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

## TL;DR

This study explores how semaglutide affects epigenetic aging in people with HIV and liver disease, finding potential links to improved liver and physical health.

## Contribution

The study is the first to examine the relationship between semaglutide treatment and epigenetic aging biomarkers in people with HIV and MASLD.

## Key findings

- A stable pace of aging was maintained over 24 weeks with semaglutide treatment.
- Participants with decreased DunedinPACE showed reduced liver fat and improved gait speed.
- Increased PCDNAmTL was associated with significantly better gait speed improvements.

## Abstract

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.

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.

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 (p = 0.024) and improved gait speed (p = 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 (p= 0.012). No significant clinical associations were observed with changes in PCGrimAge.

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.

ClinicalTrials.gov ID: NCT04216589