Decline in ovarian reserve with advancing age is associated with reduced fertility and the emergence of metabolic disturbances, osteoporosis, and neurodegeneration. Recent studies have provided insight into connections between ovarian insufficiency and systemic aging, although the basic mechanisms that promote ovarian reserve depletion remain unknown. Here, we sought to determine if chronological age is linked to changes in ovarian cellular senescence, transcriptomic, and epigenetic mechanisms in a mouse model. Histological assessments and transcriptional analyses revealed the accumulation of lipofuscin aggresomes and senescence-related transcripts (Cdkn1a, Cdkn2a, Pai-1 and Hmgb1) significantly increased with advancing age. Transcriptomic profiling and pathway analyses following RNA sequencing, revealed an upregulation of genes related to pro-inflammatory stress and cell-cycle inhibition, whereas genes involved in cell-cycle progression were downregulated; which could be indicative of senescent cell accumulation. The emergence of these senescence-related markers preceded the dramatic decline in primordial follicle reserve observed. Whole Genome Oxidative Bisulfite Sequencing (WGoxBS) found no genome-wide or genomic context-specific DNA methylation and hydroxymethylation changes with advancing age. These findings suggest that cellular senescence may contribute to ovarian aging, and thus, declines in ovarian follicular reserve. Cell-type-specific analyses across the reproductive lifespan are needed to fully elucidate the mechanisms that promote ovarian insufficiency.

随着年龄的增长，卵巢储备功能下降，与生育能力下降以及代谢紊乱、骨质疏松症和神经退行性疾病的出现有关。最近的研究深入了解了卵巢功能不全与全身衰老之间的联系，尽管促进卵巢储备耗竭的基本机制仍不清楚。在这里，我们试图在小鼠模型中确定实际年龄是否与卵巢细胞衰老、转录组和表观遗传机制的变化有关。组织学评估和转录分析显示，脂褐质聚集体和衰老相关转录本（Cdkn1a、Cdkn2a、Pai-1 和 Hmgb1）的积累随着年龄的增长而显着增加。 RNA测序后的转录组学分析和通路分析显示，与促炎应激和细胞周期抑制相关的基因上调，而与细胞周期进展相关的基因下调；这可能表明衰老细胞的积累。这些衰老相关标志物的出现先于观察到的原始卵泡储备的急剧下降。全基因组氧化亚硫酸氢盐测序 (WGoxBS) 发现，全基因组或基因组特定 DNA 甲基化和羟甲基化没有随着年龄的增长而发生变化。这些发现表明细胞衰老可能导致卵巢衰老，从而导致卵巢卵泡储备下降。需要对整个生殖寿命进行细胞类型特异性分析，以充分阐明促进卵巢功能不全的机制。