Age-associated epigenetic changes in mammalian sperm: implications for offspring health and development

Abstract

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.

H19 Sperm Methylation in Male Infertility: A Systematic Review and Meta-Analysis

“…It has also been hypothesized that age-induced changes in the sperm epigenome are profound and probably irreversible. However, to date, there has been little research on the effects of age on H19 gene methylation [ 48 ]. A study of 196 adolescent and 176 middle-aged twins failed to find a correlation between age and methylation changes in the DMR of the H19/IGF2 locus.…”

Associations of parental reproductive age and elevated blood pressure in offspring: An observational study

“…Studies have signified the role of aging oocytes which present with oocyte cytoplasmic volume decreasing ( 34 ) and mitochondrial dysfunction ( 35 ), as well as epigenetic modifications occurred in genes regulating growth and metabolism, such as histone acetylation and DNA methylation ( 36 ). Similar epigenetic changes with increasing paternal age ( 37 – 39 ) may also be associated with changes of metabolic phenotype in offspring, but the specific mechanism remained unclear. In addition, the protective effect of older paternal age we found is possibly because that older fathers are more likely to be wealthier and better educated compared with younger fathers, which enable them to provide a better and healthier child-bearing environment for children ( 40 , 41 ).…”

“…In brief, using random stratified cluster sampling method, 12-16 primary and secondary schools were selected in each province and 44,436 participants with complete information of maternal age and paternal age were included. In present study, we enrolled 39,190…”

The Sperm Small RNA Transcriptome: Implications beyond Reproductive Disorder

“…The accumulated studies on obesity using mouse models reported a diverse set of mature sperm miRNA candidates implicated in inducing metabolic disorder in the offspring. Surprisingly, only a few miRNA candidates overlapped between the studies, and some showed a contradictory expression profile as well, possibly owing to the greater length of time each study employed in establishing the obese models (10 w, 17 w, 20 w, 26 w); the change in the sperm sncRNA profile concomitant with aging [ 105 ] might have shrouded the key players in response to the excessive change in diet. Interestingly, miR-19b alone was found to play a larger role in shaping the offspring’s health, as the microinjection of synthetic miR-19b to zygote could partially recapitulate the western-like diet phenotypes in the offspring [ 99 ].…”