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Molecular basis of reproductive senescence: insights from model organisms

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Abstract

Purpose

Reproductive decline due to parental age has become a major barrier to fertility as couples have delayed having offspring into their thirties and forties. Advanced parental age is also associated with increased incidence of neurological and cardiovascular disease in offspring. Thus, elucidating the etiology of reproductive decline is of clinical importance.

Methods

Deciphering the underlying processes that drive reproductive decline is particularly challenging in women in whom a discrete oocyte pool is established during embryogenesis and may remain dormant for tens of years. Instead, our understanding of the processes that drive reproductive senescence has emerged from studies in model organisms, both vertebrate and invertebrate, that are the focus of this literature review.

Conclusions

Studies of reproductive aging in model organisms not only have revealed the detrimental cellular changes that occur with age but also are helping identify major regulator proteins controlling them. Here, we discuss what we have learned from model organisms with respect to the molecular mechanisms that maintain both genome integrity and oocyte quality.

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References

  1. Roeters van Lennep JE, Heida KY, Bots ML, Hoek A, collaborators of the Dutch Multidisciplinary Guideline Development Group on Cardiovascular Risk Management after Reproductive D. Cardiovascular disease risk in women with premature ovarian insufficiency: a systematic review and meta-analysis. Eur J Prev Cardiol. 2016;23(2):178–86. https://doi.org/10.1177/2047487314556004.

    Article  PubMed  Google Scholar 

  2. Hughes SE, Evason K, Xiong C, Kornfeld K. Genetic and pharmacological factors that influence reproductive aging in nematodes. PLoS Genet. 2007;3(2):e25. https://doi.org/10.1371/journal.pgen.0030025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Luo S, Kleemann GA, Ashraf JM, Shaw WM, Murphy CT. TGF-β and insulin signaling regulate reproductive aging via oocyte and germline quality maintenance. Cell. 2010;143(2):299–312. https://doi.org/10.1016/j.cell.2010.09.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fuchs E, Tumbar T, Guasch G. Socializing with the neighbors: stem cells and their niche. Cell. 2004;116(6):769–78. https://doi.org/10.1016/s0092-8674(04)00255-7.

    Article  CAS  PubMed  Google Scholar 

  5. Ward EJ, Shcherbata HR, Reynolds SH, Fischer KA, Hatfield SD, Ruohola-Baker H. Stem cells signal to the niche through the Notch pathway in the Drosophila ovary. Curr Biol. 2006;16(23):2352–8. https://doi.org/10.1016/j.cub.2006.10.022.

    Article  CAS  PubMed  Google Scholar 

  6. Zhao R, Xuan Y, Li X, Xi R. Age-related changes of germline stem cell activity, niche signaling activity and egg production in Drosophila. Aging Cell. 2008;7(3):344–54. https://doi.org/10.1111/j.1474-9726.2008.00379.x.

    Article  CAS  PubMed  Google Scholar 

  7. Pan L, Chen S, Weng C, Call G, Zhu D, Tang H, et al. Stem cell aging is controlled both intrinsically and extrinsically in the Drosophila ovary. Cell Stem Cell. 2007;1(4):458–69. https://doi.org/10.1016/j.stem.2007.09.010.

    Article  CAS  PubMed  Google Scholar 

  8. Kao SH, Tseng CY, Wan CL, Su YH, Hsieh CC, Pi H, et al. Aging and insulin signaling differentially control normal and tumorous germline stem cells. Aging Cell. 2015;14(1):25–34. https://doi.org/10.1111/acel.12288.

    Article  CAS  PubMed  Google Scholar 

  9. Sato E, Kimura N, Yokoo M, Miyake Y, Ikeda JE. Morphodynamics of ovarian follicles during oogenesis in mice. Microsc Res Tech. 2006;69(6):427–35. https://doi.org/10.1002/jemt.20302.

    Article  PubMed  Google Scholar 

  10. Silver LM. Mouse genetics : concepts and applications. New York: Oxford University Press; 1995.

    Google Scholar 

  11. Garigan D, Hsu AL, Fraser AG, Kamath RS, Ahringer J, Kenyon C. Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics. 2002;161(3):1101–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Killian DJ, Hubbard EJ. Caenorhabditis elegans germline patterning requires coordinated development of the somatic gonadal sheath and the germ line. Dev Biol. 2005;279(2):322–35. https://doi.org/10.1016/j.ydbio.2004.12.021.

    Article  CAS  PubMed  Google Scholar 

  13. Kocsisova Z, Kornfeld K, Schedl T. Rapid population-wide declines in stem cell number and activity during reproductive aging in C. elegans. Development. 2019;146(8). https://doi.org/10.1242/dev.173195.

  14. Narbonne P, Maddox PS, Labbe JC. DAF-18/PTEN locally antagonizes insulin signalling to couple germline stem cell proliferation to oocyte needs in C. elegans. Development. 2015;142(24):4230–41. https://doi.org/10.1242/dev.130252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Qin Z, Hubbard EJ. Non-autonomous DAF-16/FOXO activity antagonizes age-related loss of C. elegans germline stem/progenitor cells. Nat Commun. 2015;6:7107. https://doi.org/10.1038/ncomms8107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shi C, Murphy CT. Mating induces shrinking and death in Caenorhabditis mothers. Science. 2014;343(6170):536–40. https://doi.org/10.1126/science.1242958.

    Article  CAS  PubMed  Google Scholar 

  17. Hubbard EJA, Schedl T. Biology of the Caenorhabditis elegans germline stem cell system. Genetics. 2019;213(4):1145–88. https://doi.org/10.1534/genetics.119.300238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gordon KL, Payne SG, Linden-High LM, Pani AM, Goldstein B, Hubbard EJA, et al. Ectopic germ cells can induce niche-like enwrapment by neighboring body wall muscle. Curr Biol. 2019;29(5):823–33 e5. https://doi.org/10.1016/j.cub.2019.01.056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Starich TA, Hall DH, Greenstein D. Two classes of gap junction channels mediate soma-germline interactions essential for germline proliferation and gametogenesis in Caenorhabditis elegans. Genetics. 2014;198(3):1127–53. https://doi.org/10.1534/genetics.114.168815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Byrd DT, Knobel K, Affeldt K, Crittenden SL, Kimble J. A DTC niche plexus surrounds the germline stem cell pool in Caenorhabditis elegans. PLoS One. 2014;9(2):e88372. https://doi.org/10.1371/journal.pone.0088372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xie T, Spradling AC. decapentaplegic is essential for the maintenance and division of germline stem cells in the Drosophila ovary. Cell. 1998;94(2):251–60. https://doi.org/10.1016/s0092-8674(00)81424-5.

    Article  CAS  PubMed  Google Scholar 

  22. Drummond-Barbosa D. Local and physiological control of germline stem cell lineages in Drosophila melanogaster. Genetics. 2019;213(1):9–26. https://doi.org/10.1534/genetics.119.300234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wallenfang MR, Nayak R, DiNardo S. Dynamics of the male germline stem cell population during aging of Drosophila melanogaster. Aging Cell. 2006;5(4):297–304. https://doi.org/10.1111/j.1474-9726.2006.00221.x.

