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      A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans

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          Abstract

          In many organisms, dietary restriction appears to extend lifespan, at least in part, by down-regulating the nutrient-sensor TOR (Target Of Rapamycin). TOR inhibition elicits autophagy, the large-scale recycling of cytoplasmic macromolecules and organelles. In this study, we asked whether autophagy might contribute to the lifespan extension induced by dietary restriction in C. elegans. We find that dietary restriction and TOR inhibition produce an autophagic phenotype and that inhibiting genes required for autophagy prevents dietary restriction and TOR inhibition from extending lifespan. The longevity response to dietary restriction in C. elegans requires the PHA-4 transcription factor. We find that the autophagic response to dietary restriction also requires PHA-4 activity, indicating that autophagy is a transcriptionally regulated response to food limitation. In spite of the rejuvenating effect that autophagy is predicted to have on cells, our findings suggest that autophagy is not sufficient to extend lifespan. Long-lived daf-2 insulin/IGF-1 receptor mutants require both autophagy and the transcription factor DAF-16/FOXO for their longevity, but we find that autophagy takes place in the absence of DAF-16. Perhaps autophagy is not sufficient for lifespan extension because although it provides raw material for new macromolecular synthesis, DAF-16/FOXO must program the cells to recycle this raw material into cell-protective longevity proteins.

          Author Summary

          Dietary restriction (limited food intake) increases lifespan in many organisms. However, the cellular processes underlying this fascinating phenomenon are still poorly understood. When an animal is starved, it degrades and recycles its organelles and other cellular components in a process called autophagy (literally “self-eating”). Here, we have asked whether autophagy also occurs in response to dietary restriction, using the roundworm C. elegans for our studies. We find that autophagy does take place when food intake is limited. Moreover, inhibiting genes required for autophagy has little effect on well-fed animals but prevents food limitation from extending lifespan. This autophagy requires PHA-4/FOXA, a life-extension protein that regulates gene expression, suggesting that changes in gene expression are required for dietary restriction to stimulate autophagy. Because autophagy seems like such a rejuvenating process, it might seem to be sufficient to increase longevity. However, we find that, in long-lived hormone-pathway mutants, both autophagy and DAF-16/FOXO, another protein that controls gene expression, are required for longevity. We propose that autophagy frees up new resources for the cell, but that transcription factors like the DAF-16/FOXO protein must channel this raw material into new cell-protective proteins in order for lifespan to be increased.

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          Most cited references 70

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          The genetics of Caenorhabditis elegans.

          Methods are described for the isolation, complementation and mapping of mutants of Caenorhabditis elegans, a small free-living nematode worm. About 300 EMS-induced mutants affecting behavior and morphology have been characterized and about one hundred genes have been defined. Mutations in 77 of these alter the movement of the animal. Estimates of the induced mutation frequency of both the visible mutants and X chromosome lethals suggests that, just as in Drosophila, the genetic units in C. elegans are large.
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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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              Systematic functional analysis of the Caenorhabditis elegans genome using RNAi.

              A principal challenge currently facing biologists is how to connect the complete DNA sequence of an organism to its development and behaviour. Large-scale targeted-deletions have been successful in defining gene functions in the single-celled yeast Saccharomyces cerevisiae, but comparable analyses have yet to be performed in an animal. Here we describe the use of RNA interference to inhibit the function of approximately 86% of the 19,427 predicted genes of C. elegans. We identified mutant phenotypes for 1,722 genes, about two-thirds of which were not previously associated with a phenotype. We find that genes of similar functions are clustered in distinct, multi-megabase regions of individual chromosomes; genes in these regions tend to share transcriptional profiles. Our resulting data set and reusable RNAi library of 16,757 bacterial clones will facilitate systematic analyses of the connections among gene sequence, chromosomal location and gene function in C. elegans.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                pgen
                plge
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                February 2008
                15 February 2008
                2 January 2008
                : 4
                : 2
                Affiliations
                [1 ] Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America
                [2 ] Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, United States of America
                Stanford University Medical Center, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: ckenyon@ 123456biochem.ucsf.edu
                Article
                07-PLGE-RA-0723R2 plge-04-02-15
                10.1371/journal.pgen.0040024
                2242811
                18282106
                Copyright: © 2008 Hansen et al. 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 author and source are credited.
                Counts
                Pages: 14
                Categories
                Research Article
                Biochemistry
                Developmental Biology
                Genetics and Genomics
                Molecular Biology
                Caenorhabditis
                Custom metadata
                Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, et al. (2008) A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4(2): e24. doi: 10.1371/journal.pgen.0040024

                Genetics

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