Daf-2
The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm "Caenorhabditis elegans". DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging. DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens. Mutations in DAF-2 have been shown by Cynthia Kenyon to double the lifespan of the worms. In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.” Long-lived mutants. Long-lived "DAF-2" "C. elegans" mutants are resistant to the oxidizing  agent paraquat and to UV light. "DAF-2" mutants also have a higher DNA repair capability than wild-type "C. elegans". Knockdown of the nucleotide excision repair gene "Xpa-1" increases sensitivity to UV and reduces the life span of the long-lived mutants. These findings support the hypothesis that DNA damage has a significant role in the aging process. IGF-1 signal pathway. Insulin/IGF-1-like signaling is well-conserved evolutionarily across animal phyla, from single celled organisms to mammals. DAF-2 is the only member of the insulin receptor family in "C. elegans" but it corresponds, in form and function, to multiple  pathways in humans. The protein predicted from DAF-2's sequence is 35% identical to the human insulin receptor, which regulates metabolism; 34% identical to the IGF-1 receptor, which regulates growth; and 33% identical to the human insulin receptor–related receptor. In "C. elegans", the insulin/IGF-1/FOXO pathway is initiated by changes in IGF-1 levels which cause IGF-1 receptors to start a phosphorylation cascade that deactivates the FOXO transcription factor, DAF-16. When not phosphorylated, DAF-16 is active and present in the nucleus. DAF-16 is responsible for up-regulating transcription of about 100 genes that code for cell protecting products such  as heat shock proteins and antioxidants. Genetic analysis reveals that the presence of functioning DAF-16 is required to produce the extended lifespan observed in DAF-2 knock-downs. By silencing DAF-16, activation of DAF-2 receptors can ultimately compromise a cell’s ability to mitigate harmful environmental conditions. In most eukaryotes, insulin activates DAF-2 signaling. However, both human insulin and insulin coded for by orthologous genes in "C. elegans" inhibit DAF-2 receptors in "C. elegans". Role in "C. elegans" developmental stages. "Caenorhabditis elegans", which progresses through a series of larval stages into a final reproductive adult, may instead enter a less metabolically  active dauer diapause stage if food scarcity or overcrowding occurs before reaching adulthood. Disabling DAF-2 arrests development in the dauer stage which increases longevity, delays senescence and prevents reproductive maturity. Diet’s interaction with the IGF-1 pathway. Research into the interaction between diet and the insulin/IGF-1 pathway has shown sugar intake to be negatively correlated with DAF-16 activity and longevity. One study found that glucose ingestion reduced the rate of dauer formation and shortened the life-spans of DAF-2 knock-downs to resemble that of normal "C. elegans", suggesting that DAF-16 mediated gene expression associated with longevity is suppressed  by glucose ingestion. Wild type "C. elegans" fed a diet that included 2% glucose showed reduced Daf-16 activity and lifespan was shortened by 20% compared to worms fed on glucose-free media. These findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms.