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Ageing of the male germ line

Nature Reviews Urology volume 10, pages 227–234 (2013)Cite this article

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Abstract

Several studies have demonstrated a decline in the male reproductive system, sperm quality, and fertility with advancing paternal age, yet many of the biological mechanisms that underlie this process remain poorly understood. It is unclear whether the problem arises from the progenitor spermatogonial stem cells (for example, from an accumulation of DNA damage and mutations), from the somatic niche present in the testis (consisting of Sertoli and peritubular myoid cells), or from a combination of the two. Current data, albeit from a small number of studies, suggest that both factors have a role in age-associated germ cell loss. What is clear, on the other hand, is that mounting evidence links paternal age to chromosomal damage and genetic problems in the children of older fathers. The frequency of de novo mutations increases markedly with age, leading to increased risk of breast cancer, cardiac defects, developmental disorders, behavioural disorders, and neurological disease in the children of older men. The current trend towards fathering children at a later age raises concerns regarding the risk of offspring developing complex multigene diseases.

Key Points

  • Male reproductive function declines with age, as evidenced by decreased sperm quality and increased time to pregnancy

  • The quality and quantity of spermatogonial stem cells seems to decline with age, undoubtedly affecting the quality of germ cells and, ultimately, sperm

  • Alterations in DNA repair pathways in the ageing male occur concomitantly with observations of increased DNA damage in germ cells and mature sperm

  • Ageing males display increased rates of de novo mutations, which are linked to an increased risk of diseases such as autism and schizophrenia in offspring

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Figure 1: Schematic representation to depict the role of SSCs and the supporting niche in testis ageing within different scenarios.
Figure 2: Schematic representation of the effect of ageing on male germ cells.

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References

  1. Wright, W. W., Fiore, C. & Zirkin, B. R. The effect of aging on the seminiferous epithelium of the brown Norway rat. J. Androl. 14, 110–117 (1993).

    CAS  PubMed  Google Scholar 

  2. Wang, C. et al. Reproductive aging in the Brown Norway rat is characterized by accelerated germ cell apoptosis and is not altered by luteinizing hormone replacement. J. Androl. 20, 509–518 (1999).

    CAS  PubMed  Google Scholar 

  3. Molina, R. I. et al. Semen quality and aging: analysis of 9,168 samples in Cordoba, Argentina. Arch. Esp. Urol. 63, 214–222 (2010).

    Article  PubMed  Google Scholar 

  4. Cardona Maya, W., Berdugo, J. & Cadavid Jaramillo, A. The effects of male age on semen parameters: analysis of 1,364 men attending an andrology center. Aging Male 12, 100–103 (2009).

    Article  PubMed  Google Scholar 

  5. Kidd, S. A., Eskenazi, B. & Wyrobek, A. J. Effects of male age on semen quality and fertility: a review of the literature. Fertil. Steril. 75, 237–248 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Syntin, P. & Robaire, B. Sperm structural and motility changes during aging in the Brown Norway rat. J. Androl 22, 235–244 (2001).

    CAS  PubMed  Google Scholar 

  7. 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. 85, 1420–1424 (2006).

    Article  PubMed  Google Scholar 

  8. de La Rochebrochard, E., McElreavey, K. & Thonneau, P. Paternal age over 40 years: the “amber light” in the reproductive life of men? J. Androl 24, 459–465 (2003).

    Article  PubMed  Google Scholar 

  9. Ford, W. C. et al. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. The ALSPAC Study Team (Avon Longitudinal Study of Pregnancy and Childhood). Hum. Reprod. 15, 1703–1708 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Hassan, M. A. & Killick, S. R. Effect of male age on fertility: evidence for the decline in male fertility with increasing age. Fertil. Steril. 79, (Suppl. 3), 1520–1527 (2003).

    Article  PubMed  Google Scholar 

  11. Klonoff-Cohen, H. S. & Natarajan, L. The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer. Am. J. Obstet. Gynecol. 191, 507–514 (2004).

    Article  PubMed  Google Scholar 

  12. Thacker, P. D. Biological clock ticks for men too: genetic defects linked to sperm of older fathers. JAMA 291, 1683–1685 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Sloter, E. D. et al. Frequency of human sperm carrying structural aberrations of chromosome 1 increases with advancing age. Fertil. Steril. 87, 1077–1086 (2007).

