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Background  The provision of stress resistance diverts resources from development and reproduction and must therefore be tightly regulated. In  Caenorhabditis elegans , the switch to increased stress resistance to promote survival through periods of starvation is regulated by the DAF-16/FOXO transcription factor. Reduction-of-function mutations in AGE-1, the  C .  elegans  Class IA phosphoinositide 3-kinase (PI3K), increase lifespan and stress resistance in a  daf-16  dependent manner. Class IA PI3Ks downregulate FOXOs by inducing their translocation to the cytoplasm. However, the circumstances under which AGE-1 is normally activated are unclear. To address this question we used  C. elegans  first stage larvae (L1s), which when starved enter a developmentally-arrested diapause stage until food is encountered.    Results  We find that in L1s both starvation and  daf-16  are necessary to confer resistance to oxidative stress in the form of hydrogen peroxide. Accordingly, DAF-16 is localised to cell nuclei after short-term starvation. However, after long-term starvation, DAF-16 unexpectedly translocates to the cytoplasm. This translocation requires functional  age-1 . H 2 O 2  treatment can replicate the translocation and induce generation of the AGE-1 product PIP 3 . Because feeding reduces to zero in ageing adult  C. elegans , these animals may also undergo long-term starvation. Consistent with our observation in L1s, DAF-16 also translocates to the cytoplasm in old adult worms in an  age-1 -dependent manner.    Conclusion  DAF-16 is activated in the starved L1 diapause. The translocation of DAF-16 to the cytoplasm after long-term starvation may be a feedback mechanism that prevents excessive expenditure on stress resistance. H 2 O 2  is a candidate second messenger in this feedback mechanism. The lack of this response in  age-1(hx546)  mutants suggests a novel mechanism by which this mutation increases longevity.

Long-term starvation and ageing induce AGE-1/PI 3-kinase-dependent translocation of DAF-16/FOXO to the cytoplasm