Abstract
The existence of a sex gap in human health and longevity has been widely documented. Autosomal DNA methylation differences between males and females have been reported, but so far few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a meta-analysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes show age-by-sex interaction. We experimentally validated 2 regions mapping in FIGN and PRR4 genes and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the age-associated increase in epimutations and entropy, we showed that the number of probes having an age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence.
Highlights
A profound and multifaceted remodeling of DNA methylation patterns occurs during human aging [1,2,3]
We performed a meta-analysis of 4 large datasets on whole blood (Materials and Methods) to identify CpG sites with differential methylation between males and females
We used the same datasets to identify age-associated differentially methylated positions and we selected a list of 87581 probes (Bonferroni corrected p-values resulting from meta-analysis
Summary
A profound and multifaceted remodeling of DNA methylation patterns occurs during human aging [1,2,3]. Several epigenome-wide association studies (EWAS) have shown that a subset of the about 28 million CpG sites of the genome undergoes age-associated normative changes, i.e. reproducible hypermethylation or hypomethylation events that normally occur in all individuals during physiological, healthy aging (normative aging) [7, 8]. In the last 10 years an increasing number of studies identified age-associated DNA methylation changes at the level of single CpG sites, paving the way for the development of models, termed “epigenetic clocks”, that predict age starting from the epigenetic profile [11]. Epigenetic clocks are an appealing resource for chronological age estimation in forensic applications, but they have risen to the limelight because multiple reports have shown that they are sensitive to health status and are informative of the biological age of an individual. Epigenetic age deceleration was reported to be associated with successful aging and longevity [14, 15]
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