Research Paper Volume 12, Issue 23 pp 24057—24080

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

Igor Yusipov1,2, *, , Maria Giulia Bacalini3, *, , Alena Kalyakulina1, *, , Mikhail Krivonosov1, , Chiara Pirazzini3, , Noémie Gensous4, , Francesco Ravaioli4, , Maddalena Milazzo4, , Cristina Giuliani5,6, , Maria Vedunova7, , Giovanni Fiorito8,9, , Amedeo Gagliardi10,11, , Silvia Polidoro9,10,11, , Paolo Garagnani4,12,13,14, , Mikhail Ivanchenko1,2, #, , Claudio Franceschi1, #, ,

  • 1 Institute of Information Technologies, Mathematics and Mechanics, Lobachevsky University, Nizhniy Novgorod, Russia
  • 2 Mathematics of Future Technologies Center, Lobachevsky University, Nizhniy Novgorod, Russia
  • 3 IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
  • 4 Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum – University of Bologna, Bologna, Italy
  • 5 Department of Biological, Geological, and Environmental Sciences (BiGeA), Laboratory of Molecular Anthropology and Centre for Genome Biology, University of Bologna, Bologna, Italy
  • 6 School of Anthropology and Museum Ethnography, University of Oxford, Oxford, UK
  • 7 Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhni Novgorod, Nizhni Novgorod, Russia
  • 8 Department of Biomedical Sciences, University of Sassari, Italy
  • 9 Department of Epidemiology and Public Health, MRC/HPA Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK
  • 10 Italian Institute for Genomic Medicine (IIGM), Candiolo 10060, Italy
  • 11 Candiolo Cancer Institute, FPO-IRCCS, Candiolo 10060, Italy
  • 12 Department of Laboratory Medicine, Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  • 13 Applied Biomedical Research Center (CRBA), Policlinico S.Orsola-Malpighi Polyclinic, Bologna, Italy
  • 14 CNR Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, Unit of Bologna, Bologna, Italy
* Co-first authorship
# Co-senior authorship

Received: July 30, 2020       Accepted: October 19, 2020       Published: December 3, 2020
How to Cite

Copyright: © 2020 Yusipov et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


sDMPs: sex-associated differentially methylated positions; aDMPs: age-associated differentially methylated positions; saDMPs: sex- and age-associated differentially methylated positions; snaDMPs: sex- but not age-associated differentially methylated positions; saVMPs: sex-specific age-associated variably methylated positions.