Abstract
The function of 5-hydroxymethylcytosine (5hmC) is poorly understood. 5hmC is an epigenetic modification of DNA, resulting from the oxidation of 5-methylcytosine (5mC) by the Fe2+, and 2-oxoglutarate-dependent, 10–11 translocation methylcytosine dioxygenases (TET1, TET2, and TET3). Recent evidence suggests that, in addition to being an intermediate in active demethylation, 5hmC may also have an epigenetic role. 5hmC is enriched in the adult brain, where it has been implicated in regulating neurogenesis. The rate of adult neurogenesis decreases with age, however physical exercise has been shown to counteract this deficit. Here, we investigated the impact of voluntary exercise on the age-related changes of TET1, TET2, expression and 5hmC content in the hippocampus and hypothalamus. For this purpose, we used voluntary exercise in young adult (3 months) and aged (18 months) mice as a rodent model of healthy brain aging. We measured the levels of hippocampal and hypothalamic TET1, TET2 mRNA, and 5hmC and memory [Object Location (OL) test] in mice that either exercised for 1 month or remained sedentary. While aging was associated with decreased TET1 and TET2 expression, voluntary exercise counteracted the decline in expression. Moreover, aged mice that exercised had higher hippocampal 5hmC content in the promoter region of miR-137, an miRNA involved in adult neurogenesis. Exercise improved memory in aged mice, and there was a positive correlation between 5hmC miR-137 levels and performance in the OL test. In the hypothalamus neither exercise nor aging affected TET1 or TET2 expression. These results suggest that exercise partially restores the age-related decrease in hippocampal TET1 and TET2 expression, which may be linked to the improvement in memory. Future studies should further determine the specific genes where changes in 5hmC levels may mediate the exercise-induced improvements in memory and neurogenesis in aged animals.
Highlights
5′-methylcytosine (5mC) is a widely known and functionally well-understood epigenetic DNA modification
We found that voluntary exercise counteracts the age-related decrease in TET1 and TET2 expression, improves memory and increases miR-137 5hmC levels in the hippocampus of aged mice
Using a rodent model of long-term voluntary exercise, we studied the impact of physical exercise on memory, 5mC, 5hmC levels, and TET1 and TET2 expression in the hippocampus and hypothalamus of young adult and aged mice
Summary
5′-methylcytosine (5mC) is a widely known and functionally well-understood epigenetic DNA modification. Differences to the genomic locations of 5hmC enrichment indicate that 5hmC plays multiple roles, varying by tissue type (Globisch et al, 2010) and developmental stage (Ruzov et al, 2011). This is unlike 5mC, which predominantly acts as a transcriptional repressor while, when located in the gene-body, 5mC can act as a transcriptional activator (Aran et al, 2011; Jones, 2012). The causal relationship between changes in epigenetic features in the brain, such as 5hmC, and the processes controlling aging are still not clear
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