GLP-1 receptor agonists, epigenetic aging, and the prospect of pharmacological healthspan extension

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events, all-cause mortality, and systemic inflammation in randomized controlled trials, with effect sizes exceeding those predicted from glycemic and weight-related improvements alone. The convergence of these findings with a maturing body of evidence linking metabolic dysfunction to accelerated epigenetic aging has prompted renewed interest in GLP-1 RAs as candidate gerotherapeutic agents. The present review synthesizes contemporary preclinical, mechanistic, and clinical evidence relevant to this question. The SELECT trial demonstrated a 19% reduction in all-cause mortality (hazard ratio [HR] 0.81) in patients with obesity without diabetes, the FLOW trial demonstrated a 24% reduction in the primary kidney composite endpoint (HR 0.76), and the first randomized evidence of GLP-1 RA modulation of validated DNA methylation clocks was reported in 2025, with significant deceleration of DunedinPACE, PCGrimAge, and PhenoAge over 32 weeks of semaglutide therapy. Mechanistic studies have identified convergent pathways involving the hypothalamic GLP-1 receptor, AMPK/SIRT1 signaling, and microbiome-derived short-chain fatty acid production. The aggregate evidence supports the framing of GLP-1 RAs as a candidate class of geroprotective therapeutics, although definitive trials with prespecified epigenetic aging endpoints, durability follow-up, body-composition assessment, prespecified sex-stratified analyses, and adequate representation of diverse populations remain to be conducted; the pending EVOKE and EVOKE+ readouts in early Alzheimer's disease will be particularly consequential.