A restricted diet, regular exercise at the gym, not drinking too much… Acts of deprivation and suffering are supposed to guide us on our quest to the foundation of youth. Thankfully, exciting new epigenetic findings show us that it’s time to learn a lesson from the hedonists by demonstrating how environmental enrichment protects us from and reverses the effects of age-specific DNA methylation in the brain.
This pleasurable news comes at you thanks to a talented team led by Gerd Kempermann from the German Center for Neurodegenerative Diseases (DZNE). They used a model where mice were housed in either standard cages or larger enriched environments with more mice, extra toys, and tunnels for three months. Then, they measured DNA methylation in adult brain (dentate gyrus) using reduced representation bisulfite sequencing (RRBS). They found:
- Depleted methylation at CpG islands, shores, promoters, and exons
- Enriched methylation at enhancers, introns, and intergenic regions
- Differentially methylated CpGs mapping to genes involved with neuronal structure, synaptic plasticity, and hippocampal neurogenesis
- Hypomethylation of promoter CpGs at the activity-dependent transcription factor Npas4 validated by targeted bisulfite sequencing
Next, they examined the effect of age on DNA methylation changes, performing RRBS on young and old mice that were respectively housed in the standard cages or enriched environments for 4 days or one year. Here’s what they found during their splash in the fountain:
- Age-related differentially methylated genes are important for neuronal plasticity, signaling, and energy metabolism
- These genes significantly overlap with genes with altered DNA methylation following environmental enrichment
- Aging associates with a global decrease in CpG methylation and this decrease is prevented by environmental enrichment
- Some age-related differentially methylated CpGs (31.73%) are prevented by environmental enrichment
- These genes associate with Alzheimer’s disease pathology, age-related cognitive decline, and cognitive trajectories during aging
- Differentially methylated enhancer CpGs associate with the methyl-CpG-binding transcription factor Mecp2
- Most of these Mecp2 targets (87%) are hypomethylated with aging and hypermethylated by enrichment
- Aged mice have reduced Mecp2 binding, while enriched mice have increased Mecp2 binding
- Enrichment also increases the number of new neurons in the dentate gyrus
Beyond examining the preventative nature of environmental enrichment, the team also started the enrichment in aged mice to assess compensation of age-related DNA methylation changes. The pattern of DNA methylation was like mice with lifelong environmental enrichment, suggesting enrichment can restore young DNA methylation patterns in the dentate gyrus.
Senior author Gerd Kempermann is optimistic about how environmental enrichment can improve memory performance, adding, “It is fair to assume that this mental fitness is due to the stabilization of methylation patterns that we observed. Of course, the question is to what extent our findings also apply to humans. Here, the situation is likely to be more complicated. After all, it is about how living conditions influence behavior and the way humans react to external stimuli is much more complex than in mice. However, we have good reasons to believe that the basic epigenetic principles are the same in humans as in mice.”
Enrich your environment with this pleasurable experience in Nature Communications, June 2021.