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Age and Oxidative Stress in the Germ Line

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Book cover Studies on Men's Health and Fertility

Abstract

There is increasing evidence that the male reproductive system declines with advancing age Studies examining germ cells of older men have raised concerns regarding several aspects of germ cell quality. Increasing paternal age has been linked to genetic diseases (achondroplasia, Apert syndrome, and Marfan syndrome) in the offspring of these fathers; the incidence of autism and schizophrenia is also associated with increasing paternal age. Men above the age of 35 have increased incidences of anneuploidy in their sperm, decreased sperm motility, and increased chromatin aberrations in sperm associated with further problems such as decreased pregnancy rate in the partners of older males. In several tissues, aging is associated with oxidative stress. Rodent studies show that aging male germ cells display an increase in reactive oxygen species (ROS) and a reduction in the antioxidant enzymes normally present to neutralize ROS and protect the cellular structures against ROS-induced damage. This oxidative stress may be the cause of the DNA damage seen in the germ cells and could also have an effect at the stem cell level resulting in reduced germ cell quality with age.

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References

  1. Hayflick L. Biological aging is no longer an unsolved problem. Ann N Y Acad Sci. 2007;1100:1–13.

    PubMed  CAS  Google Scholar 

  2. Sartorius GA, Nieschlag E. Paternal age and reproduction. Hum Reprod Update. 2010;16:65–79.

    PubMed  Google Scholar 

  3. Singh NP, Muller CH, Berger RE. Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertil Steril. 2003;80:1420–30.

    PubMed  Google Scholar 

  4. Thacker PD. Biological clock ticks for men, too: genetic defects linked to sperm of older fathers. JAMA. 2004;291:1683–5.

    PubMed  CAS  Google Scholar 

  5. Perrin MC, Brown AS, Malaspina D. Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. Schizophr Bull. 2007;33:1270–3.

    PubMed  Google Scholar 

  6. Jin K. Modern biological theories of aging. Aging Dis. 2010;1:72–4.

    PubMed  Google Scholar 

  7. Davidovic M, Sevo G, Svorcan P, Milosevic DP, Despotovic N, Erceg P. Old age as a privilege of the “selfish ones”. Aging Dis. 2010;1:139–46.

    PubMed  Google Scholar 

  8. van Heemst D. Insulin, IGF-1 and longevity. Aging Dis. 2010;1:147–57.

    PubMed  Google Scholar 

  9. Rozemuller AJ, van Gool WA, Eikelenboom P. The neuroinflammatory response in plaques and amyloidangiopathy in Alzheimer’s disease: therapeutic implications. Curr Drug Targets CNS Neurol Disord. 2005;4:223–33.

    PubMed  CAS  Google Scholar 

  10. Brys K, Vanfleteren JR, Braeckman BP. Testing the rate-of-living/oxidative damage theory of aging in the nematode model Caenorhabditis elegans. Exp Gerontol. 2007;42:845–51.

    PubMed  CAS  Google Scholar 

  11. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–60.

    PubMed  CAS  Google Scholar 

  12. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298–300.

    PubMed  CAS  Google Scholar 

  13. Shampay J, Szostak JW, Blackburn EH. DNA sequences of telomeres maintained in yeast. Nature. 1984;310:154–7.

    PubMed  CAS  Google Scholar 

  14. Holt SE, Shay JW, Wright WE. Refining the telomere-telomerase hypothesis of aging and cancer. Nat Biotechnol. 1996;14:836–9.

    PubMed  CAS  Google Scholar 

  15. Mera SL. The role of telomeres in ageing and cancer. Br J Biomed Sci. 1998;55:221–5.

    PubMed  CAS  Google Scholar 

  16. Counter CM. The roles of telomeres and telomerase in cell life span. Mutat Res. 1996;366:45–63.

    PubMed  Google Scholar 

  17. Ishikawa F. Aging clock: the watchmaker’s masterpiece. Cell Mol Life Sci. 2000;57:698–704.

    PubMed  CAS  Google Scholar 

  18. Achi MV, Ravindranath N, Dym M. Telomere length in male germ cells is inversely correlated with telomerase activity. Biol Reprod. 2000;63:591–8.

    PubMed  CAS  Google Scholar 

  19. Rangarajan A, Weinberg RA. Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer. 2003;3:952–9.

    PubMed  CAS  Google Scholar 

  20. Kimura M, Cherkas LF, Kato BS, Demissie S, Hjelmborg JB, Brimacombe M, Cupples A, Hunkin JL, Gardner JP, Lu X, Cao X, Sastrasinh M, Province MA, Hunt SC, Christensen K, Levy D, Spector TD, Aviv A. Offspring’s leukocyte telomere length, paternal age, and telomere elongation in sperm. PLoS Genet. 2008;4:e37.

    PubMed  Google Scholar 

  21. DeVeale B, Brummel T, Seroude L. Immunity and aging: the enemy within? Aging Cell. 2004;3:195–208.

    PubMed  CAS  Google Scholar 

  22. Plackett TP, Boehmer ED, Faunce DE, Kovacs EJ. Aging and innate immune cells. J Leukoc Biol. 2004;76:291–9.

    PubMed  CAS  Google Scholar 

  23. Miller RA. The aging immune system: primer and prospectus. Science. 1996;273:70–4.

    PubMed  CAS  Google Scholar 

  24. Chakravarti B, Abraham GN. Aging and T-cell-mediated immunity. Mech Ageing Dev. 1999;108:183–206.

    PubMed  CAS  Google Scholar 

  25. Weksler ME. Changes in the B-cell repertoire with age. Vaccine. 2000;18:1624–8.

    PubMed  CAS  Google Scholar 

  26. Szakal AK, Aydar Y, Balogh P, Tew JG. Molecular interactions of FDCs with B cells in aging. Semin Immunol. 2002;14:267–74.

    PubMed  CAS  Google Scholar 

  27. Serre V, Robaire B. Distribution of immune cells in the epididymis of the aging Brown Norway rat is segment-specific and related to the luminal content. Biol Reprod. 1999;61:705–14.

    PubMed  CAS  Google Scholar 

  28. Dufour E, Larsson NG. Understanding aging: revealing order out of chaos. Biochim Biophys Acta. 2004;1658:122–32.

    PubMed  CAS  Google Scholar 

  29. Felkai S, Ewbank JJ, Lemieux J, Labbe JC, Brown GG, Hekimi S. CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans. EMBO J. 1999;18:1783–92.

    PubMed  CAS  Google Scholar 

  30. Asencio C, Rodriguez-Aguilera JC, Ruiz-Ferrer M, Vela J, Navas P. Silencing of ubiquinone biosynthesis genes extends life span in Caenorhabditis elegans. FASEB J. 2003;17:1135–7.

    PubMed  CAS  Google Scholar 

  31. Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, Ruvkun G. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet. 2003;33:40–8.

    PubMed  CAS  Google Scholar 

  32. Balin AK. Testing the free radical theory of aging. In: Adelman RC, Roth GS, editors. Testing the theories of aging. Boca Raton: CRC Press; 1983. p. 137–82.

    Google Scholar 

  33. Thomas J, Nyberg D. Vitamin E supplementation and intense selection increase clonal life span in Paramecium tetraurelia. Exp Gerontol. 1988;23:501–12.

    PubMed  CAS  Google Scholar 

  34. Kakkar R, Bains JS, Sharma SP. Effect of vitamin E on life span, malondialdehyde content and antioxidant enzymes in aging Zaprionus paravittiger. Gerontology. 1996;42:312–21.

    PubMed  CAS  Google Scholar 

  35. Munkres K, Rana RS. Antioxidants prolong life span and inhibit the senescence-dependent accumulation of fluorescent pigment (lipofuscin) in clones, of Podospora anserina. Mech Ageing Dev. 1978;7:407–15.

