Exercise Improves Neurogenesis via Restoration of Microglia to a More Youthful Phenotype – Fight Aging!

Exercise is known to improve cognitive function and neurogenesis, the process by which new neurons are created by neural stem cells and then mature to integrate into existing neural networks. Neurogenesis is best studied in the hippocampus, where it is necessary for learning and memory function to take place. It is also likely important in the very limited ability of the central nervous system to recover from injury and in general maintenance of brain tissue over time.

In today’s open access paper, researchers demonstrate that exercise reverses age-related changes in the gene expression and behavior of microglia, innate immune cells of the brain that are analogous to macrophages elsewhere in the body. They also show that microglia are necessary for the benefits of exercise to emerge. Microglia assist neurons in altering and maintaining synaptic connections in the brain, and this is one way in which the aging of microglia might be detrimental to cognitive function.

Microglia also become more inflammatory with age, however, and chronic inflammation tends to change cell behavior for the worse in all tissues. In this context, it is worth noting that exercise is known to dampen inflammation, among its many other benefits. The study here says little about the signaling mechanisms by which exercise might induce a temporary rejuvenation in microglia, however.

Exercise rejuvenates microglia and reverses T cell accumulation in the aged female mouse brain

Exercise may be useful for preventing (or reversing) age-related hippocampal deterioration and maintaining neuronal health. However, the mechanisms underlying the beneficial effects of exercise on the ageing brain remain poorly defined. We provide here a comprehensive single cell RNA-seq dataset and unbiased analyses characterising the effects of both natural ageing and exercise on cell types within the female mouse hippocampus. We show that ageing alters the relative abundance and transcriptional phenotypes of different cell types in the hippocampus.

We further demonstrate that exercise profoundly and specifically impacts the transcriptional state of microglia, reverting the gene expression signature of aged microglia towards that observed in young animals. In particular, the transcriptional profile of disease-associated microglia was markedly rejuvenated by exercise. We went on to demonstrate that microglia are required for the pro-neurogenic effects of exercise in the aged hippocampus. Importantly, however, global depletion of microglia did not affect the cognitive benefits conferred by exercise in our experimental paradigm.

Prior analyses of microglia have indicated that ageing is associated with increased expression of inflammatory factors. Here, we identified similar microglial differentially expressed genes in association with ageing, including type II interferon and immune genes Ccl2, Ccl3, Ccl4, Ccl5, Ccl7, and Ccl8. We also identified pathways enriched in aged microglia, including those regulating the TYROBP causal network, chemokine signalling, and type II interferon signalling. Strikingly, the number of microglial differentially expressed genes identified between young sedentary mice and aged exercising mice was small, reflecting their transcriptional similarity and hence the restorative impact of exercise on the microglial phenotype. Indeed, our linear regression analyses revealed that exercise had a profound and specific effect on the transcriptional signature of aged microglia, reverting their gene expression profile back towards that seen in young microglia.

Recent work from our group highlighted that microglial phenotypes can profoundly influence hippocampal neurogenesis in the injured brain. The process of adult neurogenesis itself is otherwise also well known to be regulated and/or influenced by exercise. We previously demonstrated that exercise supports both the activity and survival of neural precursors, and that microglia may play a role therein. With our unbiased single-cell transcriptomics analyses identifying microglia as the cells mostly modulated by exercise, we probed the in vivo significance of this phenomenon in relation to hippocampal neurogenesis. Here, our depletion experiments showed that the loss of microglia annulled any stimulatory effects of exercise on hippocampal neurogenesis. As technological advances progress, future studies could explore more specifically what microglial subset (or state) inhibits adult neurogenesis and/or drives the pro-neurogenic effects of exercise.