WO2022093763A1 - Méthodes et compositions pour diagnostiquer et traiter une fragilité - Google Patents

Méthodes et compositions pour diagnostiquer et traiter une fragilité Download PDF

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WO2022093763A1
WO2022093763A1 PCT/US2021/056575 US2021056575W WO2022093763A1 WO 2022093763 A1 WO2022093763 A1 WO 2022093763A1 US 2021056575 W US2021056575 W US 2021056575W WO 2022093763 A1 WO2022093763 A1 WO 2022093763A1
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iage
drug
subject
frailty
cxcl1
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PCT/US2021/056575
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David Furman
Khiem Nguyen
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Edifice Health, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
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    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
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    • A61K31/075—Ethers or acetals
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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Definitions

  • Frailty is a common syndrome that is associated with vulnerability to poor health outcomes. Frail older people have increased risk of morbidity, institutionalization and death, resulting in burden to individuals, their families, health care services and society. Assessment and treatment of the frail individual provide many challenges to clinicians working with older people. Despite frailty being increasingly recognized in the field, there is a paucity of direct evidence to guide interventions to reduce frailty.
  • Frailty is a common geriatric syndrome, characterized by decreased reserve and increased vulnerability to adverse outcomes, including falls, hospitalization, institutionalization and death.
  • the prevalence and the consequences of frailty present a considerable burden to older people, their care givers, health care services and the community. Interventions designed to reduce frailty therefore have the potential for profound and widespread benefits.
  • Future frailty outcomes are related to iAge, chronological age, BMI (body mass index), gender, and CMV status. Future frailty outcomes can be related to iAge, BMI (body mass index), gender, and CMV status. Future frailty can also be related to chronological age, BMI (body mass index), gender, and CMV status. Using a combination of all or some of these factors (iAge, chronological age, BMI (body mass index), gender, and CMV status) subjects at risk for poor frailty outcomes can be identified.
  • the future frailty score can be used to measure frailty for the patient in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years in the future.
  • the future frailty score can be used to measure frailty for the patient in 1-5, 5-10, 10- 15, 15-20, 1-10, or 10-20 years in the future.
  • An inflammatory age scoring system (iAge) combined with chronological age, BMI, gender, and/or CMV status can be used to classify patients into those likely to suffer from severe frailty and those who will not.
  • the frailty scoring system can be used to guide prophylactic therapy to lower the patient’s iAge and so reduce the risk of severe frailty.
  • the future frailty score can also be used to guide patient treatment to change BMI to reduce the risk of frailty.
  • Subjects identified as having poor future frailty outcomes can be treated to lower their iAge using the methods and compositions described herein. Lowering the subjects iAge can reduce the severity of the subject’s future frailty outcome.
  • the disclosure also describes a method for treating cardiovascular disease patients or patients at risk of cardiovascular disease whereby subjects can be stratified based on risk for cardiovascular disease based on their inflammatory factor level; and can receive individualized interventions to treat and/or reduce the inflammatory factors and improve their risk profile, cardiovascular health, and response to cardiovascular treatments.
  • An inflammatory age scoring system can be used to classify patients into those who have higher risk for cardiovascular disease versus those who have a low risk.
  • the inflammatory age scoring system can be used to guide initial therapy targeting inflammation to improve outcomes of patients receiving treatment for cardiovascular disease, and to reduce risk of cardiovascular disease in asymptomatic patients (e.g., prophylactic treatment).
  • MIG, EOTAXIN, Mip-la, LEPTIN, IL-1 ⁇ , IL-5, IFN- ⁇ and IL-4 (positive contributors) and TRAIL, IFN- ⁇ , CXCL1, IL-2, TGF- ⁇ , PAI-1 and LIF (negative contributors) are related to iAge and can be used to make up the iAge score.
  • MIG, LIF and Sirtuin-3 are strongly related to cardiac aging and risk for cardiovascular disease and can be used alone or combination with other factors to define the risk level of a patient.
  • the disclosure describes a method for treating subjects with immunotherapy (e.g., cancer patients), vaccines (e.g., subjects who will benefit from vaccination), and antipathogen therapeutics (e.g., antibiotics, antivirals, antifungals, etc.) whereby subjects can be stratified based on their inflammatory age levels; and can receive individualized interventions to reduce inflammatory age and improve clinical and immune responses to the therapeutic treatment (e.g., cancer immunotherapy, vaccination, anti-pathogen therapeutic).
  • immunotherapy e.g., cancer patients
  • vaccines e.g., subjects who will benefit from vaccination
  • antipathogen therapeutics e.g., antibiotics, antivirals, antifungals, etc.
  • An inflammatory age scoring system can be used to classify subjects (e.g., cancer patients, vaccination subjects, subjects with an infectious disease) into those who have an immune system that can mount an effective response (e.g., mount an objective clinical response to immunotherapy, produce a protective response to a vaccine, or mount an immune response against a pathogen) versus those who will not.
  • the inflammatory age scoring system can be used to guide initial therapy targeting inflammation to enable optimal objective responses in those patients who were classified as non-responders.
  • the iAge can also be used to stratify subjects for different courses of vaccines or antipathogen therapy.
  • a cytokine response score CRM can also be used to classify cancer patients into those who will mount an objective clinical response to immunotherapy versus those who will not.
  • iAge iAge, CRS, and/or Jak-STAT responses
  • the subject can be classified as a responder or a nonresponder for the immunotherapy.
  • Patients who are classified as nonresponders can be treated to lower their iAge, increase their CRS, and/or increase their Jak-STAT response so that the subject moves into a responder category.
  • Classifications are made by comparing the subjects iAge, CRS, and/or Jak- STAT response to those of patients of similar chronological age.
  • iAge, CRS, and/or Jak-STAT response places them at a younger iAge for their age cohort, or a more responsive CRS and/or Jak-STAT score the subject can be a responder for immunotherapy.
  • Subjects with older iAge for their age cohort, and/or lower scores for CRS and/or Jak-STAT can be treated to lower their iAge and/or increase their CRS and/or Jak-STAT score so that they move into a responder group for immunotherapy.
  • a subject Based on a subject’s iAge, CRS, Jak-STAT responses, cAge, and/or levels of MIG, LIF and/or SIRT3 the subject can be classified as high risk or low risk for cardiovascular disease. Patients who are classified as high risk can be treated to lower their iAge, increase their CRS, increase their Jak-STAT response, lower cAge, lower MIG, raise LIF and/or raise SIRT3 so that the subject moves into the low risk category. Classifications are made by comparing the subject’s iAge, CRS, Jak-STAT responses, cAge, and/or levels of MIG, LIF and/or SIRT3to those of patients of similar chronological age.
  • iAge When a subject’s iAge, CRS, Jak-STAT responses, cAge, and/or levels of MIG, LIF and/or SIRT3 places them at a younger iAge for their age cohort, or a more responsive CRS and/or Jak-STAT score, a lower cAge, a lower MIG, a higher LIF, and/or a higher SIRT3 the subject is less at risk for cardiovascular disease.
  • Subjects with older iAge for their age cohort, lower scores for CRS and/or Jak-STAT, older cAge, a higher MIG, a lower LIF, and/or a lower SIRT3 can be treated to lower their iAge, increase their CRS and/or Jak-STAT score, lower cAge, lower MIG, increase LIF, and/or increase SIRT3 so that they move into the lower risk cohort of patients.
  • a subject’s MIG, LIF, and Sirtuin-3 levels can also be used to classify risk for cardiovascular disease.
  • Patients can be classified by their levels of MIG, Sirtuin-3, LIF, and optionally other factors. For example, the patients can be assigned a cardiac age based on these factors with or without other factors.
  • cardiac age a patient’s levels of MIG, SIRT3, LIF, and/or cardiac age (cAge) places them in a younger quartile, quintile, decile (or other quantile) for their age cohort the subject is less at risk for cardiovascular disease.
  • Subjects with older levels of MIG, SIRT3, LIF, and/or cAge for their age cohort can be treated to lower their levels of MIG, SIRT3, LIF, and/or cAge so that they move into the lower risk cohort of patients.
  • the disclosure describes diagnosing cardiovascular disease, monitoring cardiovascular disease progression, monitoring the treatment of cardiovascular disease, prognosing cardiovascular disease, treating cardiovascular disease, alleviating symptoms of cardiovascular disease, inhibiting progression of cardiovascular disease, and preventing cardiovascular disease, in a mammal using the markers, combinations of markers, treatments, prophylactic treatments, and/or agents provided herein.
  • the disclosure describes compounds and methods for modifying iAge (or cAge or frailty score) of a subject.
  • the iAge (or cAge or frailty score) modification can reclassify the cohort of a subject undergoing anti-frailty treatment, cancer treatment, immunotherapy, or cardiovascular disease treatment.
  • the compounds and methods can modify one or more markers involved in the iAge determination.
  • the disclosure also describes methods for identifying drugs, food compounds and other molecules that modify iAge (or cAge or frailty score). These methods identify drugs, food compounds, and other molecules that interact with and modify the levels of certain markers involved with the iAge (or cAge or frailty score) determination. These drugs, food compounds, and other molecules can be used with subjects to modify their iAge (or cAge or frailty score) and so change the cohort in which the subject stratifies and so alter the response of the subject to treatment and/or risk of disease.
  • FIG. 1A, IB and 1C show graphs of iAge, naive CD8(+) T-cells, and Jak STAT signaling responses.
  • FIG. 2 shows the stratification of patients by iAge and CRS into responders and nonresponders.
  • FIG. 3 shows the stratification of cancer patients using iAge.
  • FIG. 4 depicts the fold change in MIG mRNA and SIRT3 mRNA after passage of cells following differentiation into endothelial cells from hiPSCs.
  • FIG. 5 is a bar graph showing the relative expression levels of CXCR3 in different cell types.
  • FIG. 6 is a line graph of the percent relaxation of mouse thoracic aortic sections with different acetylcholine concentrations, after exposure to different amounts of MIG (0.1 ug/ml, 1 ug/ml, and 10 ug/ml).
  • FIG. 7A and 7B shows the Modified Frailty Index used herein.
  • FIG. 8 shows a plot of calendar or iAge against total frailty score with iAge v total frailty score points in circles and Age v total frailty score in plus signs.
  • FIG. 9 shows bar graphs for the regression coefficients (with p values for some) for the Full Model for predicting future frailty using iAge, chronological age, gender, BMI and CMV status.
  • activation is defined to be a physiological condition upon exposure to a substance, allergen, drug, protein, chemical, or other stimulus, or upon removal of a substance, allergen, drug, protein, chemical or other stimulus.
  • an “antibody” is defined to be a protein functionally defined as a ligand-binding protein and structurally defined as comprising an amino acid sequence that is recognized by one of skill as being derived from the variable region of an immunoglobulin.
  • An antibody can consist of one or more polypeptides substantially encoded by immunoglobulin genes, fragments of immunoglobulin genes, hybrid immunoglobulin genes (made by combining the genetic information from different animals), or synthetic immunoglobulin genes.
  • the recognized, native, immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as myriad immunoglobulin variable region genes and multiple D-segments and J-segments.
  • Light chains are classified as either kappa or lambda.
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
  • Antibodies exist as intact immunoglobulins, as a number of well characterized fragments produced by digestion with various peptidases, or as a variety of fragments made by recombinant DNA technology. Antibodies can derive from many different species (e.g., rabbit, sheep, camel, human, or rodent, such as mouse or rat), or can be synthetic. Antibodies can be chimeric, humanized, or humaneered. Antibodies can be monoclonal or polyclonal, multiple or single chained, fragments or intact immunoglobulins.
