A Narrow Window for Exercise to Improve Neurogenesis via Growth Hormone in Aged Mice

There is mixed evidence for exercise to improve neurogenesis and cognitive function in very old mice. Researchers here suggest that this is because the duration of an exercise program matters greatly, and there is a comparatively narrow window of time in which the result is a net gain in function. This may be an example of the frailty of old age: mild stresses such as exercise that are robustly beneficial in younger individuals become more of a balancing act between cost and benefit in age-damaged individuals. The results are interesting, and will likely guide further explorations of the effects of exercise in very old human patients. That said, it isn't clear that the findings are in any way informative as to the dose-response curve for the effects of exercise on neurogenesis and cognitive function in old humans.

Hippocampal function is critical for spatial and contextual learning, and its decline with age contributes to cognitive impairment. Exercise can improve hippocampal function, however, the amount of exercise and mechanisms mediating improvement remain largely unknown. Here, we show exercise reverses learning deficits in aged (24 months) female mice but only when it occurs for a specific duration, 5 weeks, with longer or shorter periods proving ineffective.

While others have reported that a 5-week period of daily voluntary exercise results in the improvement of hippocampal cognitive function in aged mice, surprisingly, our results reveal that if we extended this period of exercise, there was abrogation of cognitive improvement. The discovery of a "sweet spot" of exercise duration critical for both neurogenic activation and improved spatial learning may help explain previous conflicting reports of the efficacy of exercise in improving cognitive improvement in aged mice.

A spike in the levels of growth hormone (GH) and a corresponding increase in neurogenesis during this sweet spot mediate this effect because blocking GH receptor with a competitive antagonist or depleting newborn neurons abrogates the exercise-induced cognitive improvement. Moreover, raising GH levels with GH-releasing hormone agonist improved cognition in nonrunners. We show that GH stimulates neural precursors directly, indicating the link between raised GH and neurogenesis is the basis for the substantially improved learning in aged animals.

Link: https://doi.org/10.1016/j.isci.2021.103275

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