    Article  PubMed  Google Scholar 

  14. Hultman, C. M. et al. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol. Psychiatry 16, 1203–1212 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Sipos, A. et al. Paternal age and schizophrenia: a population based cohort study. BMJ 329, 1070 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Clermont, Y. The cycle of the seminiferous epithelium in man. Am. J. Anat. 112, 35–51 (1963).

    Article  CAS  PubMed  Google Scholar 

  17. Johnson, L. Spermatogenesis and aging in the human. J. Androl. 7, 331–354 (1986).

    Article  CAS  PubMed  Google Scholar 

  18. Gosden, R. G., Richardson, D. W., Brown, N. & Davidson, D. W. Structure and gametogenic potential of seminiferous tubules in ageing mice. J. Reprod. Fertil. 64, 127–133 (1982).

    Article  CAS  PubMed  Google Scholar 

  19. Wang, C., Leung, A. & Sinha-Hikim, A. P. Reproductive aging in the male brown-Norway rat: a model for the human. Endocrinology 133, 2773–2781 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Ryu, B. Y., Orwig, K. E., Oatley, J. M., Avarbock, M. R. & Brinster, R. L. Effects of aging and niche microenvironment on spermatogonial stem cell self-renewal. Stem Cells 24, 1505–1511 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Paniagua, R., Nistal, M., Saez, F. J. & Fraile, B. Ultrastructure of the aging human testis. J. Electron Microsc. Tech. 19, 241–260 (1991).

    Article  CAS  PubMed  Google Scholar 

  22. Chen, H., Hardy, M. P., Huhtaniemi, I. & Zirkin, B. R. Age-related decreased Leydig cell testosterone production in the brown Norway rat. J. Androl. 15, 551–557 (1994).

    CAS  PubMed  Google Scholar 

  23. Suzuki, N. & Withers, H. R. Exponential decrease during aging and random lifetime of mouse spermatogonial stem cells. Science 202, 1214–1215 (1978).

    Article  CAS  PubMed  Google Scholar 

  24. Zhang, X., Ebata, K. T., Robaire, B. & Nagano, M. C. Aging of male germ line stem cells in mice. Biol. Reprod. 74, 119–124 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Ehmcke, J., Joshi, B., Hergenrother, S. D. & Schlatt, S. Aging does not affect spermatogenic recovery after experimentally induced injury in mice. Reproduction 133, 75–83 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Boyle, M., Wong, C., Rocha, M. & Jones, D. L. Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 1, 470–478 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Richardson, B. Impact of aging on DNA methylation. Ageing Res. Rev. 2, 245–261 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Oakes, C. C., Smiraglia, D. J., Plass, C., Trasler, J. M. & Robaire, B. Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats. Proc. Natl Acad. Sci. USA 100, 1775–1780 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Maegawa, S. et al. Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res. 20, 332–340 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rakyan, V. K. et al. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res. 20, 434–439 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Teschendorff, A. E. et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 20, 440–446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rossi, D. J. et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl Acad. Sci. USA 102, 9194–9199 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gil, J. & Peters, G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat. Rev. Mol. Cell Biol. 7, 667–677 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Quelle, D. E., Zindy, F., Ashmun, R. A. & Sherr, C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83, 993–1000 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Matheu, A. et al. Anti-aging activity of the Ink4/Arf locus. Aging Cell 8, 152–161 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Molofsky, A. V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Baarends, W. M., van der Laan, R. & Grootegoed, J. A. DNA repair mechanisms and gametogenesis. Reproduction 121, 31–39 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Fisher, H. M. & Aitken, R. J. Comparative analysis of the ability of precursor germ cells and epididymal spermatozoa to generate reactive oxygen metabolites. J. Exp. Zool. 277, 390–400 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Bauche, F., Fouchard, M. & Jegou, B. Antioxidant system in rat testicular cells. FEBS Lett. 349, 392–396 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Wood, R. D., Mitchell, M. & Lindahl, T. Human DNA repair genes, 2005. Mutat. Res. 577, 275–283 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Jaroudi, S. & SenGupta, S. DNA repair in mammalian embryos. Mutat. Res. 635, 53–77 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Schmid, T. E. et al. The effects of male age on sperm DNA damage in healthy non-smokers. Hum. Reprod. 22, 180–187 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Singh, N. P., Muller, C. H. & Berger, R. E. Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertil. Steril. 80, 1420–1430 (2003).