  • an “antibody fragment” is defined to be at least one portion of an intact antibody, or recombinant variants thereof, and refers to the antigen binding domain, e.g., an antigenic determining variable region of an intact antibody, that is sufficient to confer recognition and specific binding of the antibody fragment to a target, such as an antigen.
  • antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, scFv antibody fragments, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, and multi-specific antibodies formed from antibody fragments.
  • scFv is defined to be a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived.
  • an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise Vr-linker-Vu or may comprise Vu-linker-Vu
  • an “antigen” is defined to be a molecule that provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically-competent cells, or both.
  • any macromolecule including, but not limited to, virtually all proteins or peptides, including glycosylated polypeptides, phosphorylated polypeptides, and other post-translation modified polypeptides including polypeptides modified with lipids, can serve as an antigen.
  • antigens can be derived from recombinant or genomic DNA.
  • any DNA which comprises a nucleotide sequences or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an “antigen” as that term is used herein.
  • an antigen need not be encoded solely by a full length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to encode polypeptides that elicit the desired immune response.
  • an antigen need not be encoded by a “gene” at all.
  • an antigen can be synthesized or can be derived from a biological sample, or can be a macromolecule besides a polypeptide.
  • a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a fluid with other biological components.
  • CAR Chimeric Antigen Receptor
  • CAR Chimeric Antigen Receptor
  • a “CAR T-cell” or “CAR T-lymphocyte” are used interchangeably, and are defined to be a T-cell containing the capability of producing CAR polypeptide, regardless of actual expression level.
  • a cell that is capable of expressing a CAR is a T-cell containing nucleic acid sequences for the expression of the CAR in the cell.
  • an “effective amount” or “therapeutically effective amount” are used interchangeably, and defined to be an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result.
  • an “epitope” is defined to be the portion of an antigen capable of eliciting an immune response, or the portion of an antigen that binds to an antibody.
  • Epitopes can be a protein sequence or subsequence that is recognized by an antibody.
  • an “expression vector” and an “expression construct” are used interchangeably, and are both defined to be a plasmid, virus, or other nucleic acid designed for protein expression in a cell.
  • the vector or construct is used to introduce a gene into a host cell whereby the vector will interact with polymerases in the cell to express the protein encoded in the vector/construct.
  • the expression vector and/or expression construct may exist in the cell extrachromosomally or integrated into the chromosome. When integrated into the chromosome the nucleic acids comprising the expression vector or expression construct will be an expression vector or expression construct.
  • frailty is defined to be clinically recognizable state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with everyday or acute stressors is comprised.
  • Frailty screenings methods recommended by the International Conference of Frailty and Sarcopenia Research (ICFSR) include, for example, Rockwood’s Clinical Frailty Scale (CFS), the International Association of Nutrition and Ageing (IANA) FRAIL scale, and the Edmonton Frailty Scale (EFS). Additional frailty scoring systems includes the novel methods described herein.
  • heart failure often called congestive heart failure (CHF) or congestive cardiac failure (CCF), means a condition that occurs when the heart is unable to provide sufficient pump action to maintain blood flow to meet the needs of the body.
  • CHF congestive heart failure
  • CCF congestive cardiac failure
  • Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition is typically diagnosed by patient physical examination and confirmed with echocardiography. Common causes of heart failure include myocardial infarction and other forms of ischemic heart disease, hypertension, valvular heart disease, and cardiomyopathy.
  • the term heart failure is sometimes incorrectly used for other cardiac-related illnesses, such as myocardial infarction (heart attack) or cardiac arrest, which can cause heart failure but are not equivalent to heart failure.
  • heterologous is defined to mean the nucleic acid and/or polypeptide is not homologous to the host cell.
  • heterologous means that portions of a nucleic acid or polypeptide that are joined together to make a combination where the portions are from different species, and the combination is not found in nature.
  • the term “impaired immune function” is defined to be any reduction in immune function in an individual, as compared to a fully healthy individual. Individuals with an impaired immune function are readily identifiable by substantially increased abundance of CD8+ CD28- cells or more broadly by reduced cytokine responses, increased baseline phosphoprotein levels and other co-occurring measure.
  • inflammasome is defined as cytosolic multiprotein complexes that are composed of an inflammasome-initiating sensor, apoptosis- associated speck-like protein containing a CARD (Caspase Activation and Recruitment Domain) acts as an adaptor protein and the protease-caspase- 1.
  • Inflammasome-initiating sensors include members of the NLRs the pyrin and HIN domain-containing (also known as PYHIN, Aim 2-like receptors, or ALRs; e.g., Aim2), or the TRIM (e.g., pyrin) family.
  • Complex assembly leads to caspase-1- dependent cleavage of cytokines pro-interleukin 1 ⁇ (pro-IL- 1 ⁇ ) and pro-IL-18 into secreted mature forms.
  • pro-IL- 1 ⁇ pro-interleukin 1 ⁇
  • pro-IL-18 pro-IL-18 into secreted mature forms.
  • inflammasomes initiate pyroptotic
  • scFv single chain antibody
  • An antibody in scFv (single chain fragment variable) format consists of variable regions of heavy (VH) and light (VL) chains, which are joined together by a flexible peptide linker.
  • Frailty is a leading contributor to functional decline and early mortality in older adults.
  • the condition is defined as a clinical state in which there is an increase in an individual’s vulnerability for developing an increased dependency and/or mortality when exposed to stress.
  • Frailty can result in loss of physiological and cognitive reserves which increases susceptibility to adverse outcomes when patients are exposed to acute stressors. Stress can include, for example, extremes of heat and cold, illness, infection, injury, change in routine, and even changes in medication.
  • Stress can include, for example, extremes of heat and cold, illness, infection, injury, change in routine, and even changes in medication.
  • the way frail patients experience stress events is central to frailty.
  • a core feature of frailty is increased vulnerability to stressors due to impairments in multiple, inter- related systems that lead to decline in homeostatic reserve and resiliency. In short, frail people have a lower capacity to adapt.
  • Frailty is a predictor of vulnerability and recoverability from medical procedures and other stressors. Frailty is a prognostic factor indicating a high risk of procedural complications, disability, institutionalization, and death for patients (even in young patients). This is particularly true in intensive care unit settings.
  • ICU admission Increased life expectancy has increased the demand for ICU admission among older patients.
  • the lack of widely accepted, and validated criteria for ICU admission generates considerable variability among clinicians in the triage process, and programs promoting ICU admission increase ICU use but tend to not reduce long-term mortality.
  • intensive care physicians can be reluctant to admit older patients due to the high healthcare costs, consumption of ICU resources, and/or the lack of a clear benefit of ICU admission in these highly vulnerable patients.
  • frailty Certain long-term risk factors of frailty have been identified including, for example, overweight/obesity, physical inactivity, cardiovascular risk, and alcohol use. Frailty is also related to certain other factors such as, for example, sociodemographic factors (e.g., older age, ethnic background, neighborhood, and access to private insurance or Medicare), physical factors (e.g., obesity and activities of daily living (ADL) functional status), biological factors (e.g., sex and serum uric acid levels), lifestyle factors (e.g., higher Diet Quality Index International (DQI) score, higher fruit/vegetable consumption and higher tertile of all measures of habitual dietary resveratrol exposure), psychological factors (e.g., depressive syndromes), and presence of adverse health events (e.g., decreased cognitive state, polypharmacy, sarcopenia, falls, institutionalization, and hospitalization).
  • sociodemographic factors e.g., older age, ethnic background, neighborhood, and access to private insurance or Medicare
  • physical factors
  • Frailty screenings methods recommended by International Conference of Frailty and Sarcopenia Research include, for example, Rockwood’s Clinical Frailty Scale (CFS), Rockwood et al., A global clinical measure of fitness and frailty in elderly people.
  • CFS Clinical Frailty Scale
  • CMAJ 2005;173(5):489-95 which is incorporated by reference in its entirety for all purposes, the International Association of Nutrition and Ageing (IANA) FRAIL scale, Morley et al.
  • a Simple Frailty Questionnaire (FRAIL) Predicts Outcomes in Middle Aged African Americans. J Nutr Health Aging.
  • the CFS is based on clinical judgement, and involves a nine-point pictorial scale paired with corresponding text describing classifications of frailty.
  • the FRAIL scale comprises five components: Fatigue, Resistance, Ambulation (slow walking speed), Illness and Loss of Weight (5% or more in the previous year) and can be derived from pre-collected patient data.
  • the EFS includes nine components: functional limitation, self-reported health, general health status, cognition, social support, mood, functional performance, polypharmacy and continence, and is most commonly used in the hospital setting.
  • FIG. 7A and 7B A modified Frailty Index (FIG. 7A and 7B) was used to calculate the Frailty Index Score for each patient at each point in time.
  • the modified Frailty Index used is show in FIG. 7A and 7B.
  • Patient’s Frailty Index Scores ranged from 1 to 34.
  • a Frailty Index Score of 1-5 means the patient is very fit (e.g., the patient is robust, active, energetic, motivated, likely exercises regularly, and are among the most fit for their age group).
  • a Frailty Index Score of 6-10 means the patient is well (e.g., patients with no active disease, and are likely exercise occasionally).
  • a Frailty Index Score of 11-15 means the patient is well with a treated co-morbid disease (e.g., patient’s medical problems are well controlled, but the patient is not regularly active).
  • a Frailty Index Score of 16-20 means the patient is vulnerable to frailty (e.g., patient’s daily activities are limited, patients have slowed down, and patients are tired during the day).
  • a Frailty Index Score of 21-25 means the patient is mildly frail (e.g., patient usually needs help with high order activities of daily living (finances, transportation, heavy housework, medications)).
  • a Frailty Index Score of 26-30 means the patient is moderately frail (e.g., patient needs help with all outside activities, keeping house, and likely have problems with stairs, bathing, and dressing).
  • a Frailty Index Score greater than 30 means the patient is severely frail (e.g., patients is completely dependent for personal care).
  • Methods for predicting the future Frailty Index Score of patients use all or some of the following iAge, chronological age, gender, BMI (body mass index), and CMV status. Other factors can also be included.
  • the Full Model uses all five factors (iAge, chronological age, BMI, gender, and CMV status).
  • An iAge Model uses iAge, BMI, gender, and CMV status.
  • An Age Model uses iAge, BMI, gender, and CMV status.
  • [Frailty Index Score] b 0 + b 1 x 1 + b 2 X 2 +... b n x n b n is the regression coefficient for each variable, x n is the value for each variable, and bo is Frailty Index Score when all other variables are equal to zero.
  • the bo value is -26.3.
  • the p value for this model was .000046.
  • the Table below sets out the regression coefficients and p value for predicting the Frailty Index Score with the Full Model one (1), two (2), three (3), four (4), and five (5) in the future.
  • prophylactic treatment maybe provided to arrest the patient’s increase in Frailty Index Score, or even reverse the Frailty Index Score. Treatments could include those described below for lowering iAge, weight loss to lower BMI, and exercise (which should improve multiple axes of the Frailty Index/Score).
  • the Jak/STAT signaling pathway is critical for meeting the multiple challenges encountered by the immune system, from fighting infections to maintaining immune tolerance.
