Age-related DNA methylation changes are sex-specific: a comprehensive assessment

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 metaanalysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling www.aging-us.com AGING 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 ageassociated 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.

The Immune Factors Driving DNA Methylation Variation in Human Blood

“…This proportion is similar across different genomic regions, based on either chromatin states or CpG density (Figure S4E, I). When quantifying how sex differences in DNA methylation vary during adulthood, by adding a sex-by-age interaction term to our models ( STAR Methods ), we found only 23 CpG sites with a significant, sex-dependent effect of age (FDR < 0.05; Table S5), confirming previous findings (McCartney et al, 2019; Yusipov et al, 2020). The most associated genes are FIGN , associated with risk-taking behaviors (Karlsson Linner et al, 2019) and educational attainment (Lee et al, 2018), and PRR4 , associated with the dry eye syndrome, a hormone-dependent, late-onset disorder (Perumal et al, 2016).…”

Ageing-associated changes in DNA methylation in X and Y chromosomes

“…Other studies, while not explicitly stating whether or not sex chromosomes have been included in the analyses, report no significant findings in X or Y chromosomes related to age [ 11 , 12 , 19 , 21 , 22 , 25 , 45 ]. However, while majority of studies have not explored this, it should be noted that also autosomes can display sexually dimorphic age-associated changes in DNA methylation [ 46 ].…”

Gender Affirming Hormone Therapy induces specific DNA methylation changes in blood

“…Within this DMR, cg23256579 exhibited the greatest loss of methylation following masculinizing GAHT, with 12 out of 13 donors showing robust loss of methylation (mean Δβ -0.084, p-value 5.96E-05, Fig 4C ). The promoter region of PRR4 is known to be differentially methylated in an age-associated sex-specific manner, with people assigned male at birth starting to lose DNA methylation faster than people assigned female at birth during puberty (Inoshita et al, 2015a; McCartney et al, 2019; Suderman et al, 2017; Vershinina et al, 2021; Yusipov et al, 2020a). The sex-associated age-related methylation of cg23256579 was validated using publicly available data from another cohort (GSE131433, (Novakovic et al, 2019)) which is comprised of matched blood samples taken at birth (Guthrie cards) and in adulthood (venous blood collected at 22 to 35 years old).…”