    Article  CAS  PubMed  Google Scholar 

  24. Harrison DA, McCoon PE, Binari R, Gilman M, Perrimon N. Drosophila unpaired encodes a secreted protein that activates the JAK signaling pathway. Genes Dev. 1998;12(20):3252–63. https://doi.org/10.1101/gad.12.20.3252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kiger AA, Jones DL, Schulz C, Rogers MB, Fuller MT. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science. 2001;294(5551):2542–5. https://doi.org/10.1126/science.1066707.

    Article  CAS  PubMed  Google Scholar 

  26. Tulina N, Matunis E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling. Science. 2001;294(5551):2546–9. https://doi.org/10.1126/science.1066700.

    Article  CAS  PubMed  Google Scholar 

  27. Boyle M, Wong C, Rocha M, Jones DL. Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell. 2007;1(4):470–8. https://doi.org/10.1016/j.stem.2007.08.002.

    Article  CAS  PubMed  Google Scholar 

  28. Toledano H, D'Alterio C, Czech B, Levine E, Jones DL. The let-7-Imp axis regulates ageing of the Drosophila testis stem-cell niche. Nature. 2012;485(7400):605–10. https://doi.org/10.1038/nature11061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Epstein Y, Perry N, Volin M, Zohar-Fux M, Braun R, Porat-Kuperstein L, et al. miR-9a modulates maintenance and ageing of Drosophila germline stem cells by limiting N-cadherin expression. Nat Commun. 2017;8(1):600. https://doi.org/10.1038/s41467-017-00485-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang M, Chambers I. Segregation of the mouse germline and soma. Cell Cycle. 2019;18(22):3064–71. https://doi.org/10.1080/15384101.2019.1672466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vincent SD, Dunn NR, Sciammas R, Shapiro-Shalef M, Davis MM, Calame K, et al. The zinc finger transcriptional repressor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of primordial germ cells in the mouse. Development. 2005;132(6):1315–25. https://doi.org/10.1242/dev.01711.

    Article  CAS  PubMed  Google Scholar 

  32. Ohinata Y, Payer B, O'Carroll D, Ancelin K, Ono Y, Sano M, et al. Blimp1 is a critical determinant of the germ cell lineage in mice. Nature. 2005;436(7048):207–13. https://doi.org/10.1038/nature03813.

    Article  CAS  PubMed  Google Scholar 

  33. Tanaka SS, Toyooka Y, Akasu R, Katoh-Fukui Y, Nakahara Y, Suzuki R, et al. The mouse homolog of Drosophila Vasa is required for the development of male germ cells. Genes Dev. 2000;14(7):841–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Wei Y, Reveal B, Reich J, Laursen WJ, Senger S, Akbar T, et al. TORC1 regulators Iml1/GATOR1 and GATOR2 control meiotic entry and oocyte development in Drosophila. Proc Natl Acad Sci U S A. 2014;111(52):E5670–7. https://doi.org/10.1073/pnas.1419156112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gumienny TL, Lambie E, Hartwieg E, Horvitz HR, Hengartner MO. Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline. Development. 1999;126(5):1011–22.

    CAS  PubMed  Google Scholar 

  36. Andux S, Ellis RE. Apoptosis maintains oocyte quality in aging Caenorhabditis elegans females. PLoS Genet. 2008;4(12):e1000295. https://doi.org/10.1371/journal.pgen.1000295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Perez GI, Robles R, Knudson CM, Flaws JA, Korsmeyer SJ, Tilly JL. Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat Genet. 1999;21(2):200–3. https://doi.org/10.1038/5985.

    Article  CAS  PubMed  Google Scholar 

  38. Chu HP, Liao Y, Novak JS, Hu Z, Merkin JJ, Shymkiv Y, et al. Germline quality control: eEF2K stands guard to eliminate defective oocytes. Dev Cell. 2014;28(5):561–72. https://doi.org/10.1016/j.devcel.2014.01.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bolcun-Filas E, Rinaldi VD, White ME, Schimenti JC. Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science. 2014;343(6170):533–6. https://doi.org/10.1126/science.1247671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Malki S, van der Heijden GW, O'Donnell KA, Martin SL, Bortvin A. A role for retrotransposon LINE-1 in fetal oocyte attrition in mice. Dev Cell. 2014;29(5):521–33. https://doi.org/10.1016/j.devcel.2014.04.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Drummond-Barbosa D, Spradling AC. Stem cells and their progeny respond to nutritional changes during Drosophila oogenesis. Dev Biol. 2001;231(1):265–78. https://doi.org/10.1006/dbio.2000.0135.

    Article  CAS  PubMed  Google Scholar 

  42. Hsu HJ, Drummond-Barbosa D. Insulin levels control female germline stem cell maintenance via the niche in Drosophila. Proc Natl Acad Sci U S A. 2009;106(4):1117–21. https://doi.org/10.1073/pnas.0809144106.

    Article  PubMed  PubMed Central  Google Scholar 

  43. McLeod CJ, Wang L, Wong C, Jones DL. Stem cell dynamics in response to nutrient availability. Curr Biol. 2010;20(23):2100–5. https://doi.org/10.1016/j.cub.2010.10.038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang H, Yamashita YM. The regulated elimination of transit-amplifying cells preserves tissue homeostasis during protein starvation in Drosophila testis. Development. 2015;142(10):1756–66. https://doi.org/10.1242/dev.122663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mair W, McLeod CJ, Wang L, Jones DL. Dietary restriction enhances germline stem cell maintenance. Aging Cell. 2010;9(5):916–8. https://doi.org/10.1111/j.1474-9726.2010.00602.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Blackwell TK, Sewell AK, Wu Z, Han M. TOR signaling in Caenorhabditis elegans development, metabolism, and aging. Genetics. 2019;213(2):329–60. https://doi.org/10.1534/genetics.119.302504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Korta DZ, Tuck S, Hubbard EJ. S6K links cell fate, cell cycle and nutrient response in C. elegans germline stem/progenitor cells. Development. 2012;139(5):859–70. https://doi.org/10.1242/dev.074047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Michaelson D, Korta DZ, Capua Y, Hubbard EJ. Insulin signaling promotes germline proliferation in C. elegans. Development. 2010;137(4):671–80. https://doi.org/10.1242/dev.042523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pinkston JM, Garigan D, Hansen M, Kenyon C. Mutations that increase the life span of C. elegans inhibit tumor growth. Science. 2006;313(5789):971–5. https://doi.org/10.1126/science.1121908.

    Article  CAS  PubMed  Google Scholar 

  50. Roy D, Kahler DJ, Yun C, Hubbard EJA. Functional interactions between rsks-1/S6K, glp-1/Notch, and regulators of Caenorhabditis elegans fertility and germline stem cell maintenance. G3 (Bethesda). 2018;8(10):3293–309. https://doi.org/10.1534/g3.118.200511.

