Environmental Enrichment Can Counteract the Effects of Aging on DNA Methylation

Post by Shireen Parimoo

What's the science?

Environmental enrichment (EE) in early life and development is related to improved cognition and has been shown to reduce behavioural deficits in diseased and aging mice. The beneficial cognitive effects of EE occur due to increased neuroplasticity and neurogenesis in the hippocampus, which is important for learning and memory. Age-related cognitive decline is linked to changes in DNA methylation, an epigenetic mechanism by which methyl groups are added to DNA molecules. As a result, DNA methylation can regulate gene expression and consequently, influence aspects of neuronal development and functioning. Currently, it is not known whether EE promotes hippocampal neuroplasticity and neurogenesis through epigenetic mechanisms. This week in Nature Communications, Zocher and colleagues used DNA methylation sequencing and gene enrichment analyses to examine the impact of EE on hippocampal dentate gyrus (DG) neurons.

How did they do it?

Six-week-old female mice were raised in an enriched environment (EE) or a standard environment for three months. The authors used reduced representation bisulfite sequencing to identify regions of the genome that showed changes in DNA methylation (i.e., differentially modified genes) in the DG. They also performed gene set enrichment analysis to determine which types of neuronal pathways those differentially modified genes were involved in. To examine the effect of EE on aging, the authors compared DNA methylation and gene enrichment profiles of young and old mice raised in both a standard environment and an EE. They also compared older and younger EE mice to assess whether EE could counteract the effect of aging on DNA methylation. Additionally, they investigated whether adult exposure to EE had a similar impact on DNA methylation as lifelong EE exposure. To do this, 14- and 3-month-old mice were housed in EE and their DNA methylation and gene enrichment profiles were compared after three months. Lastly, the authors analyzed human genomic datasets to identify genes that are dysregulated in pathological aging (e.g., Alzheimer’s disease, cognitive decline). They compared these genes to the differentially modified genes in EE mice in order to understand the link between EE-induced methylation and cognition.

What did they find?

There were no global differences in DNA methylation between mice raised in EE and standard environments, but there was evidence of differential modification of genes in EE mice. That is, methylation on some locations on the genome, such as enhancer regions, resulted in gene enrichment (increased gene expression) whereas other locations were depleted (decreased gene expression). The enriched genes were involved in neuronal structure, neurotransmitter signaling, neurogenesis, and synaptic plasticity. Interestingly, enriched genes in older mice raised in a standard environment (compared to younger mice) were involved in overlapping processes with enriched genes in EE mice, indicating that EE and aging have similar effects on DNA methylation in the DG.

Enriched genes were associated with neuroplasticity, cell signaling, and hippocampal neurogenesis. In fact, there were 60% more newborn DG neurons in older EE mice than in the standard environment mice, further demonstrating that EE is associated with increased neurogenesis. Moreover, many of the genes that were enriched by EE in older mice were depleted in older mice raised in a standard environment, indicating that age-related methylation was counteracted by EE-induced methylation. This was the case in mice who were exposed to EE early on, as well as in older age. Finally, many of the genes that were differentially modified by EE in mice were also dysregulated in human adults with neuropathology (e.g., Alzheimer’s disease). Together, these findings indicate that EE alters the DNA methylation of genes that are putatively associated with cognitive functioning through their downstream effects on neural signaling, neuroplasticity, and neurogenesis.

What's the impact?

This study is the first to show that EE can alter and reverse the effects of aging on DNA methylation in mouse hippocampal DG neurons, particularly in genes involved in neuroplasticity and neurogenesis that are crucial for learning and memory. This work paves the way for future research to explore the specific mechanisms by which EE alters DNA methylation and subsequently influences cognitive functioning.

Zocher et al. Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus. Nature Communications (2021). Access the original scientific publication here.