENIOTM), and trilaciclib (i.e., G1 T28).
  • pan CDK inhibitors such as flavopiridol, olomoucine II, purvalanol A, SNS-032
  • the effective amount of the senolytic p53/pRb activator can be chosen based on effective dosages of the senolytic p53/pRb activator established in the art.
  • the effective dosages of many COX 2 inhibitors for systemic and/or local administration have been established.
  • the recommended safe daily oral dose of ibuprofen is no more than about 1200 mg.
  • Senolytic from the words “senescence” and “lytic” - destroying) molecules can selectively induce death of senescent cells. Without being bound by any theory or hypothesis, senescence is a potential tumor suppressive mechanism and possible factor that accelerates the aging process. Senolytic agents or senolytic regimen are designed to delay, prevent, alleviate, ameliorate, or reverse age-related diseases. Certain anti -cancer agents in low doses can decelerate aging and age-related diseases as these agents generally remove older cells.
  • Targeting cancer prevention pathways with anti -cancer agents may confer longevity effects by offering protection from metabolic pathologies during aging, independently of effects on cancer.
  • Senolytic drugs or regimens are agents that can kill senescent cells with minimal harm to normal cells. Certain senolytic agents promote apoptosis. Apoptosis is cel! suicide, and apoptosis of senescent cells is beneficial to the full organism. Removal of senescent cells is an appealing approach for anti-aging therapy. Senolytic strategy finds support from empirical data in mammals, parabiosis experiments, and the theory that circulating chemical signals form the basis of an epigenetic clock. Some of these circulating molecules are known to come from senescent cells. Another theory is that aging accelerates exponentially with age, as though it rvere driven by a positive feedback loop. For
  • senescent cells may secrete cytokines that make more senescent cells, thereby forming a positive feedback loop that accelerates aging.
  • short telomeres initiate
  • telomere length there is a bell-shaped curve of telomere length among the body’s cells.
  • the tail of the telomere distribution contains a few cells that are driven to senescence by having very short telomeres. As organisms age, more and more of these senescent cells accumulate, which may in turn support the positive feedback loop that accelerates aging.
  • FOXO-DRI is a senolytic agent that dissociates FQXQ4.
  • FOXO is a master transcription factor associated with aging and development. It is the mammalian homolog of the pivotal life extension protein first identified in worms as DAF16 in the 1990s.
  • FOX04 activation in a cel! can block apoptosis.
  • p53 is the most common trigger of apoptosis, the first protein biochemists usually think of in connection with apoptosis. p53 has multiple functions in the cell nucleus, but as a trigger for apoptosis, it functions through the mitochondria.
  • SI 50 SI for“selectivity index - 50%”
  • LD 50 the“lethal dose” of a toxin, the dose at which half of all cells die.
  • SFo is defined as the ratio of LD JO ’S for normal and senescent cells. It is the concentration of the agent at which half the normal cells die, divided by the concentration at which half the senescent cells die.
  • the FOX04 blocking agent FOXO-DRI has a SI50 about 12, which can leave a lot of normal cells live after usage, but is not high enough to support a useful therapy.
  • FOXO-DRI After a standard dose of FOXO-DRI is injected in humans, the cellular concentrations vary from person to person and from tissue to tissue. If the 8I 50 is low in vital tissues and organs, then toxic damage similar to chemotherapy can occur, preventing further development of such an agent.
  • FOXO-DRI is the newest senolytic agent, and it has the best ratio yet for killing senescent ceils while avoiding collateral damage to healthy cells. It cannot be taken orally and must be injected. However, because of expected toxicities, FOXO-DRI has been developed mainly as an anti-cancer agent rather than an anti-aging agent. Dasatinib and Quercetin (not via the p53 pathway) were also developed as an early proof-of-principle senolytic regimen, and both drugs were FDA approved. However, the combination was found to be too toxic to be effective. Therefore, prior to this invention, no senolytic regimen via p53 ⁇ depenent or p53-independent pathway has been successfully applied for anti-aging purposes.
  • the methods described herein comprise administering an effective amount of a NAD+ supplement, which may comprise one or more agents that increases the level or maintains a high level of NAD+.
  • a NAD+ supplement which may comprise one or more agents that increases the level or maintains a high level of NAD+.
  • the NAD ⁇ level in the body e.g, blood, tissue or cellular level
  • the NAD+ level in the body is maintained at least about any one of 100 mM, 200 mM, 300 mM, 400 mM, 500 mM, 600 mM, 700 mM, 800 mM, 900 mM, 1 mM, or higher.
  • NAD+ generation and maintenance of a high level of NAD+ can increase the body’s N AD availability, which provides adequate NAD+ to promote activation of Sirtuins (Sirtuins 1-7) even when P ARP i is activated.
  • the NAD+ concentration available before PART 1 activation can be depleted by more than 80% upon PARP1 activation.
  • the NAD+ level is maintained at the level when PARP1 is not activated in order to activate Sirtuins. Activation of PARP1 and Sirtuin can be assessed using known methods in the art, such as ELISA, and
  • the NAD+ level in ceils, tissues, and blood samples can be determined using enzymatic or cell-based colorimetric or fluorescence assays.
  • a single NAD+ supplement can reverse dyslipidemia and diseases associated thereof.
  • a single agent that increases NAD+ supply is not sufficient to initiate and achieve cellular repair and ultimate prolonging survival.
  • chronic inflammation from various causes together with aging may override the benefits of a single agent supplement approach, which may be insufficient to sustain a high level of NAD+ for rate limiting enzymatic pathways.
  • the human body responds to aging via complicated positive and negative feedback processes, such as genetic and epigenetic transcriptions, pre- and post- translational modifications, stimulatory ' and inhibitory ' small molecules, peptides, and proteins, and the presence or absence of pre-existing metabolic conditions. Most of these processes are either continuous or occurring in rapid self-reactivation downward spiraling cycles. Simply supplying NAD+ using methods and routes known in the art may be insufficient to provide sustainable and effective NAD+ levels to override this long established aging process.
  • the NAD+ supplement comprises niacin, i.e. nicotinic acid (“NA”).
  • NA is from the de novo crossover pathway.
  • a suitable dosage of NA is at least
  • the NAD+ supplement comprises one or more of nicotinamide riboside (“NR”), nicotinamide mononucleotide (“NMN”), and
  • NR, NMN and NAM are agents of the NAD salvage pathway.
