Caloric restriction attenuates age-related changes of DNA methyltransferase 3a in mouse hippocampus.

Recent studies have suggested that DNA methylation is implicated in age-related changes in gene expression as well as in cognition. DNA methyltransferase 3a (Dnmt3a), which catalyzes DNA methylation, is essential for memory formation and underlying changes in neuronal and synaptic plasticity. Because caloric restriction (CR) and upregulation of antioxidants have been suggested as strategies to attenuate age-related alterations in the brain, we hypothesized that both a diet restricted in calories and transgenic overexpression of normal human Cu/Zn superoxide dismutase 1 (SOD) attenuate age-related changes in Dnmt3a in the aging mouse hippocampus. For this purpose, we performed qualitative and quantitative analyses of Dnmt3a-immunoreactivity (IR) for the hippocampal dentate gyrus (DG), CA3 and CA1-2 regions in 12- and 24-month-old mice from 4 groups, i.e. (1) wild-type (WT) mice on a control diet (WT-CD), (2) SOD-CD mice, (3) WT mice on CR (WT-CR), and (4) SOD-CR. Qualitative analyses revealed two types of Dnmt3a immunoreactive cells: type I cells--present throughout all hippocampal cell layers showing moderate levels of nuclear Dnmt3a-IR, and type II cells--a subpopulation of hippocampal cells showing very intense nuclear Dnmt3a-IR, and colocalization with Bromodeoxyuridine. Quantitative analyses indicated that the age-related increase in Dnmt3a-IR within the CA3 and CA1-2 in type I cells was attenuated by CR, but not by SOD overexpression. In contrast, the density of type II Dnmt3a immunoreactive cells showed an age-related reduction, without significant effects of both CR and SOD. These changes in Dnmt3a levels in the mouse hippocampus may have a significant impact on gene expression and associated cognitive functioning.