Interest in GLP-1 receptor agonists has largely focused on weight loss, metabolic disease and cardiometabolic risk. New findings suggest their effects may also extend to some molecular measures associated with biological ageing.
In a post hoc analysis published in Nature Communications, researchers found that adults living with HIV-associated lipohypertrophy who received semaglutide showed slower progression of several DNA methylation-based ageing markers compared with those who received placebo.
The findings add to growing interest in whether metabolic therapies may influence the biological pathways involved in ageing and age-related disease.
The analysis drew on a 32-week, randomised, double-blind, placebo-controlled phase 2b trial originally designed to examine the effect of once-weekly semaglutide on fat distribution in people living with HIV-associated lipohypertrophy.
Lipohypertrophy refers to the accumulation of fat in particular areas of the body and may occur in people living with HIV due to a combination of HIV infection, chronic inflammation and some antiretroviral therapies. People living with HIV may also experience accelerated biological ageing, even when viral replication is well controlled, making this population of particular interest for ageing-related research.
The epigenetic analysis included 84 participants with paired blood samples available at baseline and week 32, including 45 in the semaglutide group and 39 in the placebo group. Epigenetic ageing was assessed using DNA methylation patterns, which can be used to estimate biological age and the pace at which biological ageing appears to be occurring.
Importantly, epigenetic ageing was not a pre-specified outcome of the parent trial, which means the findings should be considered exploratory.
What the researchers found
Compared with placebo, semaglutide was associated with slower biological ageing across several second- and third-generation epigenetic clocks. These included measures designed to capture ageing-related morbidity and mortality risk, as well as the pace of biological ageing.
One of the clearest findings was a nine percent reduction in the pace of biological ageing as measured by DunedinPACE, a DNA methylation biomarker that estimates how quickly a person is ageing biologically over time.
Semaglutide was also associated with significant reductions in several other ageing measures, including PhenoAge, PCGrimAge, GrimAge V2, OMICmAge and RetroAge. The effects were not uniform across all clocks, with some first-generation and resilience-related measures showing no significant change.
The researchers also examined system-specific epigenetic clocks, which estimate ageing-related changes across different physiological systems. Significant reductions were observed in measures associated with inflammation, brain, metabolic, blood, heart, kidney and liver ageing, while changes in lung, musculoskeletal, immune and hormone clocks did not reach statistical significance.
Possible mechanisms
The findings do not establish exactly how semaglutide may be influencing these ageing markers. However, the study authors suggest several possible mechanisms, including reductions in visceral adipose tissue, inflammation, metabolic stress and chronic immune activation.
This is particularly relevant in people living with HIV, where persistent low-grade inflammation and metabolic dysfunction can contribute to earlier onset of age-related conditions, including cardiovascular disease, frailty and other chronic disease risks.
The authors also note that adipose tissue may retain an epigenetic memory of obesity and metabolic dysfunction, and that therapies affecting adiposity and insulin sensitivity could potentially alter some downstream biological ageing signatures.
Study limitations
The authors not the study has several limitations that warrant consideration. The ageing markers were measured in blood, not directly in tissues such as fat, muscle, liver, kidney, heart or brain, so the organ-specific results should be viewed as indirect signals rather than evidence of tissue-level rejuvenation.
The analysis also did not examine participants’ detailed antiretroviral therapy histories, which the authors say is relevant because some HIV treatments may affect fat distribution, metabolic health, immune function and epigenetic ageing markers.
In addition, epigenetic clocks are predictive tools, not direct measures of ageing, lifespan or disease risk. Longer studies in larger and more diverse groups, including people without HIV, will be needed to show whether these changes last and whether they translate into meaningful health benefits.
The authors conclude that the findings support further investigation of semaglutide as a potential gerotherapeutic, with effects that may extend beyond weight loss and metabolic regulation to influence biological pathways linked to ageing.
