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      Absence of effects of Sir2 over-expression on lifespan in C. elegans and Drosophila

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          Abstract

          Over-expression of sirtuins (NAD +-dependent protein deacetylases) has been reported to increase lifespan in budding yeast, Caenorhabditis elegans and Drosophila melanogaster 1- 3 . Studies of gene effects on ageing are vulnerable to confounding effects of genetic background 4 . We re-examined the reported effects of sirtuin over-expression on ageing and found that standardisation of genetic background and use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high level sir-2.1 over-expression 1 abrogated the longevity increase, but not sir-2.1 over-expression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low copy number sir-2.1 over-expression 2 also abrogated longevity. A Drosophila strain with ubiquitous over-expression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported 3 , but not relative to the appropriate transgenic controls, and nor was a new line with stronger over-expression of dSir2. These findings underscore the importance of controlling for genetic background and the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life extending effect of dietary restriction (DR) on ageing in Drosophila has also been reported to be dSir2 dependent 3 . We found that DR increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects on lifespan in C. elegans and Drosophila.

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          Most cited references29

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          Mammalian sirtuins: biological insights and disease relevance.

          Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.
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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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              Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

              Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                29 July 2011
                21 September 2011
                22 March 2012
                : 477
                : 7365
                : 482-485
                Affiliations
                [1 ]Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College, London, Gower Street, London WC1E 6BT, UK
                [2 ]Department of Medical Chemistry, Semmelweis University, Tüzoltó Street 37-47, 1094 Budapest, Hungary
                [3 ]Department of Pathology, University of Washington, Seattle, WA 98195, USA
                [4 ]Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA
                [5 ]Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
                [6 ]Inserm, Unit 894, Laboratory of Neuronal Cell Biology and Pathology, 75014 Paris, France
                [7 ]Université Paris Descartes, 75014 Paris, France
                [8 ]MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
                [9 ]Max Planck Institute for Biology of Ageing, Gleueler Straße 50a, 50931 Köln, Germany.
                Author notes
                Correspondence and requests for materials should be addressed to D.G. ( david.gems@ 123456ucl.ac.uk ).
                [*]

                These authors contributed equally to this study.

                Author contributions The project was conceived by D.G. and L.P., and the experiments were designed by A.B., C.B., F.C., D.G., K.H., M.K., J.J.M., C.N., L.P., C.S. and S.V.. The experiments were performed and analyzed by C.A., D.A., C.B., F.C., J.J.M., M.G., M.H., A.M.O., M.D.P., M.R., G.L.S., M.S., G.V., R.V., S.V. and V.L.. The manuscript was written by C.B., F.C., D.G., L.P. and S.V.

                Author information Reprints and permissions information are available at www.nature.com/reprints.

                Article
                UKMS36015
                10.1038/nature10296
                3188402
                21938067
                d7165094-266b-44e6-a145-79bd3beb1fbd

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                Funding
                Funded by: Wellcome Trust :
                Award ID: 081394 || WT
                Funded by: Wellcome Trust :
                Award ID: 081394 || WT
                Categories
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                Uncategorized

                genetic background, ageing, c. elegans, sirtuin, drosophila

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