No medications prevent or reverse age-related cognitive decline. Physical activity (PA) enhances memory in rodents, but findings are mixed in human studies. As a result, exercise guidelines specific for brain health are absent. Here, we reexamine results from human studies, and suggest the use of more sensitive tasks to evaluate PA effects on age-related changes in the hippocampus, such as relational memory and mnemonic discrimination. We discuss recent advances from rodent and human studies into the underlying mechanisms at both the central and peripheral levels, including neurotrophins and myokines that could contribute to improved memory. Finally, we suggest guidelines for future research to help expedite well-founded PA recommendations for the public.

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