Department of Obstetrics and Gynecology, New York University Langone Fertility Center, New York University School of Medicine, NYU Langone Health, New York, New York; Department of Biology, San Francisco State University, San Francisco, California.
Department of Obstetrics and Gynecology, New York University Langone Fertility Center, New York University School of Medicine, NYU Langone Health, New York, New York.
Fertil Steril. 2024 Jan;121(1):4-11. doi: 10.1016/j.fertnstert.2023.11.012. Epub 2023 Nov 21.
The oocyte, a long-lived, postmitotic cell, is the locus of reproductive aging in women. Female germ cells replicate only during fetal life and age throughout reproductive life. Mechanisms of oocyte aging include the accumulation of oxidative damage, mitochondrial dysfunction, and disruption of proteins, including cohesion. Nobel Laureate Bob Edwards also discovered a "production line" during oogonial replication in the mouse, wherein the last oocytes to ovulate in the adult-derived from the last oogonia to exit mitotic replication in the fetus. On the basis of this, we proposed a two-hit "telomere theory of reproductive aging" to integrate the myriad features of oocyte aging. The first hit was that oocytes remaining in older women traversed more cell cycles during fetal oogenesis. The second hit was that oocytes accumulated more environmental and endogenous oxidative damage throughout the life of the woman. Telomeres (Ts) could mediate both of these aspects of oocyte aging. Telomeres provide a "mitotic clock," with T attrition an inevitable consequence of cell division because of the end replication problem. Telomere's guanine-rich sequence renders them especially sensitive to oxidative damage, even in postmitotic cells. Telomerase, the reverse transcriptase that restores Ts, is better at maintaining than elongating T. Moreover, telomerase remains inactive during much of oogenesis and early development. Oocytes are left with short Ts, on the brink of viability. In support of this theory, mice with induced T attrition and women with naturally occurring telomeropathy suffer diminished ovarian reserve, abnormal embryo development, and infertility. In contrast, sperm are produced throughout the life of the male by a telomerase-active progenitor, spermatogonia, resulting in the longest Ts in the body. In mice, cleavage-stage embryos elongate Ts via "alternative lengthening of telomeres," a recombination-based mechanism rarely encountered outside of telomerase-deficient cancers. Many questions about Ts and reproduction are raised by these findings: does the "normal" T attrition observed in human oocytes contribute to their extraordinarily high rate of meiotic nondisjunction? Does recombination-based T elongation render embryos susceptible to mitotic nondisjunction (and mosaicism)? Can some features of Ts serve as markers of oocyte quality?
卵母细胞是一种长寿的有丝后体细胞，是女性生殖衰老的关键。女性生殖细胞仅在胎儿期复制，并在生殖期衰老。卵母细胞衰老的机制包括氧化损伤的积累、线粒体功能障碍和蛋白质的破坏，包括凝聚。诺贝尔奖得主 Bob Edwards 还在小鼠的卵原细胞复制过程中发现了一条“生产线”，其中成年时排卵的最后一批卵母细胞来源于胎儿中最后一批退出有丝分裂复制的卵原细胞。在此基础上，我们提出了一个“端粒理论”来整合卵母细胞衰老的各种特征。第一次打击是，留在老年女性体内的卵母细胞在胎儿生殖过程中经历了更多的细胞周期。第二次打击是，卵母细胞在女性的一生中积累了更多的环境和内源性氧化损伤。端粒（Ts）可以介导这两个方面的卵母细胞衰老。端粒提供了一个“有丝分裂钟”，由于末端复制问题，Ts 的损耗是细胞分裂不可避免的结果。端粒的鸟嘌呤丰富序列使它们特别容易受到氧化损伤的影响，即使在有丝后体细胞中也是如此。端粒酶是一种逆转录酶，可以恢复 Ts，它更擅长维持而不是延长 Ts。此外，端粒酶在生殖和早期发育的大部分时间内都处于不活跃状态。卵母细胞的 Ts 很短，处于生存的边缘。支持这一理论的是，诱导 Ts 损耗的小鼠和自然发生端粒病的女性卵巢储备减少、胚胎发育异常和不孕。相比之下，精子是由有丝分裂活跃的祖细胞精原细胞在男性一生中产生的，这导致了体内最长的 Ts。在小鼠中，卵裂期胚胎通过“端粒的替代延长”来延长 Ts，这是一种很少在端粒酶缺乏的癌症之外发现的重组机制。这些发现提出了许多关于 Ts 和生殖的问题：人类卵母细胞中观察到的“正常”Ts 损耗是否导致其极高的减数分裂非整倍体率？基于重组的 Ts 延长是否使胚胎容易发生有丝分裂非整倍体（和嵌合体）？Ts 的某些特征能否作为卵母细胞质量的标志物？
