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

Corley MJ, Dwaraka VB, Pang AP, Labbato D, Smith R, Ross Eckard A, McComsey GA

Nature communications19 May 2026Cited by 7 (Europe PMC)

PMID42156721PMCIDPMC13381876DOI10.1038/s41467-026-72861-3PepBankPUB-42156721

Summary

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.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study7

7 results from studies that gave the peptide. 7 results from people.

01HumanRandomized controlled trialEfficacy outcome
In adults with HIV-associated lipohypertrophy, semaglutide reduced the PhenoAge epigenetic aging measure versus placebo over 32 weeks.
In plain wordsIn adults with HIV-related fat build-up, semaglutide slowed a biological aging clock (PhenoAge) more than placebo over 32 weeks.
Peptide
Semaglutide
Outcome
DecreasePhenoAge epigenetic clock
Study
n = 84
Comparator
Placebo
Analysis
Exploratory
Outcome group
Aging markers · Aging and longevity
Studied dose
Dose not stated · 32 weeksAs given in this study (human).
Measurements
PhenoAge change
−4.9 years/year
semaglutide vs placebo
Source sentences
Summary
PhenoAge ( - 4.9 years/year, p = 0.004)
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-4215672101
02HumanRandomized controlled trialEfficacy outcome
In adults with HIV-associated lipohypertrophy, semaglutide reduced the PCGrimAge epigenetic aging measure versus placebo over 32 weeks.
In plain wordsIn adults with HIV-related fat build-up, semaglutide slowed a biological aging clock (PCGrimAge) more than placebo over 32 weeks.
Peptide
Semaglutide
Outcome
DecreasePCGrimAge epigenetic clock
Study
n = 84
Comparator
Placebo
Analysis
Exploratory
Outcome group
Aging markers · Aging and longevity
Studied dose
Dose not stated · 32 weeksAs given in this study (human).
Measurements
PCGrimAge change
−3.1 years/year
semaglutide vs placebo
Source sentences
Summary
PCGrimAge ( - 3.1, p = 0.007)
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-4215672102
03HumanRandomized controlled trialEfficacy outcome
In adults with HIV-associated lipohypertrophy, semaglutide reduced the GrimAge V2 epigenetic aging measure versus placebo over 32 weeks.
In plain wordsIn adults with HIV-related fat build-up, semaglutide slowed a biological aging clock (GrimAge V2) more than placebo over 32 weeks.
Peptide
Semaglutide
Outcome
DecreaseGrimAge V2 epigenetic clock
Study
n = 84
Comparator
Placebo
Analysis
Exploratory
Outcome group
Aging markers · Aging and longevity
Studied dose
Dose not stated · 32 weeksAs given in this study (human).
Measurements
GrimAge V2 change
−2.3 years/year
semaglutide vs placebo
Source sentences
Summary
GrimAge V2 ( - 2.3, p = 0.009)
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-4215672103
04HumanRandomized controlled trialEfficacy outcome
In adults with HIV-associated lipohypertrophy, semaglutide reduced the OMICmAge epigenetic aging measure versus placebo over 32 weeks.
In plain wordsIn adults with HIV-related fat build-up, semaglutide slowed a biological aging clock (OMICmAge) more than placebo over 32 weeks.
Peptide
Semaglutide
Outcome
DecreaseOMICmAge epigenetic clock
Study
n = 84
Comparator
Placebo
Analysis
Exploratory
Outcome group
Aging markers · Aging and longevity
Studied dose
Dose not stated · 32 weeksAs given in this study (human).
Measurements
OMICmAge change
−2.2 years/year
semaglutide vs placebo
Source sentences
Summary
OMICmAge ( - 2.2, p = 0.009)
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-4215672104
05HumanRandomized controlled trialEfficacy outcome
In adults with HIV-associated lipohypertrophy, semaglutide reduced the RetroAge epigenetic aging measure versus placebo over 32 weeks.
In plain wordsIn adults with HIV-related fat build-up, semaglutide slowed a biological aging clock (RetroAge) more than placebo over 32 weeks.
Peptide
Semaglutide
Outcome
DecreaseRetroAge epigenetic clock
Study
n = 84
Comparator
Placebo
Analysis
Exploratory
Outcome group
Aging markers · Aging and longevity
Studied dose
Dose not stated · 32 weeksAs given in this study (human).
Measurements
RetroAge change
−2.2 years/year
semaglutide vs placebo
Source sentences
Summary
RetroAge ( - 2.2, p = 0.030)
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-4215672105
06HumanRandomized controlled trialEfficacy outcome
In adults with HIV-associated lipohypertrophy, semaglutide slowed the DunedinPACE pace of epigenetic aging by 9% versus placebo over 32 weeks.
In plain wordsIn adults with HIV-related fat build-up, semaglutide slowed a pace-of-aging measure (DunedinPACE) by 9% more than placebo over 32 weeks.
Peptide
Semaglutide
Outcome
DecreaseDunedinPACE pace of aging
Study
n = 84
Comparator
Placebo
Analysis
Exploratory
Outcome group
Aging markers · Aging and longevity
Studied dose
Dose not stated · 32 weeksAs given in this study (human).
Measurements
DunedinPACE change
−0.09 units
semaglutide vs placebo
Source sentences
Summary
DunedinPACE ( - 0.09 units, 9% slower, p = 0.01)
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-4215672106
07HumanRandomized controlled trialEfficacy outcome
In adults with HIV-associated lipohypertrophy, semaglutide produced parallel reductions in systems-based epigenetic clocks for inflammation, brain and heart aging versus placebo.
In plain wordsIn adults with HIV-related fat build-up, semaglutide lowered aging clocks for inflammation, brain and heart more than placebo over 32 weeks.
Peptide
Semaglutide
Outcome
DecreaseSystems-based clocks (inflammation, brain, heart aging)
Study
n = 84
Comparator
Placebo
Analysis
Exploratory
Outcome group
Aging markers · Aging and longevity
Studied dose
Dose not stated · 32 weeksAs given in this study (human).
Source sentences
Summary
Systems-based clocks showed parallel reductions in inflammation, brain, and heart aging measures.
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-4215672107

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
11 Oct 2026, 00:04 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

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