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

What is the Purpose of this Study?

The purpose of this study is to evaluate whether senescent cells (cells that age and permanently stop dividing but do not die) affect the body’s ability to metabolize (process) sugars. Researchers will examine various cells in fat tissue to learn more about the ways in which aging affects health. The study will also investigate new ways to identify senescent cells in the body by comparing younger and older participants. A group of older participants with a higher body mass index will be randomly assigned to 1 of 3 groups: a lifestyle intervention group with an exercise and dietary plan, a drug treatment group (dasatinib and quercetin), or placebo group (inactive substance). The combined use of dasatinib and quercetin is experimental. Participants with a normal body mass index (e.g., lean) will be assigned to a group based on age. The younger group will consist of individuals who are 18-30 years old, and the older lean group will be 65 years old or older. Study procedures include physical examinations, blood and urine laboratory assessments, physical activity/dietary assessment, insulin-resistance testing, and fat tissue biopsies.

Eligibility

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

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\
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.

Show less

Where can I participate?

Beverly

More about this Clinical Trial

What is the full name of this clinical trial?

Single nuclei RNA-seq to map adipose cellular populations and senescent cells in older subjects.

Study Details

Disease Type/Condition

Geriatrics, Metabolism, Obesity

Principal Investigator

Musi, Nicolas

Age Group

Adult

Phase

IRB Number

STUDY00002506

ClinicalTrials.gov ID

NCT05653258

Key Eligibility

ClinicalTrials.gov

How do I learn more about this study?

clinicaltrials@cshs.org

Inclusion Criteria:

Exclusion Criteria: