Minaxi S. Gami, Keaton B. Hanselman and Catherine A. Wolkow. A conserved insulin-like signaling pathway controls larval development, stress resistance and adult lifespan in Caenorhabditis elegans. Signaling downstream of the DAF-2/insulin receptor requires AGE-1, the catalytic
p110 subunit of PI3 kinase, which in turn activates serine/threonine kinases, AKT-1, AKT-2 and PDK-1. Activated AKT-1 and AKT-2 phosphorylate and antagonize DAF-16, a FOXO transcription factor. Mutations in components of the DAF-2/insulin-like signaling pathway can lead to a several fold extension in lifespan and constitutive dauer arrest. Here we describe a genetic screen for suppressors of the constitutive dauer larval arrest phenotype of
age-1(
mg109) animals. From approximately 20,000 haploid genomes, we identified 40 suppressor mutations and molecularly characterized 5 of these. We identified two mutations in
daf-16. In addition, we identified two mutations that were activating alleles of
akt-1 and
pdk-1. Finally, we describe a fifth mutation,
mg227, located on chromosome X, that does not correspond to any known dauer genes. Lifespan analysis of the suppressor mutants showed that
mg227 enhanced the
age-1(
mg109) long lifespan phenotype, whereas,
akt-1(
mg247) and
pdk-1(
mg261) did not affect lifespan of
age-1(
mg109). Both of the
daf-16 alleles suppressed the
age-1(
mg109) long lifespan phenotype.
mg227,
akt-1(
mg247) and
pdk-1(
mg261) did not alter the enhanced stress resistance phenotype of
age-1(
mg109). Consistent with previous reports, the two
daf-16 alleles suppressed the enhanced stress resistance phenotype of
age-1(
mg109). Furthermore, genetic epistasis analysis using RNAi revealed that bypass of dauer arrest in
akt-1(
mg247);
age-1(
mg109) animals was dependent on the presence of
pdk-1. Similarly, dauer bypass in
age-1(
mg109);
pdk-1(
mg261) animals was dependent on
akt-1. Interestingly, dauer bypass in
age-1(
mg109);
mg227 animals required only
akt-1, and
pdk-1 activity was dispensable in this background. The interdependence of
akt-1 and
pdk-1, even in activated forms, supports the existence of AGE-1-independent pathways for these phospholipid-dependent kinases.