  • a suitable dosage of NR, NMN, and NAM can be chosen based on a moles/L equivalent to niacin, such as about 500mg/day for NR, about 750mg/day for NMN, and about 250mg for NAM for a 60Kg adult.
  • the NAD+ supplement comprises a combination of two or more (e.g., 2, 3, 4, or more) agents from different NAD+ generation pathways, which have different pharmacokinetics, pharmacodynamics, and rates of rise of NAD+ in different tissues.
  • the combination of agents maintains a high level of NAD+ in ceils or tissues of the body, thereby mitigating the aging process and its associated diseases.
  • the NAD+ supplement comprises a combination of agents from both NAD de novo crossover pathway and the NAD salvage pathway.
  • NA and NR are among the most effective and bioavailab!e supplements to increase NAD+ and ADPR. See, Trammel et a!. Nature Communications 7: 12948 (2016). NR can be converted to NAAD through a yet unknown pathway.
  • the NAD+ supplement comprises a combination of NA and NR, which produce a high and constant level of NAD+. The methods described herein can maintain a NAD+ level over 500mM throughput cycles of NAD+ consumption, such as PARP1 activation.
  • the NAD+ supplement consists of one or more agents of the de novo crossover pathway of NAD+ generation. In some embodiments, the NAD+ supplement consists of one or more agents of the salvage pathway of NAD+ generation. In some embodiments,
  • the NAD+ supplement comprises agents from both the de novo crossover pathway and the salvage pathway of NAD+ generation.
  • the NAD+ supplement consists of nicotinic acid (NA).
  • the NAD+ supplement comprises: (a) NA, and (b) one or more agents selected from NR, NMN and NAM.
  • the NAD+ supplement consists of NA and NR.
  • the NAD+ supplement consists of NA and NMN.
  • the NAD+ supplement consists of NA and NAM.
  • the NAD+ supplement consists of NA, NR and NMN.
  • the NAD+ supplement consists of NA, NR and NAN.
  • the NAD+ supplement consists of NA, NMN and NAN. In some embodiments, the NAD+ supplement consists of NA, NR, NMN and NMN. In some embodiments, the NAD+ supplement does not comprise NA. In some embodiments, the NAD+ supplement consists of one or more agents selected from NR, NMN and NAM.
  • the NAD+ supplement is administered systemically, such as orally.
  • the effective amount of the NAD+ supplement for systemic administration is sufficient to maintain NAD+ at a level of about 200 mM to about 500 iiM.
  • the effective amount of the NAD+ supplement is sufficient to restore NAD+ to at least about any one of 50%, 60%, 70%, 80%, 90%, 100% or more of baseline level (e.g., 200 mM to about 500 mM) post P ARP 1 activation.
  • Suitable dosages for oral administration include, for example, at least about 250 mg/day of Nicotinic acid (NA) in combination with: any one of (a) at least about 5Q0mg/day of nicotinamide riboside (NR), (b) at least about 750mg/day of nicotinamide mononucleotide (NMN), and (c) at least about 250mg/day of nicotinamide (NAM).
  • NA Nicotinic acid
  • the NAD+ supplement is administered locally, such as topically.
  • the effective amount of the NAD+ supplement for local administration is sufficient to maintain NAD+ at a level of more than about 1 mM.
  • the effective amount of the NAD ⁇ supplement is sufficient to restore NAD+ level to more than about 200% of baseline level (e.g, to increase the NAD+ level from less than about 200 mM to more than about ImM) post P ARP 1/2 and CD38/157 activation.
  • supplement can be chosen based on an estimated distribution volume, pharmacokinetics, and penetration of the component to achieve a minimum of about 100 mg of NAD+ per 100 ml of body tissue targeted.
  • nicotinic acid (NA) solution is needed assuming 100% penetration, distribution and absorption.
  • Drug transport in the skin is a process involving several steps, including dissolution and release of drug from the formulation, partitioning of the drug into the stratum corneum, diffusion of the drug across the stratum corneum (e.g, by intercellular lipids), partitioning of the drug from the stratum corneum into viable epidermis layers, diffusion across the viable epidermis layers into the dermis, and absorption of the drug by capillary' vessels, which achieves systemic circulation (Kalia, Guy, 2001).
  • a second calculation yields a total delivered dose of about 40mg.
  • This presumption has a 20ug/ cnri/hr penetration, yielding a final plasma concentration of 1 nM with a half-life of 15 minutes, and assuming total delivery of NAD+ supplements is no more than about 18% of the topical formula.
  • the first calculation of 38.46 mg/100 mi is very' close to the value of 40mg in the second calculation.
  • the NAD+ supplement is formulated for local administration, and the NAD+ supplement comprises a minimum total daily dose of no less than about 10ml of 0.3% of Nicotinic acid (NA) by itself or in combination with any one or a combination of the three agents of the salvage pathway, a minimum total daily dose of no less than 10 ml of 0.6% of nicotinamide riboside (NR), a minimum total daily dose of no less than 10 ml of 0.9% of nicotinamide mononucleotide (NMN), or a minimum total daily dose of no less than 10ml of 0.3% of nicotinamide (NAM).
  • NA Nicotinic acid
  • Each of the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, seno!ylic p53/pRb activator, and NAD+ supplement described herein can be administered using a suitable route of administration, including systemic and local admini stration.
  • one or more of the insulin sensiti zer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and NAD+ supplement is administered locally.
  • one or more of the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and NAD+ supplement is administered systemically.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, or NAD+ supplement, which comprises two or more agents is administered by a combination of local and systemic routes, e.g., one agent is administered locally and another agent is administered systemicaliy.
  • routes of administration include, but are not limited to, intravenous, intra-arterial, intraperitoneal, intrapulmonary, intravesicular,
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement are administered systemicaliy.
  • Suitable systemic routes include, but are not limited to, intravenous, intramuscular, subcutaneous administration.
  • the insulin sensitizer, mTQR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, seno!ytie p53/pRb activator, and/or NAD+ supplement is via gastrointestinal route, such as orally. In some embodiments, gastrointestinal administration is preferred for long term treatment.
  • local including regional administration is used. Compared to systemic administration, local administration can achieve different phar acokinetics and pharmacodynamics for different components in combination regimen (i.e., the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and NAD+ supplement). For example, metabolism and
  • Local administration can be achieved using any suitable device, media, methodology, and route known in the art. Local administration can achieve minimal or reduced toxicity than systemic delivery of the same agent.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is formulated in a topical media such as a cream, gel, lotion, solution, serum etc. for local administration, e.g., through skin or a mucous membrane.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pKb activator, and/or NAD+ supplement is formulated with one or more agents that facilitate local delivery', e.g., enhance penetration through skin or a mucous membrane.
