Brief Summary

During the last decade, major progress on the genetics of life span has been realized through the study of long-lived mutants identified in the nematode Caenorhabditis elegans . The biochemical functions of many of these genes is now known and because they are related to processes (e.g. metabolism, free radical production) implicated in aging of vertebrates, have potential general significance to aging. The clearest example of such a biochemical convergence is the finding that an insulin-like signaling pathway regulates longevity and metabolism in C. elegans, daf-2, age-1 , and pdk-1 mutants that are components of the C. elegans insulin signaling pathway live 2x to 3x longer than wild type This insulin-like signaling pathway is part of a global endocrine system that controls whether the animals grow reproductively or arrest at the dauer diapause stage.

Genes that regulate the function of this neuroendocrine pathway were identified by two general classes of mutants: dauer defective and dauer constitutive mutants. For example, daf-2 dauer constitutive mutant animals, form dauersin the absence of high pheromone levels. Conversely, daf-16 dauer defective mutants do not form dauers under normal dauer pheromone induction conditions, and suppress the dauer constitutive phenotype induced by daf-2 mutations. The daf genes constitute multiple parallel signaling pathways that converge to regulate C. elegans diapause. The daf-2/age-1/pdk-1/daf-18/akt-1/akt-2/daf-16 subpathway corresponds an insulin-like signaling pathway, and the daf-7/daf-1/daf-4/daf-8/daf-14/daf-3 subpathway corresponds to a TGF-betalike neuroendocrine signaling pathway. Even though these pathways conspire to regulate metabolism and dauer arrest, only the daf-2 insulin like pathway has effects on the longevity of reproductively growing adults.

A large number of C. elegans insulin superfamily genes have been found and are expressed in subsets of sensory neurons, as well as the intestine and somatic gonad. Human insulin expressed using the ins-1 regulatory region antagonizes DAF-2. Since all of the INS proteins are predicted to adopt a similar tertiary structure, they may all bind to DAF-2, the only member of this receptor superfamily in the worm genome. Some INS proteins may be DAF-2 agonists while others may be antagonists. Dauer arrest in C. elegans is normally regulated by an as yet uncharacterized dauer pheromone, that is detected by sensory neurons. The dauer pheromone causes down regulation of daf-7, the TGFbeta ligand of the pathway that acts in parallel to the daf-2 pathway. It also regulates the expression of the daf-28 insulin that acts upstream of the daf-2 insulin receptor. The detection of the dauer pheromone depends on ciliated sensory endings; cGMP signaling in those sensory neurons has been implicated, suggesting that the pheromone receptor may be a 7 transmembrane receptor that couples to cGMP phosphodiesterase, as in mammalian odor sensation.

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