Overview

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).

Eligibility

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
3. All races and ethnic groups
4. Community dwelling
5. Sedentary (≤1.5 h of exercise per week)
6. Nondiabetic (fasting plasma glucose < 126 mg/dl, 2-h glucose during oral glucose tolerance test (OGTT) < 140mg/dl, and A1c < 6.5%
7. 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.

8. 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:
          1. Diabetes, clinically diagnosed or HbA1c > 6.5% and/or fasting plasma glucose > 126
             mg/dl and/or use of anti-diabetic medications.
          2. Participating in > 1.5 h of structured exercise/week
          3. Unstable weight (>3% change in last 3 months)
          4. Neurological, musculoskeletal, or other conditions that may limit subject's ability to
             complete study physical assessment and training
          5. Active autoimmune/inflammatory disease including: rheumatoid arthritis, multiple
             sclerosis, systemic lupus erythematous, inflammatory bowel disease
          6. Laboratory 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/mm³
               -  Prothrombin time (PT) > 1.0 times ULN
               -  Partial prothrombin time (PTT) > 1.0 times ULN.
          7. Active gastrointestinal disease; coagulopathy; GI bleed within 6 months
          8. Clinically significant heart disease (e.g. NYH Classification >II; ischemia)
          9. Peripheral vascular disease (claudication)
         10. QTc prolongation >45 msec
         11. Use of anti-arrhythmic medications known to cause QTc prolongation, anti-platelet or
             anti-coagulant medication (see section 5.3)
         12. Use of quinolone antibiotics or any other drugs that may prolong the QTc interval (see
             section 5.3)
         13. Pulmonary disease (COPD), severe asthma or exercise-induced asthma
         14. Recent systemic or pulmonary embolus
         15. Uncontrolled blood pressure (systolic BP>170, diastolic BP>95 mmHg)
         16. 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 use
         17. Pregnant or breastfeeding
         18. Postmenopausal women new (within 6 months) to systemic hormone replacement therapy
         19. Previous bariatric surgery
         20. History of stroke with motor disability
         21. Recent (3 years) treated cancer other than basal cell carcinoma
         22. Acute or chronic infection
         23. Medication that might interfere with metabolic studies (weight loss medication,
             systemic steroids, immunosuppressants) within 6 months (see section 5.3)
         24. Potentially senolytic agents within the last 6 months: fisetin, quercetin, luteolin,
             dasatinib, piperlongumine, or navitoclax (see section 5.3)
         25. History of allergy to dasatinib, quercetin and/or lidocaine.