Bidirectional associations between metabolic syndrome and epigenetic age acceleration: A 20-year longitudinal study in midlife adults

INTRODUCTION: Metabolic syndrome (MetS) increases with age. Epigenetic alterations reflect lifelong biological and environmental influences on aging. MetS may contribute to epigenetic age acceleration (EAA) through inflammation and oxidative stress, while elevated EAA may, in turn, exacerbate metabolic dysfunction, but long-term evidence for this bidirectional association is limited. METHODS: We analyzed data from 1452 participants in the Korean Genome and Epidemiology Study at baseline (Wave 1), 10-year (Wave 5), and 20-year (Wave 10) follow-ups. MetS severity was defined by the number of diagnostic criteria, and DNA methylation-based EAA measures (PhenoAA, Grim2AA, DunedinPACE) at Wave 5 were included. Multivariable linear regression models examined the association between MetS and EAA both cross-sectionally (at Wave 5) and longitudinally (Wave 1 MetS - Wave 5 EAA and Wave 5 EAA - Wave 10 MetS). Mediation analysis examined whether EAA mediated the association between MetS severity across waves. All models were adjusted for chronological age, sex, smoking, drinking, physical activity, education, income, and body mass index. RESULTS: Cross-sectionally, all EAA measures were associated with higher MetS severity score (β ranged 0.37-1.26, all P < 0.05). Longitudinally, earlier MetS severity was associated with EAA (Grim2AA: β = 0.25; DunedinPACE: β = 0.78, all P < 0.05) and EAA was associated with later MetS severity (Grim2AA: β = 0.03; DunedinPACE: β = 0.01, all P < 0.05). EAA partially mediated the association between earlier and later MetS severity (1.6-3.1 % mediation proportion, P < 0.05). CONCLUSION: Our findings suggest a bidirectional relationship between MetS and EAA, with biological aging potentially mediating metabolic deterioration. EAA may serve as both a marker and mediator of metabolic health, and a promising target for prevention and intervention.