Reproductive aging: biological pathways and potential interventive strategies

Yuanyuan Liu; Jinmin Gao

doi:10.1016/j.jgg.2022.07.002

Volume 50 Issue 3

Mar. 2023

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Article Navigation > Journal of Genetics and Genomics > 2023 > 50(3): 141-150

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Reproductive aging: biological pathways and potential interventive strategies

doi: 10.1016/j.jgg.2022.07.002

Center for Cell Structure and Function, College of Life Sciences, Key Laboratory of Animal Resistance Biology of Shandong Province, Shandong Normal University, Jinan, Shandong 250014, China

Funds:

This work was supported by grants from the National Natural Science Foundation of China (32022018 and 31871360 to J. Gao).

Received Date: 2022-04-24
Accepted Date: 2022-07-05
Rev Recd Date: 2022-07-01
Publish Date: 2022-07-14

Abstract

Abstract

Reproductive aging is a natural process conserved across species and is well-known in females. It shows age-related follicle depletion and reduction of oocyte quality, eventually causing reproductive senescence and menopause. Although reproductive aging in males is not well noticed as in females, it also causes infertility and has deleterious consequences on the offspring. Various factors have been suggested to contribute to reproductive aging, including oxidative stress, mitochondrial defects, telomere shortening, meiotic chromosome segregation errors and genetic alterations. With the increasing trend of pregnancy age, it is particularly crucial to find interventions to preserve or extend human fertility. Studies in humans and model organisms have provided insights into the biological pathways associated with reproductive aging, and a series of potential interventive strategies have been tested. Here, we review factors affecting reproductive aging in females and males and summarize interventive strategies that may help delay or rescue the aging phenotypes of reproduction.
- Reproductive aging,
- Infertility,
- Oocytes,
- Sperm,
- Gamete quality

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References(99)

