Environmental enrichment modulates, but does not normalize, aging-associated immune transcriptional programs after...

Area of Science:

• Neuroscience
• Genomics
• Aging Research

Background:

• Aging significantly alters hippocampal gene expression, promoting neuroinflammation and reducing neuronal and metabolic functions, which increases susceptibility to ischemic injury.
• Environmental enrichment (EE) is a known non-pharmacological intervention that promotes brain plasticity, but its systems-level effects on aging- and stroke-associated gene co-expression programs remain unassessed.
• Understanding the interplay between aging, stroke, and EE at the transcriptional level is crucial for developing effective interventions in aging populations.

Purpose of the Study:

• To investigate the impact of aging on hippocampal transcriptional architecture using weighted gene co-expression network analysis (WGCNA).
• To compare aging-associated transcriptional signatures with those induced by stroke.
• To evaluate the effects of environmental enrichment (EE) on established aging-related gene expression patterns and their overlap with stroke signatures.

Main Methods:

• Weighted gene co-expression network analysis (WGCNA) was applied to hippocampal RNA-sequencing data from aging mice.
• Gene set enrichment analysis was performed using independent stroke and aging datasets.
• Cell-type deconvolution (MuSiC) was used to assess cellular contributions to transcriptional changes, and module eigengenes were projected to evaluate EE effects.

Main Results:

• Aging significantly altered 24 gene co-expression modules, with upregulated modules enriched for neuroinflammatory pathways and downregulated modules linked to neuronal and metabolic functions.
• Aging and stroke exhibited largely distinct transcriptional signatures, with only 18 out of 29 stroke-engaged modules overlapping with age-associated modules.
• Environmental enrichment (EE) partially reversed age-suppressed gene programs but did not significantly suppress key neuroinflammatory and interferon modules most associated with the aging-stroke overlap.

Conclusions:

• Aging remodels the hippocampus by upregulating inflammatory gene programs and downregulating neuronal/metabolic networks, increasing stroke susceptibility.
• Environmental enrichment (EE) engages plasticity and glial-related mechanisms but does not fully mitigate the core inflammatory pathways driving the aging-stroke overlap.
• Complement and interferon signaling pathways are identified as priority targets for pharmacological interventions aimed at protecting aged, stroke-vulnerable populations.