10-PUB: Single Nuclei RNA-seq to Map Adipose Cellular Populations and Senescent Cells in Response to a Lifestyle or Senolytic Intervention in Older Adults with Obesity—A Double-Blind, Placebo-Controlled, Randomized Trial

Introduction & Objective: Older adults with obesity are at an increased risk for metabolic diseases and diabetes. The underlying molecular mechanisms by which increased adiposity and aging predispose individuals to metabolic diseases are not well understood. Recent data suggests that variations in adipocyte cellular subpopulations influence whole-body metabolism, and an increased burden of adipocyte senescent cells has been implicated in metabolic diseases. The purpose of this study is to conduct a double-blinded, placebo-controlled, randomized trial investigating the relations between adipose molecular signatures and cellular senescence on metabolic outcomes.

Methods: Using single nuclei RNA sequencing (SnRNA-seq), we will develop a transcriptomic atlas of human adipose tissue and analyze molecular profiles pre- and post-intervention. We will recruit a cohort of older adults with obesity (≥65 years of age; BMI=30-39.9 kg/m²; n=72). We will obtain adipose biopsies to analyze cellular/molecular profiling via snRNA-seq as it relates to phenotypic measures of insulin sensitivity, glucose tolerance, beta cell function, and hepatic lipid content compared to cohorts of younger lean (18-30 years of age; BMI=18.5-24.9 kg/m²; n = 24) and older lean (≥65 years of age; BMI=18.5-24.9 kg/m²; n=24) participants. The cohort of older adults with obesity will be randomized to one of three groups for 10 weeks: lifestyle (diet- and exercise-induced weight loss of 8-10% of body mass), senolytic (dasatinib and quercetin), or placebo.

Results & Conclusion: The findings from this study will help elucidate whether changes in global adipose molecular signatures and cellular senescence are mechanisms by which lifestyle or senolytic therapy intervention improves metabolic parameters. This information may help identify molecular targets for treating metabolic diseases.