Epigenetic clocks as mediators of health behaviors and mortality in middle-aged and older adults.
Level 3 - non-randomized controlled study
Prospective cohort study analyzing survey and mortality follow-up data
PubMed 40505553 · doi:10.1016/j.jnha.2025.100602
What was done
Researchers evaluated 2,532 adults aged 50 or older from the 1999–2002 National Health and Nutrition Examination Survey (NHANES). They assessed associations between five lifestyle domains (diet, abdominal adiposity, physical activity, smoking, alcohol) and epigenetic age acceleration (EAA) across multiple epigenetic clocks (HannumAge, HorvathAge, PhenoAge, GrimAge2, DunedinPoAm) using multivariable linear regression. Mediation models were then constructed to evaluate the extent to which EAA mediated the relationship between lifestyle habits and mortality risk.
What was found
DunedinPoAm, GrimAge2AA, and PhenoAgeAA were identified as robust mortality predictors independent of chronological age. Full adherence to healthy lifestyle behaviors significantly reduced biological aging markers: GrimAge2AA decreased by β = -5.55 years, PhenoAgeAA by β = -2.64 years, and DunedinPoAm by β = -0.06 SD. Smoking cessation showed the largest single attenuation of GrimAge2AA (10.17 years). Stratified analyses showed notable EAA mitigation among cancer patients with healthy diets (β = -0.04 SD, P interaction = 0.01) and hypertensive adults with reduced smoking (β = -0.05 SD, P interaction = 0.04). In mediation analyses, GrimAge2AA explained 63.58% of the lifestyle-survival association, DunedinPoAm explained 44.63%, and PhenoAgeAA explained 28.45%.
Why it matters
These findings suggest that biological aging pathways, particularly those captured by second- and third-generation epigenetic clocks like GrimAge2, serve as substantial mediators linking healthy daily behaviors to extended survival.
Limits
The observational cohort design precludes definitive causal claims. Lifestyle behaviors were subject to self-report and baseline measurement error. The abstract does not specify total follow-up duration, exact confidence intervals, or specific cause-of-death breakdowns.
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