Analysis of the machinery and intermediates of the 5hmC-mediated DNA demethylation pathway in aging on samples from the MARK-AGE Study

• Published in: Aging (Albany, NY.) Vol. 8; no. 9; pp. 1896 - 1922
• Main Authors: Valentini, Elisabetta, Zampieri, Michele, Malavolta, Marco, Bacalini, Maria Giulia, Calabrese, Roberta, Guastafierro, Tiziana, Reale, Anna, Franceschi, Claudio, Hervonen, Antti, Koller, Bernhard, Bernhardt, Jürgen, Slagboom, P Eline, Toussaint, Olivier, Sikora, Ewa, Gonos, Efstathios S, Breusing, Nicolle, Grune, Tilman, Jansen, Eugène, Dollé, Martijn E T, Moreno-Villanueva, María, Sindlinger, Thilo, Bürkle, Alexander, Ciccarone, Fabio, Caiafa, Paola
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 29-08-2016
• Subjects: 5-Methylcytosine - metabolism; Adult; Aged; Aging - genetics; Aging - metabolism; Dioxygenases - genetics; Dioxygenases - metabolism; DNA Methylation; Female; Gene Expression; Gene Expression Regulation; Humans; Leukocytes, Mononuclear - metabolism; Male; Middle Aged; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Research Paper; DNA hydroxymethylation; aging; genesTET; TDG
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.101022

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 of
,
and
gene 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.