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Insights into Mechanisms Causing the Maternal Age-Induced Decrease in Oocyte Quality

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Biennial Review of Infertility

Abstract

Female fertility declines with age, but the underlying mechanisms remain unclear. Here, we review the recent literature on the role of reactive oxygen species (ROS) within the oocytes. Specifically, ROS increase with age, damaging mitochondria and proteins important in oocyte maturation and meiosis. The damages to mitochondria impair ATP production. ATP levels in oocytes have been linked to successful completion of meiosis prior to ovulation and mediating the appropriate response to sperm binding. ROS also damage proteins important in DNA repair. Meiosis-specific homologs of DNA repair proteins have a critical role in recombination and preventing aneuploidy. Therefore, ROS-induced mitochondrial damage has widespread impacts on multiple aspects of oocyte quality. Some treatments are discussed which have shown to be effective in decreasing ROS-induced damage and lowering aneuploidy, providing hope to older women attempting to conceive. However, gaps in knowledge remain and require further investigation before more targeted treatments can be developed.

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References

  1. Johnson J, Bagley J, Skaznik-Wikiel M, Lee HJ, Adams GB, Niikura Y, Tschudy KS, Tilly JC, Cortes ML, Forkert R, Spitzer T, Iacomini J, Scadden DT, Tilly JL. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell. 2005;122(2):303–15.

    Article  CAS  PubMed  Google Scholar 

  2. Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428(6979):145–50.

    Article  CAS  PubMed  Google Scholar 

  3. te Velde ER, Scheffer GJ, Dorland M, Broekmans FJ, Fauser BC. Developmental and endocrine aspects of normal ovarian aging. Mol Cell Endocrinol. 1998;145(1–2):67–73.

    Article  Google Scholar 

  4. Tarin JJ, Perez-Albala S, Cano A. Cellular and morphological traits of oocytes retrieved from aging mice after exogenous ovarian stimulation. Biol Reprod. 2001;65(1):141–50.

    Article  CAS  PubMed  Google Scholar 

  5. McClellan KA, Gosden R, Taketo T. Continuous loss of oocytes throughout meiotic prophase in the normal mouse ovary. Dev Biol. 2003;258(2):334–48.

    Article  CAS  PubMed  Google Scholar 

  6. Sauer MV, Paulson RJ, Lobo RA. Pregnancy after age 50: application of oocyte donation to women after natural menopause. Lancet. 1993;341(8841):321–3.

    Article  CAS  PubMed  Google Scholar 

  7. Richards JS, Midgley Jr AR. Protein hormone action: a key to understanding ovarian follicular and luteal cell development. Biol Reprod. 1976;14(1):82–94.

    Article  CAS  PubMed  Google Scholar 

  8. Dumont J, Desai A. Acentrosomal spindle assembly and chromosome segregation during oocyte meiosis. Trends Cell Biol. 2012;22(5):241–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Gougeon A. Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod. 1986;1(2):81–7.

    CAS  PubMed  Google Scholar 

  10. Sathananthan AH, Trounson AO. Mitochondrial morphology during preimplantational human embryogenesis. Hum Reprod. 2000;15 Suppl 2:148–59.

    Article  PubMed  Google Scholar 

  11. Sathananthan AH, Selvaraj K, Girijashankar ML, Ganesh V, Selvaraj P, Trounson AO. From oogonia to mature oocytes: inactivation of the maternal centrosome in humans. Microsc Res Tech. 2006;69(6):396–407.

    Article  PubMed  Google Scholar 

  12. Li R, Albertini DF. The road to maturation: somatic cell interaction and self-organization of the mammalian oocyte. Nat Rev Mol Cell Biol. 2013;14(3):141–52.

    Article  CAS  PubMed  Google Scholar 

  13. De La Fuente R, Eppig JJ. Transcriptional activity of the mouse oocyte genome: companion granulosa cells modulate transcription and chromatin remodeling. Dev Biol. 2001;229(1):224–36.

    Article  Google Scholar 

  14. Philpott CC, Ringuette MJ, Dean J. Oocyte-specific expression and developmental regulation of ZP3, the sperm receptor of the mouse zona pellucida. Dev Biol. 1987;121(2):568–75.

    Article  CAS  PubMed  Google Scholar 

  15. Harris SE, Adriaens I, Leese HJ, Gosden RG, Picton HM. Carbohydrate metabolism by murine ovarian follicles and oocytes grown in vitro. Reproduction. 2007;134(3):415–24.

    Article  CAS  PubMed  Google Scholar 

  16. Wang Y, Mohsen AW, Mihalik SJ, Goetzman ES, Vockley J. Evidence for physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes. J Biol Chem. 2010;285(39):29834–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Van Blerkom J, Davis PW, Lee J. ATP content of human oocytes and developmental potential and outcome after in-vitro fertilization and embryo transfer. Hum Reprod. 1995;10(2):415–24.

