Ovarian failure drives systemic aging at single-cell resolution

Yet, the molecular pathways underlying the somatic aging driven by ovarian failure remain largely unexplored. We report that ovarian failure promotes systemic aging across multiple organs.

Furthermore, we show that POI triggers aging-associated transcriptional programs characterized by mitochondrial dysfunction, metabolic dysregulation, chronic inflammation, fibrosis and stem cell depletion. These changes are underpinned by sustained activation of cAMP signaling and suppression of PPAR-dependent metabolic pathways. Moreover, compared with estrogen replacement alone, ovarian transplantation restored systemic functions, particularly stem cell function, and reversed transcriptional aging signatures more broadly, indicating that ovarian function governs somatic organ aging beyond estrogen.