Complex sex-specific age-related changes in DNA methylation including variability, epimutations and entropy

Current epidemiological data indicate that, in humans, females live longer than males but experience a worse quality of life in advanced age. The reasons for this sex disparity are still unknown, but it is likely that it derives from a strict interplay between biological and cultural factors. Epigenetic modifications likely contribute to shape sex gap in aging and longevity, and genome-wide DNA methylation differences between males and females in autosomal chromosomes have been reported. Several studies showed that DNA methylation patterns are profoundly remodelled during aging, modulated in part by environmental exposures. However, few studies have specifically investigated if DNA methylation is differently affected by aging in males and females. Here we performed a meta-analysis of 4 large whole blood datasets including males and females of different ages and we compared 4 aspects of epigenetic age-dependent remodelling between males and females: normative changes, variability, epimutations, and entropy. While we did not find differences in the age-associated increase in epimutations and in entropy, we reported a list of highly reproducible sex-specific age-associated differentially methylated positions (saDMPs) and sex-specific age-associated variably methylated positions (saVMPs). We investigated the enrichment in saDMPs and saVMPs in genomic regions, imprinted and sex hormone-related genes and Reactome pathways. Furthermore, we experimentally validated the most robust saDMPs, mapping in FIGN and PRR4 genes, and showed sex-specific deviations of their methylation patterns in models of successful (centenarians) and unsuccessful (Down syndrome) aging. In conclusion, we provided a comprehensive description of sex-differences in DNA methylation changes with aging in whole blood. Our results can pave the way to the identification of possible molecular triggers of the sex gap in aging and longevity.