Epigenetic Aging and Treatment Response to Semaglutide in the SLIM LIVER Study.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), improves metabolic health and reduces liver fat in people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease (MASLD). Whether changes in epigenetic aging biomarkers reflect these clinical benefits remains unknown. METHODS: We conducted a post hoc analysis of the SLIM LIVER study (ACTG A5371), a 24-week, single-arm trial of semaglutide (1.0 mg weekly) in PWH and MASLD. Epigenetic aging was assessed at baseline and 24 weeks using DNA methylation-based epigenetic clocks: DunedinPACE (pace of aging), PCGrimAge (mortality risk), and PCDNAmTL (methylation-derived telomere length). Participants were stratified by change in epigenetic markers (decrease vs. increase); clinical responses were compared across anthropometric, metabolic, and physical function outcomes. RESULTS: We observed a stable pace of aging was maintained over 24 weeks (n=41) with a median change of DunedinPACE of +0.018 (IQR: -0.023 to +0.053), PCDNAmTL (median -0.006 kb; IQR: -0.073 to +0.054), and PCGrimAge (median +0.54 years; IQR: -0.33 to +1.26). Seventeen (41.5%) showed a decrease in DunedinPACE with significantly greater reductions in liver fat (= 0.024) and improved gait speed (= 0.081), corresponding to a ~0.8 day (minimum, -0.0048) to ~19.5 days (maximum, -0.116) deceleration. Participants with increased PCDNAmTL (n=20) similarly demonstrated significantly greater improvements in gait speed (= 0.012). No significant clinical associations were observed with changes in PCGrimAge. CONCLUSIONS: These findings provide preliminary evidence that semaglutide may modulate epigenetic age biomarkers, with DunedinPACE and PCDNAmTL tracking improvements in hepatic and physical function. Integration of epigenetic biomarkers into future trials may enhance gerotherapeutic precision by identifying individuals most likely to benefit from GLP-1RA therapy and by enabling minimally invasive monitoring of biological aging. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04216589.