Catalyst Awardee

Project Description

Leveraging Genetic Determinants of Age-Retained Brown Fat to Identify Novel Therapeutic Targets for Cardiometabolic Disease

Paul Cohen, MD, PhD |The Rockefeller University
Competition Sponsor: US National Academy of Medicine
Awardee Year: 2023

Weight gain is a common feature of human aging and contributes to decreased longevity by contributing to the risk of diabetes, heart disease, and many types of cancer. Humans possess white fat, which contributes to cardiometabolic disease and increases with aging, and brown fat, which protects against this pathology but declines with aging. Given the promise of brown fat to protect against obesity and associated diseases, the goal of this project is to understand the mechanism responsible for the age-related decline in brown adipose tissue function. We will use the power of human genetics to identify and characterize the genetic basis for age-retained brown fat function. To achieve this goal, we will utilize a unique human cohort with age-retained brown fat, that has undergone whole exome sequencing. Using a computational pipeline, we will prioritize rare coding variants predicted to be functionally deleterious that are enriched in our cohort with age-retained brown fat relative to controls. Candidate variants will then be tested in a brown fat cell line to assay their effects on cellular function. Promising candidates will then be studied further in animal models. This approach would provide the first genetic underpinnings of brown fat regulation in humans and entirely new insights into understanding healthy aging. The genes identified may also represent novel therapeutic targets for age-related weight gain and associated cardiometabolic disease.

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