Epigenetic modifications have been proposed to underlie age-related dysfunction and associated disorders. 5-
hydroxymethylcytosine (5-hmC) is a newly described epigenetic modification. It is generated by the oxidation of 5-
methylcytosine (5-mC) by the ten-eleven translocation (TET) family of enzymes. Various studies have shown that 5-hmC
is present in high levels in the brain. Its lower affinity to methyl-binding proteins as compared to 5-mC suggests that it
might have a different role in the regulation of gene expression, while it is also implicated in the DNA demethylation
process. Interestingly, various widely used methods for DNA methylation detection fail to discriminate between 5-hmC
and 5-mC, while numerous specific techniques are currently being developed. Recent studies have indicated an increase of
5-hmC with age in the mouse brain as well as an age- and gene-expression-level–related enrichment of 5-hmC in genes
implicated in neurodegeneration. These findings suggest that 5-hmC may play an important role in the etiology and course
of age-related neurodegenerative disorders. The present perspective summarizes the current knowledge on 5-hmC, discusses
methodological challenges related to its detection, and suggests future strategies for examining the functional role
of this epigenetic modification and its possible implication in aging and Alzheimer’s disease.
Keywords: Aging, Alzheimer’s disease, epigenesis, epigenetics, 5-hydroxymethylcytosine, DNA, hydroxymethylation.
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