BACKGROUND Modern reproductive behavior in most developed countries is characterized by delayed parenthood. Older gametes are generally less fertile, accumulating and compounding the effects of varied environmental exposures that are modified by lifestyle factors. Clinicians are primarily concerned with advanced maternal age, while the influence of paternal age on fertility, early development and offspring health remains underappreciated. There is a growing trend to use assisted reproductive technologies for couples of advanced reproductive age. Thus, the number of children born from older gametes is increasing. OBJECTIVE AND RATIONALE We review studies reporting age-associated epigenetic changes in mammals and humans in sperm, including DNA methylation, histone modifications and non-coding RNAs. The interplay between environment, fertility, ART and age-related epigenetic signatures is explored. We focus on the association of sperm epigenetics on epigenetic and phenotype events in embryos and offspring. SEARCH METHODS Peer-reviewed original and review articles over the last two decades were selected using PubMed and the Web of Science for this narrative review. Searches were performed by adopting the two groups of main terms. The first group included ‘advanced paternal age’, ‘paternal age’, ‘postponed fatherhood’, ‘late fatherhood’, ‘old fatherhood’ and the second group included ‘sperm epigenetics’, ‘sperm’, ‘semen’, ’epigenetic’, ‘inheritance’, ‘DNA methylation’, ‘chromatin’, ‘non-coding RNA’, ‘assisted reproduction’, ‘epigenetic clock’. OUTCOMES Age is a powerful factor in humans and rodent models associated with increased de novo mutations and a modified sperm epigenome. Age affects all known epigenetic mechanisms, including DNA methylation, histone modifications and profiles of small non-coding (snc)RNA. While DNA methylation is the most investigated, there is a controversy about the direction of age-dependent changes in differentially hypo- or hypermethylated regions with advanced age. Successful development of the human sperm epigenetic clock based on cross-sectional data and four different methods for DNA methylation analysis indicates that at least some CpG exhibit a linear relationship between methylation levels and age. Rodent studies show a significant overlap between genes regulated through age-dependent differentially methylated regions and genes targeted by age-dependent sncRNA. Both age-dependent epigenetic mechanisms target gene networks enriched for embryo developmental, neurodevelopmental, growth and metabolic pathways. Thus, age-dependent changes in the sperm epigenome cannot be described as a stochastic accumulation of random epimutations and may be linked with autism spectrum disorders. Chemical and lifestyle exposures and ART techniques may affect the epigenetic aging of sperm. Although most epigenetic modifications are erased in the early mammalian embryo, there is growing evidence that an altered offspring epigenome and phenotype is linked with advanced paternal age due to the father’s sperm accumulating epigenetic changes with time. It has been hypothesized that age-induced changes in the sperm epigenome are profound, physiological and dynamic over years, yet stable over days and months, and likely irreversible. WIDER IMPLICATIONS This review raises a concern about delayed fatherhood and age-associated changes in the sperm epigenome that may compromise reproductive health of fathers and transfer altered epigenetic information to subsequent generations. Prospective studies using healthy males that consider confounders are recommended. We suggest a broader discussion focused on regulation of the father’s age in natural and ART conceptions is needed. The professional community should be informed and should raise awareness in the population and when counseling older men.

中文翻译：

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哺乳动物精子与年龄相关的表观遗传变化：对后代健康和发育的影响

背景技术在大多数发达国家，现代生育行为的特征是生育延迟。年长的配子通常生育能力较差，会积累和复合各种环境暴露的影响，这些影响会因生活方式因素而改变。临床医生主要关注高龄产妇，而父亲年龄对生育能力、早期发育和后代健康的影响仍未得到充分认识。对高龄育龄夫妇使用辅助生殖技术的趋势越来越明显。因此，大龄配子所生的孩子数量正在增加。目标和基本原理 我们回顾了报告哺乳动物和人类精子中与年龄相关的表观遗传变化的研究，包括 DNA 甲基化、组蛋白修饰和非编码 RNA。环境、生育率之间的相互作用，探索了 ART 和年龄相关的表观遗传特征。我们专注于精子表观遗传学与胚胎和后代表观遗传和表型事件的关联。搜索方法 使用 PubMed 和 Web of Science 选择过去 20 年经过同行评审的原始文章和评论文章用于此叙述性评论。采用两组主要术语进行检索。第一组包括“高龄父亲”、“父亲年龄”、“延迟父亲身份”、“晚期父亲身份”、“高龄父亲身份”，第二组包括“精子表观遗传学”、“精子”、“精液”、“表观遗传” ，“遗传”，“DNA 甲基化”，“染色质”，“非编码 RNA”，“辅助生殖”，“表观遗传时钟”。结果 年龄是人类和啮齿动物模型的一个强大因素，与新发突变增加和精子表观基因组改变有关。年龄影响所有已知的表观遗传机制，包括 DNA 甲基化、组蛋白修饰和小非编码 (snc) RNA 的概况。虽然 DNA 甲基化是研究最多的，但随着年龄的增长，差异低甲基化或高甲基化区域的年龄依赖性变化方向存在争议。基于横截面数据和四种不同的 DNA 甲基化分析方法成功开发的人类精子表观遗传时钟表明，至少一些 CpG 表现出甲基化水平与年龄之间的线性关系。啮齿动物研究表明，通过年龄依赖性差异甲基化区域调节的基因与年龄依赖性 sncRNA 靶向的基因之间存在显着重叠。这两种依赖于年龄的表观遗传机制都针对富含胚胎发育、神经发育、生长和代谢途径。因此，精子表观基因组的年龄依赖性变化不能描述为随机表观突变的随机积累，并且可能与自闭症谱系障碍有关。化学和生活方式接触以及 ART 技术可能会影响精子的表观遗传老化。尽管大多数表观遗传修饰在早期哺乳动物胚胎中被消除，但越来越多的证据表明，由于父亲的精子随时间积累表观遗传变化，后代表观基因组和表型的改变与父亲高龄有关。据推测，年龄引起的精子表观基因组变化是深远的、生理的和动态的，多年来，但在数天和数月内保持稳定，并且可能是不可逆转的。更广泛的意义 本综述引起了对延迟父亲身份和精子表观基因组年龄相关变化的关注，这些变化可能会损害父亲的生殖健康并将改变的表观遗传信息传递给后代。建议使用考虑混杂因素的健康男性进行前瞻性研究。我们建议需要进行更广泛的讨论，重点是在自然受孕和 ART 受孕中调节父亲的年龄。专业社区应该了解情况，并在人群中和为老年男性提供咨询时提高意识。我们建议需要进行更广泛的讨论，重点是在自然受孕和 ART 受孕中调节父亲的年龄。专业社区应该了解情况，并在人群中和为老年男性提供咨询时提高意识。我们建议需要进行更广泛的讨论，重点是在自然受孕和 ART 受孕中调节父亲的年龄。专业社区应该了解情况，并在人群中和为老年男性提供咨询时提高意识。