Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1

Limited understanding exists regarding how aging impacts the cellular and molecular aspects of the human ovary. This study combines single-cell RNA sequencing and spatial transcriptomics to systematically characterize human ovarian aging. Spatiotemporal molecular signatures of the eight types of ovarian cells during aging are observed. An analysis of age-associated changes in gene expression reveals that DNA damage response may be a key biological pathway in oocyte aging. Three granulosa cells subtypes and five theca and stromal cells subtypes, as well as their spatiotemporal transcriptomics changes during aging, are identified. FOXP1 emerges as a regulator of ovarian aging, declining with age and inhibiting CDKN1A transcription. Silencing FOXP1 results in premature ovarian insufficiency in mice. These findings offer a comprehensive understanding of spatiotemporal variability in human ovarian aging, aiding the prioritization of potential diagnostic biomarkers and therapeutic strategies. Ovarian aging has an important role in health and fertility; however, the molecular mechanisms underlying it remain incompletely understood. Here the authors use single-cell and spatial transcriptomics in reproductively young, middle-aged and older human ovarian tissue to elucidate ovarian aging. They describe spatiotemporal changes in ovarian cells and highlight the important regulatory role of FOXP1.