Review of intervention effects on DNA methylation–based aging clocks in mammals
A systematized review of 35 longitudinal studies (29 human, 6 preclinical) found DNAm-based epigenetic age biomarkers modifiable by interventions, but effects were heterogeneous and depended on intervention, clock, tissue, follow-up and design; a single notion of epigenetic rejuvenation was not supported. [1]
Automatic summary · not editorially reviewed
The key findings
The systematized review included 35 longitudinal studies: 29 in humans and 6 preclinical, with human eligibility requiring at least 10 adults aged 18 or older and preclinical studies at least 5 per group. [1]
Metformin showed robust null epigenetic findings with adjusted intention-to-treat differences from −0.91 to +0.82 years across clocks (all p≥0.18), while a bezisterim sub-study reported reductions of −3.68 years in SkinBloodAge, −5.00 in Hannum and −4.77 in InflammAge. [1]
The authors concluded that DNAm-based epigenetic biomarkers are modifiable by interventions in mammals, but effects are heterogeneous and a single notion of epigenetic rejuvenation is not supported. [1]
The source at a glance
- Study type / format
- Systematized review of longitudinal intervention studies (abstract only)
- Population / context
- Human adults aged 18 or older in longitudinal intervention studies and mammalian preclinical studies.
- Summary based on
- Study abstract
- Publication status
- Preprint · peer-review status not confirmed
- Original publication
- March 10, 2026
Review scope: 35 longitudinal mammalian intervention studies
This systematized review covered longitudinal intervention studies from 2010–2025 in English and Spanish, searched in PubMed, Scopus and Cochrane CENTRAL, with selection documented using PRISMA. Human eligibility included randomized controlled trials, non-randomized controlled studies and pre–post designs with at least 10 adults aged 18 or older. Preclinical eligibility included longitudinal mammalian studies with at least 5 per group. Outcomes were changes in DNAm-based epigenetic age in years and/or pace of aging such as DunedinPACE. Data were extracted into a standardized matrix and synthesized narratively; meta-analysis was not performed because of heterogeneity.
Supporting source [1]
Mixed effects: lifestyle, compounds and blood interventions
Thirty-five studies were included: 29 human and 6 preclinical. Lifestyle interventions in humans generally showed modest effects, with more consistent signals when exposure was sustained and accompanied by plausible physiological changes; prolonged calorie restriction affected DunedinPACE with effect sizes up to d=−0.43 at 12 months and d=−0.40 at 24 months in higher-adherence participants. Exogenous compounds showed higher heterogeneity and mixed evidence: metformin showed robust null epigenetic findings with adjusted intention-to-treat differences from −0.91 to +0.82 years across clocks (all p≥0.18), while a bezisterim sub-study reported reductions of −3.68 years in SkinBloodAge, −5.00 in Hannum and −4.77 in InflammAge. Therapeutic plasma exchange with a sham arm reported decreases of about 1.3–2.6 years depending on clock and regimen, with benefits waning after treatment cessation; repeated plasmapheresis in donors was associated with increases of about +0.16–0.26 years per session across GrimAge-family clocks and about 0.003±0.001 DunedinPACE units per session.
Supporting source [1]
Preclinical signals and limits of interpretation
In rodents, plasma fractions or exosome-rich preparations and heterochronic parabiosis reported large percentage reductions across tissues, with strong dependence on exposure duration and concerns about translational uncertainty (up to about 77.6% in liver and about 68.2% in blood in one plasma-fraction study). Evidence for partial reprogramming (OSKM) was limited to a single rat study with small, near-significant trends in hippocampus-based clocks (two-sided p=0.064–0.088 across three clocks). The authors concluded that DNAm-based epigenetic biomarkers are modifiable by interventions in mammals, but effects are heterogeneous and depend on the intervention, clock construct (age versus pace or risk signatures), biological matrix, tissue, follow-up duration and study design. A single notion of epigenetic rejuvenation was not supported; effects appeared domain-specific and must be interpreted in relation to what each clock measures.
Supporting source [1]
How to interpret this
This explainer is based only on the abstract; the full text was not reviewed. The review itself synthesized studies narratively without meta-analysis because of heterogeneity, and the abstract reports no pooled estimates. Preclinical findings in rodents, including large percentage reductions, carry translational uncertainty noted by the authors.
Based on the study abstract; the full paper, tables and supplementary data were not reviewed.
Source & supporting passages
Amador Cervantes AF. · europepmc.org · March 10, 2026