ИСТИНА

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 (ART) 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 WOS. Searches were performed 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’, ‘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 sncRNA. While DNA methylation is the most investigated, there is a controversy in the direction that dominates the age-dependent changes of differentially hypo- or hypermethylated regions with 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 can be linked with autism spectrum disorders. Chemical and lifestyle exposures and ART techniques may affect epigenetic aging of sperm. Although most epigenetic modifications are erased in the early mammalian embryo, there is growing evidence that altered offspring epigenome and phenotype is linked with advanced paternal age from a father’s sperm accumulating epigenetic changes with time. It has been hypothesized that age-induced changes in the sperm epigenome are profound, physiological, dynamic over the years, stable over days/months, and likely irreversible. Wider implications This review raises a concern of delayed fatherhood and age-associated changes in sperm’s epigenome that may compromise reproductive health of fathers and transfer of altered epigenetic information to subsequent generations. Prospective studies using healthy males that consider confounders are recommended. We suggest a broader discussion focused on the regulation of father’s age in natural and ART conceptions is needed.