    PubMed  CAS  Google Scholar 

  36. Sohal RS, Sohal BH, Orr WC. Mitochondrial superoxide and hydrogen peroxide generation, protein oxidative damage, and longevity in different species of flies. Free Radic Biol Med. 1995;19:499–504.

    PubMed  CAS  Google Scholar 

  37. Orr WC, Sohal RS. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science. 1994;263:1128–30.

    PubMed  CAS  Google Scholar 

  38. Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL. Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet. 1998;19:171–4.

    PubMed  CAS  Google Scholar 

  39. Barouki R. Ageing free radicals and oxidative stress. Med Sci (Paris). 2006;22:266–72.

    Google Scholar 

  40. Schoneich C. Reactive oxygen species and biological aging: a mechanistic approach. Exp Gerontol. 1999;34:19–34.

    PubMed  CAS  Google Scholar 

  41. Lucas DT, Szweda LI. Cardiac reperfusion injury: aging, lipid peroxidation, and mitochondrial dysfunction. Proc Natl Acad Sci USA. 1998;95:510–4.

    PubMed  CAS  Google Scholar 

  42. Inal ME, Kanbak G, Sunal E. Antioxidant enzyme activities and malondialdehyde levels related to aging. Clin Chim Acta. 2001;305:75–80.

    PubMed  CAS  Google Scholar 

  43. van der Loo B, Bachschmid M, Spitzer V, Brey L, Ullrich V, Luscher TF. Decreased plasma and tissue levels of vitamin C in a rat model of aging: implications for antioxidative defense. Biochem Biophys Res Commun. 2003;303:483–7.

    PubMed  Google Scholar 

  44. Starke-Reed PE, Oliver CN. Protein oxidation and proteolysis during aging and oxidative stress. Arch Biochem Biophys. 1989;275:559–67.

    PubMed  CAS  Google Scholar 

  45. Stadtman ER. Protein oxidation and aging. Science. 1992;257:1220–4.

    PubMed  CAS  Google Scholar 

  46. Choi JH, Yu BP. Brain synaptosomal aging: free radicals and membrane fluidity. Free Radic Biol Med. 1995;18:133–9.

    PubMed  CAS  Google Scholar 

  47. Ames BN, Shigenaga MK. Oxidants are major contributors to cancer and aging. In: Halliwell B, Aruoma OI, editors. DNA and free radicals. New York: Ellis Horwood; 1993. p. 1–15.

    Google Scholar 

  48. Pérez VI, Bokov A, Van Remmen H, Mele J, Ran Q, Ikeno Y, Richardson A. Is the oxidative stress theory of aging dead? Biochim Biophys Acta. 2009;1790:1005–14.

    PubMed  Google Scholar 

  49. Jang YC, Remmen VH. The mitochondrial theory of aging: insight from transgenic and knockout mouse models. Exp Gerontol. 2009;44:256–60.

    PubMed  CAS  Google Scholar 

  50. Crow JF. The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet. 2000;1:40–7.

    PubMed  CAS  Google Scholar 

  51. Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril. 2001;75:237–48.

    PubMed  CAS  Google Scholar 

  52. Wyrobek AJ, Eskenazi B, Young S, Arnheim N, Tiemann-Boege I, Jabs EW, Glaser RL, Pearson FS, Evenson D. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc Natl Acad Sci USA. 2006;103:9601–6.

    PubMed  CAS  Google Scholar 

  53. Robaire B, Oakes C, Zubkova EV. Effects of aging on spermatogenesis and sperm function. In: Kandeel FR, Swerdloff RS, Pryor JL, editors. Male reproductive dysfunction, pathophysiology and treatment. New York: Informa Healthcare USA, Inc.; 2007. p. 101–11.

    Google Scholar 

  54. de La Rochebrochard E, de Mouzon J, Thepot F, Thonneau P. Fathers over 40 and increased failure to conceive: the lessons of in vitro fertilization in France. Fertil Steril. 2006;85:1420–4.

