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

Malene Hansen,Cynthia Kenyon,Laura L Mitic,Abha Chandra,Monica Driscoll,Brian Onken,Stuart K Kim

doi:10.1371/journal.pgen.0040024

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.

Highlights

Dietary restriction, the reduced intake of food without malnutrition, increases the lifespan of many organisms, from yeast to mammals [1]
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
Like lifespan extension itself, is not a passive consequence of food limitation, but instead involves specific transcriptional control

Summary

Introduction

The reduced intake of food without malnutrition, increases the lifespan of many organisms, from yeast to mammals [1]. Inhibition of the TOR pathway extends lifespan in yeast, worms and flies [2,3,4,5], and dietary restriction cannot further extend the lifespans of yeast, worms or flies in which the TOR pathway has been inhibited [3,4,6] This suggests that down-regulation of the TOR pathway plays an important role in the longevity response to food limitation. One could imagine that TOR inhibition extends lifespan solely by inhibiting protein synthesis Another process regulated by TOR, autophagy [12], could potentially influence the longevity of animals subjected to dietary restriction

Methods

Results

Discussion

Conclusion