Authors: Cheong MC; Na K; Kim H; Jeong SK; Joo HJ; Chitwood DJ; Paik YK
Abstract: 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 muM ( approximately EC(50)), Aza reduced total body sterol by 82.5%, confirming sterol depletion. Aza (25 muM) treatment of wild-type (N2) C. elegans grown in sitosterol (5 mug/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.Keywords: Aging/physiology; Animals; Animals, Genetically Modified; Azasteroids/toxicity; Caenorhabditis elegans/genetics/*metabolism; Cholesterol/biosynthesis/*deficiency; Lipid Metabolism/drug effects/physiology; Longevity/drug effects/*physiology; Mitochondria/physiology; Oxidative Stress/drug effects/*physiology; Reactive Oxygen Species/metabolism; Sitosterols/*metabolism
Journal: The Journal of biological chemistry
Date: Dec. 28, 2010
Select reference article to upload
Cheong MC, Na K, Kim H, Jeong SK, Joo HJ, Chitwood DJ, Paik YK (2011) A potential biochemical mechanism underlying the influence of sterol deprivation stress on Caenorhabditis elegans longevity. The Journal of biological chemistry 286: 7248-56.