    Google Scholar 

  55. de La Rochebrochard E, McElreavey K, Thonneau P. Paternal age over 40 years: the “amber light” in the reproductive life of men? J Androl. 2003;24:459–65.

    Google Scholar 

  56. de La Rochebrochard E, Thonneau P. Paternal age >or=40 years: an important risk factor for infertility. Am J Obstet Gynecol. 2003;189:901–5.

    Google Scholar 

  57. Kleinhaus K, Perrin M, Friedlander Y, Paltiel O, Malaspina D, Harlap S. Paternal age and spontaneous abortion. Obstet Gynecol. 2006;108:369–77.

    PubMed  CAS  Google Scholar 

  58. Yoon SR, Qin J, Glaser RL, Jabs EW, Wexler NS, Sokol R, Arnheim N, Calabrese P. The ups and downs of mutation frequencies during aging can account for the Apert syndrome paternal age effect. PLoS Genet. 2009;5:e1000558.

    PubMed  Google Scholar 

  59. Rolf C, Nieschlag E. Reproductive functions, fertility and genetic risks of ageing men. Exp Clin Endocrinol Diabetes. 2001;109:68–74.

    PubMed  CAS  Google Scholar 

  60. Dalman C, Allebeck P. Paternal age and schizophrenia: further support for an association. Am J Psychiatry. 2002;159:1591–2.

    PubMed  Google Scholar 

  61. Bertram L, Busch R, Spiegl M, Lautenschlager NT, Muller U, Kurz A. Paternal age is a risk factor for Alzheimer disease in the absence of a major gene. Neurogenetics. 1998;1:277–80.

    PubMed  CAS  Google Scholar 

  62. Tsuchiya KJ, Matsumoto K, Miyachi T, Tsujii M, Nakamura K, Takagai S, Kawai M, Yagi A, Iwaki K, Suda S, Sugihara G, Iwata Y, Matsuzaki H, Sekine Y, Suzuki K, Sugiyama T, Mori N, Takei N. Paternal age at birth and high-functioning autistic-spectrum disorder in offspring. Br J Psychiatry. 2008;193:316–21.

    PubMed  Google Scholar 

  63. Yang Q, Wen SW, Leader A, Chen XK, Lipson J, Walker M. Paternal age and birth defects: how strong is the association? Hum Reprod. 2007;22:696–701.

    PubMed  CAS  Google Scholar 

  64. Walter CA, Intano GW, McMahan CA, Kelner K, McCarrey JR, Walter RB. Mutation spectral changes in spermatogenic cells obtained from old mice. DNA Repair (Amst). 2004;3:495–504.

    CAS  Google Scholar 

  65. Zubkova EV, Robaire B. Effects of ageing on spermatozoal chromatin and its sensitivity to in vivo and in vitro oxidative challenge in the Brown Norway rat. Hum Reprod. 2006;21:2901–10.

    PubMed  CAS  Google Scholar 

  66. Zakhidov ST, Gopko AV, Marshak TL, Kulibin AY, Zelenina IA. Analysis of spermatogenesis in senescence-accelerated mice. Biol Bull. 2007;34:551–7.

    Google Scholar 

  67. Takahashi Y, Kuro-O M, Ishikawa F. Aging mechanisms. Proc Natl Acad Sci USA. 2000;97:12407–8.

    PubMed  CAS  Google Scholar 

  68. Chiba T, Yao J, Higami Y, Shimokawa I, Hosokawa M, Higuchi K. Identification of differentially expressed genes in senescence-accelerated mouse testes by suppression subtractive hybridization analysis. Mamm Genome. 2007;18:105–12.

    PubMed  CAS  Google Scholar 

  69. Nagai R, Saito Y, Ohyama Y, Aizawa H, Suga T, Nakamura T, Kurabayashi M, Kuroo M. Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases. Cell Mol Life Sci. 2000;57:738–46.