References

[1]	Agarwal, A., Aponte-Mellado, A., Premkumar, B.J., Shaman, A.,Gupta, S., 2012. The effects of oxidative stress on female reproduction: a review. Reprod. Biol. Endocrinol. 10, 49-49.
[2]	Astolfi, P.,Zonta, L.A., 1999. Risks of preterm delivery and association with maternal age, birth order, and fetal gender. Hum. Reprod. 14, 2891-2894.
[3]	Aston, K.I., Hunt, S.C., Susser, E., Kimura, M., Factor-Litvak, P., Carrell, D.,Aviv, A., 2012. Divergence of sperm and leukocyte age-dependent telomere dynamics: implications for male-driven evolution of telomere length in humans. Mol. Hum. Reprod. 18, 517-522.
[4]	Belloc, S., Cohen-Bacrie, P., Benkhalifa, M., Cohen-Bacrie, M., De Mouzon, J., Hazout, A.,Menezo, Y., 2008. Effect of maternal and paternal age on pregnancy and miscarriage rates after intrauterine insemination. Reprod. Biomed. Online 17, 392-397.
[5]	Ben-Meir, A., Burstein, E., Borrego-Alvarez, A., Chong, J., Wong, E., Yavorska, T., Naranian, T., Chi, M., Wang, Y., Bentov, Y., et al., 2015. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell 14, 887-895.
[6]	Ben-Meir, A., Kim, K., McQuaid, R., Esfandiari, N., Bentov, Y., Casper, R.F.,Jurisicova, A., 2019. Co-enzyme Q10 supplementation rescues cumulus cells dysfunction in a maternal aging model. Antioxidants (Basel) 8, 58.
[7]	Bertoldo, M.J., Listijono, D.R., Ho, W.J., Riepsamen, A.H., Goss, D.M., Richani, D., Jin, X.L., Mahbub, S., Campbell, J.M., Habibalahi, A., et al., 2020. NAD(+) repletion rescues female fertility during reproductive aging. Cell Rep. 30, 1670-1681.e1677.
[8]	Blengini, C.S., Nguyen, A.L., Aboelenain, M.,Schindler, K., 2021. Age-dependent integrity of the meiotic spindle assembly checkpoint in females requires aurora kinase B. Aging Cell 20, e13489.
[9]	Broekmans, F.J., Faddy, M.J., Scheffer, G.,te Velde, E.R., 2004. Antral follicle counts are related to age at natural fertility loss and age at menopause. Menopause 11, 607-614.
[10]	Burkhardt, S., Borsos, M., Szydlowska, A., Godwin, J., Williams, S.A., Cohen, P.E., Hirota, T., Saitou, M.,Tachibana-Konwalski, K., 2016. Chromosome cohesion established by Rec8-cohesin in fetal oocytes is maintained without detectable turnover in oocytes arrested for months in mice. Curr. Biol. 26, 678-685.
[11]	Canto, C., Menzies, K.J.,Auwerx, J., 2015. NAD(+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 22, 31-53.
[12]	Chatzidaki, E.E., Powell, S., Dequeker, B.J.H., Gassler, J., Silva, M.C.C.,Tachibana, K., 2021. Ovulation suppression protects against chromosomal abnormalities in mouse eggs at advanced maternal age. Curr. Biol. 31, 4038-4051.e4037.
[13]	Chen, L., Guo, S., Wei, C., Li, H., Wang, H.,Xu, Y., 2018. Effect of stem cell transplantation of premature ovarian failure in animal models and patients: a meta-analysis and case report. Exp. Ther. Med. 15, 4105-4118.
[14]	Cheng, J.M.,Liu, Y.X., 2017. Age-related loss of cohesion: causes and effects. Int. J. Mol. Sci. 18, 1578.
[15]	Chiang, T., Duncan, F.E., Schindler, K., Schultz, R.M.,Lampson, M.A., 2010. Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes. Curr. Biol. 20, 1522-1528.
[16]	Chin, R.M., Fu, X., Pai, M.Y., Vergnes, L., Hwang, H., Deng, G., Diep, S., Lomenick, B., Meli, V.S., Monsalve, G.C., et al., 2014. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510, 397-401.