    Article  PubMed  Google Scholar 

  45. Vazquez-Memije, M. E., Capin, R., Tolosa, A. & El-Hafidi, M. Analysis of age-associated changes in mitochondrial free radical generation by rat testis. Mol. Cell Biochem. 307, 23–30 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Weir, C. P. & Robaire, B. Spermatozoa have decreased antioxidant enzymatic capacity and increased reactive oxygen species production during aging in the Brown Norway rat. J. Androl. 28, 229–240 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. de Lamirande, E. & Gagnon, C. A positive role for the superoxide anion in triggering hyperactivation and capacitation of human spermatozoa. Int. J. Androl 16, 21–25 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. Aitken, R. J., Harkiss, D., Knox, W., Paterson, M. & Irvine, D. S. A novel signal transduction cascade in capacitating human spermatozoa characterised by a redox-regulated, cAMP-mediated induction of tyrosine phosphorylation. J. Cell Sci. 111 (Pt 5), 645–656 (1998).

    CAS  PubMed  Google Scholar 

  49. Aitken, R. J. & Clarkson, J. S. Cellular basis of defective sperm function and its association with the genesis of reactive oxygen species by human spermatozoa. J. Reprod. Fertil. 81, 459–469 (1987).

    Article  CAS  PubMed  Google Scholar 

  50. Aitken, R. J. et al. Relative impact of oxidative stress on the functional competence and genomic integrity of human spermatozoa. Biol. Reprod. 59, 1037–1046 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Gomez, E. et al. Development of an image analysis system to monitor the retention of residual cytoplasm by human spermatozoa: correlation with biochemical markers of the cytoplasmic space, oxidative stress, and sperm function. J. Androl. 17, 276–287 (1996).

    CAS  PubMed  Google Scholar 

  52. Zubkova, E. V. & 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. 21, 2901–2910 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Wyrobek, A. J. et al. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc. Natl Acad. Sci. USA 103, 9601–9606 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Brahem, S., Mehdi, M., Elghezal, H. & Saad, A. The effects of male aging on semen quality, sperm DNA fragmentation and chromosomal abnormalities in an infertile population. J. Assist. Reprod. Genet. 28, 425–432 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Winkle, T., Rosenbusch, B., Gagsteiger, F., Paiss, T. & Zoller, N. The correlation between male age, sperm quality and sperm DNA fragmentation in 320 men attending a fertility center. J. Assist Reprod. Genet. 26, 41–46 (2009).