    PubMed  CAS  Google Scholar 

  70. Tanemura K, Kurohmaru M, Kuramoto K, Hayashi Y. Age-related morphological changes in the testis of the BDF1 mouse. J Vet Med Sci. 1993;55:703–10.

    PubMed  CAS  Google Scholar 

  71. Walter CA, Intano GW, McCarrey JR, McMahan CA, Walter RB. Mutation frequency declines during spermatogenesis in young mice but increases in old mice. Proc Natl Acad Sci USA. 1998;95:10015–9.

    PubMed  CAS  Google Scholar 

  72. Wright WW, Fiore C, Zirkin BR. The effects of aging in the seminiferous epithelium of the Brown Norway rat. J Androl. 1993;14:110–7.

    PubMed  CAS  Google Scholar 

  73. Wang C, Leung A, Sinha-Hikim A. Reproductive aging in the male Brown-Norway rat: a model for the human. Endocrinology. 1993;133:2773–81.

    PubMed  CAS  Google Scholar 

  74. Chen H, Hardy MP, Huhtaniemi I, Zirkin BR. Age-related decreased Leydig cell testosterone production in the Brown Norway rat. J Androl. 1994;15:551–7.

    PubMed  CAS  Google Scholar 

  75. Robaire B, Syntin P, Jervis K. The coming of age of the epididymis. In: Jegou B et al., editors. Testis, epididymis and technologies in the year 2000. New York: Springer; 2000. p. 229–62.

    Google Scholar 

  76. Zirkin BR, Santulli R, Strandberg JD, Wright WW, Ewing LL. Testicular steroidogenesis in the aging Brown Norway rat. J Androl. 1993;14:118–23.

    PubMed  CAS  Google Scholar 

  77. Zirkin BR, Chen H. Regulation of Leydig cell steroidogenic function during aging. Biol Reprod. 2000;63:977–81.

    PubMed  CAS  Google Scholar 

  78. Paul C, Nagano M, Robaire B. Aging results in differential regulation of DNA repair pathways in pachytene spermatocytes in the Brown Norway rat. Biol Reprod. 2011;85(6):1269–78.

    PubMed  CAS  Google Scholar 

  79. Levy S, Serre V, Hermo L, Robaire B. The effects of aging on the seminiferous epithelium and the blood-testis barrier of the Brown Norway rat. J Androl. 1999;20:356–65.

    PubMed  CAS  Google Scholar 

  80. Neaves WB, Johnson L, Petty CS. Seminiferous tubules and daily sperm production in older adult with varied numbers of Leydig cells. Biol Reprod. 1987;36:301–8.

    PubMed  CAS  Google Scholar 

  81. Vermeulen A. Andropause. Maturitas. 2000;34:5–15.

    PubMed  CAS  Google Scholar 

  82. Serre V, Robaire B. Segment specific morphological changes in the aging Brown Norway rat epididymis. Biol Reprod. 1998;58:497–513.

    PubMed  CAS  Google Scholar 

  83. Jervis KM, Robaire B. Changes in gene expression during aging in the Brown Norway rat epididymis. Exp Gerontol. 2002;37:897–906.

    PubMed  CAS  Google Scholar 

  84. Serre V, Robaire B. Paternal age affects fertility and progeny outcome in the Brown Norway rat. Fertil Steril. 1998;70:625–31.

    PubMed  CAS  Google Scholar 

  85. Syntin B, Robaire B. Sperm motility and structural changes during aging in the Brown Norway rat. J Androl. 2001;22:235–44.

    PubMed  CAS  Google Scholar 

  86. 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;28:229–40.

    PubMed  CAS  Google Scholar 

  87. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.

    Google Scholar 

  88. Rubin H. The disparity between human cell senescence in vitro and lifelong replication in vivo. Nat Biotechnol. 2002;20:675–81.

