Systemic control and inter-organ communication of ovarian aging

Abstract

Whether ovarian aging is intrinsic and unidirectional or dynamically regulated by systemic context remains an open question for fertility and women's healthspan. To address it, we developed a mouse ovarian transcriptomic aging clock (OvaAge) and applied it, together with published transcriptomic, epigenetic and pathway-resolved DNA methylation (PathAge) clocks, multi-omic analyses and reproductive outcomes, to new reciprocal heterochronic ovary transplantation and parabiosis experiments. Ovarian molecular age shifted in both directions: aged ovaries became younger in young hosts and young ovaries became older in aged hosts, and in each case the shift was partial across transcriptomic, epigenetic and pathway-resolved measures. Ovaries from 13-month-old C57BL/6J donors supported full-term pregnancies and live births at 17-18 months of age when transplanted into young hosts, but not when transplanted into old hosts, and young ovaries supported live births in 17-18-month-old recipients. Donor ovary age altered the transcriptomic age of the uterus in both directions, while young ovaries also lowered the transcriptomic age of aged liver and brain, identifying the ovary as an active node within an inter-organ aging network. Across unilateral and bilateral transplantation and parabiosis, an older environment increased inflammatory gene expression in the ovary, whereas a younger environment reduced it and increased mitochondrial and biosynthetic programs. Integration of methylation, expression and cell-type markers linked these changes to declining oocyte-associated programs and an expanding stromal compartment enriched for multinucleated giant cells (MNGCs). MNGC-rich regions formed a reversibly remodeled, focally aged niche with distinct spatial metabolic features, and a related macrophage expression signature was detected in human ovaries. Together, these findings identify ovarian aging as a modular, bidirectionally plastic process that is regulated by the systemic environment and point to tractable intervention points.