In humans, females live longer than males but experience a worse longevity, as genome-wide autosomal DNA methylation differences between males and females have been reported. 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 shows 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 in entropy, we showed that the number of probes showing 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.

中文翻译：

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年龄相关的DNA甲基化变化是针对性别的：全面评估

在人类中，女性的寿命比男性长，但寿命却较差，因为据报道，男性和女性之间的全基因组常染色体DNA甲基化差异。到目前为止，很少有研究调查男性和女性衰老对DNA甲基化的影响是否不同。我们对4个大型全血数据集进行了荟萃分析，比较了两个性别之间表观遗传依赖年龄的重塑的四个方面：差异甲基化，变异性，表位变异和熵。我们报告说，很大一部分（43％）的性相关探针会发生与年龄相关的DNA甲基化变化，而且数量有限的探针显示出逐性别的相互作用。我们通过实验验证了FIGN和PRR4基因中的2个区域作图，并在减速（百岁老人）和加速（唐氏综合症）衰老模型中显示出其甲基化模式的性别差异。尽管我们在表观突变和熵的与年龄相关的增加中未发现性别差异，但我们表明，与甲基化相关的与年龄相关的增加的探针数量是男性的15倍。我们的结果可以为研究衰老与性别之间的相互作用提供新的表观遗传学工具，并为鉴定长寿和与年龄有关的疾病流行中性别差异的分子触发因素铺平道路。我们发现，与甲基化相比，与年龄相关的甲基化变异性增加的探针数量是男性的15倍。我们的结果可以为研究衰老与性别之间的相互作用提供新的表观遗传学工具，并为鉴定长寿和与年龄有关的疾病流行中性别差异的分子触发因素铺平道路。我们发现，与甲基化相比，与年龄相关的甲基化变异性增加的探针数量是男性的15倍。我们的结果可以为研究衰老与性别之间的相互作用提供新的表观遗传学工具，并为鉴定长寿和与年龄有关的疾病流行中性别差异的分子触发因素铺平道路。