    PubMed  CAS  Google Scholar 

  89. Crow JF, Johnson TE. Research on environmental effects in genetic studies of aging: comments. J Gerontol B Psychol Sci Soc Sci. 2005;60(1):7–11.

    PubMed  Google Scholar 

  90. Schmidt JA, Abramowitz LK, Kubota H, Wu X, Niu Z, Avarbock MR, Tobias JW, Bartolomei MS, Brinster RL. In vivo and in vitro aging is detrimental to mouse spermatogonial stem cell function. Biol Reprod. 2011;84:698–706.

    PubMed  CAS  Google Scholar 

  91. Ryu BY, Orwig KE, Oatley JM, Avarbock MR, Brinster RL. Effects of aging and niche microenvironment on spermatogonial stem cell self-renewal. Stem Cells. 2006;24:1505–11.

    PubMed  CAS  Google Scholar 

  92. Zhang X, Ebata KT, Robaire B, Nagano MC. Aging of male germ line stem cells in mice. Biol Reprod. 2006;74:119–24.

    PubMed  CAS  Google Scholar 

  93. Ehmcke J, Joshi B, Hergenrother SD, Schlatt S. Aging does not affect spermatogenic ­recovery after experimentally induced injury in mice. Reproduction. 2007;133:75–83.

    PubMed  CAS  Google Scholar 

  94. Aitken RJ, Baker MA, De Iuliis GN, Nixon B. New insights into sperm physiology and pathology. Handb Exp Pharmacol. 2010;198:99–115.

    PubMed  CAS  Google Scholar 

  95. Koppers AJ, De Iuliis GN, Finnie JM, McLaughlin EA, Aitken RJ. Significance of mitochondrial reactive oxygen species in the generation of oxidative stress in spermatozoa. J Clin Endocrinol Metab. 2008;93:3199–207.

    PubMed  CAS  Google Scholar 

  96. O’Flaherty C, de Lamirande E, Gagnon C. Reactive oxygen species modulate independent protein phosphorylation pathways during human sperm capacitation. Free Radic Biol Med. 2006;40:1045–55.

    PubMed  Google Scholar 

  97. Brasnjevic I, Hof PR, Steinbusch HW, Schmitz C. Accumulation of nuclear DNA damage or neuron loss: molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases. DNA Repair (Amst). 2008;7:1087–97.

    CAS  Google Scholar 

  98. Moller P, Lohr M, Folkmann JK, Mikkelsen L, Loft S. Aging and oxidatively damaged nuclear DNA in animal organs. Free Radic Biol Med. 2010;48:1275–85.

    PubMed  CAS  Google Scholar 

  99. Essers J, Vermeulen W, Houtsmuller AB. DNA damage repair: anytime, anywhere? Curr Opin Cell Biol. 2006;18:240–6.

    PubMed  CAS  Google Scholar 

  100. Clermont Y. Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonial renewal. Physiol Rev. 1972;52:198–236.

    PubMed  CAS  Google Scholar 

  101. Agarwal A, Makker K, Sharma R. Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol. 2008;59:2–11.

    PubMed  CAS  Google Scholar 

  102. Gharagozloo P, Aitken RJ. The role of sperm oxidative stress in male infertility and the ­significance of oral antioxidant therapy. Hum Reprod. 2011;26:1628–40.

    PubMed  Google Scholar 

  103. Hsu GW, Ober M, Carell T, Beese LS. Error-prone replication of oxidatively damaged DNA by a high-fidelity DNA polymerase. Nature. 2004;431:217–21.

    PubMed  CAS  Google Scholar 

  104. Neeley WL, Essigmann JM. Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products. Chem Res Toxicol. 2006;19:491–505.

    PubMed  CAS  Google Scholar 

  105. Muller FL, Liu Y, Van Remmen H. Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem. 2004;279:49064–73.

    PubMed  CAS  Google Scholar 

  106. Larsson NG. Somatic mitochondrial DNA mutations in mammalian aging. Annu Rev Biochem. 2010;79:683–706.

    PubMed  CAS  Google Scholar 

  107. Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Simerly C, Schatten G. Ubiquitin tag for sperm mitochondria. Nature. 1999;402:371–2.

