Semaglutide was associated with slower epigenetic aging across several blood-based DNA methylation biomarkers in patients with human immunodeficiency virus–associated lipohypertrophy, according to a posthoc exploratory analysis of a randomized trial.
Researchers analyzed paired peripheral blood mononuclear cell samples from 84 patients enrolled in a 32-week, single-center, phase 2b randomized, double-blind, placebo-controlled trial of once-weekly semaglutide vs placebo. The parent trial evaluated body fat distribution in patients with human immunodeficiency virus (HIV)–associated lipohypertrophy. Epigenetic aging was not a prespecified endpoint.
The epigenetic analysis included 45 patients assigned to semaglutide and 39 assigned to placebo. Eligible patients had documented HIV-1 infection, stable antiretroviral therapy, controlled viral load, body mass index of at least 25 kg/m², and clinical evidence of lipohypertrophy. Patients with diabetes or active cardiovascular disease were excluded. Semaglutide was titrated from 0.25 mg to 0.5 mg and then to 1.0 mg once weekly through week 32.
Researchers assessed first-, second-, and third-generation epigenetic clocks using blood samples collected at baseline and week 32. In adjusted analyses, semaglutide was associated with lower annualized epigenetic aging estimates compared with placebo across several biomarkers, particularly second- and third-generation clocks. The largest between-group differences included about 5 fewer epigenetic years per calendar year for PhenoAge, about 4 for SystemsAge, about 4 for PCPhenoAge, and about 3 for PCGrimAge. Semaglutide was also associated with a 9% slower pace of aging as measured by DunedinPACE.
Additional statistically significant findings were observed for GrimAge V1, GrimAge V2, OMICmAge, RetroAge, and PCHannum. Researchers adjusted analyses for baseline clock values, treatment group, sex, baseline body mass index, high-sensitivity C-reactive protein (hsCRP), and soluble CD163 (sCD163).
System-specific epigenetic measures also favored semaglutide for several blood-derived aging estimates. Compared with placebo, semaglutide was associated with lower aging estimates for inflammation, brain, metabolic, blood, heart, kidney, and liver systems, as well as the composite SystemsAge measure. However, lung, musculoskeletal, immune, and hormone system clocks did not reach statistical significance.
Not all biomarkers showed a response. DNAmFitAge, AdaptAge, CausAge, DamAge, the intrinsic capacity epigenetic clock, and several first-generation clocks did not show statistically significant between-group differences. DNA methylation–based immune cell deconvolution also found no statistically significant differences in estimated major peripheral immune cell populations between groups during follow-up, making major shifts in estimated blood cell composition less likely to explain the findings.
The researchers cautioned that the findings should be interpreted within the limits of the study design. The epigenetic analyses were posthoc and exploratory, the sample size was modest, follow-up was limited to 32 weeks, and P values were not adjusted for multiple comparisons. The study population was also specific: patients with controlled HIV and lipohypertrophy, without diabetes or active cardiovascular disease.
The researchers also noted that the system-specific clocks were derived from blood methylation profiles and should not be interpreted as direct evidence of tissue-level aging changes or organ rejuvenation. The analysis evaluated biomarkers rather than clinical outcomes such as frailty, age-related disease, survival, or healthspan.
The findings suggested that semaglutide might influence DNA methylation–based biomarkers associated with biological aging in this patient population, but they did not establish that semaglutide slows clinical aging or improves aging-related outcomes. The researchers wrote that prospective trials are needed to determine whether glucagon-like peptide-1 receptor agonists can be repurposed as gerotherapeutics.
Disclosures can be found in the published study.
Source: Nature Communications
