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

item Cheong, Mi
item Na, K
item Kim, H
item Chitwood, David
item Paik, Y

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/24/2010
Publication Date: 3/4/2011
Citation: Cheong, M.C., Na, K., Kim, H., Chitwood, D.J., Paik, Y.K. 2011. A potential biochemical mechanism underlying the influence of sterol deprivation stress on Caenorhabditis elegans longevity. Journal of Biological Chemistry. 286(9):7248-7256.

Interpretive Summary: Nematodes are microscopic worms that attack plant roots and annually cause ten billion dollars of crop losses in the United States. A major problem with reducing nematode-induced crop losses is that safe and effective control measures for nematodes are not available. One approach to developing new control methods is to disrupt biochemical pathways that occur only in nematodes, such as the nematode sterol pathway. Sterols are chemical compounds found in the cells of plants and animals; cholesterol is the most common sterol in animals. In previous research, ARS scientists showed that some chemical compounds that disrupt sterol biochemistry in nematodes destroy the ability of nematodes to grow and reproduce. This paper describes investigations performed by a team of Korean scientists and an ARS scientist, in which the proteins of a nonparasitic, bacterial-feeding nematode were compared before and after exposure to a sterol biochemistry inhibitor. The results indicated that many proteins were increased in abundance while others were decreased. The results are significant because they provide the best description thus far of the specific genetic and biochemical pathway involved in the shortening of nematode lifespan by sterol biochemistry inhibitors. Consequently, the results will be used by scientists who are developing safe methods for crop nematode control by interfering with the production of the naturally occurring compounds within nematodes.

Technical Abstract: To investigate the biochemical mechanism for sterol-mediated alteration in aging in Caenorhabditis elegans, we established sterol depletion conditions by treating worms with azacoprostane, which reduced mean lifespan of adult C. elegans by 35%. Proteomic analyses of egg proteins from treated and untreated worms revealed many differentially expressed proteins (>1.5-fold); several were previously known to be regulated in a daf-2 dependent manner. A 2.7-fold increase in reactive oxygen species (ROS) was observed in Aza-treated N2 (wild type) worms compared to controls, whereas not much difference in ROS production by the mev-1(kn1) mutant occurred in both Aza-treated worms and controls, thereby suggesting the presence of a direct link between ROS production in mitochondria and Aza treatment. Although SKN-1 production was reduced in ASI neurons of Aza-treated worms, there was no change in localization of SKN-1 or DAF-16 in the intestine. DAF-28, an insulin receptor agonist, was increased about 5-fold in Aza-treated N2; INS-1, an insulin receptor antagonist, was decreased. Subsequent transcriptional analysis showed that DAF-6, which encodes a patched protein containing a sterol-sensing domain, appeared to mediate modulation of DAF-28 during sterol depletion. Thus, sterol depletion by Aza caused a disturbance in mitochondrial membranes, thereby increasing ROS production sensed by amphidial neurons, which then subsequently activate insulin/IGF-1 signaling but decrease SKN-1, resulting in reduced longevity of adult C. elegans.