[17]	Christodoulaki, A., Boel, A., Tang, M., De Roo, C., Stoop, D.,Heindryckx, B., 2021. Prospects of Germline Nuclear Transfer in Women With Diminished Ovarian Reserve. Front. Endocrinol. (Lausanne) 12, 635370.
[18]	Cioppi, F., Rosta, V.,Krausz, C., 2021. Genetics of Azoospermia. Int. J. Mol. Sci. 22, 3264.
[19]	Colella, M., Cuomo, D., Peluso, T., Falanga, I., Mallardo, M., De Felice, M.,Ambrosino, C., 2021. Ovarian aging: role of pituitary-ovarian axis hormones and ncRNAs in regulating ovarian mitochondrial activity. Front. Endocrinol. 12, 791071.
[20]	Crawford, N.M.,Steiner, A.Z., 2015. Age-related infertility. Obstet. Gynecol. Clin. North Am. 42, 15-25.
[21]	Cui, X., Jing, X., Wu, X.,Yan, M., 2016. Protective effect of resveratrol on spermatozoa function in male infertility induced by excess weight and obesity. Mol. Med. Rep. 14, 4659-4665.
[22]	Darmishonnejad, Z., Tavalaee, M., Izadi, T., Tanhaei, S.,Nasr-Esfahani, M.H., 2019. Evaluation of sperm telomere length in infertile men with failed/low fertilization after intracytoplasmic sperm injection. Reprod. Biomed. Online 38, 579-587.
[23]	Day, F.R., Ruth, K.S., Thompson, D.J., Lunetta, K.L., Pervjakova, N., Chasman, D.I., Stolk, L., Finucane, H.K., Sulem, P., Bulik-Sullivan, B., et al., 2015. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat. Genet. 47, 1294-1303.
[24]	Dechanet, C., Anahory, T., Mathieu Daude, J.C., Quantin, X., Reyftmann, L., Hamamah, S., Hedon, B.,Dechaud, H., 2011. Effects of cigarette smoking on reproduction. Hum. Reprod. Update 17, 76-95.
[25]	Douhard, M., Festa-Bianchet, M.,Pelletier, F., 2020. Sons accelerate maternal aging in a wild mammal. Proc. Natl. Acad. Sci. U.S.A. 117, 4850-4857.
[26]	Duncan, F.E., Hornick, J.E., Lampson, M.A., Schultz, R.M., Shea, L.D.,Woodruff, T.K., 2012. Chromosome cohesion decreases in human eggs with advanced maternal age. Aging Cell 11, 1121-1124.
[27]	Ergenoglu, M., Yildirim, N., Yildirim, A.G., Yeniel, O., Erbas, O., Yavasoglu, A., Taskiran, D.,Karadadas, N., 2015. Effects of resveratrol on ovarian morphology, plasma anti-mullerian hormone, IGF-1 levels, and oxidative stress parameters in a rat model of polycystic ovary syndrome. Reprod. Sci. 22, 942-947.
[28]	Faid, I., Al-Hussaini, H.,Kilarkaje, N., 2015. Resveratrol alleviates diabetes-induced testicular dysfunction by inhibiting oxidative stress and c-Jun N-terminal kinase signaling in rats. Toxicol. Appl. Pharmacol. 289, 482-494.
[29]	Fitzgerald, C., Zimon, A.E.,Jones, E.E., 1998. Aging and reproductive potential in women. Yale J. Biol. Med. 71, 367-381.
[30]	Fricke, C.,Koppik, M., 2019. Male reproductive ageing: a tale of the whole ejaculate. Reproduction 158, R219-r229.
[31]	Ghosh, S., Feingold, E., Chakraborty, S.,Dey, S.K., 2010. Telomere length is associated with types of chromosome 21 nondisjunction: a new insight into the maternal age effect on Down syndrome birth. Hum. Genet. 127, 403-409.
[32]	Ghosh, S., Feingold, E.,Dey, S.K., 2009. Etiology of down syndrome: evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. Am. J. Med. Genet. A 149a, 1415-1420.
[33]	Grabowska, W., Sikora, E.,Bielak-Zmijewska, A., 2017. Sirtuins, a promising target in slowing down the ageing process. Biogerontology 18, 447-476.