  • agents that facilitate local delivery include, but are not limited to, liposomes, dendrimers and micro-emulsions or other chemical enhancers.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is locally administered via a physical method, such as heat thermal abrasion, passive, iontophoresis, electroporation, cavitational ultrasound, or
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is locally administered via an injection route, for example, intraderma! , subcutaneous, intramuscular or by injection into an organ or tissue.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is locally administered via a vascular delivery route, such as intra-arterial, via an arterial occlusion device, and/or via catheterization.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is locally administered via an intra-cavity route, e.g., by instillation into one or more specific body cavities.
  • Suitable intra-cavity routes of administration include, but are not limited to, intravesical, intra-peritoneal, intra-pleural, intra-crania!, intra nasal, retrograde and intra-ocular or topical ocular procedures.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is locally administered via a device implanted into a tissue or organ, such as a drug eluting stent, an intradermal pouch, a transderma! patch or membrane, a matrix, a gel and a reservoir (e.g., CT, MRI, or X-ray guided reservoir), etc.
  • a device implanted into a tissue or organ such as a drug eluting stent, an intradermal pouch, a transderma! patch or membrane, a matrix, a gel and a reservoir (e.g., CT, MRI, or X-ray guided reservoir), etc.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is locally administered via a suppository' preparation for rectal or vaginal application.
  • Suitable routes of administration and formulations for each agent in the combination regimen are chosen depending on the nature of the aging-related disease or condition being treated or prevented. Section“F. Indications” below further provide exemplary administration routes and methods that are suitable for particular aging-related diseases and conditions.
  • Each of the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and N AD supplement may be administered using any suitable schedule.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is administered daily or twice daily.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is administered is administered at least about any one of lx, 2x, 3x, 4x, 5x, 6x, or 7x (i.e., daily) a week.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is administered weekly.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is administered weekly without break; weekly, two out of three weeks; weekly three out of four weeks; weekly six out of seven weeks, once every two weeks; once every 3 weeks; once every 4 weeks; once every 6 weeks; once every' 8 weeks, monthly, or every two to 12 months ln some embodiments, the intervals between each administration are less than about any one of 6 months, 3 months, 1 and 1 ⁇ 2 month (6 weeks), 1 month, 20 days, 15, days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day.
  • the intervals between each administration are more than about any one of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, there is no break in the dosing schedule. In some embodiments, the interval between each administration is no more than about a week.
  • the insulin sensitizer, mTQR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and NAD+ supplement are administered with the same dosing schedule. In some embodiments, the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRh activator, and NAD+ supplement are administered with different dosing schedules.
  • the methods described herein may involve a single treatment, or repeated treatments.
  • the combination regimen is administered for any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50 or more cycles. Each cycle of administration may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks. In some embodiments, administration of the combination regimen is repeated once per week, once 2 weeks, once 3 weeks, once 4 weeks, once per month, once per 2 months, once per 3 months, once per 4 months, once per 5 months, once per 6 months, once per 7 months, once per 8 months, once per 9 months, or once per year. In some embodiments, the interval between each cycle of administration is about any one of 1 week to 2 weeks, 2 weeks to 1 month, 2 weeks to 2 months, I month to 2 months, 1 month to 3 months, 3 months to 6 months, or 6 months to a year. In some embodiments, the combination regimen is administered over a period of time, such as at least about any one of 1 month, 3 months, 6 months, 1 year, 2 years, 3 years,
  • age-related diseases include cardiovascular diseases (e.g., stroke, atherosclerosis, hypertension, heart failure), osteoporosis, insulin-resistance and type II diabetes (e.g., diabetic retinopathy, neuropathy), CNS diseases (e.g., Alzheimer's disease, Parkinson's disease), ocular diseases (e.g., age-related macular degeneration, cataracts, retinopathy), skeletal muscular diseases, skin diseases and conditions (e.g.
  • cardiovascular diseases e.g., stroke, atherosclerosis, hypertension, heart failure
  • osteoporosis e.g., insulin-resistance and type II diabetes (e.g., diabetic retinopathy, neuropathy), CNS diseases (e.g., Alzheimer's disease, Parkinson's disease), ocular diseases (e.g., age-related macular degeneration, cataracts, retinopathy), skeletal muscular diseases, skin diseases and conditions (e.g.
  • seborrheic keratosis seborrheic keratosis, actinic keratosis, hair loss and alopecia, photo-aged skin, wrinkles, and skin spots
  • auto-immune diseases e.g., systemic lupus erythematosus, psoriasis, eczema, arthritis
  • primary or metastatic cancer lesions such as skin cancer and benign prostatic hyperplasia, e.g., for prevention or as adjuvant therapy.
  • the insulin sensitizer, mTQR inhibitor, agent having dual functions as an insulin sensitizer and an mTQR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement are administered systemically (e.g., orally).
  • the aging- related disease or condition is a chronic disease or condition due to aging.
  • the aging-related disease or condition is diabetes, cardiovascular diseases (e.g., stroke, heart failure and atherosclerosis), neurodegenerative diseases (e.g, peripheral or CNS
  • neurodegenerative disease such as Alzheimer’s disease
  • metabolic syndrome e.g., fatty liver
  • osteoarthritis e.g., osteoarthritis
  • AMD age-related macular degeneration
  • the individual has a combination of any of the above aging-related diseases or conditions.
  • the insulin sensitizer comprises metformin or an insulin sensitizing nutraceutical agent.
  • the insulin sensitizer comprises TZD.
  • the TZD is administered at a dosage lower than the dosage for treating bladder cancer and cardiac failure.
  • the insulin sensitizer comprises TZD and metformin or an insulin sensitizing nutraceutical agent.
  • the mTQR inhibitor is a rapalog, such as everolimus.
  • the mTOR inhibitor comprises a pan-mTGR inhibitor (e.g., torin 2).
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor, a CDK4/6 inhibitor, a pan-CD K inhibitor, and combinations thereof.
  • the senolytic p53/pKb activator is nutlin.
  • the senolytic p53/pRb activator is a COX2 inhibitor, such as voltaren, ibuprofen or aspirin.
  • the senolytic p53/pRb activator is a CDK4/6 inhibitor and/or a pan CDK inhibitor.
  • the NAD+ supplement comprises: (a) NA, and (b) one or more of NR, NMN and NAM.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD ⁇ supplement are administered locally (e.g, topically).
