卵母细胞衰老机制的研究进展

doi:10.12280/gjszjk.20240519

摘要/Abstract

摘要：

卵巢衰老是女性衰老的开始，不仅关系到女性生殖健康，也是当前社会低生育力的重要影响因素。目前针对女性生殖衰老的机制已经从多个层次进行了广泛的研究，包括细胞水平、分子水平、系统水平以及个体水平等方面。从线粒体功能、染色体、氧化应激、能量代谢以及免疫因素等方面综述卵母细胞衰老过程中所涉及的多种生物学机制，并探索针对女性生殖衰老靶向治疗的进展，以期为预防卵巢早衰甚至延缓生殖衰老提供重要思路。

关键词: 卵母细胞, 衰老, 染色体, 线粒体, 氧化性应激, 能量代谢, 免疫因素

Abstract:

Ovarian aging is the beginning of female aging, which not only relates to women's reproductive health but also serves as an important influencing factor of the low fertility rate in the nowadays society. Currently, the mechanisms of female reproductive aging have been extensively studied from multiple levels, including cellular, molecular, systemic and individual levels. This review summarizes various biological mechanisms involved in oocyte aging, such as mitochondrial function, chromosomes, oxidative stress, energy metabolism and immune factors. It also explores the progress of targeted therapies for female reproductive aging, aiming to provide important insights for preventing premature ovarian failure and even delaying reproductive aging.

Key words: Oocytes, Aging, Chromosomes, Mitochondria, Oxidative stress, Energy metabolism, Immune factors

张江琳, 袁海宁, 张云洁, 李恒兵, 苑丽华, 孙振高. 卵母细胞衰老机制的研究进展[J]. 国际生殖健康/计划生育杂志, 2025, 44(2): 144-149.

ZHANG Jiang-lin, YUAN Hai-ning, ZHANG Yun-jie, LI Heng-bing, YUAN Li-hua, SUN Zhen-gao. Research Progress on the Mechanisms of Oocyte Aging[J]. Journal of International Reproductive Health/Family Planning, 2025, 44(2): 144-149.