  • Clearly STATs are also involved in the development and function of the immune system in humans and play a key role in maintaining immune surveillance of cancer (Nature. 2007; 450(7171):903-7; Nat Rev Cancer (2009) 9:798-809).
  • CRS cytokine response score
  • An inflammatory age scoring system can also be used to predict age- associated multimorbidity and mortality.
  • iAge can be extremely sensitive as a biomarker of cardiovascular health since elevated levels predict left ventricular remodeling and arterial stiffness even in very healthy older subject with no clinical or laboratory cardiovascular risk factors.
  • iAge can also identify subclinical immunodeficient young patients (10% of subjects 16-35 years old) who cannot mount responses to any strain of the influenza vaccine in any of the years studied (up to 6 years follow-up). These subjects are characterized by having an older-like immunological phenotype with regards to their immune cell composition, ex vivo responses to multiple acute stimuli, and expression of gene modules associated with advanced age.
  • cytokine response score CRS and iAge are independent measures of inflammation, diminished Jak-STAT signaling pathway in T cells, and low naive CD8(+) T cell counts (FIG. 1 A-C) these measures can be used to stratify cancer patients with respect to their clinical responses to immunotherapy.
  • the methods described herein use blood inflammatory markers CRS and iAge to stratify cancer patients into responder and nonresponders groups for immunotherapy.
  • the nonresponders can be treated to reduce their iAge and/or increase their CRS (and/or Jak-STAT score) so that the nonresponders obtain iAge and/or CRS (and/or Jak- STAT score) that places them into a responder group.
  • the procedure involves the extraction of peripheral blood samples by venipuncture, or by any appropriate method, from candidate cancer patients prior to infusion with immunotherapy treatment (FIG. 2).
  • Immunotherapy treatment may comprise the use of certain molecules including antibodies, small molecules, etc. against inhibitory immune receptors. Blood serum is separated from blood cells by centrifugation of clogged blood, or by any other appropriate method (FIG. 2).
  • iAge For serum protein determination, the resulting sera can be mixed with antibody -linked magnetic beads on 96-well filter-bottom plates and can be incubated at room temperature for 2 h followed by overnight incubation at 4°C. Room temperature incubation steps can be performed on an orbital shaker at 500-600 rpm. Plates can be vacuum filtered and washed twice with wash buffer, then incubated with biotinylated detection antibody for 2 h at room temperature. Samples can be then filtered and washed twice as above and re-suspended in streptavidin-PE. After incubation for 40 minutes at room temperature, two additional vacuum washes can be performed, and the samples can be re-suspended in Reading Buffer. Each sample can be measured in duplicate or triplicate. Plates can be read using a Luminex 200 instrument with a lower bound of 100 beads per sample per cytokine and mean fluorescence intensity (MFI) is recorded.
  • MFI mean fluorescence intensity
  • iAge inflammatory age
  • TRAIL -0.3760
  • IFNG -0.3235
  • EOTAXIN 0.2912
  • GROA -0.2723
  • IL2 -0.2063
  • TGFA -0.1978
  • PAI1 -0.1587
  • LIF -0.1587
  • LEPTIN 0.1549
  • MIP1A 0.1547
  • IL1B 0.1471.
  • the MFI can be multiplied by the regression coefficient for the protein, and these numbers can be all added together to give the iAge of the subject.
  • Table 1 lists the ranges of iAge within chronological age decades.
  • MIG (monokine induced by gamma interferon) is a small cytokine belonging to the CXC chemokine family. MIG is one of the chemokines which plays a role to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation. MIG regulates immune cell migration, differentiation, and activation. Tumor-infiltrating lymphocytes are a key for clinical outcomes and prediction of the response to checkpoint inhibitors. In vivo studies suggest the axis plays a tumorigenic role by increasing tumor proliferation and metastasis. MIG predominantly mediates lymphocytic infiltration to the focal sites and suppresses tumor growth. MIG binds to C-X-C motif chemokine 3 of the CXCR3 receptor.
  • TRAIL TNF-related apoptosis-inducing ligand
  • CD253 cluster of differentiation 253
  • TNFSF1O tumor necrosis factor (ligand) superfamily, member 10
  • INFG is a dimerized soluble cytokine that is the only member of the type II class of interferons.
  • IFNG is critical for innate and adaptive immunity against viral, some bacterial and protozoan infections.
  • INFG is an important activator of macrophages and inducer of Class II major histocompatibility complex (MHC) molecule expression.
  • MHC major histocompatibility complex
  • Eotaxin also known as C-C motif chemokine I I or eosinophil chemotactic protein
  • C-C motif chemokine I I or eosinophil chemotactic protein is a small cytokine belonging to the CC chemokine family. Eotaxin selectively recruits eosinophils by inducing their chemotaxis, and therefore, is implicated in allergic responses. The effects of eotaxin is mediated by its binding to a G-protein-linked receptor known as a chemokine receptor.
  • Chemokine receptors for which CCLI I is a ligand include CCR2, CCR3 and CCR5. Eotaxin is described in Kitaura et al The Journal of Biological Chemistry I 996 271: 7725-30 and Jose et al The Journal of Experimental Medicine 1994 I 79: 881-7.
  • GROA also known as CXCLI, the GROI oncogene, GROa, KC, neutrophilactivating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MSGA-a)
  • CXCLI the GROI oncogene
  • GROa the GROI oncogene
  • GROa the GROI oncogene
  • KC neutrophilactivating protein 3
  • GROA is secreted by human melanoma cells, has mitogenic properties and is implicated in melanoma pathogenesis.
  • GROA is expressed by macrophages, neutrophils and epithelial cells, and has neutrophil chemoattractant activity. This chemokine elicits its effects by signaling through the chemokine receptor CXCR2.
  • GROA is described in Haskill et al Proc. Natl. Acad. Sci. U.S.A.
  • IL-2 is one of the key cytokines with pleiotropic effects on the immune system. It is a 15.5 - 16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity.
  • the major sources of IL-2 are activated CD4+ T cells, activated CD8+ T cells, NK cells, dendritic cells and macrophages.
  • IL-2 is an important factor for the maintenance of CD4+ regulatory T cells and plays a critical role in the differentiation of CD4+ T cells into a variety of subsets.
  • T-cell differentiation programs in response to antigen, promoting naive CD4+ T-cell differentiation into T helper-1 (Thl) and T helper-2 (Th2) cells while inhibiting T helper- 17 (Th 17) differentiation.
  • TGFA transforming growth factor alpha
  • TGFA is a polypeptide of 5.7 kDa that is partially homologous to EGF.
  • TGFA is a growth factor that is a ligand for the epidermal growth factor receptor, which activates a signaling pathway for cell proliferation, differentiation and development.
  • TGFA also is a potent stimulator of cell migration.
  • TGFA can be produced in macrophages, brain cells, and keratinocytes.
  • TGFA can induce epithelial development.
  • TGFA can also upregulate TLR expression and function augmenting host cell defense mechanisms at epithelial surfaces.
  • TGFA may act as either a transmembrane-bound ligand or a soluble ligand.
  • TGFA has been associated with many types of cancers, and it may also be involved in some cases of cleft lip/palate. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.
  • PAI1 plasminogen activator inhibitor-1
  • serpin serine proteinase inhibitor
  • PAI1 is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), and hence is an inhibitor of fibrinolysis.
  • PAI1 is also a regulator of cell migration.
  • PAI1 can play a role in a number of age-related, conditions including, for example, inflammation, atherosclerosis, insulin resistance, obesity, comorbidities, and Werner syndrome.
  • PAI1 can play a host protective role during the acute phase of infection by regulating interferon gamma release.
  • IFNG regulates PAI-1 expression, which suggests an intricate interplay between PAI-1 and IFNG.
  • PAI1 can also activate macrophages through Toll-like receptor 4 (TLR4) and can promote migration of pro-cancer M2 macrophages into tumors.
  • TLR4 Toll-like receptor 4
  • LIF leukemia inhibitory factor
  • LIF is interleukin 6 class cytokine with pleiotropic effects impacting several different systems. When LIF levels drop, cells differentiate. LIF has the capacity to induce terminal differentiation in leukemic cells. Its activities include the induction of hematopoietic differentiation in normal and myeloid leukemia cells, the induction of neuronal cell differentiation, and the stimulation of acute-phase protein synthesis in hepatocytes.
  • the protein encoded by this gene is a pleiotropic cytokine with roles in several different systems.
  • LIF functions through both autocrine and paracrine manners. LIF binds to its specific receptor LIFR, then recruits gpl30 to form a high affinity receptor complex to induce the activation of the downstream signal pathways including JAK/STAT3, PI3K/AKT, ERK1/2 and mTOR signaling.
  • LIF is a multifunctional protein which has a broad biological functions in neuronal, hepatic, endocrine, inflammatory and immune systems. LIF regulates the embryonic stem cell self-renewal and is an indispensable factor to maintain mouse embryonic stem cell pluripotency. The expression of LIF is induced under inflammatory stress as an anti-inflammatory agent. [074] LEPTIN is secreted by white adipocytes into the circulation and plays a major role in the regulation of energy homeostasis. LEPTIN binds to the leptin receptor in the brain, which activates downstream signaling pathways that inhibit feeding and promote energy expenditure.
  • LEPTIN also has several endocrine functions, and is involved in the regulation of immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation and wound healing. LEPTIN can directly link nutritional status and pro-inflammatory T helper 1 immune responses, and a decrease of LEPTIN plasma concentration during food deprivation can lead to an impaired immune function. LEPTIN is associated with the pathogenesis of chronic inflammation, and elevated circulating LEPTIN levels in obesity appear to contribute to low-grade inflammation which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, type II diabetes, and degenerative disease including autoimmunity and cancer. Reduced levels of LEPTIN such as those found in malnourished individuals have been linked to increased risk of infection and reduced cell-mediated immune responses. Mutations in this gene and its regulatory regions cause severe obesity and morbid obesity with hypogonadism in human patients. A mutation in this gene has also been linked to type 2 diabetes mellitus development.
  • MIP1 A (macrophage inflammatory protein) is a member of the CC or beta chemokine subfamily. MIP1A regulates leukocyte activation and trafficking. MIP1A acts as a chemoattractant to a variety of cells including monocytes, T cells, B cells and eosinophils. MIP1 A plays a role in inflammatory responses through binding to the receptors CCR1, CCR4 and CCR5.
  • IL-1B Interleukin- 1 beta
  • IL- IB is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis.
  • LL1B is produced by activated macrophages as a proprotein, which is proteolytically processed to its active form by caspase 1 (CASP1/ICE).
  • iAge predicts pulse-wave velocity (a measure of arterial stiffness, or the rate at which pressure waves move down the vessel) which correlates with cardiovascular health.
  • Separation of immune cells may comprise the use of differential centrifugation of blood by density gradient (FIG. 2).
  • the resulting cell pellet can be suspended in warm media, wash twice and resuspended at 0.5x10 ⁇ 6 viable cells/mL.
  • 200 uL of cell sample can be plated per well in 96-well deep-well plates. After resting for 1 hour at 37°C, cells can be stimulated by adding 50 ul of cytokine (IFNa, IFNg, IL-6, IL-7, IL- 10, IL-2, or IL-21) (FIG. 2) and incubated at 37°C for 15 minutes.
