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We therefore conducted a post-hoc epigenetic analysis of a 32-week, double-blind, placebo-controlled phase 2b trial in adults with HIV-associated lipohypertrophy (semaglutide n = 45; placebo n = 39). Paired peripheral-blood methylomes were profiled to evaluate semaglutide\u2019s impact across multiple generations of DNA-methylation clocks. After adjustment for sex, BMI, hsCRP, and sCD163, semaglutide significantly decreased epigenetic aging: PCGrimAge (-3.1 years, P = 0.007), GrimAge V1 (-1.4 years, P = 0.02), GrimAge V2 (-2.3 years, P = 0.009), PhenoAge (-4.9 years, P = 0.004), and DunedinPACE (-0.09 units, \u22489 % slower pace, P = 0.01). Semaglutide also lowered the multi-omic OMICmAge clock (-2.2 years, P = 0.009) and the transposable element-focused RetroAge clock (-2.2 years, P = 0.030). Eleven organ-system clocks showed concordant decreased with semaglutide, most prominently inflammation, brain and heart, whereas an Intrinsic Capacity epigenetic clock was unchanged (P = 0.31). These findings provide, to our knowledge, the first clinical-trial evidence that semaglutide modulates validated epigenetic biomarkers of aging, justifying further evaluation of GLP-1 receptor agonists for health-span extension.<\/jats:p>","DOI":"10.1101\/2025.07.09.25331038","type":"posted-content","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T23:10:10Z","timestamp":1752534610000},"source":"Crossref","is-referenced-by-count":5,"title":["Semaglutide Slows Epigenetic Aging in People with HIV-associated lipohypertrophy: Evidence from a Randomized Controlled Trial"],"prefix":"10.64898","author":[{"given":"Michael J.","family":"Corley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun","family":"Dwaraka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina PS","family":"Pang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Labbato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison Ross","family":"Eckard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace A.","family":"McComsey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025071602151680000_2025.07.09.25331038v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu049"},{"key":"2025071602151680000_2025.07.09.25331038v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-8587(24)00271-7"},{"key":"2025071602151680000_2025.07.09.25331038v1.3","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.73420"},{"key":"2025071602151680000_2025.07.09.25331038v1.4","first-page":"376","article-title":"Individual and additive effects of vitamin D, omega-3 and exercise on DNA methylation clocks of biological aging in older adults from the DO-HEALTH trial. 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