Exercise Promotes Neurogenesis in the Aging Mouse Brain

The results of research in mice, headed by a team of researchers at the University of Queensland, has provided new insights into how exercise may help to prevent or slow cognitive decline during aging.

For the study, investigators assessed the expression of genes in individual cells in the brains of mice. Their results showed that exercise has a significant impact on gene expression in microglia, the immune cells of the central nervous system that support brain function. Specifically, the group’s studies in live mice found that exercise reverts the gene expression patterns of aged microglia to patterns seen in young microglia.

“We were both surprised and excited about the extent to which physical activity rejuvenates and transforms the composition of immune cells within the brain, in particular the way in which it was able to reverse the negative impacts of aging,” said Jana Vukovic, PhD, of The University of Queensland, in Australia. “It highlights the importance of normalizing and facilitating access to tailored exercise programs. Our findings should help different industries to design interventions for elderly individuals who are looking to maintain or improve both their physical and mental capabilities.”

Vukovic is co-corresponding author of the team’s published paper in Aging Cell, which is titled “Exercise rejuvenates microglia and reverses T cell accumulation in the aged female mouse brain.” In their report the team stated, “Here we provide unbiased analyses of single-cell RNA sequencing data, showing the impacts of exercise and aging on specific cell types in the mouse hippocampus … Taken together, our data highlight the profound impact of exercise in rejuvenating aged microglia, associated pro-neurogenic effects and on peripheral immune cell presence in the aging female mouse brain.”

Aging induces progressive physiological changes to multiple body systems over time, the authors wrote, and in humans, aging is associated with a decline in both general physical wellbeing and cognitive abilities. Moreover, they noted, “Observational studies in aged individuals consistently suggest that exercise can alleviate age-related deficits in multiple physiological systems, including the brain.” Rodent studies by the team and others have demonstrated that voluntary exercise can mitigate age-related cognitive impairment, and neurogenesis has been proposed as a potential mechanism mediating exercise-induced alleviation of age-related cognitive impairment, the authors stated. “However, the mechanisms underlying the beneficial effects of exercise on the aging brain remain poorly defined.”

For their reported study in mice, Vokovic and colleagues, including researchers at the University of Oxford, carried out single-cell RNA sequencing (scRNA-seq) and unbiased gene expression analyses to characterise the effects of both aging and voluntary wheel running on the various cell types in the hippocampus of female young, aged, sedentary and exercising mice. Their results showed that the effect of exercise on markers of aging was most pronounced in microglia compared with other evaluated cell types in the brain: astrocytes, endothelial cells, oligodendrocytes. The team stated, “Taken together, exercise ameliorated age-related changes in gene expression, such that the transcriptional profile of microglia from aged exercising mice resembled that of young mice.”

Treatments that depleted microglia revealed that these cells are required for the stimulatory effects of exercise on the formation of new neurons in the brain’s hippocampus, a region involved in memory, learning, and emotion. Their results, they noted, “… highlight a requirement for the presence of rejuvenated microglia in relation to exercise-induced neurogenesis in the hippocampus of aged mice.”

The scientists also found that allowing mice access to a running wheel prevented and/or reduced the presence of T cells in the hippocampus during aging. These immune cells are not typically found in the brain during youth, but they increase with age. “… we found that natural aging was associated with significant T cell accumulation in the brain,” the team stated. “Strikingly, we further discovered that this hallmark of brain aging was reversible, with exercise having a strong restorative effect in that it led to a marked reduction in T cell presence within the hippocampus.” It would be interesting, they suggested, “… to examine the extent to which any exercise-induced reductions in T cell presence are a factor of influence in the rejuvenation of microglia or, alternatively, whether T cells contribute to the transcriptional signature of aged hippocampal microglia.”

Summarizing their findings, the team concluded, “Overall, the transcriptional signatures presented here for microglia and other cell types in terms of aging and/or their responsiveness to exercise provide a rich resource for further functional interrogation that should help (re)define how cell states contribute to cognitive decline and/or the reversal thereof.”