Background: Middle-aged adults experience degenerative aging-related changes, often differing by sex. Research identifying sex-specific factors contributing to biological aging among middle-aged adults remains limited. This study aimed to identify sex-specific factors influencing GrimAge acceleration (GrimAA), a DNA methylation-based estimator of biological aging, among middle-aged Korean adults. Methods: Data were derived from the Korean Genome and Epidemiology Study (KoGES) cohort involving 686 middle-aged adults (422 men and 264 women). GrimAA was calculated from DNA methylation data using the GrimAge epigenetic clock. Demographic, lifestyle, clinical, and psychosocial stress variables were assessed, and sex-specific factors influencing GrimAA were identified through hierarchical multiple regression models. Results: In men, higher GrimAA was significantly associated with current smoking, current drinking, physical inactivity, and elevated Hs-CRP or HbA1C levels, whereas among women, early menopause (<50 years) emerged as a notable factor related to increased GrimAA. Hierarchical regression analyses revealed that chronological age, current smoking, and Hs-CRP were robust predictors of GrimAA in men, whereas GrimAA in women was significantly predicted by current smoking and Hs-CRP. Conclusion: Sex differences in GrimAA may result from the interplay of lifestyle behaviors, inflammatory biomarkers, and hormonal factors. Targeted interventions addressing these sex-specific determinants could be effective strategies to mitigate biological aging acceleration among middle-aged adults.
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