Biology:Paternal age effect

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Short description: Health effects of an older father at conception


The paternal age effect is the statistical relationship between the father's age at conception and biological effects on the child.[1] Such effects can relate to birthweight, congenital disorders, life expectancy and psychological outcomes.[2] A 2017 review found that while severe health effects are associated with higher paternal age, the total increase in problems caused by paternal age is low.[3] While paternal age has increased since 1960–1970, this is not seen as a major public health concern.[3]

The genetic quality of sperm, as well as its volume and motility, may decrease with age,[4][5] leading the population geneticist James F. Crow to claim that the "greatest mutational health hazard to the human genome is fertile older males".[6]

The paternal age effect was first proposed implicitly by physician Wilhelm Weinberg in 1912[7] and explicitly by psychiatrist Lionel Penrose in 1955.[8] DNA-based research started more recently, in 1998, in the context of paternity testing.

Health effects

Evidence for a paternal age effect has been proposed for a number of conditions, diseases and other effects. In many of these, the statistical evidence of association is weak, and the association may be related by confounding factors or behavioural differences.[9][3] Conditions proposed to show correlation with paternal age include the following:[10]

Single-gene disorders

Advanced paternal age may be associated with a higher risk for certain single-gene disorders caused by mutations of the FGFR2, FGFR3 and RET genes.[11] These conditions are Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, achondroplasia, thanatophoric dysplasia, multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2b.[11] The most significant effect concerns achondroplasia (a form of dwarfism), which might occur in about 1 in 1,875 children fathered by men over 50, compared to 1 in 15,000 in the general population.[12] However, the risk for achondroplasia is still considered clinically negligible.[13] The FGFR genes may be particularly prone to a paternal age effect due to selfish spermatogonial selection, whereby the influence of spermatogonial mutations in older men is enhanced because cells with certain mutations have a selective advantage over other cells (see § DNA mutations).[14]

Pregnancy effects

Several studies have reported that advanced paternal age is associated with an increased risk of miscarriage.[15] The strength of the association differs between studies.[16] It has been suggested that these miscarriages are caused by chromosome abnormalities in the sperm of aging men.[15] An increased risk for stillbirth has also been suggested for pregnancies fathered by men over 45.[16]

Birth outcomes

A systematic review published in 2010 concluded that the graph of the risk of low birthweight in infants with paternal age is "saucer-shaped" (U-shaped); that is, the highest risks occur at low and at high paternal ages.[17] Compared with a paternal age of 25–28 years as a reference group, the odds ratio for low birthweight was approximately 1.1 at a paternal age of 20 and approximately 1.2 at a paternal age of 50.[17] There was no association of paternal age with preterm births or with small for gestational age births.[17]

Mental illness

Schizophrenia is associated with advanced paternal age.[18][19][20] Some studies examining autism spectrum disorder (ASD) and advanced paternal age have demonstrated an association between the two, although there also appears to be an increase with maternal age.[21]

In one study, the risk of bipolar disorder, particularly for early-onset disease, is J-shaped, with the lowest risk for children of 20- to 24-year-old fathers, a twofold risk for younger fathers and a threefold risk for fathers >50 years old. There is no similar relationship with maternal age.[22] A second study also found a risk of schizophrenia in both fathers above age 50 and fathers below age 25. The risk in younger fathers was noted to affect only male children.[23]

A 2010 study found the relationship between parental age and psychotic disorders to be stronger with maternal age than paternal age.[24]

A 2016 review concluded that the mechanism behind the reported associations was still not clear, with evidence both for selection of individuals liable to psychiatric illness into late fatherhood and evidence for causative mutations. The mechanisms under discussion are not mutually exclusive.[25]

A 2017 review concluded that the vast majority of studies supported a relationship between older paternal age and autism and schizophrenia but that there is less convincing and also inconsistent evidence for associations with other psychiatric illnesses.[3]

Cancers

Paternal age may be associated with an increased risk of breast cancer,[26] but the association is weak and there are confounding effects.[10]

According to a 2017 review, there is consistent evidence of an increase in incidence of childhood acute lymphoblastic leukemia with paternal age. Results for associations with other childhood cancers are more mixed (e.g. retinoblastoma) or generally negative.[3]

Diabetes mellitus

High paternal age has been suggested as a risk factor for type 1 diabetes,[27] but research findings are inconsistent, and a clear association has not been established.[28][29]

