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What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol

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      Abstract

      Background

      Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingør, Denmark.

      Methodology

      Literature search in databases as PubMed and ISI Web of Science in combination with manual search was used to answer the following five questions: 1Can resveratrol be recommended in the prevention or treatment of human diseases?; 2Are there observed “side effects” caused by the intake of resveratrol in humans?; 3What is the relevant dose of resveratrol?; 4What valid data are available regarding an effect in various species of experimental animals?; 5Which relevant (overall) mechanisms of action of resveratrol have been documented?

      Conclusions/Significance

      The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects.

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      Most cited references 159

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      Dose translation from animal to human studies revisited.

      As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.
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        Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.

        Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.
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          Resveratrol improves health and survival of mice on a high-calorie diet.

          Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
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            Author and article information

            Affiliations
            [1 ]Department of Science, System and Models, Roskilde University, Roskilde, Denmark
            [2 ]Department of Dermatology, University of Wisconsin, Madison, Wisconsin, United States of America
            [3 ]Department of Animal and Dairy Science, University of Georgia, Athens, Georgia, United States of America
            [4 ]Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
            [5 ]Department of Cancer Studies and Molecular Medicine, The Biocentre, University of Leicester, Leicester, Great Britain, United Kingdom
            [6 ]Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
            [7 ]Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut, United States of America
            [8 ]INSERM U866, University of Burgundy, Dijon, France
            [9 ]Department of Biochemistry, Postgraduate Programme of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
            [10 ]Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America
            [11 ]Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
            [12 ]Laboratory of Physiological Studies, Section on Oxidative Stress Tissue Injury, National Institutes of Health, Rockville, Maryland, United States of America
            [13 ]Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India
            [14 ]College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii, United States of America
            [15 ]UFR Pharmacie, University of Bordeaux, Villenave d'Ornon, France
            [16 ]Proteomics Laboratory, Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India
            [17 ]College of Pharmacy, Seoul National University, Seoul, South Korea
            [18 ]Clinical Institute of Medical and Chemical Laboratory Diagnostics, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria
            [19 ]Department of Animal Physiology and Biochemistry, August Cieszkowski University of Agriculture, Poznan, Poland
            [20 ]Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, United States of America
            [21 ]Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, United States of America
            University of Valencia, Spain
            Author notes

            Conceived and designed the experiments: OV. Analyzed the data: OV NA CAB JAB KB AC DKD DD CG H-YL Q-YM PM NN JMP TR YS Y-JS T. Szekeres T. Szkudelski TW JMW. Wrote the paper: OV. Evaluation of the cancer preventive effect: NA KB H-YL NN JMP YS T. Szekeres. Evaluation of the CHD preventive effect: DKD PM JMW. Evaluation of the obesity/diabetes effect: CAB T. Szkudelski. Evaluation of the anti-aging/anti-inflammatory effect: JAB AC Q-YM. Evaluation of the neuroprotective effect: CG TR. Metabolism and pharmacokinetic of resveratrol: DD TW.

            Contributors
            Role: Editor
            Journal
            PLoS One
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            1932-6203
            2011
            16 June 2011
            : 6
            : 6
            3116821
            21698226
            PONE-D-11-01755
            10.1371/journal.pone.0019881
            (Editor)
            This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
            Counts
            Pages: 11
            Categories
            Research Article
            Chemistry
            Phytochemistry
            Phytopharmacology
            Medicine
            Cardiovascular
            Clinical Research Design
            Systematic Reviews
            Complementary and Alternative Medicine
            Endocrinology
            Diabetic Endocrinology
            Non-Clinical Medicine
            Health Care Policy
            Treatment Guidelines
            Nutrition
            Obesity
            Oncology
            Cancer Prevention
            Public Health
            Preventive Medicine
            Science Policy
            Research Assessment

            Uncategorized

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