The prospective association of cellular markers of biological aging with menopause in the Coronary Artery Risk Development in Young Adults Study

Objective: Evidence from cross-sectional studies mainly among postmenopausal women suggests that biological aging is associated with reproductive senescence. We evaluated the prospective association of cellular markers of biological aging measured during the premenopausal period, and changes in these markers, with age at menopause. Methods: We studied 583 premenopausal women (39% Black) from the Coronary Artery Risk Development in Young Adults Study who had data on biological aging markers in 2000-2001 and reached menopause by 2020-2021. Linear regression models were used to evaluate the association of telomere length, mitochondrial DNA copy number, intrinsic or extrinsic epigenetic age acceleration, and PhenoAge or GrimAge acceleration with age at menopause. Results: The mean age at baseline was 41.2 ± 3.3 years, with the mean age at menopause being 49.1 (median, 50) years. About one in five women had surgical menopause. In chronological age-adjusted models, only baseline GrimAge acceleration was associated with age at menopause; women whose epigenetic age was older than their chronological age reached menopause at 0.12 years (~6 weeks) earlier compared with women with equal epigenetic and chronological age (β = −0.123; 95% CI, −0.224 to −0.022; P = 0.018). However, this association was not statistically significant after adjustment for sociodemographic, behavior/lifestyle, and metabolic factors. Similar results were observed when changes in these biological aging markers were evaluated. The same associations were observed in analyses limited to women who reached natural menopause. Conclusions: Sociodemographic, behavior/lifestyle, and metabolic factors remain comparable, if not more robust predictors of the age at menopause compared with cellular measures of biological age.