Down syndrome

It appears that a paternal-age effect might exist with respect to Down syndrome, but it is very small in comparison to the maternal-age effect.[30][31]

Intelligence

A review in 2005 found a U-shaped relationship between paternal age and low intelligence quotients (IQs).[32] The highest IQ was found at paternal ages of 25–29; fathers younger than 25 and older than 29 tended to have children with lower IQs.[32] It also found that "at least a half dozen other studies ... have demonstrated significant associations between paternal age and human intelligence."[32] A 2009 study examined children at 8 months, 4 years and 7 years and found that higher paternal age was associated with poorer scores in almost all neurocognitive tests used but that higher maternal age was associated with better scores on the same tests;[33] this was a reverse effect to that observed in the 2005 review, which found that maternal age began to correlate with lower intelligence at a younger age than paternal age,[32] however two other past studies were in agreement with the 2009 study's results.[24] An editorial accompanying the 2009 paper emphasized the importance of controlling for socioeconomic status in studies of paternal age and intelligence.[34] A 2010 study from Spain also found an association between advanced paternal age and intellectual disability.[24]

On the other hand, later research concluded that previously reported negative associations might be explained by confounding factors, especially parental intelligence and education. A re-analysis of the 2009 study found that the paternal age effect could be explained by adjusting for maternal education and number of siblings.[35] A 2012 Scottish study found no significant association between paternal age and intelligence, after adjusting what was initially an inverse-U association for both parental education and socioeconomic status as well as number of siblings.[36] A 2013 study of half a million Swedish men adjusted for genetic confounding by comparing brothers and found no association between paternal age and offspring IQ.[37] Another study from 2014 found an initially positive association between paternal age and offspring IQ that disappeared when adjusting for parental IQs.[38]

Life expectancy

A 2008 paper found a U-shaped association between paternal age and the overall mortality rate in children (i.e., mortality rate up to age 18).[39] Although the relative mortality rates were higher, the absolute numbers were low, because of the relatively low occurrence of genetic abnormality. The study has been criticized for not adjusting for maternal health, which could have a large effect on child mortality.[40] The researchers also found a correlation between paternal age and offspring death by injury or poisoning, indicating the need to control for social and behavioral confounding factors.[41]

In 2012, a study showed that greater age at paternity tends to increase telomere length in offspring for up to two generations. Since telomere length has effects on health and mortality, this may have effects on health and the rate of aging in these offspring. The authors speculated that this effect may provide a mechanism by which populations have some plasticity in adapting longevity to different social and ecological contexts.[42]

Associated social and genetic characteristics

Father's age versus father's risk of death
(among French population)[43]
Father's age
at birth		 Risk of father's death
before child's 18th birthday
20 1.5%
25 2.2%
30 3.3%
35 5.4%
40 8.3%
45 12.1%

Parents do not decide when to reproduce randomly. This implies that paternal age effects may be confounded by social and genetic predictors of reproductive timing.

A simulation study concluded that reported paternal age effects on psychiatric disorders in the epidemiological literature are too large to be explained only by mutations. They conclude that a model in which parents with a genetic liability to psychiatric illness tend to reproduce later better explains the literature.[9]

Later age at parenthood is also associated with a more stable family environment, with older parents being less likely to divorce or change partners.[43] Older parents also tend to occupy a higher socio-economic position and report feeling more devoted to their children and satisfied with their family.[43] On the other hand, the risk of the father dying before the child becomes an adult increases with paternal age.[43]

To adjust for genetic liability, some studies compare full siblings. Additionally, or alternatively, studies statistically adjust for some or all of these confounding factors. Using sibling comparisons or adjusting for more covariates frequently changes the direction or magnitude of paternal age effects. For example, one study drawing on Finnish census data concluded that increases in offspring mortality with paternal age could be explained completely by parental loss.[44] On the other hand, a population-based cohort study drawing on 2.6 million records from Sweden found that risk of attention deficit hyperactivity disorder was only positively associated with paternal age when comparing siblings.[45]

Mechanisms

Several hypothesized chains of causality exist whereby increased paternal age may lead to health effects.[16][46] There are different types of genome mutations, with distinct mutation mechanisms:

  • DNA length mutations of repetitive DNA (such as telomeres and microsatellites), caused by cellular copying errors
  • DNA point mutations, caused by cellular copying errors and also by chemical and physical insults such as radiation
  • chromosome breaks and rearrangements, which can occur in the resting cell
  • epigenetic changes, i.e. methylation of the DNA, which can activate or silence certain genes, and is sometimes passed down from parent to child

