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Dietary and Aging Influences on Neuronal Function

By applying calorie restriction (CR) at 30–50% below ad libitum levels, studies in numerous species have reported increased lifespan, lowered incidence of age-related diseases, improved stress resistance, and decelerated functional decline. Regarding brain aging, CR attenuates age-related alterations in structural and neurochemical parameters and maintains behavioral function. In models of neurodegeneration, CR protects against neurotoxic insults as well as enhances neurogenesis and gliagenesis. Emerging results from studies in monkeys suggest that CR could have beneficial effects on aging and age-related diseases in human beings, although positive effects on brain aging remain unproven. Despite ample evidence of CR-related benefits and progress to identify its molecular mechanisms, application of CR as an anti-aging intervention in human beings remains problematic because of the severity and length of restriction required. To meet this challenge for potential application of CR, new research termed caloric restriction mimetics has emerged. This strategy focuses on identifying compounds that mimic CR effects by activating stress response pathways enhanced by CR, but without actually restricting caloric intake. Drugs that inhibit glycolysis (2-deoxyglucose) or enhance insulin action (metformin) are being assessed as CR mimetics. Promising results have emerged from initial studies regarding physiologic responses indicative of CR (reduced body temperature and plasma insulin) as well as protection against neurotoxicicty, enhanced dopamine action, and upregulated brainderived neurotrophic factor. However, further lifespan analyses in addition to expanded toxicity studies must be completed to assess the potential of any CR mimetic.