[34]	Gruhn, J.R., Zielinska, A.P., Shukla, V., Blanshard, R., Capalbo, A., Cimadomo, D., Nikiforov, D., Chan, A.C., Newnham, L.J., Vogel, I., et al., 2019. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 365, 1466-1469.
[35]	Hu, K.L., Ye, X., Wang, S.,Zhang, D., 2020. Melatonin application in assisted reproductive technology: a systematic review and meta-analysis of randomized trials. Front. Endocrinol. 11, 160.
[36]	Hurt, L.S., Ronsmans, C.,Quigley, M., 2006. Does the number of sons born affect long-term mortality of parents? A cohort study in rural Bangladesh. Proc Biol Sci 273, 149-155.
[37]	Hvide, H.K., Johnsen, J.,Salvanes, K.G., 2021. Parental age and birth defects: a sibling study. Eur. J. Epidemiol. 36, 849-860.
[38]	Itami, N., Shirasuna, K., Kuwayama, T.,Iwata, H., 2015. Resveratrol improves the quality of pig oocytes derived from early antral follicles through sirtuin 1 activation. Theriogenology 83, 1360-1367.
[39]	Jiao, X., Ke, H., Qin, Y.,Chen, Z., 2018. Molecular genetics of premature ovarian insufficiency. Trends Endocrinol. Metab. 29, 795-807.
[40]	Johnson, L., Zane, R.S., Petty, C.S.,Neaves, W.B., 1984. Quantification of the human sertoli cell population: its distribution, relation to germ cell numbers, and age-related decline. Biol. Reprod. 31, 785-795.
[41]	Juan, M.E., Gonzalez-Pons, E., Munuera, T., Ballester, J., Rodriguez-Gil, J.E.,Planas, J.M., 2005. Trans-resveratrol, a natural antioxidant from grapes, increases sperm output in healthy rats. J. Nutr. 135, 757-760.
[42]	Keefe, D.L., Franco, S., Liu, L., Trimarchi, J., Cao, B., Weitzen, S., Agarwal, S.,Blasco, M.A., 2005. Telomere length predicts embryo fragmentation after in vitro fertilization in women--toward a telomere theory of reproductive aging in women. Am. J. Obstet. Gynecol. 192, 1256-1260.
[43]	Kong, A., Frigge, M.L., Masson, G., Besenbacher, S., Sulem, P., Magnusson, G., Gudjonsson, S.A., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., et al., 2012. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471-475.
[44]	Kordowitzki, P., Hamdi, M., Derevyanko, A., Rizos, D.,Blasco, M., 2020. The effect of rapamycin on bovine oocyte maturation success and metaphase telomere length maintenance. Aging (Albany NY) 12, 7576-7584.
[45]	Labarta, E., de Los Santos, M.J., Escriba, M.J., Pellicer, A.,Herraiz, S., 2019. Mitochondria as a tool for oocyte rejuvenation. Fertil. Steril. 111, 219-226.
[46]	Leisegang, K., Henkel, R.,Agarwal, A., 2017. Redox Regulation of Fertility in Aging Male and the Role of Antioxidants: A Savior or Stressor. Curr. Pharm. Des. 23, 4438-4450.
[47]	Leridon, H., 2004. Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. Hum. Reprod. 19, 1548-1553.
[48]	Liu, J., Liu, M., Ye, X., Liu, K., Huang, J., Wang, L., Ji, G., Liu, N., Tang, X., Baltz, J.M., et al., 2012. Delay in oocyte aging in mice by the antioxidant N-acetyl-L-cysteine (NAC). Hum. Reprod. 27, 1411-1420.
[49]	Liu, L., Blasco, M.A.,Keefe, D.L., 2002. Requirement of functional telomeres for metaphase chromosome alignments and integrity of meiotic spindles. EMBO Rep. 3, 230-234.
[50]	Liu, L., Franco, S., Spyropoulos, B., Moens, P.B., Blasco, M.A.,Keefe, D.L., 2004. Irregular telomeres impair meiotic synapsis and recombination in mice. Proc. Natl. Acad. Sci. U.S.A. 101, 6496-6501.
[51]	Liu, M., Yin, Y., Ye, X., Zeng, M., Zhao, Q., Keefe, D.L.,Liu, L., 2013a. Resveratrol protects against age-associated infertility in mice. Hum. Reprod. 28, 707-717.