  • cytokine IFNa, IFNg, IL-6, IL-7, IL- 10, IL-2, or IL-21
  • the cells can be fixed with paraformaldehyde, permeabilized with methanol, and kept at -80C overnight. Each well can then be bar-coded using a combination of Pacific Orange and Alexa-750 dyes (Invitrogen, Carlsbad, CA) and pooled in tubes.
  • the cells can be washed with FACS buffer (PBS supplemented with 2% FBS and 0.1% soium azide), and stained with the following antibodies (all from BD Biosciences, San Jose, CA): CD3 Pacific Blue, CD4 PerCP-Cy5.5, CD20 PerCp- Cy5.5, CD33 PE-Cy7, CD45RA Qdot 605, pSTAT-1 AlexaFluor488, pSTAT-3 AlexaFluor647, pSTAT-5 PE.
  • the samples can be washed and resuspended in FACS buffer. 100,000 cells per stimulation condition are collected using DIVA 6.0 software on an LSRII flow cytometer (BD Biosciences). Data analysis can be performed using FlowJo v9.3 by gating on live cells based on forward versus side scatter profiles, then on singlets using forward scatter area versus height, followed by cell subset-specific gating.
  • Fold-change difference due to stimulation can be computed as the ratio of the cell, cytokine stimulation, phosphoprotein measure to the raw, un-normalized, cell- phosphoprotein matching baseline that was measured on the same plate.
  • the data can be normalized by scaling individual’s by the average of the assay on the day in which they were measured.
  • CRS Cytokine Response Score
  • CD8+ cells stimulate with IFNa and measure pSTATl, 3 and 5
  • CD8+ cells stimulate with IL6 and measure pSTATl, 3 and 5,
  • CD8+ cells stimulate with IFNg and measure pSTATl
  • CD8+ cells stimulate with IL21 and measure pSTATl
  • CD4+ cells stimulate with IFNa and measure pSTAT5, CD4+ cells, stimulate with IL6 and measure pSTAT5, CD20+ cells, stimulate with IFNa and measure pSTATl
  • Monocytes stimulate with IL10 and measure pSTAT3, Monocytes stimulate with IFNg and measure pSTAT3, Monocytes stimulate with IFNa and measure pSTAT3, and Monocytes stimulate with IL6 and measure pSTAT3.
  • IFNA Interferon alpha
  • IFNA is a member of the type I interferon class. And has thirteen (13) variants in humans.
  • IFNA is secreted by hematopoietic cells, predominately plasmacytoid dendritic cells.
  • IFNA can have either protective or deleterious roles.
  • IFNA can be induced by ssRNA, dsRNA, and cytosolic DNA from viruses or bacteria.
  • IFNA can induce caspase- 11 expression, which contributes to activation of non-canonical inflammasome.
  • Use of recombinant IFNA has been shown to be effective in reducing the symptoms and duration of the common cold.
  • INFG Interferon gamma
  • the encoded protein is secreted by cells of both the innate and adaptive immune systems.
  • the active protein is a homodimer that binds to the interferon gamma receptor which triggers a cellular response to viral and microbial infections. Mutations in this gene are associated with an increased susceptibility to viral, bacterial and parasitic infections and to several autoimmune diseases.
  • IL6 is a cytokine with pleiotropic effects on inflammation, immune response, and hematopoiesis. IL6 is promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis, and immune reactions. IL6 functions in inflammation and the maturation of B cells. In addition, IL6 has been shown to be an endogenous pyrogen capable of inducing fever in people with autoimmune diseases or infections. IL6 is primarily produced at sites of acute and chronic inflammation, where it is secreted into the serum and induces a transcriptional inflammatory response through interleukin 6 receptor, alpha.
  • IL6 is implicated in a wide variety of inflammation- associated disease states, including susceptibility to diabetes mellitus and systemic juvenile rheumatoid arthritis. Dysregulated, continual synthesis of IL-6 plays a pathological effect on chronic inflammation and autoimmunity. Alternative splicing results in multiple transcript variants.
  • IL10 is a cytokine with pleiotropic effects in immunoregulation and inflammation.
  • IL- 10 is an anti-inflammatory cytokine and during infection it inhibits the activity of Thl cells, NK cells, and macrophages, all of which are required for optimal pathogen clearance but also contribute to tissue damage.
  • IL 10 can directly regulate innate and adaptive Thl and Th2 responses by limiting T cell activation and differentiation in the lymph nodes as well as suppressing proinflammatory responses in tissues. It also enhances B cell survival, proliferation, and antibody production.
  • This cytokine can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway.
  • IL21 is a member of the common-gamma chain family of cytokines with immunoregulatory activity. IL21 plays a role in both the innate and adaptive immune responses by inducing the differentiation, proliferation and activity of multiple target cells including macrophages, natural killer cells, B cells, cytotoxic T cells, and epithelial cells. IL21 is important to anti-tumor and antiviral responses and also exerts major effects on inflammatory responses that promote the development of autoimmune diseases and inflammatory disorders.
  • pSTATl phosphorylated signal transducer and activator of transcription 1
  • IFNs interferons
  • cytokine KITLG/SCF cytokine KITLG/SCF
  • other cytokines and other growth factors cytokines and other growth factors.
  • type I IFN IFN-alpha and IFN-beta
  • signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2.
  • the phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus (PubMed:28753426).
  • ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state.
  • IFN-gamma type II IFN
  • STAT1 is tyrosine- and serine-phosphorylated (PubMed:26479788). It then forms a homodimer termed IFN- gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state.
  • GAF IFN- gamma-activated factor
  • pSTAT 3 phosphorylated signal transducer and activator of transcription 3 mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors. Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene. Binds to the interleukin-6 (IL-6)-responsive elements identified in the promoters of various acute-phase protein genes. Activated by IL31 through IL3 IRA.
  • coactivators such as NCOA1 or MED1
  • T-helper Thl7 or regulatory T-cells Acts as a regulator of inflammatory response by regulating differentiation of naive CD4+ T-cells into T-helper Thl7 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, disrupts STAT3 dimerization and inhibits its transcription activity.
  • pSTAT 5 phosphorylated signal transducer and activator of transcription 5
  • JNK Janus-activated kinases
  • STAT5 proteins are activated by a wide variety of hematopoietic and nonhematopoietic cytokines and growth factors, all of which use the JAK-STAT signaling pathway as their main mode of signal transduction.
  • STAT5 proteins critically regulate vital cellular functions such as proliferation, differentiation, and survival.
  • STAT5 plays an important role in the maintenance of normal immune function and homeostasis, both of which are regulated by specific members of IL-2 family of cytokines, which share a common gamma chain (y(c)) in their receptor complex.
  • STAT5 critically mediates the biological actions of members of the y(c) family of cytokines in the immune system.
  • STAT5 plays a critical role in the function and development of Tregs, and consistently activated STAT5 is associated with a suppression in antitumor immunity and an increase in proliferation, invasion, and survival of tumor cells.
  • cardiac age To derive Cardiac age (cAge), patient samples are obtained and processed similar to the description above for iAge.
  • the mean fluorescence intensity can be normalized and used for multiple regression analysis.
  • the levels of MIG, LIF and SIRT3 are diagnostic for risk of cardiovascular health.
  • Other parameters that can be used to compute cardiac age include, for example, aortic pulse wave velocity, a measure of vascular stiffness; relative wall thickness (RWT), a measure of ventricular remodeling, and early diastolic mitral annular velocities (e’), a measure of ventricular relaxation.
  • Still other parameters include, for example, sex, BMI, heart rate, systolic blood pressure, fasting glucose and total cholesterol to HDL ratio.
  • the levels of MIG, LIF, SIRT3, and/or other measurements for a subject can be compared to those of other subjects of the same age and/or different ages to determine the quantile of the subject for each factor, or for the factors of subjects of different ages.
  • Low quantile rank for MIG is diagnostic for low risk of cardiovascular disease
  • high quantile rank for MIG is diagnostic for a higher risk of cardiovascular disease.
  • High quantile rank for LIF and/or SIRT3 are diagnostic for low risk of cardiovascular disease
  • high quantile rank for LIF and/or SIRT3 are diagnostic for a higher risk of cardiovascular disease.
  • Other parameters can also be included in the analysis and, for example, high quantile rank for pulse wave velocity are diagnostic for a higher risk of cardiovascular disease, high quantile rank for abnormal RWT are diagnostic for a higher risk of cardiovascular disease, and lower quantile early diastolic mitral annular velocities are also diagnostic for higher risk of cardiovascular disease.
  • Multiple parameters and/or factors can be combined to compute cardiac age, for example, MIG, LIF and SIRT3 can be used to derive cardiac age, or these factors can be combined with other parameters (e.g., aortic pulse wave velocity, RWT, and/or early diastolic mitral annular velocities) to derive cardiac age.
  • Quantile ranks can include, for example, quartiles, quintiles or deciles.
  • SIRT3 (Situin-3, a NAD-dependent deacetylase) is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase activity. SIRT3 is a regulator of the mitochondrial adaptive response to stress, such as metabolic reprogramming and antioxidant defense mechanisms. SIRT3 mediates cellular resistance toward various forms of stress by maintaining genomic stability and mitochondrial integrity. SIRT3 is central to the maintenance of appropriate mitochondrial function by limiting oxidative stress, and reducing reactive oxygen species (ROS) production with a decrease in mitochondrial membrane potential. SIRT3 has cardio-protective properties involved in mitochondrial homeostasis, stem cell and tissue maintenance during aging, and linked to the beneficial effects of diet, caloric restriction and exercise in maintaining cardiovascular health and longevity.
  • ROS reactive oxygen species
  • Subclinical cardiac tissue remodeling and increased arterial stiffness can be found in otherwise healthy individuals with elevated levels of MIG and low levels of LIF.
  • Patients with subclinical cardiac tissue remodeling and increased arterial stiffness can be otherwise healthy individuals who have elevated levels of MIG and low levels of SIRT-3 and LIF. Cardiac tissue remodeling and increased arterial stiffness are risk factors associated with poorer outcomes in cardiovascular disease.
  • the inflammatory clock (iAge) can also be used as an early molecular marker for cardiovascular malfunctioning.
  • MIG-mediated inflammation can ensue with aging based on our findings; one that is age-intrinsic and observed in aging endothelia, and one independent of age (likely as a response to cumulative exposure to environmental insults).
  • BMI disease risk factors
  • MIG overproduction can be caused by cellular aging per-se, which triggers metabolic dysfunction with production of damage-associated molecular patterns (DAMPs) such as adenine and N4-acetylcytidine.
  • DAMPs damage-associated molecular patterns
  • NLRC4 damage-associated molecular patterns
  • Endothelium has a critical role in the etiology of hypertension and arterial stiffness, and more advanced signs of cardiovascular aging such as tissue remodeling and cardiac hypertrophy are often preceded and may be initiated by malfunctioning of aged endothelia.
  • Endothelial cells show a time-dependent increase in MIG transcript levels, which was concomitant with a drop in SIRT3 expression, and with a decrease in the number of vascular networks formed by the endothelial cells.
  • Young endothelia is a target of MIG from other sources, and MIG can down-regulate SIRT3 expression in the endothelial cells.
  • endothelia cells made from hiPSC human, induced pluripotent stem cells
  • cardiomyocytes made from hiPSC express CXCR3 he receptor for MIG.
  • MIG can act both in a paracrine fashion, wherein increasing levels of this chemokine from immune sources affect endothelial cell function, and in an autocrine fashion on endothelial cells likely producing a positive feedback loop where increasing doses of MIG and expression of its receptor in these cells leads to cumulative deterioration of endothelial function in aging.