    Article  PubMed  Google Scholar 

  56. Walter, C. A., Intano, G. W., McCarrey, J. R., McMahan, C. A. & Walter, R. B. Mutation frequency declines during spermatogenesis in young mice but increases in old mice. Proc. Natl Acad. Sci. USA 95, 10015–10019 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lowe, X. et al. Aneuploidies and micronuclei in the germ cells of male mice of advanced age. Mutat. Res. 338, 59–76 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Xiao, Y., Tates, A. D., Boei, J. & Natarajan, A. T. Aging and diethylstilbestrol-induced aneuploidy in male germ cells: a transgenic mouse model. Chromosoma 107, 507–513 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Miething, A. Arrested germ cell divisions in the ageing human testis. Andrologia 37, 10–16 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Allen, J. W., Collins, B. W. & Setzer, R. W. Spermatid micronucleus analysis of aging effects in hamsters. Mutat. Res. 316, 261–266 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Cabelof, D. C. et al. Attenuation of DNA polymerase beta-dependent base excision repair and increased DMS-induced mutagenicity in aged mice. Mutat. Res. 500, 135–145 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Intano, G. W. et al. Base excision repair is limited by different proteins in male germ cell nuclear extracts prepared from young and old mice. Mol. Cell Biol. 22, 2410–2418 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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. 85, 1269–1278 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. El-Domyati, M. M. et al. 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. 91, 2221–2229 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Ren, K. & Pena de Ortiz, S. Non-homologous DNA end joining in the mature rat brain. J. Neurochem. 80, 949–959 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Vyjayanti, V. N. & Rao, K. S. DNA double strand break repair in brain: reduced NHEJ activity in aging rat neurons. Neurosci. Lett. 393, 18–22 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Um, J. H. et al. Tissue-specific changes of DNA repair protein Ku and mtHSP70 in aging rats and their retardation by caloric restriction. Mech. Ageing Dev. 124, 967–975 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Zheng, P., Schramm, R. D. & Latham, K. E. Developmental regulation and in vitro culture effects on expression of DNA repair and cell cycle checkpoint control genes in rhesus monkey oocytes and embryos. Biol. Reprod. 72, 1359–1369 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Twigg, J. P., Irvine, D. S. & Aitken, R. J. Oxidative damage to DNA in human spermatozoa does not preclude pronucleus formation at intracytoplasmic sperm injection. Hum. Reprod. 13, 1864–1871 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Nasr-Esfahani, M. H. et al. Effect of sperm DNA damage and sperm protamine deficiency on fertilization and embryo development post-ICSI. Reprod. Biomed. Online 11, 198–205 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Dimitriadis, F. et al. Effects of primary testicular damage on sperm DNA oxidative status and embryonic and foetal development. Andrologia 41, 282–296 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Fernandez-Gonzalez, R. et al. Long-term effects of mouse intracytoplasmic sperm injection with DNA-fragmented sperm on health and behavior of adult offspring. Biol. Reprod. 78, 761–772 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Garcia-Palomares, S. et al. Long-term effects of delayed fatherhood in mice on postnatal development and behavioral traits of offspring. Biol. Reprod. 80, 337–342 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. de La Rochebrochard, E. & Thonneau, P. Paternal age >or=40 years: an important risk factor for infertility. Am. J. Obstet. Gynecol. 189, 901–905 (2003).

    Article  PubMed  Google Scholar 

  75. Kleinhaus, K. et al. Paternal age and spontaneous abortion. Obstet. Gynecol. 108, 369–377 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Astolfi, P., De Pasquale, A. & Zonta, L. A. Late paternity and stillbirth risk. Hum. Reprod. 19, 2497–2501 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Martin, J. A. et al. Births: final data for 2009. Natl Vital Stat. Rep. 60, 1–70 (2011).

    PubMed  Google Scholar 

  78. Gosden, R. G., Trasler, J., Lucifero, D. & Faddy, M. J. Rare congenital disorders, imprinted genes and assisted reproductive technology. Lancet 361, 1975–1977 (2003).

    Article  PubMed  Google Scholar 

  79. Frattarelli, J. L., Miller, K. A., Miller, B. T., Elkind-Hirsch, K. & Scott, R. T. Jr. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles. Fertil. Steril. 90, 93–103 (2007).

    Google Scholar 

  80. Borini, A. et al. Sperm DNA fragmentation: paternal effect on early post-implantation embryo development in ART. Hum. Reprod. 21, 2876–2881 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Serre, V. & Robaire, B. Paternal age affects fertility and progeny outcome in the Brown Norway rat. Fertil. Steril. 70, 625–631 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Crow, J. Spontaneous mutation as a risk factor. Exp. Clin. Immunogenet. 12, 121–128 (1995).

    CAS  PubMed  Google Scholar 

  83. Crow, J. F. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1, 40–47 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Goriely, A. & Wilkie, A. O. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am. J. Hum. Genet. 90, 175–200 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hemminki, K. & Kyyronen, P. Parental age and risk of sporadic and familial cancer in offspring: implications for germ cell mutagenesis. Epidemiology 10, 747–751 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Hemminki, K., Kyyronen, P. & Vaittinen, P. Parental age as a risk factor of childhood leukemia and brain cancer in offspring. Epidemiology 10, 271–275 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Tolarova, M. M., Harris, J. A., Ordway, D. E. & Vargervik, K. Birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity in Apert syndrome. Am. J. Med. Genet. 72, 394–398 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Rolf, C. & Nieschlag, E. Reproductive functions, fertility and genetic risks of ageing men. Exp. Clin. Endocrinol. Diabetes 109, 68–74 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Toriello, H. V. & Meck, J. M. Statement on guidance for genetic counseling in advanced paternal age. Genet. Med. 10, 457–460 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Penrose, L. S. Parental age and mutation. Lancet 269, 312–313 (1955).

