Age-Related Increase in Levels of 5-Hydroxymethylcytosine in Mouse Hippocampus is Prevented by Caloric Restriction

Abstract

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 epigenetic 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 age-related increase in the CA3 region. These region-specific findings indicate that the aging process in mice is connected with epigenetic changes and suggest that the beneficial actions of CR may be mediated via epigenetic mechanisms such as methylation and hydroxymethylation of DNA.

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

“…It has yet to be ascertained, however, whether or not these changes in the methylomic landscape are responsible for mediating any health outputs of CR. 64 DNMT modulation and longevity DNA methylation in Drosophila melanogaster is carried out by the sole methyltransferase gene dDnmt2. Lin et al ubiquitously expressed the UAS-dDnmt2 transgene driven by daughterless-GAL4 in Drosophila.…”

Epigenetics and Nutrition

“…Thus, AdoMet and AdoHcy can alter DNA methylation and histone modifications. Other foods contain anti-oxidant metabolites, which counteract reacting oxygen species (ROS) responsible for the oxidative stress influencing DNA demethylation [31][32][33][34][35]. Excessive formation of ROS and oxidative stress can lead to pathological conditions, including cancer [36,37].…”

Back to the future: transgenerational transmission of xenobiotic-induced epigenetic remodeling

“…25,146 The belief that food controls our health is not novel, but the control of gene expression by bioactive dietary compounds supplies an explanation for certain unanswered phenomena. 145,147,148 On the positive side, certain dietary compounds such as genistein, a component of soy products, epigallocatechin-3-gallate (EGCG), found in green tea, sulforaphane, normally present in cruciferous vegetables, curcumin, present in curry and turmeric, caffeic acid, one of coffee components, and resveratrol, normally associated with grapes and wild berries, show beneficial properties against several pathologies, including cancer, cardiovascular, and neurodegenerative diseases. 145 These diverse compounds interfere with DNA methylation and histone acetylation/deacetylation and methylation/demethylation, as well as with the expression of miRNAs and other non-coding RNAs, thereby altering cellular epigenetics and altering gene expression.…”