Aging disrupts spatiotemporal coordination in the cycling ovary

Abstract

Throughout the female reproductive lifespan, the ovary completes hundreds of cycles of follicle development, ovulation, and tissue regeneration1-3. These processes rely on the precise coordination of intricate multicellular interactions across time and space4. How aging disrupts these interactions, leading to the overall decline in reproductive and endocrine functions, remains understudied. To understand the multicellular dynamics that underlie ovarian function and their changes with age, here we use Slide-seq, a near-cellular spatial transcriptomics method, to profile 21 ovaries across reproductive cycles and chronological age, representing 601,831 near-cellular spots across 68 spatial transcriptomic profiles5,6. We develop a segmentation analysis to identify static snapshots of spatial niches that capture folliculogenesis in situ, allowing us to examine the multicellular dynamics of 345 oocytes, 653 follicles, and 234 corpora lutea. We find that aging disrupts both the spatial organization and temporal coordination of folliculogenesis before the cessation of cycling, leading to dysregulation of hormone production and signaling. These disruptions are marked by altered immune cell dynamics, inflammatory signaling, and global tissue disorganization that impair the cyclic remodeling required for ovarian function. Our findings reveal how multicellular niches orchestrate the reproductive and endocrine functions of the ovary and demonstrate how age-related breakdown of tissue organization across time and space precedes reproductive decline.