  • Exposure of endothelial cells to MIG can also reduce the endothelial cell’s capacity for forming tubular networks, and MIG can reduce vasorelaxation in the aorta.
  • Immunosenescence impacts both the innate and adaptive arms of the immune system and major features of immunosenescence include alteration in immune cell subset frequencies, defective antigen presentation, reduced cytotoxic function, and restricted T cell repertoire (Pawelec G, Larbi A. (2008), Immunity and ageing in man: Annual Review 2006/2007. Exper Gerontol 43:34-38; Weiskopf D, Weinberger B, GrubeckLoebenstein B. (2009), The aging of the immune system. Transpl Int. 22: 1041-1050, both of which are incorporated by reference in their entirety for all purposes).
  • Immunosenescence impacts both the host's capacity to respond to infections and the development of long-term immune memory, especially by vaccination. Immunosenescence is associated with the accumulation of memory and effector cells as a result of repeated infections and by continuous exposure to antigens (inhalant allergens, food, etc.). This chronic inflammation characterizes immunosenescence and can have a significant impact on survival and fragility. Immunosenescence can also be associated with remodeling of the immune system caused by oxidative stress. [0100] Immunosenescence can occur from an imbalance between inflammatory and antiinflammatory mechanisms producing chronic inflammation. This chronic inflammation can be due to chronic antigen stimulation occurring over the course of life and to the oxidative stress that involves the production of oxygen free radicals and toxic products. These factors are able to modify the potential of apoptotic lymphocytes, and this remodeling of the lymphocyte compartment and the chronic expression of proinflammatory cytokines are implicated in the processes of longevity and diseases related to immunosenescence.
  • P ⁇ 10- 15 The effect of chronic inflammation on the immune response was also measured using a functional immune assay (phospho-flow) in which cells are stimulated ex vivo and the phosphorylation of various intracellular proteins is measured by using antibodies against phosphorylated forms of these proteins.
  • the responses to four independent stimuli were measured in a total of 818 individuals and the fold-increase in phospho-STATl, -STAT3 and -STAT5 in B cells, total CD4 (+) T cells (and the CD45RA(+) and CD45RA(-) subsets), total CD8 (+) T cells (and the CD45RA(+) and CD45RA(-) subsets), and in monocytes were determined.
  • Immunosenescence is associated with lowered ability of the immune system to kill cancer cells, protect against infections from pathogenic organisms, and produce efficacious response to vaccines. Treating a subject to lower their iAge can reduce the immunosenescence in the subject and improve the ability of the subject’s immune system to kill cancer cells, protect against infections from pathogenic organisms, and produce efficacious responses to vaccines. Agents and methods for lowering iAge and thereby reducing immunosenescence are described below.
  • Cardiovascular disease include a class of diseases that involve the heart, the blood vessels (arteries, capillaries, and veins) or both. Cardiovascular disease refers to any disease that affects the cardiovascular system, principally cardiac disease including cardiomyopathies, vascular diseases of the brain and kidney, and peripheral arterial disease. Cardiovascular disease can refer to a disease that primarily affects the heart, and can be referred to as cardiac disease. Cardiovascular disease can refer to a disease in which the pathology begins with cardiac damage, malfunction, or malformation, as opposed to disease in which cardiac damage, malfunction, or malformation is a result of a primary pathology present at a site remote from the heart (e.g., cardiovascular disease as a comorbidity to another disease or condition).
  • cardiovascular disease as a comorbidity to another disease or condition.
  • heart failure cardiac dysrhythmias (abnormalities of heart rhythm including increased QT duration and atrial flutter and/or fibrillation), inflammatory heart disease including endocarditis (inflammation of the inner layer of the heart, the endocardium, most commonly the heart valves); inflammatory cardiomegaly (enlarged heart, cardiac hypertrophy); myocarditis (inflammation of the myocardium); valvular heart disease; congenital heart disease; and rheumatic heart disease (heart muscle and valve damage due to rheumatic fever caused by streptococcal bacteria infections) are examples of cardiac damage, malfunction, or malformation in which the primary pathology can be or is present in the heart, and subsequently can result in vascular or other systemic disease.
  • endocarditis inflammation of the inner layer of the heart, the endocardium, most commonly the heart valves
  • inflammatory cardiomegaly enlarged heart, cardiac hypertrophy
  • myocarditis inflammation of the myocardium
  • coronary heart disease also ischaemic heart disease or coronary artery disease
  • hypertensive heart disease diseases of the heart secondary to high blood pressure
  • cor pulmonale failure at the right side of the heart with respiratory system involvement
  • cerebrovascular disease disease of blood vessels that supplies to the brain such as stroke
  • peripheral arterial disease disease of blood vessels that supplies to the arms and legs
  • artherosclerosis are a result of pathology present initially at a site remote from the heart.
  • Cardiovascular disease initiated either at the heart or at a site remote from the heart can result in heart failure.
  • Cardiovascular disease can include disease in which the initial pathology is at a site remote from the heart.
  • Cardiovascular disease also includes conditions affecting the heart, heart valves, and vasculature (e.g., arteries and veins) of the body and encompasses diseases and conditions including, but not limited to arteriosclerosis, atherosclerosis, myocardial infarction, acute coronary syndrome, angina, congestive heart failure, aortic aneurysm, aortic dissection, iliac or femoral aneurysm, pulmonary embolism, primary hypertension, atrial fibrillation, stroke, transient ischemic attack, systolic dysfunction, diastolic dysfunction, myocarditis, atrial tachycardia, ventricular fibrillation, endocarditis, arteriopathy, vasculitis, atherosclerotic plaque, vulnerable plaque, acute coronary syndrome, acute ischemic attack, sudden cardiac death, peripheral vascular disease, coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease.
  • diseases and conditions including, but not limited to ar
  • Cardiomyopathy includes one or more conditions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of) selected from the group consisting of increased QT duration, arrhythmias, myocardial ischemia, hypertension and thromboembolic complications, myocardial dysfunction, cardiomyopathy, heart failure, atrial fibrillation, cardiomyopathy and heart failure, heart failure and LV dysfunction, atrial flutter and fibrillation, and, heart valve damage and heart failure.
  • cardiomyopathy does not include cardiomyopathy as a comorbidity to another disease or condition.
  • Heart failure often called congestive heart failure (CHF) or congestive cardiac failure (CCF), includes conditions that occur when the heart is unable to provide sufficient pump action to maintain blood flow to meet the needs of the body.
  • CHF congestive heart failure
  • CCF congestive cardiac failure
  • Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition is typically diagnosed by patient physical examination and confirmed with echocardiography. Common causes of heart failure include myocardial infarction and other forms of ischemic heart disease, hypertension, valvular heart disease, and cardiomyopathy.
  • Cardiovascular disease includes atherosclerosis a chronic disease process characterized by lipid deposits and fibrosis of the intima, irregularly distributed in large and medium sized arteries. The disease is progressive and most often becomes clinically manifest in the middle-aged and elderly. When severe, the atherosclerotic plaque causes a reduction of the cross-sectional area of the arterial lumen, with and without thrombosis.
  • Atherosclerotic plaques can occur in essentially any or all of the blood vessels of the body, resulting in cardiovascular diseases involving the heart (e.g., acute coronary syndrome, heart failure, and myocardial infarction), the brain (e.g., stroke, transient ischemic attack, and brain infarction), the kidney (e.g., acute and chronic kidney disease, hypertension), and the extremities (e.g., peripheral vascular disease, lower and/or upper extremity claudication, and lower and/or upper extremity ischemia).
  • Resultant ischemic manifestations include: angina pectoris, rayocardial infarction, stroke, intermittent claudication, gangrene of the lower extremities, and renovascular hypertension.
  • Atherosclerosis can be considered to be an inflammatory disease.
  • the lesions of atherosclerosis appear to represent a series of highly-specific cellular and molecular responses that can be described as an inflammatory disease. See, e.g., Ross, "Atherosclerosis— An inflammatory disease” N Engl J Med (1999), 340: 115-126; the publications cited in Ross (1999); and subsequent publications that cite Ross (1999); each of which is incorporated herein in reference in its entirety.
  • a subject can be identified as having cardiovascular disease by the presence of any one of: documented coronary artery disease, documented cerebrovascular disease, documented carotid disease, documented peripheral arterial disease, or combinations thereof.
  • a subject can also be identified as having cardiovaswcular disease if the subject is at least 45 years old and: (a) has one or more stenosis of greater than 50% in two major epicardial coronary arteries; (b) has had a documented prior MI; (c) has been hospitalized for high-risk NSTE ACS with objective evidence of ischemia (e.g., ST-segment deviation and/or biomarker positivity); (d) has a documented prior ischemic stroke; (e) has symptomatic artery disease with at least 50% carotid arterial stenosis; (0 has asymptomatic carotid artery disease with at least 70% carotid arterial stenosis per angiography or duplex ultrasound; (g) has an ankle-brachial index ("ABI”) of less than 0.9 with symptoms of
  • Subjects with cardiovascular disease or at risk for cardiovascular disease have their blood drawn and an iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and cAge are calculated as described above. If the subject’s iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge places them in the youngest quartile for their age group they can be classified as low risk for cardiovascular disease and move forward with the standard therapy (CVD patients) or no therapy (patients at risk but no CVD at the time).
  • the subject’s can be tested for Jak-STAT activity (see, e.g., Example 1 below).
  • Subject’s whose Jak-STAT activity places them in the highest quartile can be classified as low risk and move forward with standard therapy (CVD patients) or no therapy (patients at risk but no CVD at the time).
  • Subjects whose Jak-STAT activity places them in the lower three quartiles can be classified as higher risk for cardiovascular disease and can be treated to lower iAge , CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge (and increase their Jak-STAT score) into a low risk group. If the subject’s iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge places them in the oldest quartile, they can be classified as higher risk patients and can be treated to lower their iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge (see above) into a low risk group.
  • iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge places them in the youngest iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge quintile for their age group (see Table 1) they can be classified as low risk and move forward with the standard therapy (CVD patients) or no therapy (patients with no CVD at the time).
  • the subject If the subject’s iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge places them in the middle three quintiles, the subject’s blood cells (e.g., CD4+ and CD8+ cells) are stimulated and Jak-STAT activity is measured (see, e.g., Example 1 below). Subject’s whose Jak- STAT activity places them in the highest quartile can be classified as low risk and move forward with the standard therapy (CVD patients) or no therapy (patients at risk but no CVD at the time).
  • Subjects whose Jak-STAT activity places them in the lower three quartiles can be classified as higher risk and can be treated to lower iAge, CRS, cardiac marker levels (lower MIG, raise LIF, raise SIRT3), and/or cAge (and increase their Jak-STAT score) into a low risk group. If the subject’s iAge places them in the oldest quintile, they can be classified as higher risk and can be treated to lower their iAge, CRS, cardiac marker levels (lower MIG, increase LIF, increase SIRT3), and/or cAge (see above) into a low risk group of a younger iAge quintile.
  • the subject’s iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge places them in the youngest iAge tertile for their age group (see Table 1) they can be classified as low risk and move forward with the standard therapy (CVD patients) or no therapy (patients at risk but no CVD at the time). If the subject’s iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge places them in the middle tertile, the subject’s blood cells (e.g., CD4+ and CD8+ cells) are stimulated and Jak-STAT activity is measured (see, e.g., Example 1 below).
