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

Abstract

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 ageassociated 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. DNA methylation profiles tend to diverge among individuals during life course [4][5][6], shaped by an intricated combination of environmental exposures, random events and genetically-driven mechanisms. At the same time, 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 characterize aging individuals [7,8]. Despite some controversial results [9,10], at least a fraction of normative changes is tissue specific, indicating that the cellular microenvironment affects the activity of the molecular writers of DNA methylation patterns during aging. The number of studies identifying age-associated DNA methylation changes at the level of single CpG sites has exponentially increased in the last 10 years, paving the way for the development of mathematical models, termed "epigenetic clocks", that predict the age of an individual on the basis of his/her epigenetic profile [11]. Epigenetic clocks are an appealing resource for chronological age estimation in ...

A meta-analysis of brain DNA methylation across sex, age and Alzheimer’s disease points for accelerated epigenetic aging in neurodegeneration

“…Several studies have analyzed age-associated changes in DNAm in brain, both comparing fetal versus adult brains and analyzing methylation profiles across adulthood(13, 16, 38, 64-67). Our meta-analysis showes that during aging there is an increase of methylation at specific loci, accordingly to previously published data on blood (56, 68)and brain (38). As previously reported by Hernandez et al (38), also our results support the involvement of brain aDMPs in GO related to developmental processes and morphogenesis.…”

“…Among them there are sDMPs mapping in genes that have been already associated to sex differences in brain physiology and pathology, likePar-3 Family Cell Polarity Regulator Beta (PARD3B)(53), DEAF1 Transcription Factor (DEAF1)(54) and Iodothyronine Deiodinase 3 (DIO3)(55) genes. Most of these 77 probes were previously reported as differentially methylated between males and females also in previous meta-analysis on blood(56, 57).…”

Disentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear

“…In result, we obtained 9627 aVMPs for males and 2110 aVMPs for females (Supplementary File 1). Gene ontology (GO) analysis showed that both males and females aVMPs enrich ontologies related to development and ion transport (Supplementary File 2), as previously reported 21 . Interestingly, the number of aVMPs is noticeably greater for males, suggesting that methylation variability could be sex-specific.…”

“…Probes with a detection p-value > 0.01 in more than 1% of samples, probes mapping on sex chromosomes, probes with internal SNPs and cross-reactive probes 17 were excluded from each dataset, leaving 414950 and 380137 probes in GSE87571 and SATSA datasets, respectively. Since previous studies indicate differential methylation between the two sexes 18–21 , we analysed males and females separately.…”

“…Since the previous studies indicate that DNA can manifest differential methylation in males and females [17][18][19][20] , we divide each dataset in sex-specific subsets and consider them separately.…”