Zhang Yu, Bai Jie, Cui Zhaokang, Li Yu, Gao Qian, Miao Yilong, Xiong Bo
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China.
College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.
Nat Aging. 2023 Nov;3(11):1372-1386. doi: 10.1038/s43587-023-00498-8. Epub 2023 Oct 16.
Advanced age is a primary risk factor for female infertility due to reduced ovarian reserve and declining oocyte quality. However, as an important contributing factor, the role of metabolic regulation during reproductive aging is poorly understood. Here, we applied untargeted metabolomics to identify spermidine as a critical metabolite in ovaries to protect oocytes against aging. In particular, we found that the spermidine level was reduced in ovaries of aged mice and that supplementation with spermidine promoted follicle development, oocyte maturation, early embryonic development and female fertility of aged mice. By microtranscriptomic analysis, we further discovered that spermidine-induced recovery of oocyte quality was mediated by enhancement of mitophagy activity and mitochondrial function in aged mice, and this mechanism of action was conserved in porcine oocytes under oxidative stress. Altogether, our findings suggest that spermidine supplementation could represent a therapeutic strategy to ameliorate oocyte quality and reproductive outcome in cis-gender women and other persons trying to conceive at an advanced age. Future work is needed to test whether this approach can be safely and effectively translated to humans.
高龄是女性不孕的主要风险因素，原因是卵巢储备减少和卵母细胞质量下降。然而，作为一个重要的促成因素，生殖衰老过程中代谢调节的作用却鲜为人知。在此，我们应用非靶向代谢组学来确定亚精胺是卵巢中保护卵母细胞免受衰老影响的关键代谢物。具体而言，我们发现老年小鼠卵巢中的亚精胺水平降低，补充亚精胺可促进老年小鼠的卵泡发育、卵母细胞成熟、早期胚胎发育和雌性生育能力。通过微转录组分析，我们进一步发现，亚精胺诱导的卵母细胞质量恢复是通过增强老年小鼠的线粒体自噬活性和线粒体功能介导的，并且这种作用机制在氧化应激下的猪卵母细胞中是保守的。总之，我们的研究结果表明，补充亚精胺可能是一种改善顺性别女性和其他高龄备孕者卵母细胞质量和生殖结局的治疗策略。未来需要开展工作来测试这种方法能否安全有效地应用于人类。
