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

Summary

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).

Conditions

• Obesity
• Healthy Lifestyle

Interventions

OTHER

Lifestyle Intervention

1. Exercise: Subjects will undergo a combined aerobic and resistance exercise intervention. The investigators propose a multi-modal training program because they improve metabolic outcomes and adding resistance training reduces the risk of muscle loss during weight loss. Subjects will exercise in the gym for three sessions per week for 10 weeks under supervision of an exercise physiologist. On each session, aerobic exercise will be followed by resistance exercise. 2. Diet: The aim of the dietary intervention is to reduce caloric intake sufficient to result in 8-10% weight loss, while incorporating behavioral and dietary strategies to maximize adherence and to minimize risk of muscle and bone loss. Subjects will attend small-group sessions led by a dietitian for changing their dietary composition to follow American Heart Association (AHA)/American College of Cardiology (ACC) guidelines.

DRUG

Dasatinib 100 MG

100 mg of dasatinib (D) daily for 3 consecutive days plus quercetin (Q) for the same 3 consecutive days, followed by a 25-day (+/- 2 day) no-drug period to complete a single round. This will be repeated twice more until completing 3 rounds total in approximately 10 consecutive weeks.

DRUG

Quercetin 1000mg

Quercetin (Q) (4) 250 mg capsules daily (total 1000 mg daily) plus dasatinib (D) same 3 consecutive days, followed by a 25-day (+/- 2 day) no-drug period to complete a single round. This will be repeated twice more until completing 3 rounds total in approximately 10 consecutive weeks.

DRUG

Placebo

Subjects will receive a placebo (methylcellulose) to provide a similar mass, number of tablets/ capsules, and frequency as the senolytic arm.

PROCEDURE

Abdominal adipose tissue biopsy

All participants will undergo baseline biopsies of subcutaneous abdominal adipose tissue for cellular/molecular profiling via snRNA-seq

Sponsors & Collaborators

• National Institute on Aging (NIA)

  collaborator NIH

• Cedars-Sinai Medical Center

  lead OTHER

Principal Investigators

• Nicolas Musi, MD · Cedars-Sinai Medical Center

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2023-10-17

Primary Completion

2027-02-01

Completion

2028-02-01

FDA Drug

Yes

Countries

• United States

Study Locations