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

Igor Yusipov, Maria Giulia Bacalini, Alena Kalyakulina, Mikhail Krivonosov, Chiara Pirazzini, Noémie Gensous, Francesco Ravaioli, Maddalena Milazzo, Cristina Giuliani, Maria Vedunova, Giovanni Fiorito, Amedeo Gagliardi, Silvia Polidoro, Paolo Garagnani, Mikhail Ivanchenko, Claudio Franceschi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)24057-24080
Number of pages24
Issue number23
Publication statusPublished - Dec 2020


  • meta-analysis
  • methylation
  • sex
  • variability
  • whole blood

ASJC Scopus subject areas

  • Ageing
  • Cell Biology


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