  • the aging- related disease or condition is a skin disease, such as aging skin pigmentation, seborrheic keratosis, actinic keratosis, hair loss and alopecia, photo-aged skin, wrinkles, skin spots, skin cancer (e.g., for prevention or as adjuvant therapy), psoriasis, or eczema.
  • the method is for cosmetic applications, such as for treating or preventing wrinkles.
  • the aging-related disease or condition is a disease or condition of tendons, ligaments, or muscle groups, such as muscle, tendon and joint pain, inflammation or strain, including all forms of arthritis such as osteoarthritis and rheumatoid arthritis.
  • the individual has a combination of any of the above aging-related diseases or conditions.
  • the age-related disease or condition is metabolic disease, diabetes or pre-diabetes, non-alcoholic fatty liver disease, non-alcoholic steatotie hepatitis, fat reduction or“sculpture” procedures such as the surgical removal of fat using liposuction and/or the application of cold, heat, laser, ultrasound, radiofrequency ablation.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement are administered locally, such as by instillation or implantation of a local delivery device, matrix or gel in an aging sensitive tissue or organ or a focal lesion thereof.
  • the aging-related disease is chronic cystitis, and wherein the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement are administered via an intravesical gel.
  • the aging-related disease or condition is a disease in the central nervous system (e.g., Amyotrophic lateral sclerosis or Parkinson’s disease), and wherein the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement are administered intracranially or intrathecally.
  • the aging-related disease or condition is a cardiovascular disease (e.g.
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement is administered via a drug-eluting stent.
  • the aging-related disease or condition is an intra-ocular disease (e.g., AMD), and wherein the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pKb activator, and/or NAD+ supplement are administered via an intra-ocular device or as an eye drop solution.
  • the aging-related disease or condition is diabetes or liver failure
  • the insulin sensitizer, mTOR inhibitor, agent having dual functions as an insulin sensitizer and an mTOR inhibitor, senolytic p53/pRb activator, and/or NAD+ supplement are administered via CT, MRI, or X-ray guided reservoir or device insertion.
  • the method is for prevention or used in adjuvant setting.
  • adjuvant setting refers to a clinical setting in which an individual has had a history of cancer, and generally been responsive to therapy, which includes, but is not limited to, surgery, radiotherapy, and chemotherapy.
  • Treatment or administration in the“adjuvant setting” refers to a subsequent mode of treatment.
  • compositions such as pharmaceutical compositions
  • kits and articles of manufacture for carrying out any one of the methods described herein.
  • a pharmaceutical composition comprising: (i) an insulin sensitizer, (ii) an mTOR inhibitor; (iii) a senolytic p53/pRb activator, and (iv) an NAD+ supplement; and a pharmaceutically acceptable excipient
  • the insulin sensitizer comprises a TDZ (e.g., pioglitazone) and/or a biguanide (e.g., metformin).
  • the insulin sensitizer is an insulin sensitizing nutraceutical agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapalog (e.g., everolimus).
  • the mTOR inhibitor comprises a pan- mTOR inhibitor (e.g, torin I, torin 2, PP242 or INK128).
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD- ⁇ - supplement comprises NA, NR, NMN, and/or NAM.
  • a pharmaceutical composition comprising: (i) agent having dual functions as an insulin sensitizer and an mTOR inhibitor, (ii) a senolytic p53/pRb activator; and (iii) an NAD+ supplement; and a pharmaceutically acceptable excipient.
  • the agent having dual functions as an insulin-sensitizer and an mTOR inhibitor is metformin in some embodiments, the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., diclofenac), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • an implantable device for treating or preventing an aging-related disease or condition comprising: (i) an insulin sensitizer; (ii) an rnTOR inhibitor; (iii) a senolytic p53/pRb activator, and (iv) an NAD+ supplement.
  • the insulin sensitizer comprises a TDZ (e.g., piog!itazone) and/or a biguanide (e.g., metformin).
  • the insulin sensitizer is an insulin sensitizing nutraceutieal agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutieal agent, and/or a rapalog (e.g., everolimus).
  • the mTOR inhibitor comprises a pan-mTOR inhibitor (e.g., torin 1, torin 2, PP242 or INK 128).
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • the implantable device is selected from the group consisting of an intravesical or other urogenital tract gel, an intra-cranial or intra-thecal device, intra-ocular device, a drug eluting stent, and CT, MRI or X-ray guided and inserted devices.
  • an implantable device for treating or preventing an aging-related disease or condition comprising: (i) agent having dual functions as an insulin sensitizer and an mTOR inhibitor, (ii) a senolytic p53/pRb activator; and (iii) an NAD+ supplement; and a pharmaceutically acceptable excipient.
  • the agent having dual functions as an insulin-sensitizer and an mTOR inhibitor is metformin.
  • the senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., diclofenac), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • compositions described herein can be administered in a conventional dosage form prepared by mixing with a standard pharmaceutically acceptable carrier according to known techniques.
  • a standard pharmaceutically acceptable carrier can be found in: Remington: The Science and Practice of Pharmacy (2005) 21 st Edition, Philadelphia, Pa. Lippincott Williams & Wilkins.
  • the compositions may be provided as pharmaceutical preparations, examples of which include, but are not limited to mixtures, solutions, creams, liniments, eye drops, and nanoparticle compositions.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement is formulated in a pharmaceutical composition comprising a
  • the insulin sensitizer and the insulin sensitizer are pharmaceutically acceptable excipient.
  • the insulin sensitizer and the insulin sensitizer are pharmaceutically acceptable excipient.
  • the TOR inhibitor, or the agent having dual functions as an insulin sensitizer and an mTOR inhibitor; the senolytic p53/pRb activator and the NAD+ supplement are formulated in a single pharmaceutical composition.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement are formulated in two or more pharmaceutical compositions.
  • the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and the NAD+ supplement are each formulated in a different matrix for immediate or extended release.
  • the pharmaceutically acceptable excipient is a serum, gel, buffer solution, cream, lotion, liniment, ointment or combinations thereof.
  • the insulin sensitizer or the agent having dual functions as an insulin sensitizer and an mTOR inhibitor comprises metformin.
  • the insulin sensitizer is in a pharmaceutical composition comprising at least about 0.5% (w/v), at least about 0.7% (w/v), or 0.5-10% (w/v) metformin.
