The ovary is indispensable for female reproduction, and its age-dependent functional decline is the primary cause of infertility. However, the molecular basis of ovarian aging in higher vertebrates remains poorly understood. Herein, we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries. From a global view, somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region, likely constituting a hostile microenvironment that facilitates ovarian aging. Further, we uncovered that inflammation, the senescent-associated secretory phenotype, senescence, and fibrosis are the likely primary contributors to ovarian aging (PCOA). Of note, we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2 (Metallothionein 2) highly expressing spot (MT2high) characterized by high levels of inflammation, potentially serving as an aging hotspot in the primate ovary. Moreover, with advanced age, a subpopulation of MT2high accumulates, likely disseminating and amplifying the senescent signal outward. Our study establishes the first primate spatiotemporal transcriptomic atlas, advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.

中文翻译：

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时空转录组学揭示灵长类动物卵巢的衰老特征。


卵巢对于女性生殖至关重要，其随年龄增长的功能衰退是导致不孕的主要原因。然而，高等脊椎动物卵巢衰老的分子基础仍然知之甚少。在这里，我们将时空转录组学应用于年轻灵长类动物卵巢的基准结构组织以及细胞和分子决定因素，并将其与老年灵长类动物卵巢进行比较。从整体来看，非卵泡区域内的体细胞相对于卵泡区域内的体细胞经历更明显的转录波动，可能构成促进卵巢衰老的不利微环境。此外，我们发现炎症、衰老相关的分泌表型、衰老和纤维化可能是卵巢衰老（PCOA）的主要原因。值得注意的是，我们发现了一个 PCOA 特征点和一个未被重视的 MT2（金属硫蛋白 2）高表达点（MT2high）之间的空间共定位，MT2high 的特征是高水平炎症，可能是灵长类卵巢中的衰老热点。此外，随着年龄的增长，MT2high 亚群会不断积累，可能会向外传播和放大衰老信号。我们的研究建立了第一个灵长类动物时空转录组图谱，增进了我们对灵长类动物卵巢衰老机制决定因素的理解，并揭示了衰老和与年龄相关的人类卵巢疾病的潜在生物标志物和治疗靶点。