title: A role for autophagy in the extension of lifespan by dietary restriction in C. elegans.
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.
authors.affiliation: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Malene
authors.initials: M
authors.lastname: Hansen
authors.forename: Abha
authors.initials: A
authors.lastname: Chandra
authors.forename: Laura L
authors.initials: LL
authors.lastname: Mitic
authors.forename: Brian
authors.initials: B
authors.lastname: Onken
authors.forename: Monica
authors.initials: M
authors.lastname: Driscoll
authors.forename: Cynthia
authors.initials: C
authors.lastname: Kenyon
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development* / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D004032:Diet; D017238:Genes, Helminth; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
chemical_list: D029742:Caenorhabditis elegans Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D011972:Receptor, Insulin; D011978:Receptors, Nicotinic; D015534:Trans-Activators; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; C487508:Eat-2 protein, C elegans; C113277:Pha-4 protein, C elegans; C477268:bec-1 protein, C elegans; C472494:let-363 protein, C elegans; C107483:DAF-2 protein, C elegans; C510977:RAB-10 protein, C elegans