  • the insulin sensitizer comprises pioglilazone. in some embodiments, the insulin sensitizer is in a
  • the mTOR inhibitor comprises rapamycin In some embodiments, the mTOR inhibitor is in a pharmaceutical composition comprising at least about 0.01% (w/v) rapamycin.
  • the senolytic p53/pRb activator comprises aspirin. In some embodiments, the senolytic p53/pRb activator is in a pharmaceutical composition comprising at least about 1% (w/v) aspirin. In some embodiments, the senolytic p53/pRb activator is in a pharmaceutical composition comprising at least about 0.5% (w/v) or about 0.5-4% (w/v) diclofenac. In some embodiments, the senolytic p53/pRb activator comprises nutiin-3.
  • the senolytic p53/pRb activator is in a pharmaceutical composition comprising at least about 0 3% (w/v) nutiin-3.
  • the NAD+ supplement is in a pharmaceutical composition comprising; (a) at least about 0.5% (w/v) Nicotinic Acid, and (b) at least about 1% (w/v) Nicotinamide Riboside (NR), at least about 1.5% (w/v) Nicotinamide Mononucleotide (NMN), and/or at least about 0.5% (w/v) Nicotinamide (NAM).
  • the NAD+ supplement is in a pharmaceutical composition comprising at least 0.5 % (w/v) or about 0.5-6% (w/v) NR. In some embodiments, the NAD+ supplement is in a pharmaceutical composition comprising at least 0.5 % (w/v) or about 0 5-6% (w/v) NA. In some embodiments, the pharmaceutical composition further comprises vitamin D, vitamin E, vitamin A, resveratrol, pterosti!bene, L-carnitine, R-lipoic acid, leptine, a caspase inhibitor, and/or Chayote ( Sechium edule) juice or extract. In some embodiments, the pharmaceutical composition comprises at least 0.5 % (w/v), such as about 0.5-3% (w/v) pterostilbene. In some embodiments, the
  • composition further comprises about 1-10% (w/v) urea, about 1 -10% (w/v) sodium acetate, about 1-30% (w/v) ethanol, about 5-40% (w/v) PEG200, and about 5-40% (w/v) PEG400.
  • kits for treating or preventing an aging-related disease or condition comprising: (i) an insulin sensitizer, (ii) an rnTOR inhibitor; (iii) a senoiytic p53/pRb activator; and (iv) an NAD+ supplement.
  • the insulin sensitizer comprises a TDZ (e.g., pioglitazone) and/or a biguanide (e.g., metformin).
  • the insulin sensitizer is an insulin sensitizing nutraceutical agent.
  • the mTOR inhibitor comprises rapamycin or a rapamycin-like nutraceutical agent, and/or a rapalog (e.g., everolimus).
  • the mTOR inhibitor comprises a pan- mTOR inhibitor (e.g, torin 1, torin 2, PP242 or INK128).
  • the senoiytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., ibuprofen), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD+ supplement comprises NA, NR, NMN, and/or NAM.
  • the kit further comprises an instruction for carrying out any one of the methods described above.
  • kits for treating or preventing an aging-related disease or condition comprising: (i) agent having dual functions as an insulin sensitizer and an mTOR inhibitor, (ii) a senoiytic p53/pRb activator; and (iii) an NAD+ supplement; and a pharmaceutically acceptable excipient.
  • the agent having dual functions as an insulin-sensitizer and an mTOR inhibitor is metformin.
  • the senoiytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor (e.g., diclofenac), a CDK4/6 inhibitor, a pan-CDK inhibitor, and combinations thereof.
  • the NAD-- supplement comprises NA, NR, NMN, and/or NAM.
  • the kit further comprises an instruction for carrying out any one of the methods described above.
  • the kit may further comprise a description of selection of individuals suitable for treatment.
  • the kit may comprise a description of selection of individuals based on their HbAlC levels.
  • Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine- readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • the package insert contain instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.
  • kits are in suitable packaging.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information.
  • the present application thus also provides articles of manufacture, which include vials (such as sealed vials), bottles, jars, flexible packaging, and the like.
  • An“article of manufacture” is any manufacture (e.g , a package or container) or kit comprising at least one reagent, e.g., a medicament for treatment of a disease or disorder (e.g., aging-related disease or condition), or a probe for specifically detecting a biomarker (e.g., HbAlC) described herein.
  • the manufacture or kit is promoted, distributed, or sold as a unit for performing the methods described herein.
  • the arti cle of manufacture may further compri se a second container comprising a pharmaceuticaily-acceptabie buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • a method of treating or preventing an aging-related disease or condition in an individual comprising administering to the individual: (i) an effective amount of an insulin sensitizer, (ii) an effective amount of an mTOR inhibitor, (iii) an effective amount of a senolytic p53/pRb activator, and (iv) an effective amount of an NAD+ supplement.
  • mTOR inhibitor comprises rapamycin and/or a rapalog.
  • rapalog is selected from the group consisting of everolimus, tacrolimus, CC 1-779, ABT-578, AP-23675, AP-23573, AP-23841, 7-epi- rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl -rapamycin, 7-epi- thiom ethyl -rapamycin, 7-demethoxy-rapamycin, 32-demethoxy -rapamycin, 2-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desm ethyl -rapamycin, 42-0-(2- hydroxyjethyl rapamycin, and combinations thereof.
  • mTOR inhibitor comprises a pan-mTOR inhibitor.
  • pan-mTOR inhibitor is selected from the group consisting of sapanisertib (INKI28), AZD2014, torin 1, torin 2, AZD8055, PP242, KU-006379, OSI-027, WAY-600, WAE-687, WYE-354, GSK1059615, and
  • a method of treating or preventing an aging-related disease or condition in an individual comprising administering to the individual: (i) an effective amount of an agent having dual functions as an insulin sensitizer and an mTOR inhibitor, (ii) an effective amount of a senolytic p53/pRb activator, and (iii) an effective amount of an NAD+ supplement.
  • an agent having dual functions as an insulin- sensitizer and an mTOR inhibitor is metformin.
  • senolytic p53/pRb activator is selected from a nutlin or analog thereof, a COX inhibitor, a CDK4/6 inhibitor, a pan- CDK inhibitor, and combinations thereof.
  • the senolytic p53/pRb activator comprises a nutlin, and wherein the nutlin is nutlin-3A.
  • the senolytie p53/pRb activator comprises a COX inhibitor, and wherein the COX inhibitor is selected from the group consisting of aspirin, ibuprofen, naproxen, diclofenac, indomethacin, and combinations thereof.
