title: A potential biochemical mechanism underlying the influence of sterol deprivation stress on Caenorhabditis elegans longevity.
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 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.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Mi Cheong
authors.initials: MC
authors.lastname: Cheong
authors.forename: Keun
authors.initials: K
authors.lastname: Na
authors.forename: Heekyeong
authors.initials: H
authors.lastname: Kim
authors.forename: Seul-Ki
authors.initials: SK
authors.lastname: Jeong
authors.forename: Hyoe-Jin
authors.initials: HJ
authors.lastname: Joo
authors.forename: David J
authors.initials: DJ
authors.lastname: Chitwood
authors.forename: Young-Ki
authors.initials: YK
authors.lastname: Paik
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D001378:Azasteroids / Q000633:toxicity; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis / Q000172:deficiency*; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012855:Sitosterols / Q000378:metabolism*
chemical_list: D001378:Azasteroids; D017382:Reactive Oxygen Species; D012855:Sitosterols; C046857:25-azacoprostane; C025473:gamma-sitosterol; D002784:Cholesterol