Menopausal status, transition, and age at menopause with accelerated biological aging across multiple organ systems: findings from two cohort studies.

Background: Biological aging is a heterogeneous process that varies across organs and systems. The dynamic hormonal changes during the menopausal transition may have profound and organ-specific impacts on biological aging. However, the relationship between the menopausal transition and both comprehensive and organ-specific biological aging remains poorly understood. This study aimed to investigate the associations between menopausal factors and both comprehensive and organ-specific biological aging, as well as the modifying role of reproductive history.

Methods: This study included 37,244 women from the China Multi-Ethnic Cohort (CMEC) and 140,479 from the UK Biobank (UKB). Menopausal factors included menopausal status, menopausal transition, and age at menopause. Comprehensive and organ-specific biological ages (BAs) were calculated using the Klemera-Doubal method and clinical biomarkers and have been shown to predict age-related health outcomes. Multiple linear regression and change-to-change models were applied, with stratified analyses based on reproductive history.

Results: Compared with pre-menopausal women, those who were peri- or post-menopausal or had undergone hysterectomy or oophorectomy exhibited greater acceleration in comprehensive, liver, metabolic, and kidney BA. In longitudinal change-to-change models, women undergoing menopausal transition showed greater increases in comprehensive BA (CMEC: β = 1.33, 95% CI = 0.89, 1.76; UKB: β = 2.60, 95% CI = 1.91, 3.30), as well as liver, metabolic, and kidney BAs compared to those remaining pre-menopausal. Earlier age at menopause was associated with accelerated comprehensive BA in UKB (< 40 years: β = 0.69, 95% CI = 0.39, 0.98; 40-44 years: β = 0.24, 95% CI = 0.09, 0.40). Across organ-specific BAs, liver BA showed the strongest associations with menopausal factors. Reproductive history like age at live birth and number of live births emerged as potential modifiers of these associations.

Conclusions: Menopause, particularly the menopausal transition, was associated with accelerated comprehensive and organ-specific biological aging, with liver aging being most affected. These findings underscore the menopausal transition as a critical window for interventions to enhance women's health and longevity.