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Peer-reviewedCC BYNature Communications

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

  • Michael J. Corley1
  • Varun B. Dwaraka2
  • Alina P.S. Pang3
  • Danielle E. Labbato4
  • Ryan Smith2
  • Allison Ross Eckard5
  • Grace A. McComsey6,7
7 affiliations
  1. 1University of California San Diego, Department of Medicine, Division of Geriatrics and Palliative Care, La Jolla, CA, USA. [email protected]
  2. 2TruDiagnostic, Lexington, KY, USA
  3. 3University of California San Diego, Department of Medicine, Division of Geriatrics and Palliative Care, La Jolla, CA, USA
  4. 4University Hospitals Cleveland Medical Center, Cleveland, OH, USA
  5. 5Medical University of South Carolina, Charleston, SC, USA
  6. 6Case Western Reserve University, Cleveland, OH, USA. [email protected]
  7. 7University Hospitals Cleveland Medical Center, Cleveland, OH, USA. [email protected]
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{corley2026semaglutide,
  title = {{Semaglutide slows epigenetic aging in a randomized trial of HIV-associated lipohypertrophy}},
  author = {Michael J. Corley and Varun B. Dwaraka and Alina P.S. Pang and Danielle E. Labbato and Ryan Smith and Allison Ross Eckard and Grace A. McComsey},
  journal = {Nature Communications},
  year = {2026},
  month = may,
  doi = {10.1038/s41467-026-72861-3},
  url = {https://doi.org/10.1038/s41467-026-72861-3},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Semaglutide slows epigenetic aging in a randomized trial of HIV-associated lipohypertrophy
AU  - Michael J. Corley
AU  - Varun B. Dwaraka
AU  - Alina P.S. Pang
AU  - Danielle E. Labbato
AU  - Ryan Smith
AU  - Allison Ross Eckard
AU  - Grace A. McComsey
PY  - 2026
DA  - 2026/05/19
JO  - Nature Communications
DO  - 10.1038/s41467-026-72861-3
UR  - https://doi.org/10.1038/s41467-026-72861-3
AB  - 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.
SN  - 2041-1723
ER  -