Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling

Nat Genet. 2001 Jun;28(2):139-45. doi: 10.1038/88850.


The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Mutants in this pathway remain youthful and active much longer than normal animals and can live more than twice as long. This lifespan extension requires DAF-16, a forkhead/winged-helix transcription factor. DAF-16 is thought to be the main target of the DAF-2 pathway. Insulin/IGF-1 signaling is thought to lead to phosphorylation of DAF-16 by AKT activity, which in turn shortens lifespan. Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei. Disrupting Akt-consensus phosphorylation sites in DAF-16 causes nuclear accumulation in wild-type animals, but, surprisingly, has little effect on lifespan. Thus the DAF-2 pathway must have additional outputs. Lifespan in C. elegans can be extended by perturbing sensory neurons or germ cells. In both cases, lifespan extension requires DAF-16. We find that both sensory neurons and germline activity regulate DAF-16 accumulation in nuclei, but the nuclear localization patterns are different. Together these findings reveal unexpected complexity in the DAF-16-dependent pathways that regulate aging.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins*
  • Cell Nucleus / metabolism
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Germ Cells / metabolism
  • Helminth Proteins / genetics
  • Helminth Proteins / metabolism*
  • Insulin / metabolism
  • Insulin-Like Growth Factor I / metabolism*
  • Longevity / genetics
  • Mutation
  • Neurons, Afferent / pathology
  • Neurons, Afferent / physiology
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Signal Transduction*
  • Stress, Physiological
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic


  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • Helminth Proteins
  • Insulin
  • Proto-Oncogene Proteins
  • Transcription Factors
  • daf-16 protein, C elegans
  • Insulin-Like Growth Factor I
  • DAF-2 protein, C elegans
  • Receptor, Insulin
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt