LET-60 RAS modulates effects of insulin/IGF-1 signaling on development and aging in Caenorhabditis elegans

Aging Cell. 2005 Oct;4(5):235-45. doi: 10.1111/j.1474-9726.2005.00166.x.


The DAF-2 insulin/insulin-like growth factor 1 (IGF-1) receptor signals via a phosphatidylinositol 3-kinase (PI3K) pathway to control dauer larva formation and adult longevity in Caenorhabditis elegans. Yet epistasis analysis suggests signal bifurcation downstream of DAF-2. We have used epistasis analysis to test whether the Ras pathway (which plays a role in signaling from mammalian insulin receptors) acts downstream of DAF-2. We find that an activated Ras mutation, let-60(n1046gf), weakly suppresses constitutive dauer diapause in daf-2 and age-1 (PI3K) mutants. Moreover, increased Ras pathway signaling partially suppresses the daf-2 mutant feeding defect, while reduced Ras pathway signaling enhances it. By contrast, activated Ras extends the longevity induced by mutation of daf-2, while reduced Ras pathway signaling partially suppresses it. Thus, Ras pathway signaling appears to act with insulin/IGF-1 signaling during larval development, but against it during aging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / physiology*
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Epistasis, Genetic
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Insulin / metabolism*
  • Insulin-Like Growth Factor I / metabolism*
  • Longevity
  • Models, Animal
  • Phenotype
  • Phosphatidylinositol 3-Kinases / metabolism
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism*
  • Signal Transduction / physiology*
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Caenorhabditis elegans Proteins
  • Insulin
  • let-60 protein, C elegans
  • Insulin-Like Growth Factor I
  • Inositol 1,4,5-Trisphosphate
  • Phosphatidylinositol 3-Kinases
  • DAF-2 protein, C elegans
  • Receptor, Insulin
  • ras Proteins