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

Eligibility 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:
• 8. ECG value after 10 minutes of resting in the supine position in the following ranges:
• 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.