    PubMed  CAS  Google Scholar 

  108. Wai T, Ao A, Zhang X, Cyr D, Dufort D, Shoubridge EA. The role of mitochondrial DNA copy number in mammalian fertility. Biol Reprod. 2010;83:52–62.

    PubMed  CAS  Google Scholar 

  109. Intano GW, McMahan CA, Walter RB, McCarrey JR, Walter CA. Mixed spermatogenic germ cell nuclear extracts exhibit high base excision repair activity. Nucleic Acids Res. 2001;29:1366–72.

    PubMed  CAS  Google Scholar 

  110. Christmann M, Tomicic MT, Roos WP, Kaina B. Mechanisms of human DNA repair: an update. Toxicology. 2003;193:3–34.

    PubMed  CAS  Google Scholar 

  111. Aitken RJ, Gordon E, Harkiss D, Twigg JP, Milne P, Jennings Z, Irvine DS. Relative impact of oxidative stress on the functional competence and genomic integrity of human spermatozoa. Biol Reprod. 1998;59:1037–46.

    PubMed  CAS  Google Scholar 

  112. Meseguer M, Martinez-Conejero JA, O’Connor JE, Pellicer A, Remohi J, Garrido N. The significance of sperm DNA oxidation in embryo development and reproductive outcome in an oocyte donation program: a new model to study a male infertility prognostic factor. Fertil Steril. 2008;89:1191–9.

    PubMed  Google Scholar 

  113. Zenzes MT. Smoking and reproduction: gene damage to human gametes and embryos. Hum Reprod Update. 2000;6:122–31.

    PubMed  CAS  Google Scholar 

  114. Schmid TE, Eskenazi B, Baumgartner A, Marchetti F, Young S, Weldon R, Anderson D, Wyrobek AJ. The effects of male age on sperm DNA damage in healthy non-smokers. Hum Reprod. 2007;22:180–7.

    PubMed  CAS  Google Scholar 

  115. Sloter ED, Marchetti F, Eskenazi B, Weldon RH, Nath J, Cabreros D, Wyrobek AJ. Frequency of human sperm carrying structural aberrations of chromosome 1 increases with advancing age. Fertil Steril. 2007;87:1077–86.

    PubMed  Google Scholar 

  116. Sloter E, Nath J, Eskenazi B, Wyrobek AJ. Effects of male age on the frequencies of germinal and heritable chromosomal abnormalities in humans and rodents. Fertil Steril. 2004;81:925–43.

    PubMed  Google Scholar 

  117. Lowe X, Collins B, Allen J, Titenko-Holland N, Breneman J, van Beek M, Bishop J, Wyrobek AJ. Aneuploidies and micronuclei in the germ cells of male mice of advanced age. Mutat Res. 1995;338:59–76.

    PubMed  CAS  Google Scholar 

  118. Xiao Y, Tates AD, Boei J, Natarajan AT. Aging and diethylstilbestrol-induced aneuploidy in male germ cells: a transgenic mouse model. Chromosoma. 1998;107:507–13.

    PubMed  CAS  Google Scholar 

  119. Allen JW, Collins BW, Setzer RW. Spermatid micronucleus analysis of aging effects in hamsters. Mutat Res. 1996;316:261–6.

    PubMed  CAS  Google Scholar 

  120. Miething A. Arrested germ cell divisions in the ageing human testis. Andrologia. 2005;37:10–6.

    PubMed  CAS  Google Scholar 

  121. Hecht NB. Molecular mechanisms of male germ cell differentiation. Bioessays. 1998;20:555–61.

    PubMed  CAS  Google Scholar 

  122. Cabelof DC, Raffoul JJ, Yanamadala S, Ganir C, Guo Z, Heydari AR. Attenuation of DNA polymerase beta-dependent base excision repair and increased DMS-induced mutagenicity in aged mice. Mutat Res. 2002;500:135–45.

