Functional genomic approach to identify novel genes involved in the regulation of oxidative stress resistance and animal lifespan

• Published in: Aging cell Vol. 6; no. 4; pp. 489 - 503
• Main Authors: Kim, Yongsoon, Sun, Hong
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2007
• Subjects: aging; Animals; Caenorhabditis elegans; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - physiology; Calorie restriction; Drug Resistance; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Regulation; Genes, Helminth; Genomics; insulin/insulin‐like growth factor 1 signalling; lifespan; longevity; Longevity - genetics; Longevity - physiology; Mutation; Oxidative Stress - genetics; Paraquat - toxicity; reactive oxygen species; Reactive Oxygen Species - metabolism; RNA Interference
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/j.1474-9726.2007.00302.x

Summary Genetic studies in many organisms suggest that an increased animal lifespan phenotype is often accompanied by enhanced resistance toward reactive oxygen species (ROS). In Caenorhabditis elegans, mutations in daf‐2, which encode an insulin/insulin‐like growth factor 1 receptor‐like molecule, lead to an extended animal lifespan and increased resistance to ROS. We have optimized an assay to monitor ROS resistance in worms using the ROS‐generating chemical paraquat. We have employed this assay to screen the RNAi library along chromosomes III and IV for genes that, when silenced, confer paraquat resistance. The positive RNAi clones were subsequently screened for a lifespan extension phenotype. Using this approach, we have identified 84 genes that, when inactivated by RNAi, lead to significant increases in animal lifespan. Among the 84 genes, 29 were found to act in a manner dependent on daf‐16. DAF‐16, a forkhead transcription factor, is known to integrate signals from multiple pathways, including the daf‐2 pathway, to regulate animal lifespan. Most of the 84 genes have not been previously linked to aging, and potentially participate in important cellular processes such as signal transduction, cell–cell interaction, gene expression, protein degradation, and energy metabolism. Our screen has also identified a group of genes that potentially function in a nutrient‐sensing pathway to regulate lifespan in C. elegans. Our study provides a novel approach to identify genes involved in the regulation of aging.