    CAS  PubMed  Google Scholar 

  18. Yu Y, Dumollard R, Rossbach A, Lai FA, Swann K. Redistribution of mitochondria leads to bursts of ATP production during spontaneous mouse oocyte maturation. J Cell Physiol. 2010;224(3):672–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Lodish HF, Berk A, Kaiser AK, Krieger M, Scott MP, Bretscher A, Ploegh H, Matsudaira P. Molecular cell biology. 6th ed. New York, NY: W. H. Freeman; 2007.

    Google Scholar 

  20. Gaziev AI, Abdullaev S, Podlutsky A. Mitochondrial function and mitochondrial DNA maintenance with advancing age. Biogerontology. 2014;15(5):417–38.

    Article  CAS  PubMed  Google Scholar 

  21. Heytler PG. Uncouplers of oxidative phosphorylation. Methods Enzymol. 1979;55:462–72.

    Article  CAS  PubMed  Google Scholar 

  22. Ge H, Tollner TL, Hu Z, Dai M, Li X, Guan H, Shan D, Zhang X, Lv J, Huang C, Dong Q. The importance of mitochondrial metabolic activity and mitochondrial DNA replication during oocyte maturation in vitro on oocyte quality and subsequent embryo developmental competence. Mol Reprod Dev. 2012;79(6):392–401.

    Article  CAS  PubMed  Google Scholar 

  23. Takeuchi T, Neri QV, Katagiri Y, Rosenwaks Z, Palermo GD. Effect of treating induced mitochondrial damage on embryonic development and epigenesis. Biol Reprod. 2005;72(3):584–92.

    Article  CAS  PubMed  Google Scholar 

  24. Shkolnik K, Tadmor A, Ben-Dor S, Nevo N, Galiani D, Dekel N. Reactive oxygen species are indispensable in ovulation. Proc Natl Acad Sci U S A. 2011;108(4):1462–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Biggers JDWD, Dnoahue RP. The pattern of energy metabolism in the mouse oocyte and zygote. Proc Natl Acad Sci U S A. 1967;58(2):560–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Dumollard R, Duchen M, Carroll J. The role of mitochondrial function in the oocyte and embryo. Curr Top Dev Biol. 2007;77:21–49.

    Article  CAS  PubMed  Google Scholar 

  27. Zuelke KA, Jeffay SC, Zucker RM, Perreault SD. Glutathione (GSH) concentrations vary with the cell cycle in maturing hamster oocytes, zygotes, and pre-implantation stage embryos. Mol Reprod Dev. 2003;64(1):106–12.

    Article  PubMed  Google Scholar 

  28. Hill JH, Chen Z, Xu H. Selective propagation of functional mitochondrial DNA during oogenesis restricts the transmission of a deleterious mitochondrial variant. Nat Genet. 2014;46(4):389–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005;308(5730):1909–11.

    Article  CAS  PubMed  Google Scholar 

  30. Di Emidio G, Falone S, Vitti M, D’Alessandro AM, Vento M, Di Pietro C, Amicarelli F, Tatone C. SIRT1 signalling protects mouse oocytes against oxidative stress and is deregulated during aging. Hum Reprod. 2014;29:2006–17.

    Article  PubMed  Google Scholar 

  31. Schwarzer C, Siatkowski M, Pfeiffer MJ, Baeumer N, Drexler HC, Wang B, Fuellen G, Boiani M. Maternal age effect on mouse oocytes: new biological insight from proteomic analysis. Reproduction. 2014;148(1):55–72.

    Article  CAS  PubMed  Google Scholar 

  32. Tarin JJ, Perez-Albala S, Cano A. Oral antioxidants counteract the negative effects of female aging on oocyte quantity and quality in the mouse. Mol Reprod Dev. 2002;61(3):385–97.

    Article  CAS  PubMed  Google Scholar 

  33. Bogliolo L, Murrone O, Di Emidio G, Piccinini M, Ariu F, Ledda S, Tatone C. Raman spectroscopy-based approach to detect aging-related oxidative damage in the mouse oocyte. J Assist Reprod Genet. 2013;30(7):877–82.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Schie IW, Huser T. Methods and applications of Raman microspectroscopy to single-cell analysis. Appl Spectrosc. 2013;67(8):813–28.

    CAS  PubMed  Google Scholar 

  35. Kujjo LL, Acton BM, Perkins GA, Ellisman MH, D’Estaing SG, Casper RF, Jurisicova A, Perez GI. Ceramide and its transport protein (CERT) contribute to deterioration of mitochondrial structure and function in aging oocytes. Mech Ageing Dev. 2013;134(1–2):43–52.

