Stressing out new longevity mutants

Long-lived organisms are often highly resistant to a variety of stresses (of a molecular nature: heat, cold, oxidation, DNA damage, etc.). Since longevity screens are time-consuming and often technically demanding, whereas screens for stress resistance are (in relative terms) easier, it makes sense to look for long-lived mutants by first screening for stress resistance and only then taking lifespans.

This was exactly the approach taken by Kim and Sun, who report a massive haul of new longevity-related genes from a screen for paraquat-resistant worms (paraquat is a potent oxidizing agent):

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

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.

Note that the design of the screen, which used RNAi against a fraction of the genome, resulted in capture of genes whose wildtype functions shorten lifespan. Hence it’s unlikely that the new genes are simply DAF-16 targets, some of which certainly would have fallen out of an overexpression-based screen (and whose overexpression phenotypes also would have been DAF-16 independent).

The study provides a nice proof of principle that first screening for stress resistance is an efficient means to search for novel longevity-related genes. Next step (after Kim and Sun finish off the worm genome) will be to expand to different stresses and different organisms, in order to make sure that nothing quirky gets missed.

One comment

  1. This paper confirms by belief that there are between 6 and 12 genes in the C. elegans genome that do not affect lifespan.

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