    Article  CAS  Google Scholar 

  51. Roy D, Michaelson D, Hochman T, Santella A, Bao Z, Goldberg JD, et al. Cell cycle features of C. elegans germline stem/progenitor cells vary temporally and spatially. Dev Biol. 2016;409(1):261–71. https://doi.org/10.1016/j.ydbio.2015.10.031.

    Article  CAS  PubMed  Google Scholar 

  52. Hsu HJ, Drummond-Barbosa D. Insulin signals control the competence of the Drosophila female germline stem cell niche to respond to Notch ligands. Dev Biol. 2011;350(2):290–300. https://doi.org/10.1016/j.ydbio.2010.11.032.

    Article  CAS  PubMed  Google Scholar 

  53. LaFever L, Feoktistov A, Hsu HJ, Drummond-Barbosa D. Specific roles of Target of rapamycin in the control of stem cells and their progeny in the Drosophila ovary. Development. 2010;137(13):2117–26. https://doi.org/10.1242/dev.050351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Laws KM, Drummond-Barbosa D. AMP-activated protein kinase has diet-dependent and -independent roles in Drosophila oogenesis. Dev Biol. 2016;420(1):90–9. https://doi.org/10.1016/j.ydbio.2016.10.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Laws KM, Sampson LL, Drummond-Barbosa D. Insulin-independent role of adiponectin receptor signaling in Drosophila germline stem cell maintenance. Dev Biol. 2015;399(2):226–36. https://doi.org/10.1016/j.ydbio.2014.12.033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Roth TM, Chiang CY, Inaba M, Yuan H, Salzmann V, Roth CE, et al. Centrosome misorientation mediates slowing of the cell cycle under limited nutrient conditions in Drosophila male germline stem cells. Mol Biol Cell. 2012;23(8):1524–32. https://doi.org/10.1091/mbc.E11-12-0999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ueishi S, Shimizu H. Y HI. Male germline stem cell division and spermatocyte growth require insulin signaling in Drosophila. Cell Struct Funct. 2009;34(1):61–9. https://doi.org/10.1247/csf.08042.

    Article  PubMed  Google Scholar 

  58. Wei Y, Reveal B, Cai W, Lilly MA. The GATOR1 complex regulates metabolic homeostasis and the response to nutrient stress in Drosophila melanogaster. G3 (Bethesda). 2016;6(12):3859–67. https://doi.org/10.1534/g3.116.035337.

    Article  CAS  Google Scholar 

  59. Luo S, Shaw WM, Ashraf J, Murphy CT. TGF-beta Sma/Mab signaling mutations uncouple reproductive aging from somatic aging. PLoS Genet. 2009;5(12):e1000789. https://doi.org/10.1371/journal.pgen.1000789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Templeman NM, Cota V, Keyes W, Kaletsky R, Murphy CT. CREB non-autonomously controls reproductive aging through hedgehog/patched signaling. Dev Cell. 2020;54(1):92–105 e5. https://doi.org/10.1016/j.devcel.2020.05.023.

    Article  CAS  PubMed  Google Scholar 

  61. Belli M, Shimasaki S. Molecular aspects and clinical relevance of GDF9 and BMP15 in ovarian function. Vitam Horm. 2018;107:317–48. https://doi.org/10.1016/bs.vh.2017.12.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bertoldo MJ, Faure M, Dupont J, Froment P. AMPK: a master energy regulator for gonadal function. Front Neurosci. 2015;9:235. https://doi.org/10.3389/fnins.2015.00235.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Dupont J, Scaramuzzi RJ. Insulin signalling and glucose transport in the ovary and ovarian function during the ovarian cycle. Biochem J. 2016;473(11):1483–501. https://doi.org/10.1042/BCJ20160124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Guo R, Reinhardt K. Dietary polyunsaturated fatty acids affect volume and metabolism of Drosophila melanogaster sperm. J Evol Biol. 2020. https://doi.org/10.1111/jeb.13591.

  65. Wang X, Zhang L, Zhang L, Wang W, Wei S, Wang J, et al. Effects of excess sugars and lipids on the growth and development of Caenorhabditis elegans. Genes Nutr. 2020;15:1. https://doi.org/10.1186/s12263-020-0659-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Selesniemi K, Lee H-J, Muhlhauser A, Tilly JL. Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proceedings of the National Academy of Sciences. 2011.

  67. Schultz J, Redfield H. Interchromosomal effects on crossing over in Drosophila. Cold Spring Harb Symp Quant Biol. 1951;16:175–97. https://doi.org/10.1101/sqb.1951.016.01.015.

    Article  CAS  PubMed  Google Scholar 

  68. Stern C. An effect of temperature and age on crossing-over in the first chromosome of Drosophila melanogaster. Proc Natl Acad Sci U S A. 1926;12(8):530–2. https://doi.org/10.1073/pnas.12.8.530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lenz W. The effect of parental age and the number of births on congenital pathological conditions in the child. II. Acta Genet Stat Med. 1959;9:249–83.

    CAS  PubMed  Google Scholar 

  70. Lim JG, Stine RR, Yanowitz JL. Domain-specific regulation of recombination in Caenorhabditis elegans in response to temperature, age and sex. Genetics. 2008;180(2):715–26. https://doi.org/10.1534/genetics.108.090142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rose AM, Baillie DL. The effect of temperature and parental age on recombination and nondisjunction in Caenorhabditis elegans. Genetics. 1979;92(2):409–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Wood AJ, Severson AF, Meyer BJ. Condensin and cohesin complexity: the expanding repertoire of functions. Nat Rev Genet. 2010;11(6):391–404. https://doi.org/10.1038/nrg2794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cheng JM, Li J, Tang JX, Hao XX, Wang ZP, Sun TC, et al. Merotelic kinetochore attachment in oocyte meiosis II causes sister chromatids segregation errors in aged mice. Cell Cycle. 2017;16(15):1404–13. https://doi.org/10.1080/15384101.2017.1327488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Traut H. X-chromosomal nondisjunction induced by aging oocytes of Drosophila melanogaster: the special susceptibility of mature eggs. Can J Genet Cytol. 1980;22(3):433–7. https://doi.org/10.1139/g80-054.

    Article  CAS  PubMed  Google Scholar 

  75. Jeffreys CA, Burrage PS, Bickel SE. A model system for increased meiotic nondisjunction in older oocytes. Curr Biol. 2003;13(6):498–503. https://doi.org/10.1016/s0960-9822(03)00134-9.

    Article  CAS  PubMed  Google Scholar 

  76. Hall H, Hunt P, Hassold T. Meiosis and sex chromosome aneuploidy: how meiotic errors cause aneuploidy; how aneuploidy causes meiotic errors. Curr Opin Genet Dev. 2006;16(3):323–9. https://doi.org/10.1016/j.gde.2006.04.011.

    Article  CAS  PubMed  Google Scholar 

  77. Hodges CA, Revenkova E, Jessberger R, Hassold TJ, Hunt PA. SMC1beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction. Nat Genet. 2005;37(12):1351–5. https://doi.org/10.1038/ng1672.

