A potential biochemical mechanism underlying the influence of sterol deprivation stress on Caenorhabditis elegans longevity

J Biol Chem. 2011 Mar 4;286(9):7248-56. doi: 10.1074/jbc.M110.189183. Epub 2010 Dec 24.


To investigate the biochemical mechanism underlying the effect of sterol deprivation on longevity in Caenorhabditis elegans, we treated parent worms (P0) with 25-azacoprostane (Aza), which inhibits sitosterol-to-cholesterol conversion, and measured mean lifespan (MLS) in F2 worms. At 25 μM (∼EC(50)), Aza reduced total body sterol by 82.5%, confirming sterol depletion. Aza (25 μM) treatment of wild-type (N2) C. elegans grown in sitosterol (5 μg/ml) reduced MLS by 35%. Similar results were obtained for the stress-related mutants daf-16(mu86) and gas-1(fc21). Unexpectedly, Aza had essentially no effect on MLS in the stress-resistant daf-2(e1370) or mitochondrial complex II mutant mev-1(kn1) strains, indicating that Aza may target both insulin/IGF-1 signaling (IIS) and mitochondrial complex II. Aza increased reactive oxygen species (ROS) levels 2.7-fold in N2 worms, but did not affect ROS production by mev-1(kn1), suggesting a direct link between Aza treatment and mitochondrial ROS production. Moreover, expression of the stress-response transcription factor SKN-1 was decreased in amphid neurons by Aza and that of DAF-28 was increased when DAF-6 was involved, contributing to lifespan reduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Animals
  • Animals, Genetically Modified
  • Azasteroids / toxicity
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Cholesterol / biosynthesis
  • Cholesterol / deficiency*
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / physiology
  • Longevity / drug effects
  • Longevity / physiology*
  • Mitochondria / physiology
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Reactive Oxygen Species / metabolism
  • Sitosterols / metabolism*


  • Azasteroids
  • Reactive Oxygen Species
  • Sitosterols
  • 25-azacoprostane
  • gamma-sitosterol
  • Cholesterol