Mapping fat cell types and aging in older adults

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

This study is testing how different treatments, like lifestyle changes or a special medication, can improve health and fat cell function in older adults who are obese.

Quick facts

• Phase: Phase2; Phase3
• Study type: Interventional
• Enrollment: 160 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Cedars-Sinai Medical Center (Academic / other)
• Drugs / interventions: dasatinib
• Locations: 1 site (Los Angeles, California)
• Trial ID: NCT05653258 on ClinicalTrials.gov

What this trial studies

This study investigates the cellular and molecular characteristics of adipose tissue in older obese individuals through single nuclei RNA sequencing and metabolic assessments. Participants will undergo baseline biopsies and various tests to evaluate their metabolic health, physical performance, and dietary habits. Following this, older obese participants will be randomized into three groups to receive either a lifestyle intervention, senolytic treatment, or a placebo. The study aims to understand how these interventions affect cellular senescence and overall health in older adults.

Who should consider this trial

Good fit: Ideal candidates are older adults aged 65 and above with obesity (BMI 30.0-39.9) who are sedentary and nondiabetic.

Not a fit: Patients who are not obese or those with diabetes may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved strategies for managing obesity and promoting healthy aging.

How similar studies have performed: Other studies have shown promise in using lifestyle interventions and senolytics for improving health outcomes in older populations, suggesting potential success for this approach.

Eligibility criteria

Inclusion Criteria:

1. Both Sexes
2. Age: younger lean group 18-30 years with BMI 18.5-24.9 kg/m2; younger obese group 18-30 with BMI 30.0 -39.9; older obese group ≥ 65 years with BMI 30.0-39.9
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 (other than marijuana)
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.
26. Concurrent enrollment in another interventional trial.

Where this trial is running

Los Angeles, California

• Cedars Sinai Medical Center — Los Angeles, California, United States (Recruiting)

Study contacts

• Principal investigator: Nicolas Musi, MD — Cedars-Sinai Medical Center
• Study coordinator: Nicolas Musi, MD

Conditions Obesity; Healthy Lifestyle; Lifestyle intervention; Single RNA sequencing; Cell Senescence