Genome-Wide RNAi Longevity Screens in Caenorhabditis elegans

Abstract

Progress in aging research has identified genetic and environmental factors that regulate longevity across species. The nematode worm Caenorhabditis elegans is a genetically tractable model system that has been widely used to investigate the molecular mechanisms of aging, and the development of RNA interference (RNAi) technology has provided a powerful tool for performing large-scale genetic screens in this organism. Genome-wide screens have identified hundreds of genes that influence lifespan, many of which fall into distinct functional classes and pathways. The purpose of this review is to summarize the results of large-scale RNAi longevity screens in C. elegans, and to provide an in-depth comparison and analysis of their methodology and most significant findings.

Keywords: Dietary restriction; FOXO; Genomic; IGF-1; Insulin; Longevity; Mitochondria..

Fig. (1)

Simplified model of signaling pathways that influence lifespan in C. elegans. Genetic factors (rectangles) and environmental factors (ovals) that are found to affect lifespan have been grouped into several major longevity pathways. (1) Within the germline signaling pathway, mutation of mes-1 or glp-1 prevents development of germ cells and results in lifespan extension. This lifespan extension is dependent on both DAF-16 and DAF-12, a putative hormone receptor. (2) The canonical insulin/IGF-1-like signaling (IIS) pathway involves DAF- 2, an insulin-like receptor that promotes activity of the AGE-1 phosphatidylinositol-3-hyroxy kinase, which in turn antagonizes the activity of DAF-16, a FOXO-family transcription factor. Reduction of DAF-2 activity thus activates the longevity-promoting effects of DAF-16. (3) The dietary restriction (DR) pathway has been reported to act independently of IIS. Recent studies suggest that DR inhibits TOR activity, and thereby reduces protein translation and promotes autophagy in C. elegans. This model has been proposed as a possible mechanism for the lifespan-extending effects of DR. Interestingly, crosstalk exists between TOR signaling and components of other signaling pathways, such as interactions with DAF-16 or HIF-1. (4) Exposure to hypoxic conditions results in inhibition of VHL-1-dependent ubiquitination of HIF-1 and the subsequent stabilization of HIF-1 to promote lifespan extension. Deletion of hif-1, however, has also been found to have a temperaturedependent effect on lifespan, with hif-1 mutants being long-lived at 25°C but showing similar lifespan to wild-type worms at 15°C or 20°C. Temperature-dependent lifespan extension by deletion of hif-1 is dependent on DAF-16 under some conditions and may act via TOR-signaling under other conditions (dotted lines). (5) Mutation or RNAi knockdown of genes encoding components of the mitochondrial electron transport chain (ETC) can promote longevity by two different mechanisms: activating the mitochondrial unfolded protein response (UPR^mt) and stabilization of HIF-1.