Development of Calorie Restriction Mimetics as a Prolongevity Strategy

Authors

  • DONALD K. INGRAM,

    Corresponding author
    1. Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
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  • R MICHAEL ANSON,

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    • a

      Current address: R. Michael Anson, St. George's University School of Medicine, Grenada, West Indies.

  • RAFAEL DE CABO,

    1. Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
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  • JACEK MAMCZARZ,

    1. Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
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  • MIN ZHU,

    1. Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
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  • JULIE MATTISON,

    1. Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
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  • MARK A. LANE,

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    • bCurrent address: Mark A. Lane, Merck and Company, Rahway, NJ 07065.

  • GEORGE S. ROTH

    1. Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
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Address for correspondence: Donald K. Ingram, Acting Chief, Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224. Voice: 410-558-8180; fax: 410-558-8302. ingramd@grc.nia.nih.gov

Abstract

Abstract: By applying calorie restriction (CR) at 30-50% below ad libitum levels, studies in numerous species have reported increased life span, reduced incidence and delayed onset 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 antiaging strategy for humans, application of this intervention would be problematic due to the degree and length of restriction required. To meet this challenge for potential application of CR, new research to create “caloric restriction mimetics” has emerged. This strategy focuses on identifying compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. Microarray studies show that gene expression profiles of key enzymes in glucose (energy) handling pathways are modified by CR. 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 neurotoxicity, enhanced dopamine action, and upregulated brain-derived neurotrophic factor. Further life span 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.

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