Telomere length

Telomeres are repetitive genetic sequences at both ends of each chromosome that protect the structure of the chromosome.[47] As men age, most telomeres shorten, but sperm telomeres increase in length.[16] The offspring of older fathers have longer telomeres in both their sperm and white blood cells.[16][47] A large study showed a positive paternal, but no independent maternal age effect on telomere length. Because the study used twins, it could not compare siblings who were discordant for paternal age. It found that telomere length was 70% heritable.[48]

DNA point mutations

In contrast to oogenesis, the production of sperm cells is a lifelong process.[16] Each year after puberty, spermatogonia (precursors of the spermatozoa) divide meiotically about 23 times.[46] By the age of 40, the spermatogonia will have undergone about 660 such divisions, compared to 200 at age 20.[46] Copying errors might sometimes happen during the DNA replication preceding these cell divisions, which may lead to new (de novo) mutations in the sperm DNA.[14]

The selfish spermatogonial selection hypothesis proposes that the influence of spermatogonial mutations in older men is further enhanced because cells with certain mutations have a selective advantage over other cells.[46][49] Such an advantage would allow the mutated cells to increase in number through clonal expansion.[46][49] In particular, mutations that affect the RAS pathway, which regulates spermatogonial proliferation, appear to offer a competitive advantage to spermatogonial cells, while also leading to diseases associated with paternal age.[49]

DNA fragmentation

During the past two decades evidence has accumulated that pregnancy loss as well as reduced rate of success with assisted reproductive technologies is linked to impaired sperm chromosome integrity and DNA fragmentation[50]. Advanced paternal age was shown to be associated with a significant increase in DNA fragmentation in a recent systematic review (where 17 out of the 19 studies considered showed such an association)[51].

Epigenetic changes

DNA methylation

The production of sperm cells involves DNA methylation, an epigenetic process that regulates the expression of genes.[46] Improper genomic imprinting and other errors sometimes occur during this process, which can affect the expression of genes related to certain disorders, increasing the offspring's susceptibility. The frequency of these errors appears to increase with age. This could explain the association between paternal age and schizophrenia.;[52] Paternal age affects offspring's behavior, possibly via an epigenetic mechanism recruiting a transcriptional repressor REST.[53]

Semen

A 2001 review on variation in semen quality and fertility by male age concluded that older men had lower semen volume, lower sperm motility, a decreased percent of normal sperm, as well as decreased pregnancy rates, increased time to pregnancy and increased infertility at a given point in time.[54] When controlling for the age of the female partner, comparisons between men under 30 and men over 50 found relative decreases in pregnancy rates between 23% and 38%.[54]

A 2014 review indicated that increasing male age is associated with declines in many semen traits, including semen volume and percentage motility. However, this review also found that sperm concentration did not decline as male age increased.[55]

X-linked effects

Some classify the paternal age effect as one of two different types. One effect is directly related to advanced paternal age and autosomal mutations in the offspring. The other effect is an indirect effect in relation to mutations on the X chromosome which are passed to daughters who are then at risk for having sons with X-linked diseases.[56]

History

Birth defects were acknowledged in the children of older men and women even in antiquity. In book six of Plato's Republic, Socrates states that men and women should have children in the "prime of their life" which is stated to be twenty in a woman and thirty in a man. He states that in his proposed society men should be forbidden to father children in their fifties and that the offspring of such unions should be considered "the offspring of darkness and strange lust." He suggests appropriate punishments be administered to the offenders and their offspring.[57][58]

In 1912, Wilhelm Weinberg, a German physician, was the first person to hypothesize that non-inherited cases of achondroplasia could be more common in last-born children than in children born earlier to the same set of parents.[59] Weinberg "made no distinction between paternal age, maternal age and birth order" in his hypothesis. In 1953, Krooth used the term "paternal age effect" in the context of achondroplasia, but mistakenly thought the condition represented a maternal age effect.[59][60]:375 The paternal age effect for achondroplasia was described by Lionel Penrose in 1955. At a DNA level, the paternal age effect was first reported in 1998 in routine paternity tests.[61]