    PubMed  CAS  Google Scholar 

  123. El-Domyati MM, Al-Din AB, Barakat MT, El-Fakahany HM, Xu J, Sakkas D. Deoxyribonucleic acid repair and apoptosis in testicular germ cells of aging fertile men: the role of the poly(adenosine diphosphate-ribosyl)ation pathway. Fertil Steril. 2009;91:2221–9.

    PubMed  CAS  Google Scholar 

  124. Gredilla R, Garm C, Holm R, Bohr VA, Stevnsner T. Differential age-related changes in mitochondrial DNA repair activities in mouse brain regions. Neurobiol Aging. 2008;31:993–1002.

    PubMed  Google Scholar 

  125. de Souza-Pinto NC, Hogue BA, Bohr VA. DNA repair and aging in mouse liver: 8-oxodG glycosylase activity increase in mitochondrial but not in nuclear extracts. Free Radic Biol Med. 2001;30:916–23.

    PubMed  Google Scholar 

  126. Ren K, Pena de Ortiz S. Non-homologous DNA end joining in the mature rat brain. J Neurochem. 2002;80:949–59.

    PubMed  CAS  Google Scholar 

  127. Vyjayanti VN, Rao KS. DNA double strand break repair in brain: reduced NHEJ activity in aging rat neurons. Neurosci Lett. 2006;393:18–22.

    PubMed  CAS  Google Scholar 

  128. Um JH, Kim SJ, Kim DW, Ha MY, Jang JH, Chung BS, Kang CD, Kim SH. Tissue-specific changes of DNA repair protein Ku and mtHSP70 in aging rats and their retardation by caloric restriction. Mech Ageing Dev. 2003;124:967–75.

    PubMed  CAS  Google Scholar 

  129. Zawia NH, Lahiri DK, Cardozo-Pelaez F. Epigenetics, oxidative stress, and Alzheimer disease. Free Radic Biol Med. 2009;46:1241–9.

    PubMed  CAS  Google Scholar 

  130. Richardson B. Impact of aging on DNA methylation. Ageing Res Rev. 2003;2:245–61.

    PubMed  CAS  Google Scholar 

  131. Oakes CC, Smiraglia DJ, Plass C, Trasler JM, Robaire B. Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats. Proc Natl Acad Sci USA. 2003;100:1775–80.

    PubMed  CAS  Google Scholar 

  132. Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, Zhang J, Zhang N, Liang S, Donehower LA, Issa JP. Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res. 2010;20:332–40.

    PubMed  CAS  Google Scholar 

  133. Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, Beyan H, Whittaker P, McCann OT, Finer S, Valdes AM, Leslie RD, Deloukas P, Spector TD. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res. 2010;20:434–9.

    PubMed  CAS  Google Scholar 

  134. Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, Shen H, Campan M, Noushmehr H, Bell CG, Maxwell AP, Savage DA, Mueller-Holzner E, Marth C, Kocjan G, Gayther SA, Jones A, Beck S, Wagner W, Laird PW, Jacobs IJ, Widschwendter M. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 2010;20:440–6.

    PubMed  CAS  Google Scholar 

  135. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, Weissman IL. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA. 2005;102:9194–9.

    PubMed  CAS  Google Scholar 

  136. Cheng J, Türkel N, Hemati N, Fuller MT, Hunt AJ, Yamashita YM. Centrosome misorientation reduces stem cell division during ageing. Nature. 2008;456:599–604.

    PubMed  CAS  Google Scholar 

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Correspondence to Bernard Robaire PhD .

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Robaire, B., Paul, C., Selvaratnam, J. (2012). Age and Oxidative Stress in the Germ Line. In: Agarwal, A., Aitken, R., Alvarez, J. (eds) Studies on Men's Health and Fertility. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press. https://doi.org/10.1007/978-1-61779-776-7_7

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