title: Analysis of the machinery and intermediates of the 5hmC-mediated DNA demethylation pathway in aging on samples from the MARK-AGE Study.
abstract: Gradual changes in the DNA methylation landscape occur throughout aging virtually in all human tissues. A widespread reduction of 5-methylcytosine (5mC), associated with highly reproducible site-specific hypermethylation, characterizes the genome in aging. Therefore, an equilibrium seems to exist between general and directional deregulating events concerning DNA methylation controllers, which may underpin the age-related epigenetic changes. In this context, 5mC-hydroxylases (TET enzymes) are new potential players. In fact, TETs catalyze the stepwise oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), driving the DNA demethylation process based on thymine DNA glycosylase (TDG)-mediated DNA repair pathway. The present paper reports the expression of DNA hydroxymethylation components, the levels of 5hmC and of its derivatives in peripheral blood mononuclear cells of age-stratified donors recruited in several European countries in the context of the EU Project 'MARK-AGE'. The results provide evidence for an age-related decline ofTET1,TET3andTDGgene expression along with a decrease of 5hmC and an accumulation of 5caC. These associations were independent of confounding variables, including recruitment center, gender and leukocyte composition. The observed impairment of 5hmC-mediated DNA demethylation pathway in blood cells may lead to aberrant transcriptional programs in the elderly.
authors: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome 00161, Italy.|Pasteur Institute-Fondazione Cenci Bolognetti, Rome 00161, Italy.
authors: Elisabetta
authors: E
authors: Valentini
authors: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome 00161, Italy.|Pasteur Institute-Fondazione Cenci Bolognetti, Rome 00161, Italy.
authors: Michele
authors: M
authors: Zampieri
authors: National Institute of Health and Science on Aging (INRCA), Nutrition and Ageing Centre, Scientific and Technological Research Area, 60100 Ancona, Italy.
authors: Marco
authors: M
authors: Malavolta
authors: Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna 40126, Italy.|CIG-Interdepartmental Center "L. Galvani", Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy.
authors: Maria Giulia
authors: MG
authors: Bacalini
authors: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome 00161, Italy.|Pasteur Institute-Fondazione Cenci Bolognetti, Rome 00161, Italy.
authors: Roberta
authors: R
authors: Calabrese
authors: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome 00161, Italy.|Pasteur Institute-Fondazione Cenci Bolognetti, Rome 00161, Italy.
authors: Tiziana
authors: T
authors: Guastafierro
authors: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome 00161, Italy.
authors: Anna
authors: A
authors: Reale
authors: Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna 40126, Italy.|CIG-Interdepartmental Center "L. Galvani", Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy.
authors: Claudio
authors: C
authors: Franceschi
authors: The School of Medicine, The University of Tampere, 33014 Tampere, Finland.
authors: Antti
authors: A
authors: Hervonen
authors: Department for Internal Medicine, University Teaching Hospital Hall in Tirol, Tirol, Austria.
authors: Bernhard
authors: B
authors: Koller
authors: BioTeSys GmbH, 73728 Esslingen, Germany.
authors: Jürgen
authors: J
authors: Bernhardt
authors: Department of Molecular Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: P Eline
authors: PE
authors: Slagboom
authors: University of Namur, Research Unit on Cellular Biology, Namur B-5000, Belgium.
authors: Olivier
authors: O
authors: Toussaint
authors: Laboratory of the Molecular Bases of Ageing, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors: Ewa
authors: E
authors: Sikora
authors: National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
authors: Efstathios S
authors: ES
authors: Gonos
authors: Institute of Nutritional Medicine (180c), University of Hohenheim, 70599 Stuttgart, Gemany.
authors: Nicolle
authors: N
authors: Breusing
authors: German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany.
authors: Tilman
authors: T
authors: Grune
authors: Centre for Health Protection, National Institute for Public Health and the Environment, 3720 BA Bilthoven, The Netherlands.
authors: Eugène
authors: E
authors: Jansen
authors: Centre for Health Protection, National Institute for Public Health and the Environment, 3720 BA Bilthoven, The Netherlands.
authors: Martijn E T
authors: ME
authors: Dollé
authors: Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
authors: María
authors: M
authors: Moreno-Villanueva
authors: Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
authors: Thilo
authors: T
authors: Sindlinger
authors: Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
authors: Alexander
authors: A
authors: Bürkle
authors: Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy.|Shared senior authorship.
authors: Fabio
authors: F
authors: Ciccarone
authors: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome 00161, Italy.|Pasteur Institute-Fondazione Cenci Bolognetti, Rome 00161, Italy.|Shared senior authorship.
authors: Paola
authors: P
authors: Caiafa
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D049308:Dioxygenases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; D044503:5-Methylcytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C578792:TET3 protein, human; D049308:Dioxygenases
keywords: DNA hydroxymethylation; TDG; aging; genesTET