Scientific interest in paternal age effects is relevant because the average paternal age increased in countries such as the United Kingdom,[62] Australia[63] and Germany,[64] and because birth rates for fathers aged 30–54 years have risen between 1980 and 2006 in the United States.[65] Possible reasons for the increases in average paternal age include increasing life expectancy and increasing rates of divorce and remarriage.[64] Despite recent increases in average paternal age, however, the oldest father documented in the medical literature was born in 1840: George Isaac Hughes was 94 years old at the time of the birth of his son by his second wife, a 1935 article in the Journal of the American Medical Association stated that his fertility "has been definitely and affirmatively checked up medically," and he fathered a daughter in 1936 at age 96.[64][66][67]

Medical assessment

The American College of Medical Genetics recommends obstetric ultrasonography at 18–20 weeks gestation in cases of advanced paternal age to evaluate fetal development, but it notes that this procedure "is unlikely to detect many of the conditions of interest." They also note that there is no standard definition of advanced paternal age;[11] it is commonly defined as age 40 or above, but the effect increases linearly with paternal age, rather than appearing at any particular age.[68] According to a 2006 review, any adverse effects of advanced paternal age "should be weighed up against potential social advantages for children born to older fathers who are more likely to have progressed in their career and to have achieved financial security."[62]

Geneticist James F. Crow described mutations that have a direct visible effect on the child's health and also mutations that can be latent or have minor visible effects on the child's health; many such minor or latent mutations allow the child to reproduce, but cause more serious problems for grandchildren, great-grandchildren and later generations.[6]

