Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling

The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin- like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway(1-7) Muta nts in this pathway remain youthful and active much longer than normal anim als and can live more than twice as long, This lifespan extension requires DAF-16, a forkhead/winged-helix transcription factor(8,9). DAF-16 is though t to be the main target of the DAF-2 pathway. Insulin/IGF-1 signaling is th ought to lead to phosphorylation of DAF-16 by AKT activity, which in turn s hortens lifespan. Here, we show that the DAF-2 pathway prevents DAF-16 accu mulation in nuclei. Disrupting Akt-consensus phosphorylation sites in DAF-1 6 causes nuclear accumulation in wild-type animals, but, surprisingly, has little effect on lifespan. Thus the DAF-2 pathway must have additional outp uts. Lifespan in C. elegans can be extended by perturbing sensory neurons o r germ cells(10,11). In both cases, lifespan extension requires DAF-16. We find that both sensory neurons and germline activity regulate DAF-16 accumu lation in nuclei, but the nuclear localization patterns are different. Toge ther these findings reveal unexpected complexity in the DAF-16-dependent pa thways that regulate aging.