Semaglutide May Slow the Pace of Epigenetic Aging
Using epigenetic clocks, researchers found that semaglutide use was linked to a ~9% slower rate of aging in a new study.
Glucagon-like peptide 1 (GLP-1) drugs have demonstrated many unanticipated benefits, but their potential to slow biological aging may be their most universally relevant one yet.
In a recent study published in Nature Communications, researchers at the University of California San Diego (UCSD) collaborated with several partner institutions to investigate the potential of GLP-1s as gerotherapeutics—drugs that extend healthspan. They found that semaglutide, a GLP-1 drug, slowed epigenetic markers of aging compared with placebo.
GLP-1 drugs: From weight loss to longevity
GLP-1 is a naturally occurring hormone produced by intestinal cells following a meal. GLP-1 receptor activation slows gastric emptying, induces satiety, and lowers blood glucose, ultimately regulating appetite and sugar metabolism.
GLP-1 drugs were conceived to leverage this mechanism to treat diabetes, a condition characterized by elevated blood glucose. During clinical trials, researchers observed that patients were losing significant weight, and semaglutide was later approved for weight management in 2021.
Weight management has not been the only unforeseen benefit of GLP-1 drugs; another intriguing area is whether they influence biological aging.
While GLP-1 drugs can curb cardiometabolic dysfunction, reducing the risk of life-limiting and life-threatening diseases that would otherwise shorten health and lifespan, mechanistic evidence that they directly influence the biology of aging remains limited.
Can GLP-1 drugs rewind the epigenetic clock?
UCSD researchers conducted a post hoc analysis of a Phase 2b clinical trial evaluating the use of semaglutide in human immunodeficiency virus (HIV)-associated lipohypertrophy (HALS).
The Phase 2b clinical trial
The initial trial included 108 people living with HIV (PLWHIV) diagnosed with HALS. HALS is characterized by excess fat in the abdomen, upper back, breasts, and neck. Original trial endpoints included changes in visceral and subcutaneous adipose tissue, cardiometabolic markers, and body composition. Participants were randomly assigned to receive either semaglutide or a placebo once weekly for 32 weeks, in a 1:1 ratio.
While HIV is now a chronic, manageable condition, studies have demonstrated that PLWHIV experience accelerated aging. Thus, the trial cohort provided a unique clinical model for evaluating whether semaglutide influences biological aging.
In the original trial, peripheral blood samples were collected at baseline and week 32. UCSD researchers subsequently extracted and profiled DNA from 84 of these samples (45 semaglutide, 39 placebo).
The team used first-, second-, and third-generation epigenetic clocks to quantify biological age pre- and post-treatment.
Epigenetic clocks
Epigenetic clocks use DNA modifications to detect and predict aging patterns. Many clocks exist, but each requires a biological sample, a sequencer to read it, and a trained algorithm to understand and predict based on this.
- First-generation clocks predict chronological age.
- Second-generation clocks predict morbidity risk and biological age, a measure of how healthy the body is relative to its chronological age.
- Third-generation clocks measure the pace of aging.
Across several second- and third-generation epigenetic clocks, semaglutide treatment significantly slowed epigenetic aging compared with placebo. This difference persisted after adjustment for sex, BMI, and markers of inflammation.
Among the clocks estimating biological age, PhenoAge showed the strongest effect, with an annualized treatment effect equivalent to 4.9 fewer biological years of aging per year compared with placebo.
The authors also highlighted analysis results from the DunedinPACE third-generation clock: “Semaglutide was associated with a 0.09 lower pace of aging (units per year) relative to placebo, translating to an ~9% slower pace of biological aging in the semaglutide group.”
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The same trend was not seen in causality-enriched clocks, which identify epigenetic changes that cause age-related traits and diseases, rather than those that are simply correlated. These analyses produced more variable results, with no statistically significant treatment effects.
Semaglutide's impact on aging: Early signals
The study provides evidence that semaglutide influences epigenetic changes associated with aging across multiple validated clocks, supporting further studies to clarify the role of GLP-1s as gerotherapeutics.
Dr. Michael Corley, first author of the study, is already pioneering this research, having recently completed another study evaluating semaglutide's effect on epigenetic aging in HIV and liver disease.
“We are not saying that semaglutide reverses aging or makes people younger. What we are seeing is a signal that it may slow some of the biological processes associated with aging,” cautioned Corley.
“With newer GLP-1–based therapies now emerging, the field has an opportunity to test whether different drugs in this class have distinct effects on aging biology and to identify which patients may benefit most.” — Dr. Michael Corley.
The findings will need to be replicated in the general population, although Corley was enthusiastic about the translational potential. “Many of the biological processes we study in HIV are also central to aging in the general population,” he noted. “Because these processes can emerge earlier or be more pronounced in people with HIV, this community can help us identify interventions that may improve healthspan more broadly.”
Larger, longitudinal clinical trials will be needed to determine whether changes in epigenetic clocks translate into healthier aging, lower disease risk, and longer lifespan. Future studies will also need to clarify why semaglutide influenced some epigenetic clocks but not others, and to determine which clocks best reflect clinically meaningful changes in this context.
Reference: Corley MJ, Dwaraka VB, Pang AP, et al. Semaglutide slows epigenetic aging in a randomized trial of HIV-associated lipohypertrophy. Nat Commun. 2026. doi: 10.1038/s41467-026-72861-3
This article is a rework of a press release issued by the University of California, San Diego. Material has been edited for length and content.
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