See also

  • Maternal age effect
  • Pregnancy over age 50

References

  1. ↑ "paternal age effect". http://medical-dictionary.thefreedictionary.com/paternal+age+effect. 
  2. ↑ Amaral, David; Dawson, Geraldine; Geschwind, Daniel (2011-06-17). Autism Spectrum Disorders. Oxford University Press, USA. ISBN 9780195371826. https://books.google.com/books?id=Prf0InCqQS0C&pg=PA837. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Is advanced paternal age a health risk for the offspring?". Fertility and Sterility 107 (2): 312–318. February 2017. doi:10.1016/j.fertnstert.2016.12.019. PMID 28088314. 
  4. ↑ Gurevich, Rachel (June 10, 2008). "Does Age Affect Male Fertility?". About.com:Fertility. About.com. http://infertility.about.com/od/causesofinfertility/f/maleagefertile.htm. 
  5. ↑ "The effects of advanced paternal age on fertility". Asian Journal of Andrology 15 (6): 723–8. November 2013. doi:10.1038/aja.2013.92. PMID 23912310. 
  6. ↑ 6.0 6.1 "The high spontaneous mutation rate: is it a health risk?". Proceedings of the National Academy of Sciences of the United States of America 94 (16): 8380–6. August 1997. doi:10.1073/pnas.94.16.8380. PMID 9237985. Bibcode: 1997PNAS...94.8380C. 
  7. ↑ Weinberg, W (1912). "Zur Vererbung des Zwergwuchses" (in de). Arch Rassen-u Gesell Biol 9: 710–718. NAID 10017956735. 
  8. ↑ "Parental age and mutation". Lancet 269 (6885): 312–3. August 1955. doi:10.1016/s0140-6736(55)92305-9. PMID 13243724. 
  9. ↑ 9.0 9.1 "Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations". Nature Genetics 48 (7): 718–24. July 2016. doi:10.1038/ng.3577. PMID 27213288. 
  10. ↑ 10.0 10.1 Tournaye, Herman (June 2009). "Male Reproductive Ageing". in Bewley, Susan; Ledger, William; Nikolaou, Dimitrios. Reproductive Ageing. Cambridge University Press. pp. 95–104. ISBN 978-1-906985-13-4. https://books.google.com/books?id=-SlaAQAAQBAJ&pg=PA95. 
  11. ↑ 11.0 11.1 11.2 "Statement on guidance for genetic counseling in advanced paternal age". Genetics in Medicine 10 (6): 457–60. June 2008. doi:10.1097/GIM.0b013e318176fabb. PMID 18496227. 
  12. ↑ "The effects of advanced paternal age on fertility". Asian Journal of Andrology 15 (6): 723–8. November 2013. doi:10.1038/aja.2013.92. PMID 23912310. 
  13. ↑ "The participation of prospective fathers in preconception care". Clinical Medicine Insights. Reproductive Health 7: 1–9. January 2013. doi:10.4137/CMRH.S10930. PMID 24453513. 
  14. ↑ 14.0 14.1 "Male biological clock: a critical analysis of advanced paternal age". Fertility and Sterility 103 (6): 1402–6. June 2015. doi:10.1016/j.fertnstert.2015.03.011. PMID 25881878. 
  15. ↑ 15.0 15.1 "Effects of Advanced Paternal Age on Reproduction and Outcomes in Offspring". NeoReviews 16 (2): e69 –e83. 2015. doi:10.1542/neo.16-2-e69. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 "Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring". Reproductive Biology and Endocrinology 13 (1): 35. April 2015. doi:10.1186/s12958-015-0028-x. PMID 25928123. 
  17. ↑ 17.0 17.1 17.2 "Paternal factors and low birthweight, preterm, and small for gestational age births: a systematic review". American Journal of Obstetrics and Gynecology 202 (2): 103–23. February 2010. doi:10.1016/j.ajog.2009.08.026. PMID 20113689. 
  18. ↑ "Paternal age, de novo mutations and schizophrenia". Molecular Psychiatry 19 (3): 274–5. March 2014. doi:10.1038/mp.2013.76. PMID 23752248. 
  19. ↑ Schizophrenia and Psychotic Spectrum Disorders. Oxford University Press. 1 April 2016. ISBN 9780199378074. https://books.google.com/books?id=guomDAAAQBAJ&q=Increased%20father%20age%20not%20proven%20to%20schizophrenia%20however%20findings%20do%20not%20%20consistently%20support&pg=PA47. 
  20. ↑ "Paternal age as a risk factor for schizophrenia: how important is it?". Schizophrenia Research 114 (1–3): 1–5. October 2009. doi:10.1016/j.schres.2009.06.017. PMID 19683417. 
  21. ↑ "Prenatal and perinatal risk factors for autism: a review and integration of findings". Archives of Pediatrics & Adolescent Medicine 161 (4): 326–33. April 2007. doi:10.1001/archpedi.161.4.326. PMID 17404128. 
  22. ↑ "Advancing paternal age and bipolar disorder". Archives of General Psychiatry 65 (9): 1034–40. September 2008. doi:10.1001/archpsyc.65.9.1034. PMID 18762589. 
  23. ↑ Miller, Brian; Messias, Erick; Miettunen, Jouko; Alaräisänen, Antti; Järvelin, Marjo-Riita; Koponen, Hannu; Räsänen, Pirkko; Isohanni, Matti et al. (September 2011). "Meta-analysis of Paternal Age and Schizophrenia Risk in Male Versus Female Offspring". Schizophrenia Bulletin 37 (5): 1039–1047. doi:10.1093/schbul/sbq011. PMID 20185538. 
