Body-wide multi-omic counteraction of aging with GLP-1R agonism

Abstract

Identifying practical ways to counteract aging and associated degenerative disorders is urgently needed. We performed deep molecular profiling and functional assessments in aging male mice to show that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment broadly counteracts age-related changes. In mice treated with a GLP-1RA from 11 months for 30 weeks, we observed strong body-wide multi-omic age-counteracting effects and improved selected physical functions. Importantly, the effects were specific to aged mice, not young adults, and were attained with a relatively low dose that minimally affected food intake or body weight. With GLP-1RA treatment beginning at 18 months for 13 weeks, the molecular age-counteracting effects were even stronger and largely dependent on hypothalamic GLP-1R, pointing to a brain-body axis of aging modulation. Comparison with mammalian target of rapamycin (mTOR) inhibition, a proven anti-aging strategy, revealed strong multi-omic similarities. Our findings have broad implications for the mechanisms behind GLP-1RAs' pleiotropic benefits, guiding clinical trials, and informing development of anti-aging-based therapeutics.

Keywords: GLP-1R agonist; aging; brain-body interaction; exenatide; mTOR inhibition; multi-omics; rapamycin.