Systemic Age-Associated DNA Hypermethylation of ELOVL2 Gene: In Vivo and In Vitro Evidences of a Cell Replication Process.

Maria Giulia Bacalini, Joris Deelen, Chiara Pirazzini, Marco De Cecco, Cristina Giuliani, Catia Lanzarini, Francesco Ravaioli, Elena Marasco, Diana van Heemst, H Eka D Suchiman, Roderick Slieker, Enrico Giampieri, Rina Recchioni, Fiorella Marcheselli, Stefano Salvioli, Giovanni Vitale, Fabiola Olivieri, Annemieke M W Spijkerman, Martijn E T Dollé, John M Sedivy, Gastone Castellani, Claudio Franceschi, Pieternella E Slagboom, Paolo Garagnani

Journal: The journals of gerontology. Series A, Biological sciences and medical sciences 2017;72(8):1015-1023

PMID: 27672102

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Abstract

Epigenetic remodeling is one of the major features of the aging process. We recently demonstrated that DNA methylation of ELOVL2 and FHL2 CpG islands is highly correlated with age in whole blood. Here we investigated several aspects of age-associated hypermethylation of ELOVL2 and FHL2. We showed that ELOVL2 methylation is significantly different in primary dermal fibroblast cultures from donors of different ages. Using epigenomic data from public resources, we demonstrated that most of the tissues show ELOVL2 and FHL2 hypermethylation with age. Interestingly, ELOVL2 hypermethylation was not found in tissues with very low replication rate. We demonstrated that ELOVL2 hypermethylation is associated with in vitro cell replication rather than with senescence. We confirmed intra-individual hypermethylation of ELOVL2 and FHL2 in longitudinally assessed participants from the Doetinchem Cohort Study. Finally we showed that, although the methylation of the two loci is not associated with longevity/mortality in the Leiden Longevity Study, ELOVL2 methylation is associated with cytomegalovirus status in nonagenarians, which could be informative of a higher number of replication events in a fraction of whole-blood cells. Collectively, these results indicate that ELOVL2 methylation is a marker of cell divisions occurring during human aging.

Address: Department of Experimental, Diagnostic and Specialty Medicine.; Interdepartmental Center "L. Galvani," University of Bologna, Bologna, Italy.; Personal Genomics S.r.l., Verona, Italy.; Department of Molecular Epidemiology, Leiden University Medical Center, The Netherlands.; Max Planck Institute for Biology of Ageing, Köln, Germany.; Department of Experimental, Diagnostic and Specialty Medicine.; Interdepartmental Center "L. Galvani," University of Bologna, Bologna, Italy.; Department of Molecular Biology, Cell Biology and Biochemistry, Center for Genomics and Proteomics, Brown University, Providence, Rhode Island.; Department of Biological, Geological and Environmental Sciences.; Department of Experimental, Diagnostic and Specialty Medicine.; Department of Molecular Epidemiology, Leiden University Medical Center, The Netherlands.; Department of Physics and Astronomy, University of Bologna, Italy.; Center of Clinical Pathology and Innovative Therapy, INRCA-IRCCS National Institute, Ancona, Italy.; Centro di Ricerche e Tecnologie Biomediche, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Italy.; Department of Clinical Sciences and Community Health, University of Milan, Italy.; Center of Clinical Pathology and Innovative Therapy, INRCA-IRCCS National Institute, Ancona, Italy.; Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy.; Centre for Nutrition, Prevention and Health Services.; Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.; Department of Experimental, Diagnostic and Specialty Medicine.; Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy.; IRCCS Institute of Neurological Sciences, Bologna, Italy.

DOI: 10.1093/gerona/glw185

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MeSH Terms: Acetyltransferases, Aged, Aging, Cell Proliferation, Cells, Cultured, Cellular Senescence, CpG Islands, DNA Methylation, Epigenesis, Genetic, Fatty Acid Elongases, Female, Humans, LIM-Homeodomain Proteins, Longevity, Longitudinal Studies, Male, Middle Aged, Muscle Proteins, Transcription Factors