Multimodal data analysis reveals asynchronous aging dynamics across female reproductive organs.

Abstract

Female reproductive aging has systemic health implications, yet tissue-level dynamics remain poorly understood. Here we integrate deep learning analysis of 1,112 histology images with RNA sequencing from 659 samples across seven female reproductive organs in donors aged 20-70 years. We uncover asynchronous trajectories: the ovary ages gradually, whereas the uterus shows an abrupt molecular and morphological shift around menopause. This uterine transition is independently supported by plasma proteomics data from a large population cohort, indicating that organ-linked aging signatures are detectable in circulation. Tissue segmentation highlights the myometrium as strongly age affected, with extracellular matrix remodeling and immune activation. Epithelial tissues also show coordinated age-related remodeling, with a sharp menopausal transition in the vaginal epithelium. Multi-omics factor analysis links these histological changes to nonlinear gene-expression shifts enriched for reproductive traits, including pelvic organ prolapse and age at menarche. Together, these findings establish menopause as a key inflection point in female aging and provide a tissue-resolved, multi-dataset framework for late-life health.