The highly conserved insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) pathways play critical roles in aging in multiple species. Mutations in DAF-2, the C. elegans insulin/IGF-1 receptor ortholog, double adult lifespan by activating the DAF-16/FOXO transcription factor. A deletion in the TOR target ribosomal S6 kinase (S6K) encoded by
rsks-1 lead to a moderate lifespan extension in C. elegans. IIS and TOR act in a parallel but interactive manner to modulate growth, but whether and how they interact to determine lifespan is not known. Here we show that a
daf-2 rsks-1 double mutant extends lifespan by nearly 5-fold compared to wild-type animals, and this synergistic extension of lifespan depends on DAF-16 activities. Gene expression profile studies indicate that there are large amount of genes differentially expressed in the very long-lived
daf-2 rsks-1 animals. Through RNAi screens, we have identified suppressor genes that mediate the synergistic longevity phenotype of the
daf-2 rsks-1 double mutant. Among these is a g regulatory subunit of the 5'-AMP-activated protein kinase (AMPK) complex. AMPK activities are elevated in the
daf-2 rsks-1 mutant as indicated by increased transcription of AMPK g and phosphorylation of AMPK a. Furthermore, a deletion in the AMPK a catalytic subunit gene
aak-2 also abolishes the synergistic longevity phenotype. Since AMPK directly activates DAF-16, our results indicate a positive feedback regulation of DAF-16 by DAF-2, S6K and AMPK. Therefore, our findings identify a critical role for AMPK-mediated interaction between
daf-2 and
rsks-1 that result in synergistic lifespan extension.