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      Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster

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          Summary

          The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated, increases life span in evolutionarily diverse organisms including mammals. The central component of this pathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-described drug approved for human use. We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants. Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat. Analysis of the underlying mechanisms revealed that rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, through alterations to both autophagy and translation. Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms.

          Highlights

          ► Rapamycin, a drug that inhibits TOR pathway, improves longevity in Drosophila ► Rapamycin longevity effects are mediated through the TOR pathway ► Life span extension by rapamycin is through translation changes and autophagy ► Rapamycin extends life span beyond dietary restriction and mild IIS mutations

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          Most cited references 58

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          TOR signaling in growth and metabolism.

          The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. Here, highlighting contributions from studies in model organisms, we review mammalian TOR complexes and the signaling branches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1), which is sensitive to rapamycin, and TORC2, which is not. The physiological consequences of mammalian TORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
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            Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

            Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruit flies1–5. However, whether inhibition of mTOR signalling can extend life in a mammalian species was unknown. We report here that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. Based on age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. These are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
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              Regulation of translation initiation in eukaryotes: mechanisms and biological targets.

              Translational control in eukaryotic cells is critical for gene regulation during nutrient deprivation and stress, development and differentiation, nervous system function, aging, and disease. We describe recent advances in our understanding of the molecular structures and biochemical functions of the translation initiation machinery and summarize key strategies that mediate general or gene-specific translational control, particularly in mammalian systems.
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                Author and article information

                Journal
                Cell Metab
                Cell Metab
                Cell Metabolism
                Cell Press
                1550-4131
                1932-7420
                06 January 2010
                06 January 2010
                : 11
                : 1
                : 35-46
                Affiliations
                [1 ]Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK
                [2 ]Max Planck Institute for Biology of Aging, Gleueler Straße 50a, 50931 Köln, Germany
                Author notes
                []Corresponding author l.partridge@ 123456ucl.ac.uk
                [3]

                These authors contributed equally to this work

                Article
                CMET672
                10.1016/j.cmet.2009.11.010
                2824086
                20074526
                © 2010 ELL & Excerpta Medica.

                This document may be redistributed and reused, subject to certain conditions.

                Categories
                Article

                Cell biology

                proteins, humdisease

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