    Article  CAS  PubMed  Google Scholar 

  78. Subramanian VV, Bickel SE. Aging predisposes oocytes to meiotic nondisjunction when the cohesin subunit SMC1 is reduced. PLoS Genet. 2008;4(11):e1000263. https://doi.org/10.1371/journal.pgen.1000263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Khetani RS, Bickel SE. Regulation of meiotic cohesion and chromosome core morphogenesis during pachytene in Drosophila oocytes. J Cell Sci. 2007;120(Pt 17):3123–37. https://doi.org/10.1242/jcs.009977.

    Article  CAS  PubMed  Google Scholar 

  80. Krishnan B, Thomas SE, Yan R, Yamada H, Zhulin IB, McKee BD. Sisters unbound is required for meiotic centromeric cohesion in Drosophila melanogaster. Genetics. 2014;198(3):947–65. https://doi.org/10.1534/genetics.114.166009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yan R, McKee BD. The cohesion protein SOLO associates with SMC1 and is required for synapsis, recombination, homolog bias and cohesion and pairing of centromeres in Drosophila meiosis. PLoS Genet. 2013;9(7):e1003637. https://doi.org/10.1371/journal.pgen.1003637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chiang T, Duncan FE, Schindler K, Schultz RM, Lampson MA. Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes. Curr Biol. 2010;20(17):1522–8. https://doi.org/10.1016/j.cub.2010.06.069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lister LM, Kouznetsova A, Hyslop LA, Kalleas D, Pace SL, Barel JC, et al. Age-related meiotic segregation errors in mammalian oocytes are preceded by depletion of cohesin and Sgo2. Curr Biol. 2010;20(17):1511–21. https://doi.org/10.1016/j.cub.2010.08.023.

    Article  CAS  PubMed  Google Scholar 

  84. Stemmann O, Zou H, Gerber SA, Gygi SP, Kirschner MW. Dual inhibition of sister chromatid separation at metaphase. Cell. 2001;107(6):715–26. https://doi.org/10.1016/s0092-8674(01)00603-1.

    Article  CAS  PubMed  Google Scholar 

  85. Chiang T, Schultz RM, Lampson MA. Age-dependent susceptibility of chromosome cohesion to premature separase activation in mouse oocytes. Biol Reprod. 2011;85(6):1279–83. https://doi.org/10.1095/biolreprod.111.094094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Nabti I, Grimes R, Sarna H, Marangos P, Carroll J. Maternal age-dependent APC/C-mediated decrease in securin causes premature sister chromatid separation in meiosis II. Nat Commun. 2017;8:15346. https://doi.org/10.1038/ncomms15346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Burkhardt S, Borsos M, Szydlowska A, Godwin J, Williams SA, Cohen PE, et al. Chromosome cohesion established by Rec8-cohesin in fetal oocytes is maintained without detectable turnover in oocytes arrested for months in mice. Curr Biol. 2016;26(5):678–85. https://doi.org/10.1016/j.cub.2015.12.073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Severson AF, Meyer BJ. Divergent kleisin subunits of cohesin specify mechanisms to tether and release meiotic chromosomes. Elife. 2014;3:e03467. https://doi.org/10.7554/eLife.03467.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Unal E, Heidinger-Pauli JM, Koshland D. DNA double-strand breaks trigger genome-wide sister-chromatid cohesion through Eco1 (Ctf7). Science. 2007;317(5835):245–8. https://doi.org/10.1126/science.1140637.

    Article  CAS  PubMed  Google Scholar 

  90. Perkins AT, Bickel SE. Using fluorescence in situ hybridization (FISH) to monitor the state of arm cohesion in prometaphase and metaphase I Drosophila oocytes. J Vis Exp. 2017;130. https://doi.org/10.3791/56802.

  91. Perkins AT, Greig MM, Sontakke AA, Peloquin AS, McPeek MA, Bickel SE. Increased levels of superoxide dismutase suppress meiotic segregation errors in aging oocytes. Chromosoma. 2019;128(3):215–22. https://doi.org/10.1007/s00412-019-00702-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yun Y, Wei Z, Hunter N. Maternal obesity enhances oocyte chromosome abnormalities associated with aging. Chromosoma. 2019;128(3):413–21. https://doi.org/10.1007/s00412-019-00716-6.

    Article  CAS  PubMed  Google Scholar 

  93. Cheng S, Lu Y, Liu G, Wang SQ. Finite cohesion due to chain entanglement in polymer melts. Soft Matter. 2016;12(14):3340–51. https://doi.org/10.1039/c6sm00142d.

    Article  CAS  PubMed  Google Scholar 

  94. Watanabe Y, Nurse P. Cohesin Rec8 is required for reductional chromosome segregation at meiosis. Nature. 1999;400(6743):461–4. https://doi.org/10.1038/22774.

    Article  CAS  PubMed  Google Scholar 

  95. Zielinska AP, Bellou E, Sharma N, Frombach AS, Seres KB, Gruhn JR, et al. Meiotic kinetochores fragment into multiple lobes upon cohesin loss in aging eggs. Curr Biol. 2019;29(22):3749–65 e7. https://doi.org/10.1016/j.cub.2019.09.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kitajima TS, Ohsugi M, Ellenberg J. Complete kinetochore tracking reveals error-prone homologous chromosome biorientation in mammalian oocytes. Cell. 2011;146(4):568–81. https://doi.org/10.1016/j.cell.2011.07.031.

    Article  CAS  PubMed  Google Scholar 

  97. Watanabe Y. Geometry and force behind kinetochore orientation: lessons from meiosis. Nat Rev Mol Cell Biol. 2012;13(6):370–82. https://doi.org/10.1038/nrm3349.

    Article  CAS  PubMed  Google Scholar 

  98. Cimini D, Howell B, Maddox P, Khodjakov A, Degrassi F, Salmon ED. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J Cell Biol. 2001;153(3):517–27. https://doi.org/10.1083/jcb.153.3.517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Shomper M, Lappa C, FitzHarris G. Kinetochore microtubule establishment is defective in oocytes from aged mice. Cell Cycle. 2014;13(7):1171–9. https://doi.org/10.4161/cc.28046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cheng JM, Liu YX. Age-related loss of cohesion: causes and effects. Int J Mol Sci. 2017;18(7). https://doi.org/10.3390/ijms18071578.

  101. Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S, Kopecka A, et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet. 2004;36(7):744–9. https://doi.org/10.1038/ng1382.

    Article  CAS  PubMed  Google Scholar 

  102. Shimoi G, Tomita M, Kataoka M, Kameyama Y. Destabilization of spindle assembly checkpoint causes aneuploidy during meiosis II in murine post-ovulatory aged oocytes. J Reprod Dev. 2019;65(1):57–66. https://doi.org/10.1262/jrd.2018-056.

    Article  CAS  PubMed  Google Scholar 

  103. Steuerwald N, Cohen J, Herrera RJ, Sandalinas M, Brenner CA. Association between spindle assembly checkpoint expression and maternal age in human oocytes. Mol Hum Reprod. 2001;7(1):49–55. https://doi.org/10.1093/molehr/7.1.49.

