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<p>Glucagon-like peptide-1 (GLP-1) receptor agonists have attracted interest as gerotherapeutics, yet clinical-trial evidence for their effects on biological aging is lacking. We report a post hoc exploratory epigenetic age analysis of a 32-week, randomized, double-blind, placebo-controlled phase 2b trial (NCT04019197) of semaglutide in adults with human immunodeficiency virus (HIV)-associated lipohypertrophy (semaglutide <i>n</i> = 45; placebo <i>n</i> = 39). The parent trial’s primary endpoint was change in visceral adipose tissue, with secondary cardiometabolic and body-composition endpoints; epigenetic aging was not pre-specified. To address this gap, we profiled peripheral-blood DNA methylation (DNAm) at baseline and week 32 to assess semaglutide versus placebo on first-, second-, and third-generation epigenetic aging measures. In adjusted analyses, semaglutide reduced epigenetic aging across multiple second- and third-generation clocks, including PhenoAge ( − 4.9 years/year, <i>p</i> = 0.004), PCGrimAge ( − 3.1, <i>p</i> = 0.007), GrimAge V2 ( − 2.3, <i>p</i> = 0.009), OMICmAge ( − 2.2, <i>p</i> = 0.009), RetroAge ( − 2.2, <i>p</i> = 0.030), and DunedinPACE ( − 0.09 units, 9% slower, <i>p</i> = 0.01). Systems-based clocks showed parallel reductions in inflammation, brain, and heart aging measures. The post hoc design, modest sample size, HIV-specific cohort, and 32-week follow-up limit generalizability. Prospective trials are needed to determine whether GLP-1 receptor agonists can be repurposed as gerotherapeutics.</p>

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Semaglutide slows epigenetic aging in a randomized trial of HIV-associated lipohypertrophy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Michael J. Corley,
  • Varun B. Dwaraka,
  • Alina PS Pang,
  • Danielle Labbato,
  • Ryan Smith,
  • Allison Ross Eckard,
  • Grace A. McComsey

摘要

Glucagon-like peptide-1 (GLP-1) receptor agonists have attracted interest as gerotherapeutics, yet clinical-trial evidence for their effects on biological aging is lacking. We report a post hoc exploratory epigenetic age analysis of a 32-week, randomized, double-blind, placebo-controlled phase 2b trial (NCT04019197) of semaglutide in adults with human immunodeficiency virus (HIV)-associated lipohypertrophy (semaglutide n = 45; placebo n = 39). The parent trial’s primary endpoint was change in visceral adipose tissue, with secondary cardiometabolic and body-composition endpoints; epigenetic aging was not pre-specified. To address this gap, we profiled peripheral-blood DNA methylation (DNAm) at baseline and week 32 to assess semaglutide versus placebo on first-, second-, and third-generation epigenetic aging measures. In adjusted analyses, semaglutide reduced epigenetic aging across multiple second- and third-generation clocks, including PhenoAge ( − 4.9 years/year, p = 0.004), PCGrimAge ( − 3.1, p = 0.007), GrimAge V2 ( − 2.3, p = 0.009), OMICmAge ( − 2.2, p = 0.009), RetroAge ( − 2.2, p = 0.030), and DunedinPACE ( − 0.09 units, 9% slower, p = 0.01). Systems-based clocks showed parallel reductions in inflammation, brain, and heart aging measures. The post hoc design, modest sample size, HIV-specific cohort, and 32-week follow-up limit generalizability. Prospective trials are needed to determine whether GLP-1 receptor agonists can be repurposed as gerotherapeutics.