[52]	Liu, M.J., Sun, A.G., Zhao, S.G., Liu, H., Ma, S.Y., Li, M., Huai, Y.X., Zhao, H.,Liu, H.B., 2018. Resveratrol improves in vitro maturation of oocytes in aged mice and humans. Fertil. Steril. 109, 900-907.
[53]	Liu, Q., Zhang, J., Tang, Y., Ma, Y., Xue, Z.,Wang, J., 2022. The effects of human umbilical cord mesenchymal stem cell transplantation on female fertility restoration in mice. Curr. Gene Ther. 22, 319-330.
[54]	Liu, Y., He, X.Q., Huang, X., Ding, L., Xu, L., Shen, Y.T., Zhang, F., Zhu, M.B., Xu, B.H., Qi, Z.Q., et al., 2013b. Resveratrol protects mouse oocytes from methylglyoxal-induced oxidative damage. PLoS One 8, e77960.
[55]	Ma, R., Zhang, Y., Zhang, L., Han, J.,Rui, R., 2015. Sirt1 protects pig oocyte against in vitro aging. Anim. Sci. J. 86, 826-832.
[56]	Mahmoud, A.M., Goemaere, S., El-Garem, Y., Van Pottelbergh, I., Comhaire, F.H.,Kaufman, J.M., 2003. Testicular volume in relation to hormonal indices of gonadal function in community-dwelling elderly men. J. Clin. Endocrinol. Metab. 88, 179-184.
[57]	Matzkin, M.E., Calandra, R.S., Rossi, S.P., Bartke, A.,Frungieri, M.B., 2021. Hallmarks of Testicular Aging: The Challenge of Anti-Inflammatory and Antioxidant Therapies Using Natural and/or Pharmacological Compounds to Improve the Physiopathological Status of the Aged Male Gonad. Cells 10.
[58]	McIntosh, G.C., Olshan, A.F.,Baird, P.A., 1995. Paternal age and the risk of birth defects in offspring. Epidemiology 6, 282-288.
[59]	Merriman, J.A., Jennings, P.C., McLaughlin, E.A.,Jones, K.T., 2012. Effect of aging on superovulation efficiency, aneuploidy rates, and sister chromatid cohesion in mice aged up to 15 months. Biol. Reprod. 86, 49.
[60]	Miller, B., Messias, E., Miettunen, J., Alaraisanen, A., Jarvelin, M., Koponen, H., Rasanen, P., Isohanni, M.,Kirkpatrick, B., 2011. Meta-analysis of paternal age and schizophrenia risk in male versus female offspring. Schizophr. Bull. 37, 1039-1047.
[61]	Miller, E.C., Wilczek, A., Bello, N.A., Tom, S., Wapner, R.,Suh, Y., 2022. Pregnancy, preeclampsia and maternal aging: from epidemiology to functional genomics. Ageing Res. Rev. 73, 101535.
[62]	Minamoto, T., Nakayama, K., Ishibashi, T., Ishikawa, M., Nakamura, K., Yamashita, H., Shanta, K., Mahmud, H.M., Razia, S., Iida, K., et al., 2020. Pregnancy by assisted reproductive technology is associated with shorter telomere length in neonates. Int. J. Mol. Sci. 21, 9688.
[63]	Naess, OE., Mortensen, L.H., Vikanes, A.,Smith, G.D., 2017. Offspring sex and parental health and mortality. Sci Rep 7, 5285-5285.
[64]	Nagaoka, S.I., Hodges, C.A., Albertini, D.F.,Hunt, P.A., 2011. Oocyte-specific differences in cell-cycle control create an innate susceptibility to meiotic errors. Curr. Biol. 21, 651-657.
[65]	Niu, Y., Zhou, W., Nie, Z., Shin, K.,Cui, X., 2020. Melatonin enhances mitochondrial biogenesis and protects against rotenone-induced mitochondrial deficiency in early porcine embryos. J. Pineal Res. 68, e12627.
[66]	Orrenius, S., Gogvadze, V.,Zhivotovsky, B., 2007. Mitochondrial oxidative stress: implications for cell death. Annu. Rev. Pharmacol. Toxicol. 47, 143-183.
[67]	Pan, X.H., Zhang, X.J., Yao, X., Tian, N.N., Yang, Z.L., Wang, K., Zhu, X.Q., Zhao, J., He, J., Cai, X.M., et al., 2021. Effects and mechanisms of mUCMSCs on ovarian structure and function in naturally ageing C57 mice. J. Ovarian Res. 14, 133-133.
