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Age-related DNA methylation changes are sex-specific: a comprehensive assessment
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Abstract 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.
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“As advanced aging is the strongest factor for AD, we also compared our results with those from Yusipov et al. [94] and McCartney et al. [35], which identified 8 and 52 autosomal CpGs differentially affected by aging, but we did not find any overlap with these previous studies.”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [94]
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Metadata
- Authors
- Yusipov, I., Bacalini, M. G., Kalyakulina, A., Krivonosov, M., Pirazzini, C., Gensous, N., Ravaioli, F., Milazzo, M., Giuliani, C., Vedunova, M., Fiorito, G., Gagliardi, A., Polidoro, S., Garagnani, P., Ivanchenko, M., & Franceschi, C.
- Affiliations
- N. I. Lobachevsky State University of Nizhny Novgorod (RU)
- Istituto delle Scienze Neurologiche di Bologna (IT)
- University of Bologna (IT)
- University of Oxford (GB)
- University of Sassari (IT)
- Italian institute for Genomic Medicine (IT)
- Karolinska University Hospital (SE)
- Corresponding author
- Bacalini, Maria Giulia
- ORCID
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2020-12-03
- Volume
- 12
- Issue
- 23
- Pages
- 24057-24080
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC7762479
- OpenAlex
- W3108393015
- Cited by
- 148
- References
- 69
- Citations by year
- 2026: 13 · 2025: 27 · 2024: 37 · 2023: 19 · 2022: 41 · 2021: 11
- FWCI
- 1.84
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Aging (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Funders
- EU Joint Programme – Neurodegenerative Disease Research
- European Commission (H2020, 634821)
- Ministry of Education and Science of the Russian Federation (075-15-2019-871)
- Horizon 2020 Framework Programme (634821)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- DNA methylation, sex differences, epigenetics, centenarians, Down syndrome, epimutations, longevity, age-related diseases
- MeSH terms
- ATPases Associated with Diverse Cellular Activities, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Aging, Down Syndrome, Female, Humans, Longevity, Male, Microtubule-Associated Proteins, Middle Aged, Sex Factors, CpG Islands, DNA Methylation, Databases, Genetic, Epigenesis, Genetic, Proline-Rich Protein Domains, Young Adult
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