  • blood cells e.g., CD4+ and CD8+ cells
  • Subjects whose Jak-STAT activity places them in the highest quartile can be classified as low risk and move forward with the standard therapy (CVD patients) or no therapy (patients at risk but no CVD at the time).
  • Subjects whose Jak-STAT activity places them in the lower three quartiles can be classified as higher risk and can be treated to lower iAge, CRS, cardiac marker levels (lower MIG, increase LIF, increase SIRT3), and/or cAge (and increase their Jak-STAT score) into a low risk group.
  • iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge places them in the oldest tertile, they can be classified as higher risk and are treated to lower their iAge, CRS, cardiac marker levels (lower MIG, increase LIF, increase SIRT3), and/or cAge (see above) into a low risk group of a younger iAge, CRS, cardiac marker levels (MIG, LIF, SIRT3), and/or cAge tertile.
  • a personalized initial therapy to reduce iAge can be generated (FIG. 3).
  • Patients following personalized recommendations can be monitored weekly for changes in iAge and/or cAge until they reach optimal levels (below group average for a given age bracket) and they convert into a responder treatment phenotype (FIG. 3) and/or lower risk for cardiovascular disease. The patient is then classified as a responder and is suitable for immunotherapy treatment, or lower risk for CVD.
  • a subject may reduce their iAge with treatments that lower the levels of TRAIL, IFNG, GROA, IL2, TGFA, PAI1, and/or LIF to their optimal levels for a person’s chronological age.
  • a subject may reduce their cAge with treatments that raise the levels of LIF or SIRT3
  • a subject may also reduce their iAge with treatments that raise the levels of MIG, EOTAXIN, LEPTIN, IL-1B, or MIP1 A to their optimal levels for a person’s age.
  • a subject may also reduce their cAge with treatments that lower the levels of MIG.
  • a subject may also reduce their iAge and/or cAge by reducing any systemic chronic inflammation, using any of the following, whether alone or in combination: (1) pharmacological treatment, including without limitation anti-inflammatory drugs (NS AIDs such as, for example, aspirin, ibuprofen, naproxen, diclofenac, celecoxib, oxaprozin, piroxicam, indomethacin, meloxicam, fenoprofen, diflunisal, etodolac, ketorolac, meclofenamate, nabum etone) or corticosteroids (e.g., glucocorticoids, mineralocorticoids); (2) neutraceuticals or nutritional supplements, including without limitation fish oil, lipoic acid, and curcumin, or spices/herbs such as ginger, garlic, turmeric, hyssop, cannabis, Harpagophytum procumbens, and cayenne; (3) dietary change,
  • Cardiac markers can be improved by providing a subject with treatments that improve the level of the cardiac marker (lowering cAge).
  • a subject’s cardiac marker score (cAge) can be lowered by reducing the MIG in a patient, increasing Sirtuin-3 in the patient, increasing LIF in the patient, and/or reducing cell signaling from CXCR3 (the receptor for MIG).
  • CXCR3 the receptor for MIG
  • agents are known which can reduce MIG expression, increase Sirtuin-3 expression, increase LIF activity (or LIF like activity), and/or act as antagonists for CXCR3 (the receptor for MIG).
  • Agents that can lower MIG include, for example arsenic trioxide, Roxarsone, Selenium, and/or a variety of antibodies.
  • Antibodies include, for example, MIG-2F5.5 (anti -human CXCL9 antibody, BioLegend Cat.
  • AS 2 O 3 Arsenic tri oxide (AS 2 O 3 ), a component of traditional Chinese medicine, has been used successfully for the treatment of acute promyelocytic leukemia (APL), andAS 2 O 3 is of potential therapeutic value for the treatment of other promyelocytic malignancies and some solid tumors including breast cancer.
  • AS 2 O 3 treatment changed the expression level of several genes that involved in cell cycle regulation, signal transduction, and apoptosis.
  • AS 2 O 3 treatment increased the mRNA and protein levels of the cell cycle inhibitory proteins, p21 and p27.
  • Roxarsone is an organoarsonic acid where the organyl group is 4-hydroxy-3- nitrophenyl. It has a role as a coccidiostat, an antibacterial drug, an agrochemical and an animal growth promotant. It is an organoarsonic acid and a member of 2- nitrophenols. Roxarsone was found to exhibit a higher angiogenic index than As 111 at lower concentrations. Increased endothelial nitric oxide synthase (eNOS) activity was observed for roxarsone but not for As ni -induced angiogenesis. However, As 111 caused more rapid and pronounced phosphorylation of eNOS.
  • eNOS endothelial nitric oxide synthase
  • Se is a potential anticarcinogenic nutrient, and the essential role of Se in cell growth is well recognized but certain cancer cells appear to have acquired a survival advantage under conditions of Se-deficiency. Se can exert its effects through increasing the expression of a humoral defense gene (A2M) and tumor suppressor- related genes (IGFBP3, HHIP) while decreasing pro-inflammatory gene (MIG, HSPB2) expression.
  • A2M humoral defense gene
  • IGFBP3, HHIP tumor suppressor-related genes
  • MIG pro-inflammatory gene
  • Agents that raise Sirtuin-3 levels include, for example, Berberine and Resveratrol.
  • Berberine molecular formula C20H19NO5 and molecular weight of 353.36
  • OTC Over-the-Counter
  • Berberine has been shown to regulate glucose and lipid metabolism in vitro and in vivo.
  • Berberine is also a potent oral hypoglycemic agent with beneficial effects on lipid metabolism.
  • Resveratrol (3,5,4'-trihydroxy-trans-stilbene) belongs to polyphenols’ stilbenoids group, possessing two phenol rings linked to each other by an ethylene bridge. This natural polyphenol has been detected in more than 70 plant species, especially in grapes’ skin and seeds, and was found in discrete amounts in red wines and various human foods. It is a phytoalexin that acts against pathogens, including bacteria and fungi. As a natural food ingredient, numerous studies have demonstrated that resveratrol possesses a very high antioxidant potential. Resveratrol also exhibit antitumor activity, and is considered a potential candidate for prevention and treatment of several types of cancer.
  • resveratrol anticancer properties have been confirmed by many in vitro and in vivo studies, which shows that resveratrol is able to inhibit all carcinogenesis stages (e.g., initiation, promotion and progression). Even more, other bioactive effects, namely as anti-inflammatory, anticarcinogenic, cardioprotective, vasorelaxant, phytoestrogenic and neuroprotective have also been reported.
  • Agents that raise LIF levels include Aminodarone, arsenic trioxide, Azathioprine, Estradiol, Chlorambucil, Clomiphene, Coumaphos, Cyclosporine, decitabine, Cisplatin, Vincristine, Formaldehyde, Glucose, Hydrogen Peroxide, letrozole, Lindane, Methotrexate, Quercetin, Oxyquinoline, resorcinol, resveratrol, Silicon Dioxide, Tretinoin, and troglitazone.
  • LIF LIF protein kinase
  • IL-1 ⁇ , IL-1 ⁇ , TGF- ⁇ and tumor necrosis factor-a can all increase the transcription of LIF mRNA.
  • TNF- ⁇ tumor necrosis factor-a
  • the induction of LIF by IL-1 ⁇ and TNF- ⁇ was also observed in gingival fibroblasts and several cell types in human airways.
  • the induction of LIF expression by other cytokines, including IL-6, IL-2 has been observed in different cell types, including airway smooth-muscles and MT-2 cells.
  • the expression of LIF can also be inhibited by some factors, including la, 25- dihydroxyvitamin D3 and dexamethasone.
  • LIF promoter The analysis of the LIF promoter revealed that transcription factor STAT5 can bind to the LIF promoter and induce its expression in myeloid cell lines.
  • the LIF promoter region contains several ETS binding sites. The binding of ETS transcription factors to the LIF promoter is critical for the induction of LIF in response to T cell activators.
  • Amiodarone is a primarily a class III anti arrhythmic and is one of the most commonly used anti-arrhythmic drugs. While the United States FDA has labeled amiodarone for the treatment of life-threatening ventricular arrhythmias, the drug is commonly used off-label to treat supraventricular tachyarrhythmias such as atrial fibrillation as well as for the prevention of ventricular tachyarrhythmias (VTs) in high-risk patients. Like other antiarrhythmic drugs of this class, amiodarone works primarily by blocking potassium rectifier currents that are responsible for repolarization of the heart during phase 3 of the cardiac action potential.
  • Clomiphene is an ovulatory stimulant designated chemically as 2-[p-(2- chloro-l,2-diphenylvinyl)phenoxy]tri ethylamine citrate (1 : 1). It has the molecular formula of C26H28C1NO • C6H8O7 and a molecular weight of 598.09.
  • Clomiphene is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors. Clomiphene initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The first endocrine event in response to a course of clomiphene therapy is an increase in the release of pituitary gonadotropins.
  • Coumaphos is an organothiophosphate insecticide, an organic thiophosphate and an organochlorine compound. It has a role as an agrochemical, an acaricide, an antinematodal drug, an avicide and an EC 3.1.1.8 (cholinesterase) inhibitor.
  • Coumaphos is used for control of a wide variety of insects on cattle and parasitic mites (Varroa jacobson) on bees. It is also used in veterinary medicine for the treatment of screwworms, maggots, and ear ticks on livestock. In humans coumaphos causes muscarinic effects (parasympathetic), nicotinic effects (sympathetic and motor), and CNS effects associated with massive overstimulation of the chlorinergic system.
  • Lindane also known as gamma-hexachlorocyclohexane ( ⁇ -HCH), gammaxene, and Gammallin is an organochlorine chemical and an isomer of hexachlorocyclohexane that has been used both as an agricultural insecticide and as a pharmaceutical treatment for lice and scabies.
  • Lindane is a neurotoxin that interferes with GABA neurotransmitter function by interacting with the GABAA receptor- chloride channel complex at the picrotoxin binding site.
  • lindane affects the nervous system, liver, and kidneys, and may well be a carcinogen.
  • Oxyquinoline is a heterocyclic phenol and Oxyquinoline Sulfate is its salt, both of which are described as cosmetic biocides for use in cosmetic formulations. Oxyquinoline can be used as an antiseptic, disinfectant, and has pesticide properties. Oxy quinoline is also a chelating agent which has been used for the quantitative determination of metal ions.
  • Decitabine (5-aza-2'-deoxy cytidine or 5-Aza-Cdr) is a cytosine analogue that was first synthesized in the early 1960s by Pliml and Sorm and is currently marketed as Dacogen® by Eisai (Tokyo, Japan). It differs from deoxycytidine by the substitution of nitrogen for carbon at the 5-position of the pyrimidine ring. It was noted to have an antileukemic effect in cell lines, with more potency in vitro than cytarabine. Initially, its cytotoxicity was attributed to its ability to impair DNA synthesis and cause DNA damage similar to other antimetabolites.
  • decitabine induces differentiation by reversing DNA methylation-induced gene silencing.
  • decitabine is phosphorylated and activated by the enzyme deoxycytidine kinase to its triphosphate form aza-dCTP. It then competes with and replaces cytosine in the CpG (cytosine-guanosine dinucleotide) islands that occur in clusters in promoter regions.
  • aza-dCTP inhibits methylation of the promoter by forming a covalent bond with the enzyme DNA methyltransferase (DNMT), and thereby traps and contributes to degradation of the enzyme.
  • DNMT DNA methyltransferase
  • Chlorambucil and Cisplatin are alkylating agents used to treat cancer.
