This Directions article examines the mechanisms by which a father’s 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 (∼two 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 ‘faulty male’ 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.

中文翻译：

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父亲年龄、新生突变和后代健康？解决老龄化问题的新方向


这篇方向文章探讨了父亲的年龄影响孩子健康和福祉的机制。这些影响是重大的，包括不良出生结局、显性遗传病、神经精神疾病和各种先天性发育缺陷。除了年龄之外，各种环境和生活方式因素也通过雄性生殖系介导的变化影响后代的健康。这张动态生殖系对各种内在和外在因素作出反应的图片与三项研究的结果形成鲜明对比，三项研究表明雄性生殖系的突变发生率较低，并且随着父亲年龄的增长呈现线性、单调的增加（~2每年都有新的突变）。虽然对这种突变模式的传统解释是复制错误的节拍性重复，但另一种模型围绕“有缺陷的男性”假设。根据这一概念，雄性种系的遗传完整性会受到年龄和各种其他因素的动态影响，而正是这种损伤的异常修复驱动了突变。幸运的是，精子发生过程中的 DNA 校对非常有效，这些突变细胞要么通过凋亡/铁死亡来修复或删除。突变生殖细胞似乎只有两种机制可以逃脱这种凋亡命运：（i）如果生殖细胞获得突变，通过增强增殖或抑制凋亡，允许其克隆扩张（自私选择假说）或（ii）如果基因受损的精子设法使卵母细胞受精，然后卵母细胞由于 DNA 修复缺陷（卵母细胞共谋假说）而以突变（或表突变）的形式修复损伤。 对这些拟议机制的探索不仅应该帮助我们更好地了解父亲年龄影响的病因学，而且还可以为潜在的补救途径提供信息。