Spatial transcriptomic characteristics of the aging human ovary

Ovarian aging is a complex process that compromises fertility and elevates the risk of reproductive disorders. To elucidate its spatiotemporal dynamics, we integrated single-nucleus RNA sequencing and spatial transcriptomics to construct a comprehensive aging atlas of 12 human ovarian tissues spanning ages 12-54. Our analysis revealed aging-associated transcriptomic shifts, including impaired mitochondrial oxidative phosphorylation and reproductive structure development in aged human ovaries. We identified a novel endothelial cell (EDC) subtype, CLDN5⁺ blood EDCs, which exhibited unique functional specialization as (semi-professional) antigen-presenting cells. In contrast to other cell types that lost cell identity during aging, CLDN5⁺ blood EDCs displayed transcriptomic sensitivity to aging, characterized by enhanced antigen-presenting capabilities, and heightened inflammatory activity. Spatial mapping further uncovered immunoglobulin-expressing cell (IGHG1+/IGKC+) accumulation in the ovarian periphery, correlating with advancing age. Critically, aging disrupted global cellular connectivity while amplifying the DLK1:NOTCH3 axis between theca cells and CLDN5⁺ blood EDCs, which may contribute to the dysregulation of ovarian functions. The progressively upregulation of DLK1 indicates it as a robust biomarker of ovarian aging. This study significantly enhances our comprehension of the underlying mechanisms of human ovarian aging and concurrently pinpoints potential therapeutic avenues for addressing related disorders.