[68]	Perkins, A.T., Das, T.M., Panzera, L.C.,Bickel, S.E., 2016. Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors. Proc. Natl. Acad. Sci. U.S.A. 113, E6823-e6830.
[69]	Pines, A., 2011. Male menopause: is it a real clinical syndrome? Climacteric 14, 15-17.
[70]	Pittenger, M.F., Discher, D.E., Peault, B.M., Phinney, D.G., Hare, J.M.,Caplan, A.I., 2019. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ. Regen. Med. 4, 22.
[71]	Riris, S., Webster, P.,Homer, H., 2014. Digital multiplexed mRNA analysis of functionally important genes in single human oocytes and correlation of changes in transcript levels with oocyte protein expression. Fertil. Steril. 101, 857-864.
[72]	Ruth, K.S., Day, F.R., Hussain, J., Martinez-Marchal, A., Aiken, C.E., Azad, A., Thompson, D.J., Knoblochova, L., Abe, H., Tarry-Adkins, J.L., et al., 2021. Genetic insights into biological mechanisms governing human ovarian ageing. Nature 596, 393-397.
[73]	Salvatore, G., De Felici, M., Dolci, S., Tudisco, C., Cicconi, R., Campagnolo, L., Camaioni, A.,Klinger, F.G., 2021. Human adipose-derived stromal cells transplantation prolongs reproductive lifespan on mouse models of mild and severe premature ovarian insufficiency. Stem Cell Res. Ther. 12, 537-537.
[74]	Sasaki, H., Hamatani, T., Kamijo, S., Iwai, M., Kobanawa, M., Ogawa, S., Miyado, K.,Tanaka, M., 2019. Impact of oxidative stress on age-associated decline in oocyte developmental competence. Front. Endocrinol. (Lausanne) 10, 811.
[75]	Schmidt, J.A., Oatley, J.M.,Brinster, R.L., 2009. Female mice delay reproductive aging in males. Biol. Reprod. 80, 1009-1014.
[76]	Selesniemi, K., Lee, H.J.,Tilly, J.L., 2008. Moderate caloric restriction initiated in rodents during adulthood sustains function of the female reproductive axis into advanced chronological age. Aging Cell 7, 622-629.
[77]	Sherman, S.L., Petersen, M.B., Freeman, S.B., Hersey, J., Pettay, D., Taft, L., Frantzen, M., Mikkelsen, M.,Hassold, T.J., 1994. Non-disjunction of chromosome 21 in maternal meiosis I: evidence for a maternal age-dependent mechanism involving reduced recombination. Hum. Mol. Genet. 3, 1529-1535.
[78]	Stone, B.A., Alex, A., Werlin, L.B.,Marrs, R.P., 2013. Age thresholds for changes in semen parameters in men. Fertil. Steril. 100, 952-958.
[79]	Tamura, H., Takasaki, A., Miwa, I., Taniguchi, K., Maekawa, R., Asada, H., Taketani, T., Matsuoka, A., Yamagata, Y., Shimamura, K., et al., 2008. Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J. Pineal Res. 44, 280-287.
[80]	Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J.N., Rovio, A.T., Bruder, C.E., Bohlooly, Y.M., Gidlof, S., Oldfors, A., Wibom, R., et al., 2004. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417-423.
[81]	Wang, H., Zhu, S., Wu, X., Liu, Y., Ge, J., Wang, Q.,Gu, L., 2021a. NAMPT reduction-induced NAD(+) insufficiency contributes to the compromised oocyte quality from obese mice. Aging Cell 20, e13496.
[82]	Wang, J., Jia, R., Gong, H., Celi, P., Zhuo, Y., Ding, X., Bai, S., Zeng, Q., Yin, H., Xu, S., et al., 2021b. The effect of oxidative stress on the chicken ovary: involvement of microbiota and melatonin interventions. Antioxidants (Basel) 10, 1422.
