Semaglutide Slows Epigenetic Aging in People with HIV-associated lipohypertrophy: Evidence from a Randomized Controlled Trial

Semaglutide is a once-weekly GLP-1 receptor agonist that has been proposed as a gerotherapeutic, yet no data exist on its effects on epigenetic aging. We therefore conducted a post-hoc epigenetic analysis of a 32-week, double-blind, placebo-controlled phase 2b trial in adults with HIV-associated lipohypertrophy (semaglutide n = 45; placebo n = 39). Paired peripheral-blood methylomes were profiled to evaluate semaglutide’s impact across multiple generations of DNA-methylation clocks. After adjustment for sex, BMI, hsCRP, and sCD163, semaglutide significantly decreased epigenetic aging: PCGrimAge (-3.1 years, P = 0.007), GrimAge V1 (-1.4 years, P = 0.02), GrimAge V2 (-2.3 years, P = 0.009), PhenoAge (-4.9 years, P = 0.004), and DunedinPACE (-0.09 units, ≈9 % slower pace, P = 0.01). Semaglutide also lowered the multi-omic OMICmAge clock (-2.2 years, P = 0.009) and the transposable element-focused RetroAge clock (-2.2 years, P = 0.030). Eleven organ-system clocks showed concordant decreased with semaglutide, most prominently inflammation, brain and heart, whereas an Intrinsic Capacity epigenetic clock was unchanged (P = 0.31). These findings provide, to our knowledge, the first clinical-trial evidence that semaglutide modulates validated epigenetic biomarkers of aging, justifying further evaluation of GLP-1 receptor agonists for health-span extension.