参考文献 47

[1]	Adhikari D, Lee IW, Yuen WS, et al. Oocyte mitochondria-key regulators of oocyte function and potential therapeutic targets for improving fertility[J]. Biol Reprod, 2022, 106(2):366-377. doi: 10.1093/biolre/ioac024. pmid: 35094043
[2]	Joubert F, Puff N. Mitochondrial Cristae Architecture and Functions: Lessons from Minimal Model Systems[J]. Membranes(Basel), 2021, 11(7):465. doi: 10.3390/membranes11070465.
[3]	Berry BJ, Vodicková A, Müller-Eigner A, et al. Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan[J]. Nat Aging, 2023, 3(2):157-161. doi: 10.1038/s43587-022-00340-7.
[4]	Zaib S, Hayyat A, Ali N, et al. Role of Mitochondrial Membrane Potential and Lactate Dehydrogenase A in Apoptosis[J]. Anticancer Agents Med Chem, 2022, 22(11):2048-2062. doi: 10.2174/1871520621666211126090906.
[5]	Güçlü E, Çınar A, Dursun HG, et al. Tomentosin induces apoptosis in pancreatic cancer cells through increasing reactive oxygen species and decreasing mitochondrial membrane potential[J]. Toxicol In Vitro, 2022,84:105458. doi: 10.1016/j.tiv.2022.105458.
[6]	Han X, Xing L, Hong Y, et al. Nuclear RNA homeostasis promotes systems-level coordination of cell fate and senescence[J]. Cell Stem Cell, 2024, 31(5):694-716.e11. doi: 10.1016/j.stem.2024.03.015.
[7]	Zhang Y, Bai J, Cui Z, et al. Polyamine metabolite spermidine rejuvenates oocyte quality by enhancing mitophagy during female reproductive aging[J]. Nat Aging, 2023, 3(11):1372-1386. doi: 10.1038/s43587-023-00498-8. pmid: 37845508
[8]	May-Panloup P, Desquiret V, Morinière C, et al. Mitochondrial macro-haplogroup JT may play a protective role in ovarian ageing[J]. Mitochondrion, 2014, 18:1-6. doi: 10.1016/j.mito.2014.08.002. pmid: 25132080
[9]	Liu BH, Xu CZ, Liu Y, et al. Mitochondrial quality control in human health and disease[J]. Mil Med Res, 2024, 11(1):32. doi: 10.1186/s40779-024-00536-5.
[10]	Jin X, Wang K, Wang L, et al. RAB7 activity is required for the regulation of mitophagy in oocyte meiosis and oocyte quality control during ovarian aging[J]. Autophagy, 2022, 18(3):643-660. doi: 10.1080/15548627.2021.1946739.
[11]	Nolfi-Donegan D, Braganza A, Shiva S. Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement[J]. Redox Biol, 2020,37:101674. doi: 10.1016/j.redox.2020.101674.
[12]	Kobayashi H, Yoshimoto C, Matsubara S, et al. Altered Energy Metabolism, Mitochondrial Dysfunction, and Redox Imbalance Influencing Reproductive Performance in Granulosa Cells and Oocyte During Aging[J]. Reprod Sci, 2024, 31(4):906-916. doi: 10.1007/s43032-023-01394-7.
[13]	Kirillova A, Smitz J, Sukhikh GT, et al. The Role of Mitochondria in Oocyte Maturation[J]. Cells, 2021, 10(9):2484. doi: 10.3390/cells10092484.
[14]	张楠, 张珏, 林戈. 哺乳动物卵母细胞的DNA损伤与修复研究进展[J]. 遗传, 2023, 45(5):379-394. doi: 10.16288/j.yczz.23-018.
[15]	Zhao RZ, Jiang S, Zhang L, et al. Mitochondrial electron transport chain, ROS generation and uncoupling (Review)[J]. Int J Mol Med, 2019, 44(1):3-15. doi: 10.3892/ijmm.2019.4188.
[16]	Hori YS, Kuno A, Hosoda R, et al. Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress[J]. PLoS One, 2013, 8(9):e73875. doi: 10.1371/journal.pone.0073875.
[17]	Vo KCT, Sato Y, Kawamura K. Improvement of oocyte quality through the SIRT signaling pathway[J]. Reprod Med Biol, 2023, 22(1):e12510. doi: 10.1002/rmb2.12510.
[18]	Ming PF, Huang YY, Dong YL, et al. Regulation of LKB1-AMPKα-SIRT1 Signal Pathway in Lipid Metabolism in the Adipose Tissue of Dairy Cows[J]. Biotechnol Bull, 2019, 35(2):176-181.
[19]	You Y, Liang W. SIRT1 and SIRT6: The role in aging-related diseases[J]. Biochim Biophys Acta Mol Basis Dis, 2023, 1869(7): 166815. doi: 10.1016/j.bbadis.2023.166815.
[20]	Liu Y, Wei H, Li J. A review on SIRT3 and its natural small molecule activators as a potential Preventive and therapeutic target[J]. Eur J Pharmacol, 2024,963:176155. doi: 10.1016/j.ejphar.2023.176155.
[21]	Wang B, Wang Y, Zhang J, et al. ROS-induced lipid peroxidation modulates cell death outcome: mechanisms behind apoptosis, autophagy, and ferroptosis[J]. Arch Toxicol, 2023, 97 (6):1439-1451.doi: 10.1007/s00204-023-03476-6. pmid: 37127681
[22]	Kobayashi H, Imanaka S. Recent progress in metabolomics for analyzing common infertility conditions that affect ovarian function[J]. Reprod Med Biol, 2024, 23(1):e12609. doi: 10.1002/rmb2.12609.
[23]	Ademowo OS, Dias H, Burton D, et al. Lipid (per) oxidation in mitochondria: an emerging target in the ageing process?[J]. Biogerontology, 2017, 18(6):859-879. doi: 10.1007/s10522-017-9710-z. pmid: 28540446
