Environmental enrichment restores a young DNA methylation landscape in the aged mouse hippocampus [Experiment 2]

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 counteracted 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 known to control neuronal functions. 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 rejuvenating effects of environmental enrichment at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions. Overall design: Mice of different ages were housed in standard housing conditions or in environmental enrichment. DNA methylation profiling was performed by Reduced Representation BIsulfite Sequencing on micro-dissected dentate gyrus tissue. Reduced representation bisulfite sequencing was performed on a total of 24 samples.