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. 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.