    Article  CAS  PubMed  Google Scholar 

  104. Collins JK, Lane SIR, Merriman JA, Jones KT. DNA damage induces a meiotic arrest in mouse oocytes mediated by the spindle assembly checkpoint. Nat Commun. 2015;6:8553. https://doi.org/10.1038/ncomms9553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lane SIR, Morgan SL, Wu T, Collins JK, Merriman JA, ElInati E, et al. DNA damage induces a kinetochore-based ATM/ATR-independent SAC arrest unique to the first meiotic division in mouse oocytes. Development. 2017;144(19):3475–86. https://doi.org/10.1242/dev.153965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Marangos P, Stevense M, Niaka K, Lagoudaki M, Nabti I, Jessberger R, et al. DNA damage-induced metaphase I arrest is mediated by the spindle assembly checkpoint and maternal age. Nat Commun. 2015;6:8706. https://doi.org/10.1038/ncomms9706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Grell EH. Genetic analysis of aspartate aminotransferase isozymes from hybrids between Drosophila melanogaster and Drosophila simulans and mutagen-induced isozyme variants. Genetics. 1976;83(4):753–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Hawley RS, Irick H, Zitron AE, Haddox DA, Lohe A, New C, et al. There are two mechanisms of achiasmate segregation in Drosophila females, one of which requires heterochromatic homology. Dev Genet. 1992;13(6):440–67. https://doi.org/10.1002/dvg.1020130608.

    Article  CAS  PubMed  Google Scholar 

  109. Karpen GH, Le MH, Le H. Centric heterochromatin and the efficiency of achiasmate disjunction in Drosophila female meiosis. Science. 1996;273(5271):118–22. https://doi.org/10.1126/science.273.5271.118.

    Article  CAS  PubMed  Google Scholar 

  110. Dernburg AF, Sedat JW, Hawley RS. Direct evidence of a role for heterochromatin in meiotic chromosome segregation. Cell. 1996;86(1):135–46. https://doi.org/10.1016/s0092-8674(00)80084-7.

    Article  CAS  PubMed  Google Scholar 

  111. Hughes SE, Gilliland WD, Cotitta JL, Takeo S, Collins KA, Hawley RS. Heterochromatic threads connect oscillating chromosomes during prometaphase I in Drosophila oocytes. PLoS Genet. 2009;5(1):e1000348. https://doi.org/10.1371/journal.pgen.1000348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Giauque CC, Bickel SE. Heterochromatin-associated proteins HP1a and Piwi collaborate to maintain the association of achiasmate homologs in Drosophila oocytes. Genetics. 2016;203(1):173–89. https://doi.org/10.1534/genetics.115.186460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hughes SE, Miller DE, Miller AL, Hawley RS. Female meiosis: synapsis, recombination, and segregation in Drosophila melanogaster. Genetics. 2018;208(3):875–908. https://doi.org/10.1534/genetics.117.300081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Fledel-Alon A, Wilson DJ, Broman K, Wen X, Ober C, Coop G, et al. Broad-scale recombination patterns underlying proper disjunction in humans. PLoS Genet. 2009;5(9):e1000658. https://doi.org/10.1371/journal.pgen.1000658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Koehler KE, Hassold TJ. Human aneuploidy: lessons from achiasmate segregation in Drosophila melanogaster. Ann Hum Genet. 1998;62(Pt 6):467–79. https://doi.org/10.1046/j.1469-1809.1998.6260467.x.

    Article  CAS  PubMed  Google Scholar 

  116. Bisig CG, Guiraldelli MF, Kouznetsova A, Scherthan H, Hoog C, Dawson DS, et al. Synaptonemal complex components persist at centromeres and are required for homologous centromere pairing in mouse spermatocytes. PLoS Genet. 2012;8(6):e1002701. https://doi.org/10.1371/journal.pgen.1002701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Qiao H, Chen JK, Reynolds A, Hoog C, Paddy M, Hunter N. Interplay between synaptonemal complex, homologous recombination, and centromeres during mammalian meiosis. PLoS Genet. 2012;8(6):e1002790. https://doi.org/10.1371/journal.pgen.1002790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Previato de Almeida L, Evatt JM, Chuong HH, Kurdzo EL, Eyster CA, Gladstone MN, et al. Shugoshin protects centromere pairing and promotes segregation of nonexchange partner chromosomes in meiosis. Proc Natl Acad Sci U S A. 2019;116(19):9417–22. https://doi.org/10.1073/pnas.1902526116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Capalbo A, Hoffmann ER, Cimadomo D, Ubaldi FM, Rienzi L. Human female meiosis revised: new insights into the mechanisms of chromosome segregation and aneuploidies from advanced genomics and time-lapse imaging. Hum Reprod Update. 2017;23(6):706–22. https://doi.org/10.1093/humupd/dmx026.

    Article  CAS  PubMed  Google Scholar 

  120. Ottolini CS, Capalbo A, Newnham L, Cimadomo D, Natesan SA, Hoffmann ER, et al. Generation of meiomaps of genome-wide recombination and chromosome segregation in human oocytes. Nat Protoc. 2016;11(7):1229–43. https://doi.org/10.1038/nprot.2016.075.

    Article  CAS  PubMed  Google Scholar 

  121. Vargas E, McNally K, Friedman JA, Cortes DB, Wang DY, Korf IF, et al. Autosomal trisomy and triploidy are corrected during female meiosis in Caenorhabditis elegans. Genetics. 2017;207(3):911–22. https://doi.org/10.1534/genetics.117.300259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–217. https://doi.org/10.1016/j.cell.2013.05.039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kushnir VA, Ludaway T, Russ RB, Fields EJ, Koczor C, Lewis W. Reproductive aging is associated with decreased mitochondrial abundance and altered structure in murine oocytes. J Assist Reprod Genet. 2012;29(7):637–42. https://doi.org/10.1007/s10815-012-9771-5.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Simsek-Duran F, Li F, Ford W, Swanson RJ, Jones HW, Castora FJ. Age-associated metabolic and morphologic changes in mitochondria of individual mouse and hamster oocytes. PLoS One. 2013;8(5):e64955. https://doi.org/10.1371/journal.pone.0064955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Erwin AA, Blumenstiel JP. Aging in the Drosophila ovary: contrasting changes in the expression of the piRNA machinery and mitochondria but no global release of transposable elements. BMC Genomics. 2019;20(1):305. https://doi.org/10.1186/s12864-019-5668-3.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Bohnert KA, Kenyon C. A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage. Nature. 2017;551(7682):629–63.

    Article  CAS  Google Scholar 

  127. Murakoshi Y, Sueoka K, Takahashi K, Sato S, Sakurai T, Tajima H, et al. Embryo developmental capability and pregnancy outcome are related to the mitochondrial DNA copy number and ooplasmic volume. J Assist Reprod Genet. 2013;30(10):1367–75. https://doi.org/10.1007/s10815-013-0062-6.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Peluso JJ, Butcher RL. The effect of follicular aging on the ultrastructure of the rat oocyte. Fertil Steril. 1974;25(6):494–502.

    Article  CAS  Google Scholar 

  129. Müller-Höcker J, Schäfer S, Weis S, Münscher C, Strowitzki T. Morphological-cytochemical and molecular genetic analyses of mitochondria in isolated human oocytes in the reproductive age. Mol Hum Reprod. 1996;2(12):951–8. https://doi.org/10.1093/molehr/2.12.951.

    Article  PubMed  Google Scholar 

  130. Tarín JJ, Pérez-Albalá S, Cano A. Cellular and morphological traits of oocytes retrieved from aging mice after exogenous ovarian stimulation. Biol Reprod. 2001;65(1):141–50. https://doi.org/10.1095/biolreprod65.1.141.

    Article  PubMed  Google Scholar 

  131. Tilly JL, Sinclair DA. Germline energetics, aging, and female infertility. Cell Metab. 2013;17(6):838–50. https://doi.org/10.1016/j.cmet.2013.05.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Hamatani T, Falco G, Carter MG, Akutsu H, Stagg CA, Sharov AA, et al. Age-associated alteration of gene expression patterns in mouse oocytes. Hum Mol Genet. 2004;13(19):2263–78. https://doi.org/10.1093/hmg/ddh241.

    Article  CAS  PubMed  Google Scholar 

  133. Ben-Meir A, Burstein E, Borrego-Alvarez A, Chong J, Wong E, Yavorska T, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell. 2015;14(5):887–95. https://doi.org/10.1111/acel.12368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Tatone C, Carbone MC, Falone S, Aimola P, Giardinelli A, Caserta D, et al. Age-dependent changes in the expression of superoxide dismutases and catalase are associated with ultrastructural modifications in human granulosa cells. Mol Hum Reprod. 2006;12(11):655–60. https://doi.org/10.1093/molehr/gal080.

    Article  CAS  PubMed  Google Scholar 

  135. Wang S, Zheng Y, Li J, Yu Y, Zhang W, Song M, et al. Single-cell transcriptomic atlas of primate ovarian aging. Cell. 2020;180(3):585-600.e19. https://doi.org/10.1016/j.cell.2020.01.009.

    Article  CAS  PubMed  Google Scholar 

  136. Tsakiri EN, Sykiotis GP, Papassideri IS, Gorgoulis VG, Bohmann D, Trougakos IP. Differential regulation of proteasome functionality in reproductive vs. somatic tissues of Drosophila during aging or oxidative stress. FASEB J. 2013;27(6):2407–20. https://doi.org/10.1096/fj.12-221408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lim J, Luderer U. Oxidative damage increases and antioxidant gene expression decreases with aging in the mouse ovary. Biol Reprod. 2011;84(4):775–82. https://doi.org/10.1095/biolreprod.110.088583.

    Article  CAS  PubMed  Google Scholar 

  138. Matos L, Stevenson D, Gomes F, Silva-Carvalho JL, Almeida H. Superoxide dismutase expression in human cumulus oophorus cells. Mol Hum Reprod. 2009;15(7):411–9. https://doi.org/10.1093/molehr/gap034.

    Article  CAS  PubMed  Google Scholar 

  139. Peters AE, Mihalas BP, Bromfield EG, Roman SD, Nixon B, Sutherland JM. Autophagy in female fertility: a role in oxidative stress and aging. Antioxid Redox Signal. 2020;32(8):550–68. https://doi.org/10.1089/ars.2019.7986.

    Article  CAS  PubMed  Google Scholar 

  140. Cai H, Li Y, Li H, Niringiyumukiza JD, Zhang M, Chen L, et al. Identification and characterization of human ovary-derived circular RNAs and their potential roles in ovarian aging. Aging (Albany NY). 2018;10(9):2511–34. https://doi.org/10.18632/aging.101565.

    Article  CAS  Google Scholar 

  141. Zhang X, Wu XQ, Lu S, Guo YL, Ma X. Deficit of mitochondria-derived ATP during oxidative stress impairs mouse MII oocyte spindles. Cell Res. 2006;16(10):841–50. https://doi.org/10.1038/sj.cr.7310095.

    Article  CAS  PubMed  Google Scholar 

  142. Wilding M, Dale B, Marino M, di Matteo L, Alviggi C, Pisaturo ML, et al. Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos. Hum Reprod. 2001;16(5):909–17. https://doi.org/10.1093/humrep/16.5.909.

    Article  CAS  PubMed  Google Scholar 

  143. Fragouli E, Spath K, Alfarawati S, Kaper F, Craig A, Michel CE, et al. Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential. PLoS Genet. 2015;11(6):e1005241. https://doi.org/10.1371/journal.pgen.1005241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Faraci C, Annis S, Jin J, Li H, Khrapko K, Woods DC. Impact of exercise on oocyte quality in the POLG mitochondrial DNA mutator mouse. Reproduction. 2018;156(2):185–94. https://doi.org/10.1530/REP-18-0061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Tarín JJ, Pérez-Albalá S, Cano A. Oral antioxidants counteract the negative effects of female aging on oocyte quantity and quality in the mouse. Molecular Reproduction and Development. 2002;61(3).

  146. Bertoldo MJ, Listijono DR, Ho WJ, Riepsamen AH, Goss DM, Richani D, et al. NAD+ repletion rescues female fertility during reproductive aging. Cell Rep. 2020;30(6):1670-81.e7. https://doi.org/10.1016/j.celrep.2020.01.058.

    Article  CAS  Google Scholar 

  147. Amaral S, Mota P, Rodrigues AS, Martins L, Oliveira PJ, Ramalho-Santos J. Testicular aging involves mitochondrial dysfunction as well as an increase in UCP2 levels and proton leak. FEBS Lett. 2008;582(30):4191–6. https://doi.org/10.1016/j.febslet.2008.11.020.

    Article  CAS  PubMed  Google Scholar 

  148. Weir CP, Robaire B. Spermatozoa have decreased antioxidant enzymatic capacity and increased reactive oxygen species production during aging in the Brown Norway rat. J Androl. 2007;28(2):229–40. https://doi.org/10.2164/jandrol.106.001362.

    Article  CAS  PubMed  Google Scholar 

  149. Liao CH, Chen BH, Chiang HS, Chen CW, Chen MF, Ke CC, et al. Optimizing a male reproductive aging mouse model by D-galactose injection. Int J Mol Sci. 2016;17(1). https://doi.org/10.3390/ijms17010098.

  150. Liu J, Liu M, Ye X, Liu K, Huang J, Wang L, et al. Delay in oocyte aging in mice by the antioxidant N-acetyl-L-cysteine (NAC). Hum Reprod. 2012;27(5):1411–20. https://doi.org/10.1093/humrep/des019.

    Article  CAS  PubMed  Google Scholar 

  151. Zhang M, Lu Y, Chen Y, Zhang Y, Xiong B. Insufficiency of melatonin in follicular fluid is a reversible cause for advanced maternal age-related aneuploidy in oocytes. Redox Biol. 2020;28:101327. https://doi.org/10.1016/j.redox.2019.101327.

    Article  CAS  PubMed  Google Scholar 

  152. Meyer JN, Boyd WA, Azzam GA, Haugen AC, Freedman JH, Van Houten B. Decline of nucleotide excision repair capacity in aging Caenorhabditis elegans. Genome Biol. 2007;8(5):R70. https://doi.org/10.1186/gb-2007-8-5-r70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J. Aging and genome maintenance: lessons from the mouse? Science. 2003;299(5611):1355–9. https://doi.org/10.1126/science.1079161.

    Article  CAS  PubMed  Google Scholar 

  154. Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW. DNA repair, genome stability, and aging. Cell. 2005;120(4):497–512. https://doi.org/10.1016/j.cell.2005.01.028.

    Article  CAS  PubMed  Google Scholar 

  155. Goukassian D, Gad F, Yaar M, Eller MS, Nehal US, Gilchrest BA. Mechanisms and implications of the age-associated decrease in DNA repair capacity. FASEB J. 2000;14(10):1325–34. https://doi.org/10.1096/fj.14.10.1325.

    Article  CAS  PubMed  Google Scholar 

  156. Wylie A, Lu WJ, D'Brot A, Buszczak M, Abrams JM. p53 activity is selectively licensed in the Drosophila stem cell compartment. Elife. 2014;3:e01530. https://doi.org/10.7554/eLife.01530.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Xing Y, Su TT, Ruohola-Baker H. Tie-mediated signal from apoptotic cells protects stem cells in Drosophila melanogaster. Nat Commun. 2015;6:7058. https://doi.org/10.1038/ncomms8058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Artoni F, Kreipke RE, Palmeira O, Dixon C, Goldberg Z, Ruohola-Baker H. Loss of foxo rescues stem cell aging in Drosophila germ line. Elife. 2017;6. https://doi.org/10.7554/eLife.27842.

  159. Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, et al. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci Transl Med. 2013;5(172):172ra21. https://doi.org/10.1126/scitranslmed.3004925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Titus S, Stobezki R, Oktay K. Impaired DNA repair as a mechanism for oocyte aging: is it epigenetically determined? Semin Reprod Med. 2015;33(6):384–8. https://doi.org/10.1055/s-0035-1567824.

    Article  CAS  PubMed  Google Scholar 

  161. Govindaraj V, Keralapura Basavaraju R, Rao AJ. Changes in the expression of DNA double strand break repair genes in primordial follicles from immature and aged rats. Reprod Biomed Online. 2015;30(3):303–10. https://doi.org/10.1016/j.rbmo.2014.11.010.

    Article  CAS  PubMed  Google Scholar 

  162. Zhang D, Zhang X, Zeng M, Yuan J, Liu M, Yin Y, et al. Increased DNA damage and repair deficiency in granulosa cells are associated with ovarian aging in rhesus monkey. J Assist Reprod Genet. 2015;32(7):1069–78. https://doi.org/10.1007/s10815-015-0483-5.

    Article  PubMed  PubMed Central  Google Scholar 

  163. Bhargava V, Goldstein CD, Russell L, Xu L, Ahmed M, Li W, et al. GCNA preserves genome integrity and fertility across species. Dev Cell. 2020;52(1):38–52 e10. https://doi.org/10.1016/j.devcel.2019.11.007.

    Article  CAS  PubMed  Google Scholar 

  164. Degtyareva NP, Greenwell P, Hofmann ER, Hengartner MO, Zhang L, Culotti JG, et al. Caenorhabditis elegans DNA mismatch repair gene msh-2 is required for microsatellite stability and maintenance of genome integrity. Proc Natl Acad Sci U S A. 2002;99(4):2158–63. https://doi.org/10.1073/pnas.032671599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Kalmbach KH, Antunes DM, Kohlrausch F, Keefe DL. Telomeres and female reproductive aging. Semin Reprod Med. 2015;33(6):389–95. https://doi.org/10.1055/s-0035-1567823.

    Article  CAS  PubMed  Google Scholar 

  166. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19(18):2100–10. https://doi.org/10.1101/gad.1346005.

    Article  CAS  PubMed  Google Scholar 

  167. Liu L, Trimarchi JR, Smith PJ, Keefe DL. Mitochondrial dysfunction leads to telomere attrition and genomic instability. Aging Cell. 2002;1(1):40–6. https://doi.org/10.1046/j.1474-9728.2002.00004.x.

    Article  CAS  PubMed  Google Scholar 

  168. Keefe DL, Liu L. Telomeres and reproductive aging. Reprod Fertil Dev. 2009;21(1):10–4. https://doi.org/10.1071/rd08229.

    Article  CAS  PubMed  Google Scholar 

  169. Keefe DL, Liu L, Marquard K. Telomeres and aging-related meiotic dysfunction in women. Cell Mol Life Sci. 2007;64(2):139–43. https://doi.org/10.1007/s00018-006-6466-z.

    Article  CAS  PubMed  Google Scholar 

  170. Rocca MS, Foresta C, Ferlin A. Telomere length: lights and shadows on their role in human reproduction. Biol Reprod. 2019;100(2):305–17. https://doi.org/10.1093/biolre/ioy208.

    Article  PubMed  Google Scholar 

  171. Yamada-Fukunaga T, Yamada M, Hamatani T, Chikazawa N, Ogawa S, Akutsu H, et al. Age-associated telomere shortening in mouse oocytes. Reprod Biol Endocrinol. 2013;11:108. https://doi.org/10.1186/1477-7827-11-108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Zhang JM, Zou L. Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks. Cell Biosci. 2020;10:30. https://doi.org/10.1186/s13578-020-00391-6.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Yanowitz JL. Genome integrity is regulated by the Caenorhabditis elegans Rad51D homolog rfs-1. Genetics. 2008;179(1):249–62. https://doi.org/10.1534/genetics.107.076877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Sinnige T, Yu A, Morimoto RI. Challenging proteostasis: role of the chaperone network to control aggregation-prone proteins in human disease. Adv Exp Med Biol. 2020;1243:53–68. https://doi.org/10.1007/978-3-030-40204-4_4.

    Article  CAS  PubMed  Google Scholar 

  175. Noormohammadi A, Calculli G, Gutierrez-Garcia R, Khodakarami A, Koyuncu S, Vilchez D. Mechanisms of protein homeostasis (proteostasis) maintain stem cell identity in mammalian pluripotent stem cells. Cell Mol Life Sci. 2018;75(2):275–90. https://doi.org/10.1007/s00018-017-2602-1.

    Article  CAS  PubMed  Google Scholar 

  176. Fredriksson Å, Johansson Krogh E, Hernebring M, Pettersson E, Javadi A, Almstedt A, et al. Effects of aging and reproduction on protein quality control in soma and gametes of Drosophila melanogaster. Aging Cell. 2012;11(4):634–43. https://doi.org/10.1111/j.1474-9726.2012.00823.x.

