Semaglutide lowered age estimates in HIV patients with excess belly fat
Over 32 weeks, the PhenoAge blood-based aging measure changed at an annualized rate 4.9 years per year lower with semaglutide than with placebo.
Double-blind, placebo-controlled, registered NCT04019197
Limit: Changes in blood immune cell composition could partly explain the lower age estimates
Stake: Authors work for TruDiagnostic.
Edited by Boris Djordjevic · AgingResearch.News
Researchers analyzed 84 adults with controlled human immunodeficiency virus (HIV) infection and lipohypertrophy, or excess central body fat. Their average age was 49, and 42% were women. The randomized, double-blind trial compared weekly semaglutide injections with placebo for 32 weeks. Doses rose from 0.25 milligrams for four weeks to 0.5 milligrams for four weeks, then 1.0 milligram for 24 weeks.
The analysis included 45 semaglutide recipients and 39 placebo recipients. Researchers measured chemical tags on DNA in blood cells to calculate aging estimates before and after treatment. Semaglutide reduced several estimates relative to placebo, including a 9% slower measured pace of aging. In the original 108-person trial, eight participants (15%) in each group stopped early.
Why it matters
Measuring biological aging offers a way to investigate drugs as potential aging-targeted therapies. The authors called for prospective trials to determine whether semaglutide and related drugs could serve that purpose.
Caveats
Blood-based aging estimates are proxies; this unplanned exploratory analysis included only trial completers with paired samples and covered 32 weeks. The HIV-specific population limits generalizability, and the trial excluded people with diabetes or active cardiovascular disease.
From the paper
- Participants
We first quantified biological age using established first, second, and third- generation epigenetic clocks in biobanked longitudinal peripheral-blood mononuclear cells from 84 total participants (45 semaglutide, 39 placebo) using epigenetic DNA-methylation data obtained at baseline and week 32.
Results, Post hoc epigenetic age analysis of a randomized trial of semaglutide
- Who took part
The trial aimed to evaluate the effects of the GLP-1 receptor agonist semaglutide on adipose tissue quantity and distribution in individuals with HIV-associated lipohypertrophy over a 32-week period.
Results, Post hoc epigenetic age analysis of a randomized trial of semaglutide
- Ages
For the epigenetic analysis, at baseline, the 84 participants (45 semaglutide, 39 placebo) were middle-aged, with a mean ± standard deviation (SD) age of 49 ± 12 years and well balanced between treatment arms (48 ± 13 vs. 50 ± 12 years).
Results, Post hoc epigenetic age analysis of a randomized trial of semaglutide
- Sex
42% were women overall, but men were slightly over-represented in the semaglutide group (67% vs. 49%).
Results, Post hoc epigenetic age analysis of a randomized trial of semaglutide
- Result
Among second-generation clocks, PhenoAge showed the largest reduction (−4.90 years/year [95% CI: −8.16 to −1.63], P = 0.004), followed by PCPhenoAge (−3.68 years/year [−6.80 to −0.56], P = 0.022) and PCGrimAge (−3.08 years/year [−5.29 to −0.86], P = 0.007).
Results, Semaglutide slows epigenetic aging across multiple DNA methylation clocks
- GrimAge V2
Participants randomized to semaglutide exhibited a 1.39 years/year lower GrimAge V1 estimate compared to placebo (95% CI: −2.72 to −0.05, P = 0.042), with a more pronounced effect for GrimAge V2 (−2.26 years/year [−3.94 to −0.59], P = 0.009), consistent with the enhanced sensitivity of V2 to cardiometabolic and inflammatory components …
Results, Semaglutide reduction in epigenetic age as measured by GrimAge and GrimAgeV2 using Biolearn
- DunedinPACE
For DunedinPACE, semaglutide was associated with a 0.09 lower pace of aging (units per year) relative to placebo (95% CI: −0.17 to −0.02, P = 0.010), translating to an approximately 9% slower pace of biological aging in the semaglutide group.
Results, Semaglutide slows epigenetic aging across multiple DNA methylation clocks
- Inflammation
The largest effects were observed in the Inflammation (−5.01 years [95% CI: −8.51 to −1.51], p = 0.006), Brain (−4.99 years [−8.42 to −1.56], p = 0.005), and Metabolic (−4.72 years [−8.22 to −1.21], p = 0.009) clocks.
Results, Semaglutide broadly decelerates multi-system epigenetic aging across 11 system clocks
Quoted word for word from the full text on PubMed Central.
The paper
Semaglutide slows epigenetic aging in a randomized trial of HIV-associated lipohypertrophy
University of California San Diego; University Hospitals Cleveland Medical Center
Nature Communications, May 19, 2026, Open access
