{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:40:57Z","timestamp":1791470457464,"version":"4.3.4"},"reference-count":104,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T00:00:00Z","timestamp":1727913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>This Directions article examines the mechanisms by which a father\u2019s age impacts the health and wellbeing of his children. Such impacts are significant and include adverse birth outcomes, dominant genetic conditions, neuropsychiatric disorders, and a variety of congenital developmental defects. As well as age, a wide variety of environmental and lifestyle factors are also known to impact offspring health via changes mediated by the male germ line. This picture of a dynamic germ line responsive to a wide range of intrinsic and extrinsic factors contrasts with the results of trio studies indicating that the incidence of mutations in the male germ line is low and exhibits a linear, monotonic increase with paternal age (\u223ctwo new mutations per year). While the traditional explanation for this pattern of mutation has been the metronomic plod of replication errors, an alternative model pivots around the \u2018faulty male\u2019 hypothesis. According to this concept, the genetic integrity of the male germ line can be dynamically impacted by age and a variety of other factors, and it is the aberrant repair of such damage that drives mutagenesis. Fortunately, DNA proofreading during spermatogenesis is extremely effective and these mutant cells are either repaired or deleted by apoptosis\/ferroptosis. There appear to be only two mechanisms by which mutant germ cells can escape this apoptotic fate: (i) if the germ cells acquire a mutation that by enhancing proliferation or suppressing apoptosis, permits their clonal expansion (selfish selection hypothesis) or (ii) if a genetically damaged spermatozoon manages to fertilize an oocyte, which then fixes the damage as a mutation (or epimutation) as a result of defective DNA repair (oocyte collusion hypothesis). Exploration of these proposed mechanisms should not only help us better understand the aetiology of paternal age effects but also inform potential avenues of remediation.<\/jats:p>","DOI":"10.1093\/humrep\/deae230","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T17:38:05Z","timestamp":1727977085000},"page":"2645-2654","source":"Crossref","is-referenced-by-count":30,"title":["Paternal age, <i>de novo<\/i> mutations, and offspring health? New directions for an ageing problem"],"prefix":"10.1093","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9152-156X","authenticated-orcid":false,"given":"Robert John","family":"Aitken","sequence":"first","affiliation":[{"name":"Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, School of Environmental and Life Sciences, College of Engineering Science and Environment, University of Newcastle , Callaghan, NSW 2308,","place":["Australia"]},{"name":"Infertility and Reproduction Program, Hunter Medical Research Institute , New Lambton Heights, NSW 2305,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,10,3]]},"reference":[{"key":"2024121017575297300_deae230-B1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ajhg.2015.05.008","article-title":"Post-zygotic point mutations are an underrecognized source of de novo genomic variation","volume":"97","author":"Acuna-Hidalgo","year":"2015","journal-title":"Am J Hum Genet"},{"key":"2024121017575297300_deae230-B2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1136\/jmedgenet-2013-101951","article-title":"Autism traits in the RASopathies","volume":"51","author":"Adviento","year":"2014","journal-title":"J Med Genet"},{"key":"2024121017575297300_deae230-B3","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.rbmo.2022.03.012","article-title":"Role of sperm DNA damage in creating de-novo mutations in human offspring: the 'post-meiotic oocyte hypothesis","volume":"45","author":"Aitken","year":"2022","journal-title":"Reprod Biomed Online"},{"key":"2024121017575297300_deae230-B4","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1093\/humrep\/deac011","article-title":"The changing tide of human fertility","volume":"37","author":"Aitken","year":"2022","journal-title":"Hum Reprod"},{"key":"2024121017575297300_deae230-B5","doi-asserted-by":"crossref","DOI":"10.1017\/9781108935593","volume-title":"The Infertility Trap: Why Life Choices Impact Your Fertility and Why We Must Act Now","author":"Aitken","year":"2022"},{"key":"2024121017575297300_deae230-B6","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1093\/humrep\/dead157","article-title":"Male reproductive ageing: a radical road to ruin","volume":"38","author":"Aitken","year":"2023","journal-title":"Hum Reprod"},{"key":"2024121017575297300_deae230-B7","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3390\/life14030369","article-title":"The global decline in human fertility: the post-transition trap hypothesis","volume":"14","author":"Aitken","year":"2024","journal-title":"Life"},{"key":"2024121017575297300_deae230-B8","doi-asserted-by":"crossref","first-page":"1364352","DOI":"10.3389\/frph.2024.1364352","article-title":"What is driving the global decline of human fertility? 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