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

By M. Hansen, Abha Chandra, Laura Mitic, Brian Onken, Monica Driscoll, C. Kenyon. PLoS Genetics, 2008

781 citations recorded by the source corpus.

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.

Subfields: Aging

View Paper: https://www.semanticscholar.org/paper/aa6dd297642d39be4b3622505ca2c0f3c07093f0

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Citations in the corpus

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity (2015, background): “Accordingly, increased autophagy is essential for lifespan extension in dietary restriction conditions or TOR inhibition in C. elegans (Hansen et al., 2008).”
Phosphatidylinositol-5-phosphate 4-kinases regulate cellular lipid metabolism by facilitating autophagy (2018, background): “Several studies have shown that impaired autophagy in C. elegans reduces lifespan and enhances sensitivity to metabolic stress (Hansen et al., 2008; Possik et al., 2014).”
With TOR less is more: a key role for the conserved nutrient sensing TOR pathway in aging (2010, positive): “As inhibition of autophagy does not compromise the life span of control animals in both worms and flies (Hansen et al., 2008; Melendez et al., 2003; Ren et al., 2009), this observation supports the idea that enhanced autophagy may extend life span.”
mTOR signaling in growth control and disease (2012, neutral): “A similar effect has been seen in Caenorhabditis elegans, where dsRNA against TOR does not extend the lifespan of eat-2mutant worms, which have impaired feeding behavior and represent a genetic model for DR (Hansen et al., 2008).”
Autophagy: Renovation of Cells and Tissues (2011, background): “…of the autophagy-related genes are required for life-span extension induced by inhibition of insulin/IGF-like signaling and calorie restriction (Hansen et al., 2008; Hars et al., 2007; Jia and Levine, 2007; Melé ndez et al., 2003; Tó th et al., 2008), although not all autophagy-related genes…”
Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster (2010, methodology): “The concentration of rapamycin in flies fed on 200 mM food, measured by mass spectrometry, was 3.3 ± 0.2 ng/mg wet weight, comparable to the effective dose administered to mice for life span analysis (Harrison et al., 2009).”
mTOR: from growth signal integration to cancer, diabetes and ageing (2010, methodology): “Autophagy was required for lifespan extension by virtually all protocols in worms and flie”