Development of calorie restriction mimetics as a prolongevity strategy
D.K. Ingram
Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224 USA
By applying calorie restriction (CR) at 30-50% below ad libitum levels,
studies in numerous species have reported increased lifespan, reduced
incidence of age-related diseases, improved stress resistance, and
decelerated functional decline. Whether this nutritional intervention
is relevant to human aging remains to be determined; however, evidence
emerging from CR studies in nonhuman primates suggests that response to
CR in primates parallels that observed in rodents. To evaluate CR
effects in humans, clinical trials have been initiated. Even if
evidence could substantiate CR as an effective anti-aging strategy for
humans, application of this intervention would be problematic due to
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 physiological responses
indicative of CR (reduced body temperature and plasma insulin) as well
as protection against neurotoxicicty, enhanced dopamine action, and
upregulated brain-derived neurotrophic factor. Further lifespan
analyses in addition to expanded toxicity studies must be completed to
assess the potential of any CR mimetic, but this strategy now appears
to offer a very promising and expanding research field.
Key words:
nutrition, insulin, glucose, metformin, dopamine
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