Using single-nucleus RNA sequencing and spatial transcriptomics across 12 human ovaries (ages 12–54), researchers built a comprehensive aging atlas of the ovary. They identified a novel endothelial cell subtype (CLDN5+ blood EDCs) that acts as a semi-professional antigen-presenting cell and becomes increasingly inflammatory with age. Unlike other ovarian cell types that lose identity during aging, these cells grow more transcriptomically reactive. Aging also disrupted global cellular communication while amplifying a DLK1:NOTCH3 signaling axis between theca cells and CLDN5+ endothelial cells. Immunoglobulin-expressing cells accumulated at the ovarian periphery with age. Elevated DLK1 was also found in granulosa cells from women with primary ovarian insufficiency, pointing to shared mechanisms and potential therapeutic targets.
