Transcriptomic Profiling Reveals Biphasic Regulatory Instability and Late-Stage Proteostatic Decline in Aging Mouse Oocytese

<b>Background:</b> Maternal aging progressively compromises oocyte competence, yet the precise molecular trajectory across the reproductive lifespan remains insufficiently defined. <b>Methods:</b> Here, we mapped the transcriptomic landscape of mouse germinal vesicle (GV) oocytes across three distinct reproductive stages: post-pubertal peak fertility (Young, 8 weeks), fertility decline (Middle, 12 months), and reproductive senescence (Old, 18 months). <b>Results:</b> Our bioinformatic analyses reveal that oocyte aging follows a biphasic nonlinear trajectory. The transition from Young to Middle age marked the most profound period of transcriptional destabilization, characterized by 1197 DEGs and extensive perturbation of metabolic and signaling networks. To elucidate the regulatory drivers of this early drift, we performed transcription factor binding site (TFBS) analysis, which identified massive regulatory potential involving master regulators such as LHX8, MYC, and GATA4. Interestingly, despite the predicted extensive TF-target interactions, the mRNA expression levels of these TFs remained stable across age groups. This discrepancy suggests that the observed transcriptional dysregulation is likely associated by age-associated epigenetic modifications that alter chromatin accessibility or binding efficiency, rather than TF depletion. In the subsequent transition from Middle to Old age, the landscape shifted from active perturbation to systemic collapse. This late stage was characterized by mitochondrial respiratory dysfunction and severe proteostatic stress. <b>Conclusions:</b> Colectively, our findings define oocyte aging as a biphasic transition from compensatory resistance to systemic collapse. We identify midlife as the critical inflection point of regulatory remodeling, followed by terminal network exhaustion in senescence. This framework provides a molecular foundation for therapeutic and rejuvenation strategies aimed at mitigating age-associated infertility.