    Article  CAS  PubMed  Google Scholar 

  36. Yamada-Fukunaga T, Yamada M, Hamatani T, Chikazawa N, Ogawa S, Akutsu H, Miura T, Miyado K, Tarin JJ, Kuji N, Umezawa A, Yoshimura Y. Age-associated telomere shortening in mouse oocytes. Reprod Biol Endocrinol. 2013;11(1):108.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Wilding M, Dale B, Marino M, di Matteo L, Alviggi C, Pisaturo ML, Lombardi L, De Placido G. Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos. Hum Reprod. 2001;16(5):909–17.

    Article  CAS  PubMed  Google Scholar 

  38. Simsek-Duran F, Li F, Ford W, Swanson RJ, Jones Jr HW, Castora FJ. Age-associated metabolic and morphologic changes in mitochondria of individual mouse and hamster oocytes. PLoS One. 2013;8(5):e64955.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Piko L, Taylor KD. Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos. Dev Biol. 1987;123(2):364–74.

    Article  CAS  PubMed  Google Scholar 

  40. Murakoshi Y, Sueoka K, Takahashi K, Sato S, Sakurai T, Tajima H, Yoshimura Y. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, Oktay K. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci Transl Med. 2013;5(172):172ra21.

    Article  PubMed  Google Scholar 

  42. Matsumine M, Shibata N, Ishitani K, Kobayashi M, Ohta H. Pentosidine accumulation in human oocytes and their correlation to age-related apoptosis. Acta Histochem Cytochem. 2008;41(4):97–104.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Santonocito M, Guglielmino MR, Vento M, Ragusa M, Barbagallo D, Borzi P, Casciano I, Scollo P, Romani M, Tatone C, Purrello M, Di Pietro C. The apoptotic transcriptome of the human MII oocyte: characterization and age-related changes. Apoptosis. 2013;18(2):201–11.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. Elizur SE, Lebovitz O, Orvieto R, Dor J, Zan-Bar T. Reactive oxygen species in follicular fluid may serve as biochemical markers to determine ovarian aging and follicular metabolic age. Gynecol Endocrinol. 2014;30:705–7.

    Article  CAS  PubMed  Google Scholar 

  46. Dumollard R, Marangos P, Fitzharris G, Swann K, Duchen M, Carroll J. Sperm-triggered [Ca2+] oscillations and Ca2+ homeostasis in the mouse egg have an absolute requirement for mitochondrial ATP production. Development. 2004;131(13):3057–67.

    Article  CAS  PubMed  Google Scholar 

  47. Wakai T, Zhang N, Vangheluwe P, Fissore RA. Regulation of endoplasmic reticulum Ca(2+) oscillations in mammalian eggs. J Cell Sci. 2013;126(Pt 24):5714–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Thouas GA, Trounson AO, Wolvetang EJ, Jones GM. Mitochondrial dysfunction in mouse oocytes results in preimplantation embryo arrest in vitro. Biol Reprod. 2004;71(6):1936–42.

    Article  CAS  PubMed  Google Scholar 

  49. Yang HW, Hwang KJ, Kwon HC, Kim HS, Choi KW, Oh KS. Detection of reactive oxygen species (ROS) and apoptosis in human fragmented embryos. Hum Reprod. 1998;13(4):998–1002.

    Article  CAS  PubMed  Google Scholar 

  50. Wakefield SL, Lane M, Mitchell M. Impaired mitochondrial function in the preimplantation embryo perturbs fetal and placental development in the mouse. Biol Reprod. 2011;84(3):572–80.

    Article  CAS  PubMed  Google Scholar 

  51. Thouas GA, Trounson AO, Jones GM. Developmental effects of sublethal mitochondrial injury in mouse oocytes. Biol Reprod. 2006;74(5):969–77.

    Article  CAS  PubMed  Google Scholar 

  52. 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.

    Article  CAS  PubMed  Google Scholar 

  53. Wang Q, Chi MM, Schedl T, Moley KH. An intercellular pathway for glucose transport into mouse oocytes. Am J Physiol Endocrinol Metab. 2012;302(12):E1511–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Nagaoka SI, Hodges CA, Albertini DF, Hunt PA. Oocyte-specific differences in cell-cycle control create an innate susceptibility to meiotic errors. Curr Biol. 2011;21(8):651–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Lee J. Roles of cohesin and condensin in chromosome dynamics during mammalian meiosis. J Reprod Dev. 2013;59(5):431–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Xu H, Beasley MD, Warren WD, van der Horst GT, McKay MJ. Absence of mouse REC8 cohesin promotes synapsis of sister chromatids in meiosis. Dev Cell. 2005;8(6):949–61.