  • Chlorambucil is in the class of nitrogen mustards, and Cisplatin is a platinum based- agent.
  • Chlorambucil produces its anti-cancer effects by interfering with DNA replication and damaging the DNA in a cell. The DNA damage induces cell cycle arrest and cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of Bcl-2-associated X protein, an apoptosis promoter.
  • Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis. The damaged DNA elicits DNA repair mechanisms and activates apoptosis.
  • Vincristine is a chemotherapy drug that belongs to a group of drugs called vinca alkaloids. Vincristine works by stopping the cancer cells from separating into 2 new cells. Vincristine works partly by binding to the tubulin protein, stopping the tubulin dimers from polymerizing to form microtubules, causing the cell to be unable to separate its chromosomes during the metaphase. The cell then undergoes apoptosis.
  • Letrozole is an aromatase inhibitor which is used in the treatment of hormonally -responsive breast cancer after surgery. Letrozole is also for ovulation induction. Letrozole blocks the production of estrogens in this way by competitive, reversible binding to the heme of its cytochrome P450 unit. Letrozole has shown to reduce estrogen levels by 98 percent while raising testosterone levels.
  • Tretinoin is a derivative of vitamin A. It is used on the skin (topically) in the treatment of mild to moderate acne and on skin that has been damaged by excessive exposure to the sun. Tretinoin irritates the skin and causes the cells of the skin to grow (divide) and die more rapidly, increasing the turnover of cells. Tretinoin can also induce acute promyelocytic leukemia cells to differentiate and stops them from proliferating; in people there is evidence that it forces the primary cancerous promyelocytes to differentiate into their final form.
  • Estradiol is the main circulating oestrogen in women and reaches a plasma concentration of 30-400 pg/mL before menopause. Estradiol regulates growth and the development of the reproductive system, also, helps to maintain the osseous tissue, the central nervous system and the vasodilatation in the vascular tissue. The protective effect of Estradiol in the vasculature and against cardiovascular disease (CVD) has been demonstrated in several hormone replacement studies. Estradiol activates BK channels via a process that requires the presence of the pi subunit. Valverde et al.
  • Estradiol affected BK channels by binding to pi, but it is still a matter of debate whether the agonistic action of Estradiol on BK channels is caused by its binding to the pi subunit or to the ⁇ / ⁇ 1 complex. Moreover, the molecular nature of the Estradiol binding site and the mode of action of the hormone are at present unknown. Acute application of Estradiol (100 nM) decreases smooth muscle excitability by activating BK channels. Notably, Estradiol or its membrane-impermeant form (E2-BSA) can induce a fast increase in BK channel activity in MCF-7 breast epithelial cancer cells with an EC50 of 80 pM reaching a maximal effect at 10 nM34.
  • E2-BSA membrane-impermeant form
  • Estradiol Rapid effects of Estradiol have also been reported in neurons of the area postrema where nanomolar concentrations of E2 can decrease the firing rate most probably by increasing BK current35. All these examples underscore the physiological importance of the regulation of BK channels by E2 and made worthwhile efforts in determining the molecular nature of the interaction between this hormone and the BK channel.
  • Cyclosporine has been a core component of immunosuppression in both immune dysregulatory disorders and organ transplantation.
  • immune disorders involving ophthalmologic, dermatologic, hematologic, gastroenterologic, neurologic, or musculoskeletal systems cyclosporine has demonstrated marked efficacy in relieving clinical symptoms and reversing pathological developments. Additionally, after the drug’s implementation in transplantation medicine, rates of acute rejection and one-year graft survival have improved dramatically.
  • Methotrexate is a chemotherapy agent and immune system suppressant. It is used to treat cancer, autoimmune diseases, ectopic pregnancy, and for medical abortions. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, and osteosarcoma. Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease. It can be given by mouth or by injection. Methotrexate is an antimetabolite of the antifolate type. It is thought to affect cancer and rheumatoid arthritis by two different pathways.
  • methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis.
  • DHFR dihydrofolate reductase
  • the affinity of methotrexate for DHFR is about 1000-fold that of folate.
  • DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate.
  • Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis.
  • folate is essential for purine and pyrimidine base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.
  • Troglitazone is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones.
  • Troglitazone is an oral antihyperglycemic agent which acts primarily by decreasing insulin resistance.
  • Troglitazone is used in the management of type II diabetes.
  • Troglitazone binds to nuclear receptors (PPAR) that regulate the transcription of a number of insulin responsive genes critical for the control of glucose and lipid metabolism.
  • PPAR nuclear receptors
  • Troglitazone decrease nuclear factor kappa- B (NF-KB) and increase its inhibitor (IKB).
  • Azathioprine is a purine analogue with cytotoxic and immunosuppressive activity.
  • Azathioprine is a prodrug that is converted by hepatic xanthine oxidase to its active metabolite 6-mercaptopurine (6-MP).
  • 6-MP is further metabolized by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into 6-thioguanosine-5'- phosphate (6-thio-GMP) and 6-thioinosine monophosphate (6-thio-IMP), both inhibit nucleotide conversions and de novo purine synthesis.
  • HGPRT hypoxanthine-guanine phosphoribosyltransferase
  • 6-thio-GMP 6-thioguanosine-5'- phosphate
  • IMP 6-thioinosine monophosphate
  • Quercetin a flavonoid found in fruits and vegetables, has unique biological properties that may improve mental/physical performance and reduce infection risk. These properties form the basis for potential benefits to overall health and disease resistance, including anti-carcinogenic, anti-inflammatory, antiviral, antioxidant, and psychostimulant activities, as well as the ability to inhibit lipid peroxidation, platelet aggregation and capillary permeability, and to stimulate mitochondrial biogenesis. Quercetin is a naturally occurring polar auxin transport inhibitor. Quercetin inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor a (TNF- ⁇ ) production in macrophages and LPS-induced IL-8 production in lung A549 cells.
  • LPS lipopolysaccharide
  • TNF- ⁇ tumor necrosis factor a
  • quercetin can inhibit LPS-induced mRNA levels ofTNF- ⁇ and interleukin IL-1 ⁇ , this effect of quercetin resulted in a diminished apoptotic neuronal cell death induced by microglial activation. Quercetin inhibits production of inflammation-producing enzymes (cyclooxygenase (COX) and lipoxygenase (LOX)).
  • COX cyclooxygenase
  • LOX lipoxygenase
  • PI3K phosphatidylinositol-3 -Kinase
  • TLR4 Toll Like Receptor 4
  • MyD88/PI3K complex formation limits activation of downstream signaling pathways in RAW 264.7 cells.
  • It can also inhibit FcsRI-mediated release of pro-inflammatory cytokines, tryptase and histamine from human umbilical cord blood-derived cultured mast cells (hCBMCs); this inhibition appears to involve in inhibition of calcium influx, as well as phospho- protein kinase C (PKC).
  • hCBMCs human umbilical cord blood-derived cultured mast cells
  • Resorcinol is an organic compound with the formula C 6 H 4 (OH) 2 .
  • Resorcinol is used as an antiseptic and disinfectant in topical pharmaceutical products in the treatment of skin disorders and infections such as acne, seborrheic dermatitis, eczema, psoriasis, corns, calluses, and warts. It is also used to treat corns, calluses, and warts. It exerts a keratolytic activity.
  • Agents that reduce expression of CXCR3 include, for example, formaldehyde and taurine.
  • Agents that are antagonists for CXCR3 include, for example, piperazinyl-piperi dines (e.g., SCH546738), 8-azaquinazolinones (e.g., AMG 487), 3-phenyl-3H-quinazolin-4-ones, aryl piperazine, 4-aryl-5- piperazinylthiazoles, arylpiperazines, benzetimide derivatives, imidazolidines, imidazolium, lysergic acid derivative, diaminocyclobutenediones, zinc phthalocyanine, and NBI-74330.
  • any of the foregoing antibodies or fragments thereof can include a protracting moiety that extends a half-life (T 1/2 ) or/and the duration of action of the antibody.
  • the protracting moiety can extend the circulation T 1/2 , blood T 1/2 , plasma T 1/2 , serum T 1/2 , terminal T 1/2 , biological T 1/2 , elimination T 1/2 or functional T 1/2 , or any combination thereof, of the antibody.
  • One or more protracting moieties can be combined (covalently or noncovalently) with an antibody.
  • Protracting moieties include, for example, hydrophilic polymers (e.g., PEG, dextran, etc.), a synthetic polymer, glycosylation, human serum albumin (HSA) or a portion thereof (e.g., domain III) that binds to the neonatal Fc receptor (FcRn), or a carboxy- terminal peptide (CTP).
  • hydrophilic polymers e.g., PEG, dextran, etc.
  • HSA human serum albumin
  • FcRn neonatal Fc receptor
  • CTP carboxy- terminal peptide
  • Additional agents that can alter iAge by affecting genes involved in systemic chronic inflammation comprising MIG, TNFSF10, IFNg, CCL11 or CXCL1 are listed below in Tables 2, 3 and 4. These molecules were obtained using methods described below with a combined confidence score >500 (q value of ⁇ 0.05, nominal p value of ⁇ 0.005)
  • Table 2 shows drugs and other molecules that can change iAge by interacting with immune genes involved in the inflammatory response including MIG, TNFSF10, IFNg, CCL11 or CXCL1 and changing the levels of these proteins in the subject.
  • Table 3 shows food compounds and other molecules that can change iAge by interacting with immune genes involved in the inflammatory response including MIG, TNFSF10, IFNg, CCL11 or CXCL1 and changing the levels of these proteins in the subject.
  • Table 4 shows drugs that can upregulate or downregulate MIG, TNFSF10, IFNg, CCL11 or CXCL1, and whether the up- or down-regulation is beneficial (lowers) or detrimental (raises) to iAge.
  • Other drugs and other molecules that interact with genes/proteins involved in inflammation and/or the inflammatory response can be used to reduce the iAge of the subject through indirect effects on the levels of the iAge markers which are described above.
  • Other food compounds or other molecules that interact with genes/proteins involved in inflammation and/or the inflammatory response can be used to reduce the iAge of the subject through indirect effects on the levels of the iAge markers which are described above.
  • the STITCH database v. 5.0 can be used as the compound-gene interaction database to find immune genes with which a drug or food compound interacts. Compound-protein interactions are extracted from the STITCH database v5.0 by matching the InChi keys of drugs/food compounds. STITCH collects information from multiple sources and individual scores from each source are combined into an overall confidence score.
  • the immune gene set is then matched with the two compound - gene interaction datasets above to extract immune genes that interact with drugs or food compounds.
  • This set of drugs will be used as a training set to train machine learning models.
  • STITCH database v5.0 Compound-protein interactions are extracted from the STITCH database v5.0 by matching the InChi keys of drugs/food compounds.
  • STICH collects information from multiple sources and individual scores from each source are combined into an overall confidence score.
  • the threshold for the significant score is not set at a fixed value and considered as an adjustable parameter for ML model optimization.
  • the gene profile for each compound is represented as a sparse matrix, in which a ‘ 1’ indicates genes that directly interact with the compound and a ‘0’ for all other genes.
  • the network propagation ( Random Walk with Restart ) algorithm is then applied to spread this gene profile on to the human interactome. As a result, a genome-wide profile of gene scores is obtained for each compound.
  • the restart parameter ‘c’ is considered as an adjustable parameter for ML model optimization.
