Abstract
The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracts age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is critical to neuronal function. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the stimulating effects of environmental enrichment on hippocampal plasticity at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.
Highlights
The decline of brain function during aging is associated with epigenetic changes, including DNA methylation
We investigate the influence of ENR on DNA methylation patterns in the hippocampal dentate gyrus and find that ENR counteracts aging-induced DNA methylation changes at genes related to neuronal plasticity and adult hippocampal neurogenesis
We found that genes at which ENR counteracted age-related methylation changes were significantly enriched for genes functionally involved in adult hippocampal neurogenesis as annotated in mammalian adult neurogenesis gene ontology (MANGO) (Fig. 4b)
Summary
The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the stimulating effects of environmental enrichment on hippocampal plasticity at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions. Since neuronal DNA methylation patterns are plastic and sensitive to environmental experiences, behavioral interventions could potentially rescue aberrant DNA methylation changes and thereby promote brain health in old age. We investigate the influence of ENR on DNA methylation patterns in the hippocampal dentate gyrus and find that ENR counteracts aging-induced DNA methylation changes at genes related to neuronal plasticity and adult hippocampal neurogenesis. Our results highlight the potential of lifetime experiences to influence brain health in old age and provide a possible mechanism underlying the effects of lifestyle factors on brain aging
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