    Article  CAS  PubMed  Google Scholar 

  57. Tachibana-Konwalski K, Godwin J, van der Weyden L, Champion L, Kudo NR, Adams DJ, Nasmyth K. Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes. Genes Dev. 2010;24(22):2505–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Murdoch B, Owen N, Stevense M, Smith H, Nagaoka S, Hassold T, McKay M, Xu H, Fu J, Revenkova E, Jessberger R, Hunt P. Altered cohesin gene dosage affects Mammalian meiotic chromosome structure and behavior. PLoS Genet. 2013;9(2):e1003241.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Tsutsumi M, Fujiwara R, Nishizawa H, Ito M, Kogo H, Inagaki H, Ohye T, Kato T, Fujii T, Kurahashi H. Age-related decrease of meiotic cohesins in human oocytes. PLoS One. 2014;9(5):e96710.

    Article  PubMed Central  PubMed  Google Scholar 

  60. Fragouli E, Wells D, Delhanty JD. Chromosome abnormalities in the human oocyte. Cytogenet Genome Res. 2011;133(2–4):107–18.

    Article  CAS  PubMed  Google Scholar 

  61. Merriman JA, Jennings PC, McLaughlin EA, Jones KT. Effect of aging on superovulation efficiency, aneuploidy rates, and sister chromatid cohesion in mice aged up to 15 months. Biol Reprod. 2012;86(2):49.

    Article  PubMed  Google Scholar 

  62. Dailey T, Dale B, Cohen J, Munne S. Association between nondisjunction and maternal age in meiosis-II human oocytes. Am J Hum Genet. 1996;59(1):176–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Yun Y, Lane SI, Jones KT. Premature dyad separation in meiosis II is the major segregation error with maternal age in mouse oocytes. Development. 2014;141(1):199–208.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Shomper M, Lappa C, FitzHarris G. Kinetochore microtubule establishment is defective in oocytes from aged mice. Cell Cycle. 2014;13(7):1171–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Duncan FE, Hornick JE, Lampson MA, Schultz RM, Shea LD, Woodruff TK. Chromosome cohesion decreases in human eggs with advanced maternal age. Aging Cell. 2012;11(6):1121–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Merriman JA, Lane SI, Holt JE, Jennings PC, Garcia-Higuera I, Moreno S, McLaughlin EA, Jones KT. Reduced chromosome cohesion measured by interkinetochore distance is associated with aneuploidy even in oocytes from young mice. Biol Reprod. 2013;88(2):31.

    Article  PubMed  Google Scholar 

  67. Liu J, Liu M, Ye X, Liu K, Huang J, Wang L, Ji G, Liu N, Tang X, Baltz JM, Keefe DL, Liu L. Delay in oocyte aging in mice by the antioxidant N-acetyl-L-cysteine (NAC). Hum Reprod. 2012;27(5):1411–20.

    Article  CAS  PubMed  Google Scholar 

  68. Ruder EH, Hartman TJ, Reindollar RH, Goldman MB. Female dietary antioxidant intake and time to pregnancy among couples treated for unexplained infertility. Fertil Steril. 2014;101(3):759–66.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Houten SM, Wanders RJ. A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis. 2010;33(5):469–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Abdelrazik H, Sharma R, Mahfouz R, Agarwal A. L-carnitine decreases DNA damage and improves the in vitro blastocyst development rate in mouse embryos. Fertil Steril. 2009;91(2):589–96.

    Article  CAS  PubMed  Google Scholar 

  71. Talebi A, Zavareh S, Kashani MH, Lashgarbluki T, Karimi I. The effect of alpha lipoic acid on the developmental competence of mouse isolated preantral follicles. J Assist Reprod Genet. 2012;29(2):175–83.

    Article  PubMed Central  PubMed  Google Scholar 

  72. Palikaras K, Tavernarakis N. Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp Gerontol. 2014;56:182–8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA

    Anna L. Boudoures

  2. Department of Gynecological Research, Washington University School of Medicine, St. Louis, MO, USA

    Kelle H. Moley MD

Authors
  1. Anna L. Boudoures
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  2. Kelle H. Moley MD
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Correspondence to Kelle H. Moley MD .

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Editors and Affiliations

  1. Professor, Departments of Surgery (Urology), Obstetrics and Gynecology, and Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA

    Douglas T. Carrell

  2. James J. Colt Professor of Urology, Chairman, Department of Urology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York, USA

    Peter N. Schlegel

  3. Professor, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Catherine Racowsky

  4. Scientific Director, Reproductive Medicine Unit, S.I.S.M.E.R. s.r.l., Day Surgery Clinic della Riproduzione (SISMeR), Bologna, Bologna, Italy

    Luca Gianaroli

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Boudoures, A.L., Moley, K.H. (2015). Insights into Mechanisms Causing the Maternal Age-Induced Decrease in Oocyte Quality. In: Carrell, D., Schlegel, P., Racowsky, C., Gianaroli, L. (eds) Biennial Review of Infertility. Springer, Cham. https://doi.org/10.1007/978-3-319-17849-3_4

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