  • ML can use Linear SVM as a classifier for optimization.
  • the interaction score threshold can be set at 600, the restart parameter ‘c’ for network propagation can be set at 0.1.
  • Linear SVM can be used to identify anti-inflammatory drugs based on their genome-wide profile obtained from network propagation.
  • the regularization parameter ‘C; can be optimized during the model training using a nested cross- validation strategy.
  • the F-score that balances sensitivity and specificity, is used to evaluate the outcome of each model.
  • the best model is defined as a model with the highest F-score.
  • the anti-inflammatory ‘likeness’ of drugs is calculated using the selected model. These values are used to identify potential drugs for anti-inflammatory repurposing. Similarly, the selected model is applied to the food compound dataset. The probability estimates for the anti-inflammatory activity of each food compound are calculated. Food compounds with high anti-inflammatory probability (i.e, > 0.8) are selected for validation.
  • Medication usage is represented as a sparse matrix, in which ‘ 1 ’ indicates the patient took at least one of the drugs in that group and ‘0’ indicates none of the drugs in that group was not taken.
  • prophylactic treatment can be used to prevent a patient from progressing to more severe frailty, and in some cases, treatment can reverse a patient’s Frailty Index Score (and future Frailty Index Score) of the patient. As the future Frailty Index Score advances to more severe Frailty, more aggressive measures can be taken to lower the patient’s future Frailty Index Score.
  • treatments for reducing the iAge score of a patient can be used to reduce the Frailty Index Score of the patient.
  • Any drug or food that can lower the iAge score of the patient can also lower the present and future Frailty Index Score of the patient.
  • Weight loss can also reduce the future Frailty Index Score.
  • Regular exercise can also improve the future frailty score by impacting several of the axes (e.g., iAge and BMI).
  • Example 1 iAge correlates with naive CD8(+) T cells and with the ex vivo Jak-STAT signaling responses to stimulation
  • FIG. IB volcano plot, result of a multiple regression analysis with permutation tests to estimate false discovery rates (Benjamini -Hochberg FDR) (y-axis) as a function of the regression coefficients obtained for iAge after adjusting for Age, Gender and cytomegalovirus status.
  • FIG. 1C normalized ex vivo CD8(+) T cell phosphor-STAT-1 responses to Interleukin-6. The lower tertile for iAge shows significantly more robust responses than the higher tertile for iAge (C).
  • iAge is negatively correlated with naive CD8(+) T cells and with the ex vivo Jak-STAT signaling responses to stimulation.
  • Example 2 Stratification of cancer patients using iAge and CRS [0165]
  • a blood sample is obtained from patients prior to immunotherapy treatment. Serum and immune cells are separated by standard methods. Serum samples are used to measure protein concentration for inflammatory age (iAge) determination; and cells are cytokine-stimulated ex vivo to measure phosphorylation of intracellular signal transducer and activator of transcription (STAT) proteins to derive a cytokine response score (CRS).
  • STAT cytokine response score
  • iAge and CRS can independently predict patient’s response to immunotherapy treatment.
  • FIG. 2 shows a flow diagram of this process.
  • iAge and CRS can be used to stratify cancer patients prior to treatment as responders versus non-responder for immunotherapy.
  • Example 3 Stratification of cancer patients using iAge
  • iAge can be used to classify cancer patients into responder and non-responders to immunotherapy treatment (A), and to derive iAge individual inflammatory protein signature (barcode), which is fed to iAge personalized recommendation engine to create an individualized initial therapy aimed to reduce iAge, inform medical decision and hence, convert those non-responder patients into responder patients (suitable for immunotherapy) (B).
  • barcode individual inflammatory protein signature
  • FIG. 3 shows a flow diagram of this process.
  • iAge is used to stratify patients for cancer immunotherapy and help convert non-responders into responder for immunotherapy.
  • Example 4 Endothelial cells derived from hiPSCs produce MIG
  • hiPSCs Human induced pluripotent stem cells
  • Human induced pluripotent stem cells were made as described in Example 4. Expression of the MIG receptor, CXCR3, was measured in young cardiomyocytes derived from hiPSCs (hiPSC-CM) as well as in hiPSC-ECs (endothelial cells derived from hiPSC), HUVEC cells, freshly isolated fibroblasts and hiPSCs.
  • hiPSC-CM young cardiomyocytes derived from hiPSCs
  • hiPSC-ECs endothelial cells derived from hiPSC
  • HUVEC cells freshly isolated fibroblasts and hiPSCs.
  • FIG. 6 shows a line graph of percent relaxation of mouse thoracic aortic sections to Acetylcholine after exposure to different amounts of MIG.
  • FIG. 6 shows impaired vascular reactivity with increasing concentrations of MIG.
  • MIG causes a dose-dependent effect on vasorelaxation in treated aortas demonstrating that MIG impairs vascular function, and can contribute to arterial stiffness and premature aging of the cardiovascular system.
  • Example 7 iAge and Frailty
  • Frailty Index Scores ranged from 1 to 34.
  • a Frailty Index Score of 1-5 means the patient is very fit (e.g., the patient is robust, active, energetic, motivated, likely exercises regularly, and are among the most fit for their age group).
  • a Frailty Index Score of 6-10 means the patient is well (e.g., patients with no active disease, and are likely exercise occasionally).
  • a Frailty Index Score of 11-15 means the patient is well with a treated co-morbid disease (e.g., patient’s medical problems are well controlled, but the patient is not regularly active).
  • a Frailty Index Score of 16- 20 means the patient is vulnerable to frailty (e.g., patient’s daily activities are limited, patients have slowed down, and patients are tired during the day).
  • a Frailty Index Score of 21-25 means the patient is mildly frail (e.g., patient usually needs help with high order activities of daily living (finances, transportation, heavy housework, medications)).
  • a Frailty Index Score of 26-30 means the patient is moderately frail (e.g., patient needs help with all outside activities, keeping house, and likely have problems with stairs, bathing, and dressing).
  • a Frailty Index Score greater than 30 means the patient is severely frail (e.g., patients is completely dependent for personal care).
  • Table 5 shows the Frailty Index Scores for the patients using the modified Frailty Index of FIG. 7A and 7B.
  • a plot of these patients showing their total Frailty Index score in 2015 versus their iAge in 2010 (circles) or their chronological age in 2010 (plus signs) is shown in FIG. 8. The plots show that iAge in 2010 correlates with Total Frailty score in 2015.
  • FIG. 9 shows the regression coefficients and p values for iAge and chronological age (in 2010) with Frailty Index Score five (5) years later (2015). Both iAge and chronological age have significant p values for the future Frailty Index Score.
  • Three models for future (5 years) Frailty Index Score were used: a Full Model which measured iAge, chronological age, BMI (body mass index), gender, and CMV status; an iAge Model which measured iAge, BMI (body mass index), gender, and CMV status; and an Age Model which measured chronological age, BMI (body mass index), gender, and CMV status. Table 6 below shows data for these models: Table 6.
  • #Df is the degrees of freedom (number of features added to the model).
  • LogLik represents the logarithmic transformation of the likelihood function which measures the goodness of fit of a statistical model to a sample of data. The likelihood function assumes this form L( ⁇
  • x) f(x
  • Log Likelihood value is a measure of goodness of fit for any model. Higher the value, better is the model.
  • Chisq is the Chi- square value which is the squared ratio of the estimate to the standard error of the respective predictor or predictors in our case.
  • the likelihood ratio test which we used here to compare models, computes ⁇ 2 and rejects the assumption if ⁇ 2 is larger than a Chi-Square percentile with k degrees of freedom, where the percentile corresponds to the confidence level P ⁇ 0.01.
  • Pr(>Chisq) is the probability that the estimate Chi- Square is as extreme as, or more so, than what has been observed under the null hypothesis.
  • the null hypothesis being that the models are equally good at predicting frailty. If Pr(>Chisq) or P value is ⁇ 0.05, we reject the null hypothesis.
  • the Full Model, iAge Model and Age Model used a multiple regression model for predicting future Frailty Index Score. The following equation was used to calculate the future Frailty Index Score.
  • [Frailty Index Score] b 0 + b 1 x 1 + b 2 X 2 +... b n x n b n is the regression coefficient for each variable, x n is the value for each variable, and bo is the Frailty Index Score when all other variables are equal to zero.
  • Sorafenib 5.16E-11 4.11E-09 TNFSF10 727 Vorinostat 6.65E-10 4.63E-08 TNFSF10 751 Azacitidine 6.29E-07 2.50E-05 TNFSF10 700
  • Chromium_Cr-51 4.66E-11 3.89E-09 IFNG 774 Pentoxifylline 2.63E-09 1.57E-07 IFNG 914 Budesonide 3.59E-09 2.06E-07 IFNG 728 Dexamethasone 5.51E-09 2.88E-07 IFNG 700 Betamethasone 5.51E-09 2.88E-07 IFNG 700 Isoprenaline 1.94E-06 6.66E-05 IFNG 700 Benzylpenicillin 5.06E-06 0.000156574 IFNG 953 Decitabine 1.02E-05 0.000294988 IFNG 700 Titanium_dioxide 1.23E-05 0.000348701 IFNG 700 Fenofibrate 0.000204957 0.003979987 IFNG 800 Dronabinol 0.000285001 0.005230242 IFNG 751 Glucosamine 0.000561713 0.009380608 IFNG 800 Acetylcysteine 0.00057
  • Gallocatechin_3-gallate 2.62E-11 3.01E-09 CXCL1 629 ent-Gallocatechin_3-gallate 2.62E-11 3.01E-09 CXCL1 629 ent-Epigallocatechin_3-gallate 2.62E-11 3.01E-09 CXCL1 629 Epigallocatechin_3-gallate 2.62E-11 3.01E-09 CXCL1 629 Histamine 1.78E-10 1.81E-08 CXCL1 918 Epiestradiol 3.21E-07 2.05E-05 CXCL1 831 Silica 3.65E-07 2.29E-05 CXCL1 707 n-butanoate 4.85E-07 2.88E-05 CXCL1 629
  • Leukotriene_E4 6.45E-05 0.002647045 CXCL1 900 leukotriene-C4 0.000124578 0.004473114 CXCL1 900
  • Tatridin B 0.000473125 0.01244933 CXCL1 900

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Abstract

Sont divulguées ici des méthodes et des compositions pour modifier le score d'indice de fragilité d'un patient en modifiant l'âge inflammatoire (iAge) et/ou l'indice de masse corporelle (IMC) du patient. Sont également divulguées ici des méthodes de prédiction du score d'indice de fragilité futur d'un patient à l'aide de l'iAge, de l'âge chronologique, de l'IMC, du sexe et/ou de l'état CMV. Ces méthodes peuvent identifier les patients susceptibles de présenter des résultats de fragilité indésirables dans le futur, ce qui permet d'administrer une thérapie prophylactique à ces patients pour réduire et/ou prévenir ces résultats de fragilité indésirables.
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Citations (3)

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WO2019165145A1 (fr) * 2018-02-21 2019-08-29 Iuve, Inc. Méthode de mesure de vieillissement dû à une inflammation chronique systémique
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WO2019165145A1 (fr) * 2018-02-21 2019-08-29 Iuve, Inc. Méthode de mesure de vieillissement dû à une inflammation chronique systémique
WO2019209949A1 (fr) * 2018-04-24 2019-10-31 Genome Protection. Inc. Procédés pour améliorer la fragilité et le vieillissement
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