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. 2025 Jul;29(7):100602.
doi: 10.1016/j.jnha.2025.100602. Epub 2025 Jun 11.

Epigenetic clocks as mediators of health behaviors and mortality in middle-aged and older adults

Xing-Ling Chen  1 , Qiang-Qiang Zhao  1 , Sheng-Rong Lin  1 , Xing-Ling He  1 , Xiao-Jiao Zhang  1 , Si-Jing Li  1 , Zi-Ru Li  1 , Jia-Hui Chen  1 , Hua Zhang  2 , Xiao-Fang Li  2 , Yue-Hui Zhou  2 , Hui-Li Liao  3 , Shu-Ning Sun  4 , Zhong-Qi Yang  5 , Shi-Hao Ni  6 , Lu Lu  7
Affiliations

Epigenetic clocks as mediators of health behaviors and mortality in middle-aged and older adults

Xing-Ling Chen et al. J Nutr Health Aging. 2025 Jul.

Abstract

Background: The impact of healthy lifestyles on epigenetic age acceleration (EAA) and mortality in middle-aged/ senior populations remains unclear. This study investigates associations between lifestyle factors, EAA biomarkers, and mortality risk.

Method: The 2532 adults of 50 years or older that registered in NHANES between 1999-2002.This study evaluated compares first- to third-generation epigenetic clocks (HannumAge, HorvathAge, PhenoAge, GrimAge2, DunedinPoAm) in predicting mortality risk associations between five lifestyle domains (diet, abdominal adiposity, physical activity, smoking, alcohol) and EAA were analyzed via multivariable regression, with mediation models testing EAA's role in lifestyle-mortality relationships.

Results: Survival curves results identified DunedinPoAm, GrimAge2AA, and PhenoAgeAA as robust biomarkers of accelerated biological aging, independent of chronological age. In multivariable linear regression models, full adherence to healthy behaviors reduced GrimAge2AA by β = -5.55 years, PhenoAgeAA by β = -2.64 years, and DunedinPoAm by β = -0.06 SD, with smoking cessation demonstrating the strongest GrimAge2AA attenuation (10.17 years). Stratified analyses revealed pronounced benefits: cancer patients adhering to healthy diets (β = -0.04 SD, P for interaction = 0.01) and hypertensive individuals reducing smoking (β = -0.05 SD, P for interaction = 0.04) showed significant EAA mitigation. The sensitivity analysis is consistent with the original results. Mediation analyses indicated GrimAge2AA accounted for 63.58% of lifestyle-survival associations, DunedinPoAm (44.63%) and PhenoAgeAA (28.45%).

Conclusions: These findings suggest that comprehensive adherence to healthy lifestyle behaviors is associated with reduced epigenetic aging, supporting their potential utility as targets for mortality risk mitigation. And emphasize the utility of epigenetic clocks in precision gerontology.

Keywords: Biological aging; Drinking; Epigenetic age acceleration; Healthy diet; Smoking.

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Conflict of interest statement

Declaration of competing interest The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Correlations Between Epigenetic Clocks, Epigenetic Age Acceleration and Chronological Age. Abbreviations: AA, age acceleration.
Fig. 2
Fig. 2
Cox Proportional Hazards Models of 5 Epigenetic Age Acceleration and All-cause Mortality. Abbreviations: AA, age acceleration; PSM, propensity score matching.
Fig. 3
Fig. 3
Bivariate Associations Between Healthy Lifestyle and Epigenetic Age in Selected Clocks. Models adjusted for age, sex, ethnicity, marital status, educational level, household income, hypertension, diabetes, cardiovascular disease, and cancer. Abbreviations: AA, age acceleration; CI, confidenceinterval; WWI, weight-adjusted waist index; HEI, health eating index; MET-PA, metabolic equivalent of task for physical activity level.
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