Ovarian aging is characterized by declines in follicular reserve and the emergence of mitochondrial dysfunction, reactive oxygen species production, inflammation, and fibrosis, which eventually results in menopause. Menopause is associated with increased systemic aging and the development of numerous comorbidities; therefore, the attenuation of ovarian aging could also delay systemic aging processes in women. Recent work has established that the anti-diabetic drug Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor, elicits benefits on aging-related outcomes, likely through the modulation of nutrient-sensing pathways and metabolic homeostasis. Given that nutrient-sensing pathways play a critical role in controlling primordial follicle activation, we sought to determine if chronic Cana administration would delay ovarian aging and curtail the emergence of pathological hallmarks associated with reproductive senescence. We found that mice receiving Cana maintained their ovarian reserve through 12 months of age, which was associated with declines in primordial follicles FoxO3a phosphorylation, a marker of activation, when compared to the age-matched controls. Furthermore, Cana treatment led to decreased collagen, lipofuscin, and T cell accumulation at 12 months of age. Whole ovary transcriptomic and proteomic analyses revealed subtle improvements, predominantly in mitochondrial function and the regulation of cellular proliferation. Pathway analyses of the transcriptomic data revealed a downregulation in cell proliferation and mitochondrial dysfunction signatures, with an upregulation of oxidative phosphorylation. Pathway analyses of the proteomic data revealed declines in signatures associated with PI3K/AKT activity and lymphocyte accumulation. Collectively, we demonstrate that Cana treatment can delay ovarian aging in mice and could potentially have efficacy for delaying ovarian aging in women.

卵巢衰老的特征是卵泡储备下降和线粒体功能障碍、活性氧产生、炎症和纤维化的出现，最终导致更年期。更年期与全身性衰老增加和多种合并症的发展有关;因此，卵巢衰老的减弱也可以延缓女性的全身衰老过程。最近的工作已经确定，抗糖尿病药物 Canagliflozin （Cana） 是一种钠-葡萄糖转运蛋白 2 抑制剂，可能通过调节营养感应途径和代谢稳态，对衰老相关结果有益。鉴于营养感应通路在控制原始卵泡激活中起关键作用，我们试图确定慢性 Cana 给药是否会延缓卵巢衰老并减少与生殖衰老相关的病理特征的出现。我们发现接受 Cana 的小鼠在 12 个月大时保持卵巢储备，与年龄匹配的对照相比，这与原始卵泡 FoxO3a 磷酸化（激活标志物）的下降有关。此外，Cana 治疗导致 12 个月大时胶原蛋白、脂褐素和 T 细胞积累减少。全卵巢转录组学和蛋白质组学分析揭示了细微的改善，主要是线粒体功能和细胞增殖的调节。转录组数据的通路分析显示细胞增殖和线粒体功能障碍特征下调，氧化磷酸化上调。蛋白质组学数据的通路分析显示，与 PI3K/AKT 活性和淋巴细胞积累相关的特征下降。 总的来说，我们证明了 Cana 治疗可以延缓小鼠的卵巢衰老，并且可能对延缓女性卵巢衰老具有疗效。