Single-Cell Transcriptomic Atlas of Primate Ovarian Aging

Si Wang ¹, Yuxuan Zheng ², Jingyi Li ³, Yang Yu ⁴, Weiqi Zhang ⁵, Moshi Song ⁶, Zunpeng Liu ⁷, Zheying Min ⁸, Huifang Hu ⁷, Ying Jing ⁷, Xiaojuan He ⁹, Liang Sun ¹⁰, Lifang Ma ⁸, Concepcion Rodriguez Esteban ¹¹, Piu Chan ⁹, Jie Qiao ⁸, Qi Zhou ¹², Juan Carlos Izpisua Belmonte ¹³, Jing Qu ¹⁴, Fuchou Tang ¹⁵, Guang-Hui Liu ¹⁶

Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. Indepth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders.