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      A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice

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          Abstract

          Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg −1 day −1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.

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          Most cited references39

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          Sirtuin activators mimic caloric restriction and delay ageing in metazoans.

          Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.
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            Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

            In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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              Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans.

              Many conditions that shift cells from states of nutrient utilization and growth to states of cell maintenance extend lifespan. We have carried out a systematic lifespan analysis of conditions that inhibit protein synthesis. We find that reducing the levels of ribosomal proteins, ribosomal-protein S6 kinase or translation-initiation factors increases the lifespan of Caenorhabditis elegans. These perturbations, as well as inhibition of the nutrient sensor target of rapamycin (TOR), which is known to increase lifespan, all increase thermal-stress resistance. Thus inhibiting translation may extend lifespan by shifting cells to physiological states that favor maintenance and repair. Interestingly, different types of translation inhibition lead to one of two mutually exclusive outputs, one that increases lifespan and stress resistance through the transcription factor DAF-16/FOXO, and one that increases lifespan and stress resistance independently of DAF-16. Our findings link TOR, but not sir-2.1, to the longevity response induced by dietary restriction (DR) in C. elegans, and they suggest that neither TOR inhibition nor DR extends lifespan simply by reducing protein synthesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2008
                4 June 2008
                : 3
                : 6
                : e2264
                Affiliations
                [1 ]LifeGen Technologies, LLC, Madison, Wisconsin, United States of America
                [2 ]Department of Medical Genetics, University of Wisconsin, Madison, Wisconsin, United States of America
                [3 ]Department of Genetics, University of Wisconsin, Madison, Wisconsin, United States of America
                [4 ]Division of Kinesiology, University of Michigan, Ann Arbor, Michigan, United States of America
                [5 ]Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [6 ]Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
                [7 ]R&D Human Nutrition and Health, DSM Nutritional Products Ltd., Basel, Switzerland
                [8 ]Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
                [9 ]Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
                [10 ]Department of Aging and Geriatrics and College of Medicine, University of Florida, Gainesville, Florida, United States of America
                [11 ]Section on Statistical Genetics, Department of Biostatistics and Clinical Nutrition Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [12 ]Department of Medicine and Veterans Administration Hospital, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
                AgroParisTech, France
                Author notes

                Conceived and designed the experiments: TP RW. Performed the experiments: TK JV EA TH. Analyzed the data: TP JW RW JB. Contributed reagents/materials/analysis tools: DA JW GC CL KS YW DR JM. Wrote the paper: TP RW JB.

                Article
                08-PONE-RA-03607R1
                10.1371/journal.pone.0002264
                2386967
                18523577
                86627f8b-d10e-47c4-9cc2-5ee9f4b929c7
                Barger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 12 February 2008
                : 20 April 2008
                Page count
                Pages: 10
                Categories
                Research Article
                Nutrition
                Genetics and Genomics/Bioinformatics
                Genetics and Genomics/Gene Expression
                Physiology/Physiogenomics

                Uncategorized
                Uncategorized

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