Age-related DNA Methylation Changes Are Sex-specific: a Comprehensive Assessment

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2020 Dec 4

PMID 33276343

Citations 49

Authors

Igor Yusipov

Maria Giulia Bacalini

Alena Kalyakulina

Mikhail Krivonosov

Chiara Pirazzini

Noemie Gensous

Francesco Ravaioli

Maddalena Milazzo

Cristina Giuliani

Maria Vedunova

Giovanni Fiorito

Amedeo Gagliardi

Silvia Polidoro

Paolo Garagnani

Mikhail Ivanchenko

Claudio Franceschi

Affiliations

Soon will be listed here.

Abstract

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 and 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.

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References

Ciccarone F, Tagliatesta S, Caiafa P, Zampieri M . DNA methylation dynamics in aging: how far are we from understanding the mechanisms?. Mech Ageing Dev. 2017; 174:3-17. DOI: 10.1016/j.mad.2017.12.002. View

Palli D, Berrino F, Vineis P, Tumino R, Panico S, Masala G . A molecular epidemiology project on diet and cancer: the EPIC-Italy Prospective Study. Design and baseline characteristics of participants. Tumori. 2004; 89(6):586-93. DOI: 10.1177/030089160308900602. View

Tajuddin S, Hernandez D, Chen B, Noren Hooten N, Mode N, Nalls M . Novel age-associated DNA methylation changes and epigenetic age acceleration in middle-aged African Americans and whites. Clin Epigenetics. 2019; 11(1):119. PMC: 6700815. DOI: 10.1186/s13148-019-0722-1. View

Vinuela A, Brown A, Buil A, Tsai P, Davies M, Bell J . Age-dependent changes in mean and variance of gene expression across tissues in a twin cohort. Hum Mol Genet. 2017; 27(4):732-741. PMC: 5886097. DOI: 10.1093/hmg/ddx424. View

McNally F, Roll-Mecak A . Microtubule-severing enzymes: From cellular functions to molecular mechanism. J Cell Biol. 2018; 217(12):4057-4069. PMC: 6279391. DOI: 10.1083/jcb.201612104. View

Zeng Y, Nie C, Min J, Chen H, Liu X, Ye R . Sex Differences in Genetic Associations With Longevity. JAMA Netw Open. 2018; 1(4):e181670. PMC: 6173523. DOI: 10.1001/jamanetworkopen.2018.1670. View

Ostan R, Monti D, Gueresi P, Bussolotto M, Franceschi C, Baggio G . Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine. Clin Sci (Lond). 2016; 130(19):1711-25. PMC: 4994139. DOI: 10.1042/CS20160004. View

Singmann P, Shem-Tov D, Wahl S, Grallert H, Fiorito G, Shin S . Characterization of whole-genome autosomal differences of DNA methylation between men and women. Epigenetics Chromatin. 2015; 8:43. PMC: 4615866. DOI: 10.1186/s13072-015-0035-3. View

Perumal N, Funke S, Pfeiffer N, Grus F . Characterization of lacrimal proline-rich protein 4 (PRR4) in human tear proteome. Proteomics. 2014; 14(13-14):1698-709. DOI: 10.1002/pmic.201300039. View

10.

Ochsner S, Abraham D, Martin K, Ding W, McOwiti A, Kankanamge W . The Signaling Pathways Project, an integrated 'omics knowledgebase for mammalian cellular signaling pathways. Sci Data. 2019; 6(1):252. PMC: 6823428. DOI: 10.1038/s41597-019-0193-4. View

11.

Inoshita M, Numata S, Tajima A, Kinoshita M, Umehara H, Yamamori H . Sex differences of leukocytes DNA methylation adjusted for estimated cellular proportions. Biol Sex Differ. 2015; 6:11. PMC: 4480901. DOI: 10.1186/s13293-015-0029-7. View

12.

Li S, Lund J, Christensen K, Baumbach J, Mengel-From J, Kruse T . Exploratory analysis of age and sex dependent DNA methylation patterns on the X-chromosome in whole blood samples. Genome Med. 2020; 12(1):39. PMC: 7189689. DOI: 10.1186/s13073-020-00736-3. View

13.

Jones M, Islam S, Edgar R, Kobor M . Adjusting for Cell Type Composition in DNA Methylation Data Using a Regression-Based Approach. Methods Mol Biol. 2015; 1589:99-106. DOI: 10.1007/7651_2015_262. View

14.

Horvath S, Garagnani P, Bacalini M, Pirazzini C, Salvioli S, Gentilini D . Accelerated epigenetic aging in Down syndrome. Aging Cell. 2015; 14(3):491-5. PMC: 4406678. DOI: 10.1111/acel.12325. View

15.

Austad S, Fischer K . Sex Differences in Lifespan. Cell Metab. 2016; 23(6):1022-1033. PMC: 4932837. DOI: 10.1016/j.cmet.2016.05.019. View

16.

Horvath S, Raj K . DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018; 19(6):371-384. DOI: 10.1038/s41576-018-0004-3. View

17.

Bennett-Baker P, Wilkowski J, Burke D . Age-associated activation of epigenetically repressed genes in the mouse. Genetics. 2004; 165(4):2055-62. PMC: 1462878. DOI: 10.1093/genetics/165.4.2055. View

18.

Aryee M, Jaffe A, Corrada-Bravo H, Ladd-Acosta C, Feinberg A, Hansen K . Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014; 30(10):1363-9. PMC: 4016708. DOI: 10.1093/bioinformatics/btu049. View

19.

Wang Y, Karlsson R, Jylhava J, Hedman A, Almqvist C, Karlsson I . Comprehensive longitudinal study of epigenetic mutations in aging. Clin Epigenetics. 2019; 11(1):187. PMC: 6902582. DOI: 10.1186/s13148-019-0788-9. View

20.

Teschendorff A, Gao Y, Jones A, Ruebner M, Beckmann M, Wachter D . DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer. Nat Commun. 2016; 7:10478. PMC: 4740178. DOI: 10.1038/ncomms10478. View