Systemic Age-Associated DNA Hypermethylation of ELOVL2 Gene: In Vivo and In Vitro Evidences of a Cell Replication Process.
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.
Department of Experimental, Diagnostic and Specialty Medicine.|Interdepartmental Center "L. Galvani," University of Bologna, Bologna, Italy.|Personal Genomics S.r.l., Verona, Italy.
Maria Giulia
MG
Bacalini
Department of Molecular Epidemiology, Leiden University Medical Center, The Netherlands.|Max Planck Institute for Biology of Ageing, Köln, Germany.
Joris
J
Deelen
Department of Experimental, Diagnostic and Specialty Medicine.|Interdepartmental Center "L. Galvani," University of Bologna, Bologna, Italy.
Chiara
C
Pirazzini
Department of Molecular Biology, Cell Biology and Biochemistry, Center for Genomics and Proteomics, Brown University, Providence, Rhode Island.
Marco
M
De Cecco
Department of Biological, Geological and Environmental Sciences.
Cristina
C
Giuliani
Department of Experimental, Diagnostic and Specialty Medicine.|Interdepartmental Center "L. Galvani," University of Bologna, Bologna, Italy.
Catia
C
Lanzarini
Department of Experimental, Diagnostic and Specialty Medicine.
Francesco
F
Ravaioli
Department of Experimental, Diagnostic and Specialty Medicine.
Elena
E
Marasco
Department of Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
Diana
D
van Heemst
Department of Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
H Eka D
HED
Suchiman
Department of Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
Roderick
R
Slieker
Department of Physics and Astronomy, University of Bologna, Italy.
Enrico
E
Giampieri
Center of Clinical Pathology and Innovative Therapy, INRCA-IRCCS National Institute, Ancona, Italy.
Rina
R
Recchioni
Center of Clinical Pathology and Innovative Therapy, INRCA-IRCCS National Institute, Ancona, Italy.
Fiorella
F
Marcheselli
Department of Experimental, Diagnostic and Specialty Medicine.|Interdepartmental Center "L. Galvani," University of Bologna, Bologna, Italy.
Stefano
S
Salvioli
Centro di Ricerche e Tecnologie Biomediche, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Italy.|Department of Clinical Sciences and Community Health, University of Milan, Italy.
Giovanni
G
Vitale
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.
Fabiola
F
Olivieri
Centre for Nutrition, Prevention and Health Services.
Annemieke M W
AMW
Spijkerman
Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
Martijn E T
MET
Dollé
Department of Molecular Biology, Cell Biology and Biochemistry, Center for Genomics and Proteomics, Brown University, Providence, Rhode Island.
John M
JM
Sedivy
Department of Physics and Astronomy, University of Bologna, Italy.
Gastone
G
Castellani
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.
Claudio
C
Franceschi
Department of Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
Pieternella E
PE
Slagboom
Department of Experimental, Diagnostic and Specialty Medicine.|Interdepartmental Center "L. Galvani," University of Bologna, Bologna, Italy.
Paolo
P
Garagnani
D000123:Acetyltransferases / Q000378:metabolism*; D000368:Aged; D000375:Aging / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D018899:CpG Islands / Q000502:physiology; D019175:DNA Methylation / Q000502:physiology*; D044127:Epigenesis, Genetic; D000081031:Fatty Acid Elongases; D005260:Female; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008136:Longevity / Q000502:physiology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
C000630967:ELOVL2 protein, human; C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases
Biomarker; Epigenetics; FHL2; Methylation
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