  • wdierein the senolytie p53/pRb activator comprises a pan CDK inhibitor, and wherein the pan CDK inhibitor is selected from the group consisting of flavopiridol, olomoucine II, purvalanol A, SNS-032, dinaciclib, MK-7965,
  • the senolytie p53/pRb activator comprises a CDK4/6 inhibitor
  • wlierein the CDK4/6 inhibitor is selected from the group consisting of ribociclib, palbociclib, abemaciclib, and trilaciclib.
  • the method of any one of embodiments 1-16, wdierein the NAD+ supplement comprises Nicotinic Acid (NA), Nicotinamide Riboside (NR), Nicotinamide Mononucleotide (NMN), and/or Nicotinamide (NAM).
  • Nicotinic Acid NA
  • Nicotinamide Riboside NR
  • Nicotinamide Mononucleotide NNN
  • Nicotinamide NAM
  • the NAD+ supplement comprises: (a) NA and (b) one or more of NR, NMN and NAM.
  • the NAD+ supplement comprises NR and NA.
  • the insulin sensitizer, the mTQR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytie p53/pRb activator and/or the NAD+ supplement are nutraceutical agents.
  • the aging-related disease or condition is selected from the group consisting of cancer, cardiovascular diseases, central nervous system diseases, Alzheimer's disease, Parkinson's disease, age-related macular degeneration, cataract, retinopathy, skeletal muscular diseases, osteoporosis, arthritis, insulin-resistance and type II diabetes, benign prostatic hyperplasia, systemic lupus erythematosus, auto-immune diseases, psoriasis, aging skin pigmentation, seborrheic keratosis, actinic keratosis, hair loss, alopecia, photo-aged skin, wrinkles, skin spots, skin cancer, eczema, pain, inflammation or strain of muscle, tendon or joint, lipolysis, post !ipectomy and liposuction, non-alcoholic fatty liver disease, non-alcoholic steatotic hepatitis, arthritis, and combinations thereof.
  • the method is selected from the group consisting of cancer, cardiovascular diseases, central nervous system diseases, Alzheimer's disease, Parkinson
  • the aging-related disease or condition is obesity, non-alcoholic fatty liver disease, non-alcoholic steatotie hepatitis, pre-diabetic, diabetes type II and other fat or inflammatory' induced metabolic imbalances (e.g , hypercholesterolemia).
  • any one of embodiments 1-24, wherein the insulin sensitizer, the mTQR inhibitor, the agent having dual functions as an insulin sensitizer and an mTQR inhibitor, the senolytic p53/pKb activator, and/or the NAD+ supplement is administered systemically.
  • any one of embodiments 1-24 wherein the insulin sensitizer, mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTQR inhibitor, the senolytic p53/pRb activator and/or the NAD+ supplement is administered via a combination of local and systemic routes.
  • any one of embodiments 1-24 wherein the insulin sensitizer, the mTQR inhibitor, the agent having dual functions as an insulin sensitizer and an mTQR inhibitor, the senolytic p53/pRb activator, and/or the NAD+ supplement is administered locally.
  • cardiovascular diseases central nervous system diseases, Alzheimer's disease,
  • Parkinson's disease age-related macular degeneration, cataract, retinopathy, skeletal muscular diseases, aging skin pigmentation, seborrheic keratosis, actinic keratosis, hair loss, alopecia, photo-aged skin, wrinkles, skin spots, skin cancer, psoriasis, eczema, pain. inflammation or strain of muscle, tendon or joint, lipofysis, post lipectomy and liposuction, non-alcoholic faty liver disease, non-alcoholic steatotic hepatitis, and combinations thereof.
  • the implanted device is selected from the group consisting of an intravesical or other urogenital tract gel, an intra-cranial or intra-thecal device, intra-ocular device, a drug-eluting stent, and CT, MRi or X-ray guided and inserted devices
  • any one of embodiments 1-31, wherein the insulin sensitizer, the mTOR inhibitor, the agent having dual functions as an insulin sensitizer and an mTOR inhibitor, the senolytic p53/pRb activator, and/or the NAEM- supplement is formulated in a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
  • any one of embodiments 32-36, wherein the insulin sensitizer or the agent having dual functions as an insulin sensitizer and an mTOR inhibitor is in a pharmaceutical composition comprising at least about 0.5% (e.g., about 0.5-10%, w/v) metformin.
  • senolytic p53/pRb activator is in a pharmaceutical composition comprising at least about 0.5% (e.g., about 0.5-4%, w/v) diclofenac.
  • NAD+ supplement is in a pharmaceutical composition comprising: (a) at least about 0.5% (w/v) Nicotinic Acid, and (b) at least about 0.5% (w/v) Nicotinamide Riboside (NR), at least about 1.5% (w/v) Nicotinamide Mononucleotide (NMN), and/or at least about 0.5% (w/v) Nicotinamide (NAM).
  • a pharmaceutical composition comprising: (a) at least about 0.5% (w/v) Nicotinic Acid, and (b) at least about 0.5% (w/v) Nicotinamide Riboside (NR), at least about 1.5% (w/v) Nicotinamide Mononucleotide (NMN), and/or at least about 0.5% (w/v) Nicotinamide (NAM).
  • NAD+ supplement is in a pharmaceutical composition comprising at least 0.5 % (e.g., about 0.5-6%, w/v) NR and/or at least 0.5 % (e.g., about 0.5-6%, w/v) NA
  • the method further comprises administering to the individual pterostilbene in a pharmaceutical composition comprising at least 0.5 % (e.g, about 0.5-3%, w/v) pterostilbene.
  • a pharmaceutical composition comprising at least 0.5 % (e.g, about 0.5-3%, w/v) pterostilbene.
  • a method of decelerating, stabilizing, ameliorating, or reversing one or more signs of aging in a mammalian cell comprising contacting the mammalian cell with:
  • a method of decelerating, stabilizing, ameliorating, or reversing one or more signs of aging in a mammalian cell comprising contacting the mammalian cell with:
  • a pharmaceutical composition comprising:
  • a pharmaceutical composition comprising:
  • a pharmaceutical composition comprising about 0.5-10% (w/v) metformin, about 0.5-4% (w/v) diclofenac, about 0.5-6% (w/v) nicotinamide riboside, about 0.5-6% (w/v) nicotinic acid, about 0.5-10% (w7v) pterostilbene, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of embodiment 55 wherein the pharmaceutical composition is formulated for topical administration.