  24. ↑ 24.0 24.1 24.2 "Differences in maternal and paternal age between schizophrenia and other psychiatric disorders". Schizophrenia Research 116 (2–3): 184–90. February 2010. doi:10.1016/j.schres.2009.11.006. PMID 19945257. 
  25. ↑ "Paternal age and psychiatric disorders: A review". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 174 (3): 202–213. April 2017. doi:10.1002/ajmg.b.32508. PMID 27770494. 
  26. ↑ "Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence". The Lancet. Oncology 8 (12): 1088–1100. December 2007. doi:10.1016/S1470-2045(07)70377-7. PMID 18054879. 
  27. ↑ "Diabetes". Chronic Disease Epidemiology and Control (3rd ed.). Washington, DC: American Public Health Association. 2010. p. 301. ISBN 9780875531922. https://books.google.com/books?id=wSM-AQAAQBAJ&pg=PA301. 
  28. ↑ "Maternal age at birth and childhood type 1 diabetes: a pooled analysis of 30 observational studies". Diabetes 59 (2): 486–94. February 2010. doi:10.2337/db09-1166. PMID 19875616. 
  29. ↑ "Epidemiology of Type 1 Diabetes". Textbook of Diabetes. John Wiley & Sons. 2011. p. 39. ISBN 9781444348064. https://books.google.com/books?id=mGV4wu8AkPwC&pg=PT117. 
  30. ↑ "Parental-age effects in Down syndrome". Journal of Genetics 88 (1): 1–7. April 2009. doi:10.1007/s12041-009-0001-6. PMID 19417538. 
  31. ↑ "Down syndrome, paternal age and education: comparison of California and the Czech Republic". BMC Public Health 5: 69. June 2005. doi:10.1186/1471-2458-5-69. PMID 15963229. 
  32. ↑ 32.0 32.1 32.2 32.3 "Paternal age and intelligence: implications for age-related genomic changes in male germ cells". Psychiatric Genetics 15 (2): 117–25. June 2005. doi:10.1097/00041444-200506000-00008. PMID 15900226. 
  33. ↑ Brayne, Carol, ed (March 2009). "Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood". PLOS Medicine 6 (3): e40. doi:10.1371/journal.pmed.1000040. PMID 19278291. 
  34. ↑ "Contrasting effects of maternal and paternal age on offspring intelligence: the clock ticks for men too". PLOS Medicine 6 (3): e42. March 2009. doi:10.1371/journal.pmed.1000042. PMID 19278293. 
  35. ↑ "Negative effects of paternal age on children's neurocognitive outcomes can be explained by maternal education and number of siblings". PLOS ONE 5 (9): e12157. September 2010. doi:10.1371/journal.pone.0012157. PMID 20856853. Bibcode: 2010PLoSO...512157E. 
  36. ↑ "Paternal age in relation to offspring intelligence in the West of Scotland Twenty-07 prospective cohort study". PLOS ONE 7 (12): e52112. 2012-12-13. doi:10.1371/journal.pone.0052112. PMID 23272219. Bibcode: 2012PLoSO...752112W. 
  37. ↑ "Is later better or worse? Association of advanced parental age with offspring cognitive ability among half a million young Swedish men". American Journal of Epidemiology 177 (7): 649–55. April 2013. doi:10.1093/aje/kws237. PMID 23467498. 
  38. ↑ "The effect of paternal age on offspring intelligence and personality when controlling for paternal trait level". PLOS ONE 9 (2): e90097. 2014-02-25. doi:10.1371/journal.pone.0090097. PMID 24587224. Bibcode: 2014PLoSO...990097A. 
  39. ↑ "Paternal age and mortality in children". European Journal of Epidemiology 23 (7): 443–7. 2008. doi:10.1007/s10654-008-9253-3. PMID 18437509. 
  40. ↑ "In this particular study, no adjustment was made for the health of the mother, and this could have had a large effect on child mortality." National Health Service (UK), "Older Dads and the Death of Children," (accessed 15 November 2013)
  41. ↑ Tournaye 2009, p. 102
  42. ↑ "Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants". Proceedings of the National Academy of Sciences of the United States of America 109 (26): 10251–6. June 2012. doi:10.1073/pnas.1202092109. PMID 22689985. Bibcode: 2012PNAS..10910251E. 
  43. ↑ 43.0 43.1 43.2 43.3 "Demographic and medical consequences of the postponement of parenthood". Human Reproduction Update 18 (1): 29–43. 2012. doi:10.1093/humupd/dmr040. PMID 21989171. 
  44. ↑ "The association between advanced maternal and paternal ages and increased adult mortality is explained by early parental loss". Social Science & Medicine 119: 215–23. October 2014. doi:10.1016/j.socscimed.2014.06.008. PMID 24997641. 
  45. ↑ "Paternal age at childbearing and offspring psychiatric and academic morbidity". JAMA Psychiatry 71 (4): 432–8. April 2014. doi:10.1001/jamapsychiatry.2013.4525. PMID 24577047. 
