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      Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

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          Abstract

          Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruit flies 15. 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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          Most cited references 29

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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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            Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients.

             M Kaeberlein (2005)
            Calorie restriction increases life span in many organisms, including the budding yeast Saccharomyces cerevisiae. From a large-scale analysis of 564 single-gene-deletion strains of yeast, we identified 10 gene deletions that increase replicative life span. Six of these correspond to genes encoding components of the nutrient-responsive TOR and Sch9 pathways. Calorie restriction of tor1D or sch9D cells failed to further increase life span and, like calorie restriction, deletion of either SCH9 or TOR1 increased life span independent of the Sir2 histone deacetylase. We propose that the TOR and Sch9 kinases define a primary conduit through which excess nutrient intake limits longevity in yeast.
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              Genetics: influence of TOR kinase on lifespan in C. elegans.

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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                16 November 2009
                8 July 2009
                16 July 2009
                16 January 2010
                : 460
                : 7253
                : 392-395
                Affiliations
                [1 ]The Jackson Laboratory, Bar Harbor, ME 04609 USA
                [2 ]Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, Department of Pharmacology, and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, Texas 78229 USA
                [3 ]Institute of Biotechnology/Department of Molecular Medicine, and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, Texas 78245 USA
                [4 ]Department of Physiology and Barshop Institute for Longevity and Aging Studies at The University of Texas Health Science Center at San Antonio, TX 78229 USA
                [5 ]Division of Aging Biology, National Institute on Aging, Bethesda, MD 20892, USA
                [6 ]Unit for Laboratory Animal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109-2200 USA
                [7 ]Environmental Medicine, NY University School of Medicine, NY 10016 USA
                [8 ]Wake Forest University School of Medicine, Department of Internal Medicine: Section on Gerontology and Geriatrics Winston-Salem NC 27157 USA
                [9 ]Department of Psychiatry, The University of Texas Health Science Center at San Antonio, TX 78229 USA
                [10 ]Department of Pathology and Geriatrics Center, University of Michigan; and Ann Arbor VA Medical Center, Ann Arbor, MI 48109-2200 USA
                Author notes
                Correspondence and requests for materials should be addressed to D.E H. ( avid.harrison@ 123456jax.org )
                [†]

                Present address: Department of Aging and Geriatric Research, College of Medicine, Institute on Aging, University of Florida, Gainesville, FL 32611.

                [*]

                These three authors contributed equally to this study.

                Article
                nihpa127666
                10.1038/nature08221
                2786175
                19587680
                Funding
                Funded by: National Institute on Aging : NIA
                Award ID: U01 AG022307-05S1 ||AG
                Funded by: National Institute on Aging : NIA
                Award ID: U01 AG022307-05 ||AG
                Funded by: National Institute on Aging : NIA
                Award ID: U01 AG022307-04 ||AG
                Funded by: National Institute on Aging : NIA
                Award ID: U01 AG022307-03 ||AG
                Funded by: National Institute on Aging : NIA
                Award ID: U01 AG022307-02 ||AG
                Funded by: National Institute on Aging : NIA
                Award ID: U01 AG022307-01 ||AG
                Funded by: National Institute on Aging : NIA
                Award ID: P30 AG013319-149002 ||AG
                Funded by: National Institute on Aging : NIA
                Award ID: P30 AG013319-139002 ||AG
                Funded by: National Institute on Aging : NIA
                Award ID: P30 AG013319-129002 ||AG
                Funded by: National Institute on Aging : NIA
                Award ID: P30 AG013319-119002 ||AG
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