    Article  CAS  PubMed  Google Scholar 

  91. Frans, E. M. et al. Advancing paternal age and bipolar disorder. Arch. Gen. Psychiatry 65, 1034–1040 (2008).

    Article  PubMed  Google Scholar 

  92. Grigoroiu-Serbanescu, M. et al. Paternal age effect on age of onset in bipolar I disorder is mediated by sex and family history. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 159, 567–579 (2012).

    Article  Google Scholar 

  93. Flatscher-Bader, T. et al. Increased de novo copy number variants in the offspring of older males. Transl. Psychiatry 1, e34 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Dalman, C. & Allebeck, P. Paternal age and schizophrenia: further support for an association. Am. J. Psychiatry 159, 1591–1592 (2002).

    Article  PubMed  Google Scholar 

  96. Bertram, L. et al. Paternal age is a risk factor for Alzheimer disease in the absence of a major gene. Neurogenetics 1, 277–280 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Olshan, A. F., Schnitzer, P. G. & Baird, P. A. Paternal age and the risk of congenital heart defects. Teratology 50, 80–84 (1994).

    Article  CAS  PubMed  Google Scholar 

  98. Green, R. F. et al. Association of paternal age and risk for major congenital anomalies from the National Birth Defects Prevention Study, 1997 to 2004. Ann. Epidemiol. 20, 241–249 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Smith, R. G. et al. Advancing paternal age is associated with deficits in social and exploratory behaviors in the offspring: a mouse model. PLoS One 4, e8456 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Foldi, C. J., Eyles, D. W., McGrath, J. J. & Burne, T. H. Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice. Eur. J. Neurosci. 31, 556–564 (2010).

    Article  PubMed  Google Scholar 

  101. Saha, S., Barnett, A. G., Buka, S. L. & McGrath, J. J. Maternal age and paternal age are associated with distinct childhood behavioural outcomes in a general population birth cohort. Schizophr. Res. 115, 130–135 (2009).

    Article  PubMed  Google Scholar 

  102. Gavrilov, L. A. & Gavrilova, N. S. When should fatherhood stop? Science 277, 17–18 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. Gavrilov, L. A. et al. Mutation load and human longevity. Mutat. Res. 377, 61–62 (1997).

    Article  CAS  PubMed  Google Scholar 

  104. Crow, J. F. Age and sex effects on human mutation rates: an old problem with new complexities. J. Radiat. Res. 47 (Suppl. B), B75–B82 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Eisenberg, D. T., Hayes, M. G. & Kuzawa, C. W. Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. Proc. Natl Acad. Sci. USA 109, 10251–10256 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kimura, M. et al. Offspring's leukocyte telomere length, paternal age, and telomere elongation in sperm. PLoS Genet. 4, e37 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Goriely, A. et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat. Genet. 41, 1247–1252 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Orioli, I. M., Castilla, E. E., Scarano, G. & Mastroiacovo, P. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. Am. J. Med. Genet. 59, 209–217 (1995).

    Article  CAS  PubMed  Google Scholar 

  109. Glaser, R. L. et al. Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am. J. Hum. Genet. 66, 768–777 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Murdoch, J. L., Walker, B. A. & McKusick, V. A. Parental age effects on the occurrence of new mutations for the Marfan syndrome. Ann. Hum. Genet. 35, 331–336 (1972).

    Article  CAS  PubMed  Google Scholar 

  111. Schuffenecker, I. et al. Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine. Am. J. Hum. Genet. 60, 233–237 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Carlson, K. M. et al. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am. J. Hum. Genet. 55, 1076–1082 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Choi, J. Y. et al. Association of paternal age at birth and the risk of breast cancer in offspring: a case control study. BMC Cancer 5, 143 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

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    Catriona Paul & Bernard Robaire

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Paul, C., Robaire, B. Ageing of the male germ line. Nat Rev Urol 10, 227–234 (2013). https://doi.org/10.1038/nrurol.2013.18

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  • DOI: https://doi.org/10.1038/nrurol.2013.18

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