  46. ↑ 46.0 46.1 46.2 46.3 46.4 46.5 "Paternal age and mental health of offspring". Fertility and Sterility 103 (6): 1392–6. June 2015. doi:10.1016/j.fertnstert.2015.04.015. PMID 25956369. 
  47. ↑ 47.0 47.1 "Advanced paternal age and reproductive outcome". Asian Journal of Andrology 14 (1): 69–76. January 2012. doi:10.1038/aja.2011.69. PMID 22157982. 
  48. ↑ "Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect". European Journal of Human Genetics 21 (10): 1163–8. October 2013. doi:10.1038/ejhg.2012.303. PMID 23321625. 
  49. ↑ 49.0 49.1 49.2 ""Selfish spermatogonial selection": a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders". The American Journal of Psychiatry 170 (6): 599–608. June 2013. doi:10.1176/appi.ajp.2013.12101352. PMID 23639989. 
  50. ↑ Chan PTK, Robaire B. Advanced Paternal Age and Future Generations. Front Endocrinol (Lausanne). 2022 Jun 9;13:897101. doi: 10.3389/fendo.2022.897101. PMID: 35757433; PMCID: PMC9218097
  51. ↑ Gonzalez DC, Ory J, Blachman-Braun R, Nackeeran S, Best JC, Ramasamy R. Advanced Paternal Age and Sperm DNA Fragmentation: A Systematic Review. World J Mens Health. 2022 Jan;40(1):104-115. doi: 10.5534/wjmh.200195. Epub 2021 Apr 16. PMID: 33987998; PMCID: PMC8761235
  52. ↑ "Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia". Schizophrenia Bulletin 33 (6): 1270–3. November 2007. doi:10.1093/schbul/sbm093. PMID 17712030. 
  53. ↑ Yoshizaki, Kaichi; Koike, Tasuku; Kimura, Ryuichi; Kikkawa, Takako; Oki, Shinya; Koike, Kohei; Mochizuki, Kentaro; Inada, Hitoshi et al. (15 February 2019). Paternal age affects offspring's behavior possibly via an epigenetic mechanism recruiting a transcriptional repressor REST. doi:10.1101/550095. https://www.biorxiv.org/content/biorxiv/early/2019/02/15/550095.full.pdf. 
  54. ↑ 54.0 54.1 "Effects of male age on semen quality and fertility: a review of the literature". Fertility and Sterility 75 (2): 237–48. February 2001. doi:10.1016/S0015-0282(00)01679-4. PMID 11172821. 
  55. ↑ "Consistent age-dependent declines in human semen quality: a systematic review and meta-analysis". Ageing Research Reviews 19: 22–33. January 2015. doi:10.1016/j.arr.2014.10.007. PMID 25462195. 
  56. ↑ "Definition of Advanced paternal age". http://www.medterms.com/script/main/art.asp?articlekey=33298. Retrieved 13 June 2023. 
  57. ↑ "The Internet Classics Archive | the Republic by Plato". http://classics.mit.edu/Plato/republic.6.v.html. 
  58. ↑ Galton, D J (1 August 1998). "Greek theories on eugenics.". Journal of Medical Ethics 24 (4): 263–267. doi:10.1136/jme.24.4.263. ISSN 0306-6800. PMID 9752630. 
  59. ↑ 59.0 59.1 Crow, James F. (October 2000). "The origins, patterns and implications of human spontaneous mutation". Nature Reviews Genetics 1 (1): 40–47. doi:10.1038/35049558. PMID 11262873. 
  60. ↑ "Comments on the estimation of the mutation rate for achondroplasia". American Journal of Human Genetics 5 (4): 373–6. December 1953. PMID 13104383. 
  61. ↑ "Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat". American Journal of Human Genetics 62 (6): 1408–15. June 1998. doi:10.1086/301869. PMID 9585597. 
  62. ↑ 62.0 62.1 "Advanced paternal age: how old is too old?". Journal of Epidemiology and Community Health 60 (10): 851–3. October 2006. doi:10.1136/jech.2005.045179. PMID 16973530. 
  63. ↑ Australian Bureau of Statistics (11 November 2009). "3301.0 - Births, Australia, 2008. Summary of findings. Births". http://www.abs.gov.au/ausstats/abs@.nsf/Products/92A449676DCE3145CA25766A00120E3D?opendocument. 
  64. ↑ 64.0 64.1 64.2 "Reproductive functions of the ageing male". Human Reproduction Update 10 (4): 327–39. 2004. doi:10.1093/humupd/dmh030. PMID 15192059. 
  65. ↑ "Births: final data for 2006". National Vital Statistics Reports 57 (7): 1–104. 2009. https://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_07.pdf. Retrieved 25 February 2010. 
  66. ↑ "A case of authenticated fertility in a man, aged 94". J Am Med Assoc 105 (18): 1423–4. 1935. doi:10.1001/jama.1935.92760440002009a. 
  67. ↑ "A father again at 96; North Carolinan's baby a sister to boy born two years ago". The New York Times. Associated Press: p. 10. 4 June 1936. https://www.nytimes.com/1936/06/04/archives/a-father-again-at-96-north-carolinans-baby-a-sister-to-boy-born-two.html. 
  68. ↑ "Advancing paternal age and psychiatric disorders". World Psychiatry 14 (1): 91–3. February 2015. doi:10.1002/wps.20190. PMID 25655163. 

Further reading

External links



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