[24]	Li Y, Zhao T, Li J, et al. Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the Pathogenesis and Treatment of Aging-related Diseases[J]. J Immunol Res, 2022,2022:2233906. doi: 10.1155/2022/2233906.
[25]	Park SU, Walsh L, Berkowitz KM. Mechanisms of ovarian aging[J]. Reproduction, 2021, 162(2):R19-R33. doi: 10.1530/REP-21-0022.
[26]	Lamb NE, Yu K, Shaffer J, et al. Association between maternal age and meiotic recombination for trisomy 21[J]. Am J Hum Genet, 2005, 76(1):91-99. doi: 10.1086/427266. pmid: 15551222
[27]	Bai L, Li P, Xiang Y, et al. BRCA1 safeguards genome integrity by activating chromosome asynapsis checkpoint to eliminate recombination-defective oocytes[J]. Proc Natl Acad Sci U S A, 2024, 121(19):e2401386121. doi: 10.1073/pnas.2401386121.
[28]	Liu C, Zuo W, Yan G, et al. Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects and aneuploidy[J]. Nat Aging, 2023, 3(6):670-687. doi: 10.1038/s43587-023-00419-9.
[29]	Takenouchi O, Sakakibara Y, Kitajima TS. Live chromosome identifying and tracking reveals size-based spatial pathway of meiotic errors in oocytes[J]. Science, 2024, 385(6706):eadn5529. doi: 10.1126/science.adn5529.
[30]	Zhu Z, Xu W, Liu L. Ovarian aging: mechanisms and intervention strategies[J]. Med Rev(2021), 2022, 2(6):590-610. doi: 10.1515/mr-2022-0031.
[31]	Haseeb MA, Bernys AC, Dickert EE, et al. An RNAi screen to identify proteins required for cohesion rejuvenation during meiotic prophase in Drosophila oocytes[J]. G3(Bethesda), 2024, 14(8):jkae123. doi: 10.1093/g3journal/jkae123.
[32]	Wassmann K. Separase Control and Cohesin Cleavage in Oocytes: Should I Stay or Should I Go?[J]. Cells, 2022, 11(21):3399. doi: 10.3390/cells11213399.
[33]	Mihalas BP, Pieper GH, Aboelenain M, et al. Age-dependent loss of cohesion protection in human oocytes[J]. Curr Biol, 2024, 34(1):117-131.e5. doi: 10.1016/j.cub.2023.11.061.
[34]	Bao S, Yin T, Liu S. Ovarian aging: energy metabolism of oocytes[J]. J Ovarian Res, 2024, 17(1):118. doi: 10.1186/s13048-024-01427-y. pmid: 38822408
[35]	Smits M, Schomakers BV, van Weeghel M, et al. Human ovarian aging is characterized by oxidative damage and mitochondrial dysfunction[J]. Hum Reprod, 2023, 38(11):2208-2220. doi: 10.1093/humrep/dead177.
[36]	Covarrubias AJ, Perrone R, Grozio A, et al. NAD+ metabolism and its roles in cellular processes during ageing[J]. Nat Rev Mol Cell Biol, 2021, 22(2):119-141. doi: 10.1038/s41580-020-00313-x.
[37]	Fukamizu Y, Uchida Y, Shigekawa A, et al. Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women[J]. Sci Rep, 2022, 12(1):14442. doi: 10.1038/s41598-022-18272-y. pmid: 36002548
[38]	Johmura Y, Yamanaka T, Omori S, et al. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders[J]. Science, 2021, 371(6526):265-270. doi: 10.1126/science.abb5916. pmid: 33446552
[39]	Li M, Wang Y, Wei X, et al. AMPK-PDZD8-GLS1 axis mediates calorie restriction-induced lifespan extension[J]. Cell Res, 2024, 34(11):806-809. doi: 10.1038/s41422-024-01021-3.
[40]	Silva J, Lima F, Souza A, et al. Interleukin-1β and TNF-α systems in ovarian follicles and their roles during follicular development, oocyte maturation and ovulation[J]. Zygote, 2020, 28(4):270-277. doi: 10.1017/S0967199420000222. pmid: 32383419
[41]	Szeliga A, Calik-Ksepka A, Maciejewska-Jeske M, et al. Autoimmune Diseases in Patients with Premature Ovarian Insufficiency-Our Current State of Knowledge[J]. Int J Mol Sci, 2021, 22(5):2594. doi: 10.3390/ijms22052594.
[42]	Lliberos C, Liew SH, Zareie P, et al. Evaluation of inflammation and follicle depletion during ovarian ageing in mice[J]. Sci Rep, 2021, 11(1):278. doi: 10.1038/s41598-020-79488-4. pmid: 33432051
[43]	Zhang L, Pitcher LE, Yousefzadeh MJ, et al. Cellular senescence: a key therapeutic target in aging and diseases[J]. J Clin Invest, 2022, 132(15):e158450. doi: 10.1172/JCI158450.
[44]	Kang MH, Kim YJ, Cho MJ, et al. Mitigating Age-Related Ovarian Dysfunction with the Anti-Inflammatory Agent MIT-001[J]. Int J Mol Sci, 2023, 24(20):15158. doi: 10.3390/ijms242015158.
[45]	Ali I, Padhiar AA, Wang T, et al. Stem Cell-Based Therapeutic Strategies for Premature Ovarian Insufficiency and Infertility: A Focus on Aging[J]. Cells, 2022, 11(23):3713. doi: 10.3390/cells11233713.
[46]	Li Z, Qi H, Li Z, et al. Research progress on the premature ovarian failure caused by cisplatin therapy[J]. Front Oncol, 2023,13:1276310. doi: 10.3389/fonc.2023.1276310.
[47]	Wang Y, Pope I, Brennan-Craddock H, et al. A primary effect of palmitic acid on mouse oocytes is the disruption of the structure of the endoplasmic reticulum[J]. Reproduction, 2021, 163(1):45-56. doi: 10.1530/REP-21-0332.