Aberrations in epigenetic marks have been associated with aging of the brain while caloric restriction (CR) and
upregulation of endogenous antioxidants have been suggested as tools to attenuate the aging process. We have recently
observed age-related increases in levels of 5-methylcytidine (5-mC) and DNA methyltransferase 3a (Dnmt3a) in the
mouse hippocampus. Most of those age-related changes in these epigenetically relevant markers were prevented by CR
but not by transgenic overexpression of the endogenous antioxidant superoxide dismutase 1 (SOD1). As recent work has
suggested a distinct role for hydroxymethylation in epigenetic regulation of gene expression in the brain, the current study
investigated age-related changes of 5-hydroxymethylcytosine (5-hmC) in the mouse hippocampus, and furthermore tested
whether CR and transgenic upregulation of SOD1 affected any age-related changes in 5-hmC. Immunohistochemical
analyses of 5-hmC in 12- and 24-month-old wild-type and transgenic mice overexpressing SOD1, which were kept under
either a control or a calorie restricted diet, revealed an increase of 5-hmC immunoreactivity occurring with aging in the
hippocampal dentate gyrus, CA3 and CA1-2 regions. Moreover, CR, but not overexpression of SOD1, prevented the agerelated
increase in the CA3 region. These findings indicate that the aging process in mice is connected with changes in
epigenetic machinery in the hippocampus and suggest that CR acts by influencing epigenetic regulation.
Keywords: Aging, epigenesis, epigenetics, DNA hydroxymethylation, 5-hydroxymethylcytosine, caloric restriction, antioxidants,
superoxide dismutase (SOD), hippocampus.
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