Developmental arrest in the dauer larval stage. Scale bar indicates 100 microns. (A) A wild-type adult hermaphrodite that is reproductively active and laying eggs. Under normal growth conditions, wild-type animals proceed through development to become fertile adults. (B) An age-1(mg109) animal arrested as a dauer larvae. Dauer larvae are morphologically distinct from reproductive adults and are nonreproductive. (C) A sterile age-1(mg109) adult. Under semipermissive conditions, some mutant animals can bypass dauer arrest, but form sterile, adult-sized animals lacking functional gonads (Gottlieb & Ruvkun, 1994).

Pathways controlling longevity in collaboration with DAF-16/FOXO in Caenorhabditis elegans. Orange designates genes whose loss-of-function phenotype is increased lifespan while blue designates genes whose loss-of-function phenotype is reduced lifespan. (A) Ligands activate the DAF-2/InsR receptor that recruits AGE-1/PI3K to the cell membrane. AGE-1/PI3K generates phospholipid signals, PIPs, which activate serine/threonine kinases AKT-1, -2, PDK-1 and SGK-1. These kinases phosphorylate DAF-16/FOXO preventing nuclear translocation. DAF-18/PTEN negatively regulates AGE-1 signaling by dephosphorylating PIPs. (B) In response to cellular stress, JNK-1 promotes DAF-16 translocation into the nucleus, activating genes to increase stress resistance (Oh et al., 2005). HSF-1 is activated by stress and promotes the expression of hsps in collaboration with DAF-16 (Hsu et al., 2003; Morley & Morimoto, 2004). BAR-1/beta-catenin acts as a cofactor for DAF-16-mediated expression of antioxidant genes and is required for wild-type lifespan (Essers et al., 2005). (C) Pathways that sense metabolic status and prolong lifespan. TOR is a sensor of nutrient availability that coordinates protein synthesis and metabolism in both vertebrates and invertebrates. In C. elegans, mutations inactivating TOR, encoded by the let-363 gene, cause developmental arrest and can increase adult lifespan in a daf-16-independent manner (Vellai et al., 2003; Jia et al., 2004). daf-15 encodes the RAPTOR subunit for TOR/LET-363 and is transcriptionally repressed by DAF-16/FOXO (Jia et al., 2004). Metabolic status can also be transduced by the NAD-dependent protein deacetylase, SIR-2.1. Increased sir-2.1 activity increases lifespan in a daf-16-dependent manner, and DAF-16 may be a substrate for SIR-2.1 deacetylation (Tissenbaum & Guarente, 2001).