Prevention of age-related changes in hippocampal levels of 5-methylcytidine by caloric restriction

Abstract

Aberrant DNA methylation patterns have been linked to molecular and cellular alterations in the aging brain. Caloric restriction (CR) and upregulation of antioxidants have been proposed as interventions to prevent or delay age-related brain pathology. Previously, we have shown in large cohorts of aging mice, that age-related increases in DNA methyltransferase 3a (Dnmt3a) immunoreactivity in the mouse hippocampus were attenuated by CR, but not by overexpression of superoxide dismutase 1 (SOD1). Here, we investigated age-related alterations of 5-methylcytidine (5-mC), a marker of DNA methylation levels, in a hippocampal subregion-specific manner. Examination of 5-mC immunoreactivity in 12- and 24-month-old wild type (WT) mice on control diet, mice overexpressing SOD1 on control diet, wild type mice on CR, and SOD1 mice on CR, indicated an age-related increase in 5-mC immunoreactivity in the hippocampal dentate gyrus, CA3, and CA1–2 regions, which was prevented by CR but not by SOD1 overexpression. Moreover, positive correlations between 5-mC and Dnmt3a immunoreactivity were observed in the CA3 and CA1–2. These findings suggest a crucial role for DNA methylation in hippocampal aging and in the mediation of the beneficial effects of CR on aging.

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

“…62 An age-related increase in 5mC occurs in these regions as well as the hippocampal dentate gyrus and is also attenuated by CR. 63 Similarly, 5hmC content increases with age in all three of these regions, and CR opposes this age-related increase in the CA3 region, further implicating methylomics in hippocampal aging. 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.…”

Epigenetic epidemiology in psychiatry: A translational neuroscience perspective

“…In addition, recent findings on an aging mouse cohort kept under controlled environmental conditions throughout live showed that the level of the major de novo methylation enzyme Dnmt3a increased with age in the hippocampus [24], and correlated with age-related increase in levels of 5-methyl cytidine (5-mC). The same study showed that caloric restriction, which increases lifespan and prevents age-related alterations and pathology in various animal species [25][26][27][28], was able to prevent these age-related changes in hippocampal levels of Dnmt3a [24] and 5-mC (Prevention of age-related changes in hippocampal levels of 5-methylcytidine by caloric restriction [29]. The speculation of a causal involvement of epigenetic mechanisms in age-related decline of functional abilities of the brain [30] is in line with i) findings that age-related memory disturbances in mice are associated with altered chromatin plasticity (in particular with dysregulation of H4k12ac) in the hippocampus [31], and ii) the link between sirtuins, i.e.…”

MS-Based Metabolomics for the Investigation of Neuro-Metabolic Changes Associated with BDE-47 Exposure in C57BL/6 Mice

“…5) which is a methylated nucleoside originating from RNA degradation. The elevated level of 5-methylcytidine, a biomarker of DNA methylation levels, has been associated with hippocampal aging and blockage of long-term memory storage in human [35,36]. Thus, the simultaneously increased level of SAM, a methyl donor and 5-methylcytidine, suggested that BDE-47 could induce extra DNA methylation by disturbing methionine metabolism.…”