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      The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing

      review-article
      *
      Philosophical Transactions of the Royal Society B: Biological Sciences
      The Royal Society
      daf-2, daf-16, FOXO, history, insulin, IFG-1

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          Abstract

          Inhibiting insulin/IGF-1 signalling extends lifespan and delays age-related disease in species throughout the animal kingdom. This life-extension pathway, the first to be defined, was discovered through genetic studies in the small roundworm Caenorhabditis elegans. This discovery is described here.

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          Most cited references47

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          daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.

          A C. elegans neurosecretory signaling system regulates whether animals enter the reproductive life cycle or arrest development at the long-lived dauer diapause stage. daf-2, a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member. Decreases in DAF-2 signaling induce metabolic and developmental changes, as in mammalian metabolic control by the insulin receptor. Decreased DAF-2 signaling also causes an increase in life-span. Life-span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism, diapause, and longevity.
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            The plasticity of aging: insights from long-lived mutants.

            Mutations in genes affecting endocrine signaling, stress responses, metabolism, and telomeres can all increase the life spans of model organisms. These mutations have revealed evolutionarily conserved pathways for aging, some of which appear to extend life span in response to sensory cues, caloric restriction, or stress. Many mutations affecting longevity pathways delay age-related disease, and the molecular analysis of these pathways is leading to a mechanistic understanding of how these two processes--aging and disease susceptibility--are linked.
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              Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation.

              The genetic analysis of life span has revealed many interesting genes and pathways; however, our understanding of aging has been limited by the lack of a way to assay the aging process itself. Here we show that the tissues of aging worms have a characteristic appearance that is easy to recognize and quantify using Nomarski optics. We have used this assay to determine whether life-span mutations affect the rate of aging, to identify animals that age more rapidly than normal, and to infer the cause of death in C. elegans. Mutations that reduce insulin/IGF-1 signaling double the life span of C. elegans, and we find that tissue decline is slowed in these mutants. Thus this endocrine system appears to influence the rate at which tissues age. This effect extends even to the germline, which is the only mitotically active tissue in the adult. We find that Nomarski microscopy also allows a ready distinction between short-lived mutants that age more rapidly than normal and those that are simply sick, and we have identified an RNAi clone that confers a dramatic rapid-aging phenotype. This clone encodes the C. elegans heat-shock factor (HSF), a transcription factor that regulates the response to heat and oxidative stress. This suggests that heat-shock proteins, many of which act as chaperones, may function in normal animals to slow the rate of aging. Finally, we have identified a cause of death of C. elegans: namely, proliferating bacteria. This suggests that increased susceptibility to bacterial infections contributes to mortality in these animals, just as it does in humans.
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                Author and article information

                Journal
                Philos Trans R Soc Lond B Biol Sci
                RSTB
                royptb
                Philosophical Transactions of the Royal Society B: Biological Sciences
                The Royal Society
                0962-8436
                1471-2970
                12 January 2011
                12 January 2011
                : 366
                : 1561 , Discussion Meeting issue 'The new science of ageing' organized and edited by Linda Partridge, Gillian Bates and Janet Thornton
                : 9-16
                Affiliations
                simpleUniversity of California, San Francisco , CA 94158, USA
                Author notes
                Article
                rstb20100276
                10.1098/rstb.2010.0276
                3001308
                21115525
                253e8e5a-45a5-4e12-8548-669f8c850181
                This Journal is © 2011 The Royal Society

                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 work is properly cited.

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                Philosophy of science
                foxo,ifg-1,daf-16,insulin,daf-2,history
                Philosophy of science
                foxo, ifg-1, daf-16, insulin, daf-2, history

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