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 of TET1, TET3 and TDG 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.

journal_name

Aging (Albany NY)

journal_title

Aging

authors

Valentini E,Zampieri M,Malavolta M,Bacalini MG,Calabrese R,Guastafierro T,Reale A,Franceschi C,Hervonen A,Koller B,Bernhardt J,Slagboom PE,Toussaint O,Sikora E,Gonos ES,Breusing N,Grune T,Jansen E,Dollé ME,Moreno-Vi

doi

10.18632/aging.101022

subject

Has Abstract

pub_date

2016-08-29 00:00:00

pages

1896-1922

issue

9

issn

1945-4589

pii

101022

journal_volume

8

pub_type

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