Single Nuclei RNA-seq to Map Adipose Cellular Populations and Senescent Cells in Older Subjects.

All participants will undergo baseline biopsies of subcutaneous abdominal adipose tissue for cellular/molecular profiling via snRNA-seq and metabolic/physiological assessments (insulin sensitivity, glucose tolerance, and β-cell function). Older obese participants will be randomized into three arms: lifestyle intervention (n=24), senolytics (n=24), or placebo (n=24).

Inclusion Criteria:1) Both Sexes 2) Age: younger lean group 18-30 years with BMI 18.5-24.9 kg/m2; older lean group ≥ 65 years with BMI 2) All races and ethnic groups 3) Community dwelling 4) Sedentary (≤1.5 h of exercise per week) 5) Nondiabetic (fasting plasma glucose < 126 mg/dl, 2-h glucose during oral glucose tolerance test (OGTT) < 140mg/dl, and A1c < 6.5% 6) For all female participants who are women of childbearing potential (WOCBP), who are not pregnant or breast feeding, at least one of the following conditions must apply: A documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy Use of a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency (implantable progesterone-only hormone contraception, intrauterine hormone releasing system, bilateral tubal occlusion, vasectomized partner) during the intervention period of the study and for at least 30 days after the last dose of study intervention to eliminate any reproductive safety risk of the study drug.Use of a contraceptive method that is highly effective (with a failure rate of <1% per year), with high user dependency, (oral/intravaginal/injectable combined estrogen and progesterone contraception, oral/injectable progesterone only hormone contraception, sexual abstinence) during the intervention period and for at least 30 days after the last dose of study intervention to eliminate any reproductive safety risk of the study drug. In addition to the highly effective methods: male or female condom with or without spermicide; cervical cap, diaphragm, or sponge with spermicide; a combination of male condom with either cervical cap, diaphragm, or sponge with spermicide.7) ECG value after 10 minutes of resting in the supine position in the following ranges: 120ms<PR<220ms: QRS<120ms; QTc<430ms for males and QTc<450ms for females and normal ECG tracing, unless the investigator considers the ECG abnormality to be not clinically relevant.Exclusion Criteria:Diabetes, clinically diagnosed or HbA1c > 6.5% and/or fasting plasma glucose > 126 mg/dl and/or use of anti-diabetic medications.Participating in > 1.5 h of structured exercise/weekUnstable weight (>3% change in last 3 months)Compromised musculoskeletal function, including pain, weakness, stiffness, joint noises and decreased range of motionActive autoimmune/inflammatory disease including: rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, inflammatory bowel diseaseLaboratory parameters outside the normal range:impaired kidney function (eGFR < 30ml/min/1.73m² as calculated by the CKD-EPI equation);impaired liver function (AST or ALT level > 2 times upper limit of normal (ULN);total Bilirubin level > 1.5 times ULN;TSH > 1.5 times ULN or < lower limit of normal (LLN);Hemoglobin <10.0 g/dl; Platelets <125,000 cell/mm³;Platelets < 125,000 cell/mm³Prothrombin time (PT) > 1.0 times ULNPartial prothrombin time (PTT) > 1.0 times ULN.Active gastrointestinal disease; coagulopathy; GI bleed within 6 monthsClinically significant heart disease (e.g. NYH Classification >II; ischemia)Peripheral vascular disease (claudication)QTc prolongation >45 msecUse of anti-arrhythmic medications known to cause QTc prolongation, anti-platelet or anti-coagulant medication (see section 5.3)Use of quinolone antibiotics or any other drugs that may prolong the QTc interval (see section 5.3)Pulmonary disease (COPD), severe asthma or exercise-induced asthmaRecent systemic or pulmonary embolusUncontrolled blood pressure (systolic BP>170, diastolic BP>95 mmHg)Smoking, alcohol use (history of regular alcohol consumption exceeding 7 drinks/week for female participants or 14 drinks/week for male participants. 1 drink = 5 ounces [150ml] of wine or 12 ounces [360ml] of beer or 1.5 ounces [45ml] of hard liquor) or recreational drug usePregnant or breastfeedingPostmenopausal women new (within 6 months) to systemic hormone replacement therapyPrevious bariatric surgeryHistory of stroke with motor disabilityRecent (3 years) treated cancer other than basal cell carcinomaAcute or chronic infectionMedication that might interfere with metabolic studies (weight loss medication, systemic steroids, immunosuppressants) within 6 months (see section 5.3)Potentially senolytic agents within the last 6 months: fisetin, quercetin, luteolin, dasatinib, piperlongumine, or navitoclax (see section 5.3)History of allergy to dasatinib, quercetin and/or lidocaine.