Menopause transition timing reflects systemic biological aging

Abstract Natural menopause marks the end of female reproductive capacity, yet its relationship with biological aging remains unclear. Earlier menopause has been associated with reduced lifespan and increased disease risk, but whether menopause itself accelerates aging or reflects an underlying faster biological aging trajectory remains unresolved. Here, we combined animal models of menopausal transition with epigenetic analyses in postmenopausal women, to investigate this relationship. In rats, neither ovariectomy-induced menopause nor natural reproductive senescence resulted in increased epigenetic age acceleration. In postmenopausal women, accelerated epigenetic aging was observed only in individuals who reached postmenopause earlier than the cohort median, independent of metabolic health status. Exploratory differential DNA methylation analysis suggested an association between age at menopause and pathways involved in longevity, chromatin regulation, and neurodegeneration. Together, these findings support a model in which the timing of reproductive aging reflects systemic biological aging rather than driving it, positioning age at menopause as a potential biomarker of the rate of biological aging.