Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Biol Reprod. 2022 Feb 22;106(2):351-365. doi: 10.1093/biolre/ioab241.
The ovary is the first organ to age in humans with functional decline evident already in women in their early 30s. Reproductive aging is characterized by a decrease in oocyte quantity and quality, which is associated with an increase in infertility, spontaneous abortions, and birth defects. Reproductive aging also has implications for overall health due to decreased endocrinological output. Understanding the mechanisms underlying reproductive aging has significant societal implications as women globally are delaying childbearing and medical interventions have greatly increased the interval between menopause and total lifespan. Age-related changes inherent to the female gamete are well-characterized and include defects in chromosome and mitochondria structure, function, and regulation. More recently, it has been appreciated that the extra-follicular ovarian environment may have important direct or indirect impacts on the developing gamete, and age-dependent changes include increased fibrosis, inflammation, stiffness, and oxidative damage. The cumulus cells and follicular fluid that directly surround the oocyte during its final growth phase within the antral follicle represent additional critical local microenvironments. Here we systematically review the literature and evaluate the studies that investigated the age-related changes in cumulus cells and follicular fluid. Our findings demonstrate unique genetic, epigenetic, transcriptomic, and proteomic changes with associated metabolomic alterations, redox status imbalance, and increased apoptosis in the local oocyte microenvironment. We propose a model of how these changes interact, which may explain the rapid decline in gamete quality with age. We also review the limitations of published studies and highlight future research frontiers.
卵巢是人类中最早衰老的器官，女性在 30 岁出头时就已经出现功能下降。生殖衰老的特征是卵母细胞数量和质量下降，这与不孕、自然流产和出生缺陷的增加有关。生殖衰老也会对整体健康产生影响，因为内分泌输出减少。了解生殖衰老的机制具有重要的社会意义，因为全球女性都在推迟生育，而医疗干预大大延长了绝经和总寿命之间的间隔。女性配子固有的与年龄相关的变化特征明显，包括染色体和线粒体结构、功能和调节的缺陷。最近，人们认识到卵巢外的环境可能对正在发育的配子有重要的直接或间接影响，年龄相关的变化包括纤维化、炎症、僵硬和氧化损伤的增加。在窦卵泡内卵母细胞最后生长阶段直接围绕卵母细胞的颗粒细胞和卵泡液代表了额外的关键局部微环境。在这里，我们系统地回顾了文献，并评估了研究卵母细胞微环境中与年龄相关的颗粒细胞和卵泡液变化的研究。我们的研究结果表明，局部卵母细胞微环境中存在独特的遗传、表观遗传、转录组和蛋白质组变化，以及相关的代谢组改变、氧化还原状态失衡和细胞凋亡增加。我们提出了一个解释这些变化如何相互作用的模型，这可能解释了随着年龄的增长配子质量迅速下降的原因。我们还回顾了已发表研究的局限性，并强调了未来的研究前沿。