  • the pharmaceutical composition of embodiment 55 or 56 further comprising about 1-10% (w/v) urea, about 1-10% (w/v) sodium acetate, about 1-30% (w/v) ethanol, about 5-40% (w/v) PEG200, and about 5-40% (w/v) PEG400.
  • a kit for treating or preventing an aging-related disease or condition comprising:
  • a kit for treating or preventing an aging-related disease or condition comprising:
  • An implantable device for treating or preventing an aging-related disease or condition comprising:
  • An implantable device for treating or preventing an aging-related disease or condition comprising:
  • the invention is based on preliminary data from clinical trials of two exemplary anti aging combination regimen as described below.
  • the clinical trials (A-C) were interventional, Phase I/II open label, studies of two combination regimens for promoting healthy aging in human individuals.
  • systemic Trial A studied a four-component combination regimen consisting of an insulin sensitizer, a senolytic p53 activator, an mTOR inhibitor, and a NAD ⁇ supplement, which was administered systemically.
  • Rapamycin was stopped on the 14 th w ? eek and an office examination and laboratory assays in the same week. All other medications such as ibuprofen (bid for 2 days/week), nicotinic acid (NA) and nicotinamide riboside (NR), and metformin twice daily continued on the 14 th week. All medications were resumed as of the 15 week for 6 more weeks (second cycle). Then, rapamycin alone was stopped in the 7 th week in this second cycle. Subsequent treatment cycles are the same: 6 w'eeks rapamycin on and 1 week off, accompanied by examination and laboratory assay in the 7 th week.
  • All other medications such as ibuprofen (bid for 2 days/week), nicotinic acid (NA) and nicotinamide riboside (NR), and metformin twice daily continued on the 14 th week. All medications were resumed as of the 15 week for 6 more weeks (second cycle). Then, rapamycin alone was stopped
  • the second clinical trial (“local Trial B”) studied a three-component combination regimen consisting of an agent having dual functions as an insulin sensitizer and an mTOR inhibitor, a senolytic p53 activator, and a NAD+ supplement in treating osteoarthritis, which was administered topically.
  • LASO aqueous spasmodic serum
  • metformin 2% aqueous spasmodic acid 1.5%
  • nicotinamide riboside 3% aqueous spasmodic acid 1.5%
  • pterostilbene 1.5% a phase I three-step escalating modified Fibonacci study involved groups of three patients being treated with either diclofenac 2% serum, followed by a washout period of two weeks before a metformin 2% serum, and then after a second washout period of two weeks, to start finally the LASO serum.
  • the serum was applied to locally to a kno n inflamed, or stiffness, or painful joint site in the peripheral joints such as the knees, fingers, wrist or the spine.
  • the third clinical trial (“local Trial C”) studied the efficacy of the LA80 serum in promoting post iipolysis fat homeostasis, and treating diabetic type 2 glucose resistance, non- alcoholic fatty liver disease, non-alcoholic steatotic hepatitis for post Iipolysis fat homeostasis, diabetic type 2 glucose resistance, non-alcoholic fatty liver disease, non-alcoholic steatotic hepatitis LASO was applied in groups of three patients in three escalating steps as a modified Fibonacci study. The target was abdominal fat. LASO was applied up to 15 cc onto the abdominal fat twice daily followed by a massage.
  • Healthy individuals of either gender and at least 50 years old and no history of diabetes (Type 1 or Type 2), and having an Hbalc (Hemoglobin A1C) level of 6.4 or less were eligible to enroll in the study. About 20 individuals are targeted to be enrolled in the study. These inclusion criteria were chosen to study subjects who may have evidence of impaired glucose regulation, but are not yet diabetic.
  • Exclusion criteria for this clinical trial included: (!) serious chronic or acute illness, including cancer, clinically significant congestive heart failure, COPD, inflammatory conditions, serum creatinine > 1.4 mg/dl (female) or > 1.5 mg/di (male), active liver disease, history of metabolic acidosis, poorly controlled hypertension, epilepsy, recent (within 3 months) CVD event (Ml, PTC A, CABG, stroke), history of bariatric or other gastric surgery, cigarette smoking, binge alcohol use (>7 drinks in 24 hrs); (2) treatment with drugs known to influence insulin sensitivity and/or immune functions (other diabetes medications, systemic glucocorticoids); and hypersensitivity to any component of the treatment or formulation.
  • the primary outcome measures the safety of the combination regimen, as assessed at 14 weeks, 28 weeks and 1 year from the inception of the treatment. This outcome addresses safety concerns related to long-term inhibition of mTOR by administration of rapamycin or metformin, with or without a nutraceutical agent.
  • the primary outcome measures of local Trial B also include the efficacy evaluated by WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) at 14 and 28 weeks.
  • the primary outcome measures of local Trial C include efficacy of fat weight reduction, both subcutaneous and visceral wise as assessed by a DEXA scan, as well as insulin sensitivity index such as fasting glucose, Hbalc or HQMA-IR, liver function tests and IL6 as an inflammatory markers.
  • the secondary outcomes include the following; (1) assessment of insulin sensitivity and insulin secretion at 14, 28 weeks and every 6-7 months afterwards post treatment by C peptide, fasting glucose and Hbalc; (2) determination of telomere length at week 14 and at 6-7 months afterwards post treatment and then yearly afterwards; (3) determination of IL6 level at week 14 and t 6-7 months afterwards post treatment and then yearly afterwards; and (4) assessment of rates of aging-related diseases at week 14 and at 6-7 months afterwards post treatment and then yearly afterwards.
  • Aging-related diseases assessed in this experiment include cancer, cardiovascular, central nervous system diseases (e.g., Alzheimer’s), and metabolic diseases (e.g., type 2 diabetes).
  • the rates of incidence of aging-related diseases in individuals treated with the combination regimen in the long-term may show a decrease compared with historic controls;
  • Insulin sensitivity is estimated from insulin and glucose levels obtained following the standard meal challenge, using HOMA-IR, or a modification of the Matsuda index, or with triglycerides level and glucose/insulin level.
  • Telomere length in cells from PBMC or oral mucous membrane samples from individuals treated with the combination regimen is determined. The telomere length may be stabilized, shortened, or prolonged in response to the combination regimen and aging.
  • the assay used is Tel o Year and telomere lengths are measured at week 14, and at 6-7 months afterwards post treatment and then yearly afterwards; (7)
  • the IL6 level is a good measurement of inflammation related to aging, which may stabilize, decrease or increase in response to the combination regimen.
