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Proteasomal regulation of the hypoxic response modulates aging in C. elegans.

The Caenorhabditis elegans von Hippel-Lindau tumor suppressor homolog VHL-1 is a cullin E3 ubiquitin ligase that negatively regulates the hypoxic response by promoting ubiquitination and degradation of the hypoxic response transcription factor HIF-1. Here, we report that loss of VHL-1 significantly increased life span and enhanced resistance to polyglutamine and beta-amyloid toxicity. Deletion of HIF-1 was epistatic to VHL-1, indicating that HIF-1 acts downstream of VHL-1 to modulate aging and proteotoxicity. VHL-1 and HIF-1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. These findings define VHL-1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.

Pubmed ID: 19372390


  • Mehta R
  • Steinkraus KA
  • Sutphin GL
  • Ramos FJ
  • Shamieh LS
  • Huh A
  • Davis C
  • Chandler-Brown D
  • Kaeberlein M


Science (New York, N.Y.)

Publication Data

May 29, 2009

Associated Grants

  • Agency: NIA NIH HHS, Id: 1R01AG031108-01
  • Agency: NIA NIH HHS, Id: P30AG013280
  • Agency: NIA NIH HHS, Id: R01 AG031108
  • Agency: NIA NIH HHS, Id: R01 AG031108-01A1

Mesh Terms

  • Aging
  • Amyloid beta-Peptides
  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Caloric Restriction
  • Cullin Proteins
  • Female
  • Fertility
  • Gene Expression Regulation
  • Homeostasis
  • Insulin
  • Longevity
  • Male
  • Models, Animal
  • Oxygen
  • Peptides
  • Proteasome Endopeptidase Complex
  • RNA Interference
  • Receptor, Insulin
  • Signal Transduction
  • Transcription Factors
  • Ubiquitination