A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans
Open accessAbstract
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.
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Activation of macroautophagy is a common feature of all the long-lived mutant worms, including the models for dietary restriction.
“Activation of macroautophagy is a common feature of all the long-lived mutant worms, including the models for dietary restriction (Hansen et al., 2008; Hars et al., 2007; Melendez et al., 2003; Tóth et al., 2008).”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Hansen et al., 2008
The Results and Discussion support increased autophagy in long-lived dietary-restriction eat-2 mutants. But the Discussion reports no increase in the autophagy reporter’s foci in long-lived rsks-1 mutants, contrary to the claim that activation is a feature of all long-lived mutant worms. The authors note that autophagy in other tissues remains possible. (LLM, conf=0.85)
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Experimental — accuracy not yet measuredFunctional macroautophagy is necessary to attain the maximal lifespan extension mediated by mutations in the nutrient-sensor TOR, the tumor suppressor protein p53, and the lifespan prolonging effect of Sirt-1.
“Functional macroautophagy has also proven necessary to attain the maximal lifespan extension mediated by mutations in other genes such as the nutrient-sensor TOR (Hansen et al., 2008), the tumor suppressor protein p53 (Tavernarakis et al., 2008) and even the lifespan prolonging effect of Sirt-1 (Morselli et al., 2010).”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Hansen et al., 2008
RAB7 is needed for the clearance of autophagic compartments, most likely for the fusion of amphisomes with lysosomes.
“RAB7 is also needed for the clearance of”
From Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). (2016) · cites this paper as [1704]
The Results section on rab-10 reports that inhibiting RAB-10 increases autophagy, but does not address RAB7. The Introduction describes autophagosomes being degraded in lysosomes; neither it nor the passages retrieved by searching for RAB7 and amphisome–lysosome fusion establishes RAB7’s role in clearance. Page numbers are unavailable in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measuredIncreased autophagy is necessary for lifespan extension by reduced insulin-like signaling and dietary restriction in worms.
“In worms, increased autophagy is necessary for lifespan extension by reduced insulin-like signaling (50) and dietary restriction (51).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [51]
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- Authors
- Hansen, M., Chandra, A., Mitic, L. L., Onken, B., Driscoll, M., & Kenyon, C.
- Affiliations
- University of California, San Francisco (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Kenyon, Cynthia
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-02-15
- Volume
- 4
- Issue
- 2
- Pages
- e24
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC2242811
- OpenAlex
- W1994305081
- Cited by
- 766
- References
- 70
- Citations by year
- 2026: 24 · 2025: 31 · 2024: 25 · 2023: 31 · 2022: 32 · 2021: 36 · 2020: 42 · 2019: 51 · 2018: 34 · 2017: 32 · 2016: 50 · 2015: 42 · 2014: 53 · 2013: 44 · 2012: 45
- FWCI
- 18.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Ellison Medical Foundation
- Larry L. Hillblom Foundation
- Massachusetts General Hospital
- National Institutes of Health
- University of California, San Francisco
- National Institute on Aging (R01AG024882, T32AG000278)
- National Institute of Diabetes and Digestive and Kidney Diseases (T90DK070135)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Keywords
- autophagy, lifespan extension, dietary restriction, TOR signaling, Caenorhabditis elegans, PHA-4, DAF-16/FOXO, daf-2 mutant, longevity, nutrient sensing
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Autophagy, Diet, Longevity, Models, Biological, Mutation, Receptor, Insulin, Receptors, Nicotinic, Trans-Activators, Caenorhabditis elegans, Genes, Helminth, Phosphotransferases (Alcohol Group Acceptor), Phosphatidylinositol 3-Kinases, rab GTP-Binding Proteins, Caenorhabditis elegans Proteins, Animals, Genetically Modified, Vesicular Transport Proteins, RNA Interference
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