  • the 1L6 level is measured at week 14, and at 6-7 months afterwards post treatment and then yearly afterwards; (8) Fat stored as subcutaneous, visceral adipose tissue and muscle mass at w3 ⁇ 4ek 14, and at 6-7 months afterwards post treatment and then yearly afterwards; (9) Liver functions assay, albumin level and eGFR are also measured accordingly.
  • Investigational outcome measures assess the efficacy of the combination regimen in individuals having different levels of glucose regulation capacity. Individuals are classified into three groups: those with Hbalc level of 5 6 or below, those with Hbalc level of 5.7 to 6.0, and those with Hbalc of 6.1 to 6.4.
  • the insulin sensitivity outcome as defined by HOMA-IR, 11.6 level, telomere length and NAD+ (metabolomes) levels of the three groups of individuals are compared.
  • Individuals with mTOR activation may have more insulin resistant cells driven into irreversible senescence so that mTOR inhibition has less anti-aging effect when combined with senolytic p53 therapy. This effect may be more apparent in individuals having a high insulin resistant factor to start with, such as those with a HOMA-IR over 2.
  • Table 1 and FIG. 1 show results from Patient 1 on the systemic Trial A, who has been treated with the combination regimen for over 1 year.
  • Table 2 and FIG. 2 show results from Patient 2 on the systemic Trial A, who has been treated with the combination regimen for over 1 year.
  • Table 4 and FIG. 3 show results from Patient 1 on the local Trial C, who has been treated with the combination regimen from April 2018 to October 2018.

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Abstract

La présente invention concerne des méthodes, des compositions et des kits permettant de traiter ou de prévenir une maladie ou un trouble lié au vieillissement chez un individu. La méthode consiste à administrer un régime combiné, comprenant : un sensibilisateur à l'insuline, un inhibiteur de mTOR, ou un agent ayant des fonctions doubles de sensibilisateur à l'insuline et d'inhibiteur de mTOR ; un activateur de p53/pRb sénolytique ; et un complément de NAD+. Chaque constituant du régime combiné peut être administré par voie systémique ou locale. De nombreux produits pharmaceutiques cliniquement disponibles sont appropriés pour être utilisés dans ce régime combiné.
PCT/US2018/062067 2017-11-22 2018-11-20 Méthodes et compositions anti vieillissement WO2019104065A1 (fr)

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WO2021237193A1 (fr) * 2020-05-22 2021-11-25 Georgetown University Utilisation de précurseurs de nad+, d'inhibiteurs de sting et d'agonistes de fxr permettant d'inhiber la libération de cytokine induite par sars-cov-2 (covid-19)
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WO2021254750A1 (fr) * 2020-06-19 2021-12-23 Unilever Ip Holdings B.V. Utilisation de composés d'indole pour traiter les signes du vieillissement de la peau
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WO2023038027A1 (fr) * 2021-09-07 2023-03-16 国立大学法人京都大学 Méthode de criblage de médicament sénolytique et médicament sénolytique
RU2806599C1 (ru) * 2022-05-25 2023-11-01 Общество с ограниченной ответственностью "СИСТЕМА-БИОТЕХ" Косметическая композиция с антивозрастной активностью для предотвращения старения и корректировки возрастных изменений кожи, ее применение (варианты)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5536729A (en) * 1993-09-30 1996-07-16 American Home Products Corporation Rapamycin formulations for oral administration
US20020128278A1 (en) * 1999-04-29 2002-09-12 Samuel Rahbar Pentoxifylline, pioglitazone and metformin are inhibitors of formation of advanced glycation endproducts (AGE's)
US20030170287A1 (en) * 2002-01-10 2003-09-11 Prescott Margaret Forney Drug delivery systems for the prevention and treatment of vascular diseases
US20060229265A1 (en) * 2005-03-30 2006-10-12 Sirtris Pharmaceuticals, Inc. Nicotinamide riboside and analogues thereof
US20120283269A1 (en) * 2009-11-04 2012-11-08 Health Research Inc. Method and Compositions for Suppression of Aging
WO2017062311A1 (fr) * 2015-10-07 2017-04-13 Huizenga Joel Réinitialisation de voies biologiques de défense contre et de réparation d'une détérioration causée par le vieillissement humain

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5536729A (en) * 1993-09-30 1996-07-16 American Home Products Corporation Rapamycin formulations for oral administration
US20020128278A1 (en) * 1999-04-29 2002-09-12 Samuel Rahbar Pentoxifylline, pioglitazone and metformin are inhibitors of formation of advanced glycation endproducts (AGE's)
US20030170287A1 (en) * 2002-01-10 2003-09-11 Prescott Margaret Forney Drug delivery systems for the prevention and treatment of vascular diseases
US20060229265A1 (en) * 2005-03-30 2006-10-12 Sirtris Pharmaceuticals, Inc. Nicotinamide riboside and analogues thereof
US20120283269A1 (en) * 2009-11-04 2012-11-08 Health Research Inc. Method and Compositions for Suppression of Aging
WO2017062311A1 (fr) * 2015-10-07 2017-04-13 Huizenga Joel Réinitialisation de voies biologiques de défense contre et de réparation d'une détérioration causée par le vieillissement humain

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHOI ET AL.: "Cyclooxygenase-2 functionally inactivates p53 through a physical interaction with p53", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - MOLECULAR CELL RESEARCH, vol. 1793, no. 8, 2009, pages 1354 - 1365, XP026336410, doi:10.1016/j.bbamcr.2009.05.006 *
DING ET AL.: "Current Perspective in the Discovery of Anti-aging Agents from Natural Products", NATURAL PRODUCTS AND BIOPROSPECTING, vol. 7, no. 5, 31 May 2017 (2017-05-31) - October 2017 (2017-10-01), pages 335 - 404, XP055615517 *
LEONTIEVA ET AL.: "Gerosuppression by pan-mTOR inhibitors", AGING, vol. 8, no. 12, 30 December 2016 (2016-12-30), pages 3535 - 3549, XP055615511 *
PALMIERI ET AL.: "Ultrasound Lipolysis and Suction Lipectomy for Treatment of Obesity", THE AMERICAN JOURNAL OF COSMETIC SURGERY, vol. 14, no. 3, 1 September 1997 (1997-09-01), pages 289 - 296, XP055615514 *
PANTZIARKA ET AL.: "Repurposing Drugs in Oncology (ReDO) - diclofenac as an anti-cancer agent", ECANCERMEDICALSCIENCE, vol. 10, 2016, pages 1 - 32, XP002791052 *

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