Hippocampal gene expression patterns linked to late-life physical activity opposes age and AD-related transcriptional decline

Exercise has emerged as a powerful variable that can improve cognitive function and delay age-associated cognitive decline and Alzheimers disease (AD), however, the underlying mechanisms are poorly understood. To determine if protective mechanisms may occur at the transcriptional level, we used microarrays to investigate the relationship between physical activity levels and gene expression patterns in the cognitively-intact aged human hippocampus. In parallel, hippocampal gene expression patterns associated with Aging and AD were assessed using publicly available microarray data profiling hippocampus from young (20-59 yrs), cognitively-intact aging (73-95 yrs) and age-matched AD cases. To identify anti-Aging/AD transcription patterns associated with physical activity, probesets significantly associated with both physical activity and Aging/AD were identified and their directions of expression change in each condition were compared. Remarkably, of the 2138 probesets significant in both datasets, nearly 95% showed opposite transcription patterns with physical activity compared to Aging/AD. The majority (>70%) of these anti-Aging/AD genes showed increased expression with physical activity and decreased expression in Aging/AD. Enrichment analysis of the anti-Aging/AD genes showing increased expression in association with physical activity revealed strong overrepresentation of mitochondrial energy production and synaptic function, along with axonal function and myelin integrity. Synaptic genes were notably enriched for synaptic vesicle priming, release and recycling, glutamate and GABA signaling and synaptic spine plasticity. Anti-Aging/AD genes showing decreased expression in association with physical activity were enriched for transcription-related function. These data suggest that physical activity preserves a more youthful profile in the hippocampus across multiple biological processes, providing a potential molecular foundation for how physical activity can delay age- and AD-related decline of hippocampal function.

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