[83]	Wang, X.,Proud, C.G., 2006. The mTOR pathway in the control of protein synthesis. Physiology (Bethesda) 21, 362-369.
[84]	Webster, A.,Schuh, M., 2017. Mechanisms of Aneuploidy in Human Eggs. Trends Cell Biol. 27, 55-68.
[85]	Weichhart, T., 2018. mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review. Gerontology 64, 127-134.
[86]	Weiss, G., Goldsmith, L.T., Taylor, R.N., Bellet, D.,Taylor, H.S., 2009. Inflammation in reproductive disorders. Reprod. Sci. 16, 216-229.
[87]	Winship, A.L., Stringer, J.M., Liew, S.H.,Hutt, K.J., 2018. The importance of DNA repair for maintaining oocyte quality in response to anti-cancer treatments, environmental toxins and maternal ageing. Hum. Reprod. Update 24, 119-134.
[88]	Xie, F., Zhang, J., Zhai, M., Liu, Y., Hu, H., Yu, Z., Zhang, J., Lin, S., Liang, D.,Cao, Y., 2021. Melatonin ameliorates ovarian dysfunction by regulating autophagy in PCOS via the PI3K-Akt pathway. Reproduction 162, 73-82.
[89]	Yamada-Fukunaga, T., Yamada, M., Hamatani, T., Chikazawa, N., Ogawa, S., Akutsu, H., Miura, T., Miyado, K., Tarin, J.J., Kuji, N., et al., 2013. Age-associated telomere shortening in mouse oocytes. Reprod. Biol. Endocrinol. 11, 108.
[90]	Yang, L., Lin, X., Tang, H., Fan, Y., Zeng, S., Jia, L., Li, Y., Shi, Y., He, S., Wang, H., et al., 2020a. Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD(+) redox. Aging Cell 19, e13206.
[91]	Yang, Q., Cong, L., Wang, Y., Luo, X., Li, H., Wang, H., Zhu, J., Dai, S., Jin, H., Yao, G., et al., 2020b. Increasing ovarian NAD(+) levels improve mitochondrial functions and reverse ovarian aging. Free Radic. Biol. Med. 156, 1-10.
[92]	Yi, S., Zheng, B., Zhu, Y., Cai, Y., Sun, H.,Zhou, J., 2020. Melatonin ameliorates excessive PINK1/Parkin-mediated mitophagy by enhancing SIRT1 expression in granulosa cells of PCOS. Am. J. Physiol. Endocrinol. Metab. 319, E91-e101.
[93]	Yorino, S.,Kawamura, K., 2020. Rapamycin treatment maintains developmental potential of oocytes in mice and follicle reserve in human cortical fragments grafted into immune-deficient mice. Mol. Cell. Endocrinol. 504, 110694.
[94]	Zhang, C., Tao, L., Yue, Y., Ren, L., Zhang, Z., Wang, X., Tian, J.,An, L., 2021a. Mitochondrial transfer from induced pluripotent stem cells rescues developmental potential of in vitro fertilized embryos from aging females†. Biol. Reprod. 104, 1114-1125.
[95]	Zhang, F., Liu, M.,Gao, J., 2022. Alterations in synaptonemal complex coding genes and human infertility. Int. J. Biol. Sci. 18, 1933-1943.
[96]	Zhang, L., Zhang, Z., Wang, J., Lv, D., Zhu, T., Wang, F., Tian, X., Yao, Y., Ji, P.,Liu, G., 2019. Melatonin regulates the activities of ovary and delays the fertility decline in female animals via MT1/AMPK pathway. J. Pineal Res. 66, e12550.
[97]	Zhang, X.M., Li, L., Xu, J.J., Wang, N., Liu, W.J., Lin, X.H., Fu, Y.C.,Luo, L.L., 2013. Rapamycin preserves the follicle pool reserve and prolongs the ovarian lifespan of female rats via modulating mTOR activation and sirtuin expression. Gene 523, 82-87.
[98]	Zhang, Z., He, C., Gao, Y., Zhang, L., Song, Y., Zhu, T., Zhu, K., Lv, D., Wang, J., Tian, X., et al., 2021b. α-ketoglutarate delays age-related fertility decline in mammals. Aging Cell 20, e13291.
[99]	Zhu, J.L., Madsen, K.M., Vestergaard, M., Basso, O.,Olsen, J., 2005. Paternal age and preterm birth. Epidemiology 16, 259-262.