Isola José V V, Biswas Subhasri, Jayarathne Hashan, Hubbart Chase R, Hense Jessica D, Matsuzaki Satoshi, Kinter Michael T, Humphries Kenneth M, Ocañas Sarah R, Sadagurski Marianna, Stout Michael B
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13 Street, Chapman E306, Oklahoma City, OK, 73104, USA.
Department of Biological Sciences, Institute of Environmental Health Sciences, Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA.
Geroscience. 2024 Dec 14. doi: 10.1007/s11357-024-01465-w.
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减少以及线粒体功能障碍、活性氧生成、炎症和纤维化的出现，最终导致绝经。绝经与全身衰老加剧和多种合并症的发生有关；因此，减缓卵巢衰老也可能延缓女性的全身衰老进程。最近的研究表明，抗糖尿病药物卡格列净（Cana），一种钠-葡萄糖协同转运蛋白2抑制剂，可能通过调节营养感应途径和代谢稳态，对与衰老相关的结果产生有益影响。鉴于营养感应途径在控制原始卵泡激活中起关键作用，我们试图确定长期给予Cana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治疗的小鼠在12个月龄时保持了卵巢储备，与年龄匹配的对照组相比，这与原始卵泡中激活标志物FoxO3a磷酸化水平的下降有关。此外，Cana治疗导致12个月龄时胶原蛋白、脂褐素和T细胞积累减少。全卵巢转录组和蛋白质组分析显示有细微改善，主要体现在线粒体功能和细胞增殖调节方面。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有效。