    Article  CAS  PubMed  Google Scholar 

  177. Goudeau J, Aguilaniu H. Carbonylated proteins are eliminated during reproduction in C. elegans. Aging Cell. 2010;9(6):991–1003. https://doi.org/10.1111/j.1474-9726.2010.00625.x.

    Article  CAS  PubMed  Google Scholar 

  178. Hernebring M, Brole’ G, Aguilaniu H, Semb H, Nystro T. Elimination of damaged proteins during differentiation of embryonic stem cells. PNAS. 2015:7700–5.

  179. Yao Q, Liang Y, Shao Y, Bian W, Fu H, Xu J, et al. Advanced glycation end product concentrations in follicular fluid of women undergoing IVF/ICSI with a GnRH agonist protocol. Reprod Biomed Online. 2018;36(1):20–5. https://doi.org/10.1016/j.rbmo.2017.09.003.

    Article  CAS  PubMed  Google Scholar 

  180. Sato M, Sato K. Degradation of paternal mitochondria by fertilization-triggered autophagy in C. elegans embryos. Science. 2011;334(6059):1141–4. https://doi.org/10.1126/science.1210333.

    Article  CAS  PubMed  Google Scholar 

  181. Sharpley MS, Marciniak C, Eckel-Mahan K, McManus M, Crimi M, Waymire K, et al. Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition. Cell. 2012;151(2):333–43. https://doi.org/10.1016/j.cell.2012.09.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Politi Y, Gal L, Kalifa Y, Ravid L, Elazar Z, Arama E. Paternal mitochondrial destruction after fertilization is mediated by a common endocytic and autophagic pathway in Drosophila. Dev Cell. 2014;29(3):305–20. https://doi.org/10.1016/j.devcel.2014.04.005.

    Article  CAS  PubMed  Google Scholar 

  183. Kimura M, Itoh N, Takagi S, Sasao T, Takahashi A, Masumori N, et al. Balance of apoptosis and proliferation of germ cells related to spermatogenesis in aged men. J Androl. 2003;24(2):185–91. https://doi.org/10.1002/j.1939-4640.2003.tb02661.x.

    Article  PubMed  Google Scholar 

  184. David DC, Ollikainen N, Trinidad JC, Cary MP, Burlingame AL, Kenyon C. Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol. 2010;8(8):e1000450. https://doi.org/10.1371/journal.pbio.1000450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Mihalas BP, Bromfield EG, Sutherland JM, De Iuliis GN, McLaughlin EA, Aitken RJ, et al. Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity. J Biol Chem. 2018;293(49):18944–64. https://doi.org/10.1074/jbc.RA118.005751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Zimmerman SM, Hinkson IV, Elias JE, Kim SK. Reproductive aging drives protein accumulation in the uterus and limits lifespan in C. elegans. PLoS Genet. 2015;11(12):e1005725. https://doi.org/10.1371/journal.pgen.1005725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Andaloussi AE, Habib S, Soylemes G, Laknaur A, Elhusseini H, Al-Hendy A, et al. Defective expression of ATG4D abrogates autophagy and promotes growth in human uterine fibroids. Cell Death Discov. 2017;3:17041. https://doi.org/10.1038/cddiscovery.2017.41.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Duncan FE, Jasti S, Paulson A, Kelsh JM, Fegley B, Gerton JL. Age-associated dysregulation of protein metabolism in the mammalian oocyte. Aging Cell. 2017;16(6):1381–93. https://doi.org/10.1111/acel.12676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Assou S, Cerecedo D, Tondeur S, Pantesco V, Hovatta O, Klein B, et al. A gene expression signature shared by human mature oocytes and embryonic stem cells. BMC Genomics. 2009;10:10. https://doi.org/10.1186/1471-2164-10-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Tamura H, Kawamoto M, Sato S, Tamura I, Maekawa R, Taketani T, et al. Long-term melatonin treatment delays ovarian aging. J Pineal Res. 2017;62(2). https://doi.org/10.1111/jpi.12381.

  191. Meneau F, Dupre A, Jessus C, Daldello EM. Translational control of Xenopus oocyte meiosis: toward the genomic era. Cells. 2020;9(6). https://doi.org/10.3390/cells9061502.

  192. Greenblatt EJ, Obniski R, Mical C, Spradling AC. Prolonged ovarian storage of mature Drosophila oocytes dramatically increases meiotic spindle instability. Elife. 2019;8. https://doi.org/10.7554/eLife.49455.

  193. Greenblatt EJ, Spradling AC. Fragile X mental retardation 1 gene enhances the translation of large autism-related proteins. Science. 2018;361(6403):709–12. https://doi.org/10.1126/science.aas9963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Crosnoe LE, Kim ED. Impact of age on male fertility. Curr Opin Obstet Gynecol. 2013;25(3):181–5. https://doi.org/10.1097/GCO.0b013e32836024cb.

    Article  PubMed  Google Scholar 

  195. Fonseka KG, Griffin DK. Is there a paternal age effect for aneuploidy? Cytogenet Genome Res. 2011;133(2-4):280–91. https://doi.org/10.1159/000322816.

    Article  CAS  PubMed  Google Scholar 

  196. Gao Z, Moorjani P, Sasani TA, Pedersen BS, Quinlan AR, Jorde LB, et al. Overlooked roles of DNA damage and maternal age in generating human germline mutations. Proc Natl Acad Sci U S A. 2019;116(19):9491–500. https://doi.org/10.1073/pnas.1901259116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Jenkins TG, Aston KI, Pflueger C, Cairns BR, Carrell DT. Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility. PLoS Genet. 2014;10(7):e1004458. https://doi.org/10.1371/journal.pgen.1004458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Milekic MH, Xin Y, O'Donnell A, Kumar KK, Bradley-Moore M, Malaspina D, et al. Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression. Mol Psychiatry. 2015;20(8):995–1001. https://doi.org/10.1038/mp.2014.84.

    Article  CAS  PubMed  Google Scholar 

  199. Denomme MM, Haywood ME, Parks JC, Schoolcraft WB, Katz-Jaffe MG. The inherited methylome landscape is directly altered with paternal aging and associated with offspring neurodevelopmental disorders. Aging Cell. 2020:e13178. https://doi.org/10.1111/acel.13178.

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This work was funded by grants from the National Institutes of Health (R01GM104007) to JLY and (R01AG051659) to AG, a grant from the Global Consortium for Reproductive Longevity and Equality to CQC, and a Children’s Hospital of Pittsburgh Research Advisory Committee (RAC) fellowship to JAL.

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  1. Magee-Womens Research Institute, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA, 15213, USA

    Cristina Quesada-Candela & Judith L. Yanowitz

  2. Departments of Pediatrics, Developmental Biology and Cell Biology and Physiology, John G. Rangos Sr. Research Center, University of Pittsburgh School of Medicine, Room 7129, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA

    Julia Loose & Arjumand Ghazi

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Quesada-Candela, C., Loose, J., Ghazi, A. et al. Molecular basis of reproductive senescence: insights from model organisms. J Assist Reprod Genet 38, 17–32 (2021). https://doi.org/10.1007/s10815-020-01959-4

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