Lifespan in C. elegans is determined by multiple genetic pathways and processes. The DAF-2 insulin/IGF-1 pathway, the reproductive system, food intake, and mitochondrial activity (1, 2, 3) have all been shown to regulate aging: lifespan extensions of 15 to 600% occur in animals defect in one or more of these processes (1, 4, 5). The FOXO-family transcription factor DAF-16 is required for the lifespan extension observed in
daf-2 mutants, as well as in animals defective in germline signaling (1). However,
daf-16 is not required for the lifespan extension induced by perturbations of mitochondrial activities (2, 3) or in calorically restricted animals (5, 6). How are these pathways related and what genes work in these processes to regulate aging? To clarify how the known aging pathways and processes differ in regulating longevity and to identify new genes involved in lifespan regulation, we carried out a genome-wide RNA interference (RNAi) screen. Specifically, we looked for bacterial RNAi clones that extended lifespan. Our RNAi feeding library contains 87% of the predicted C. elegans open reading frames. In addition to known lifespan genes, we identified 28 new genes whose wild-type function is required to prevent lifespan extension. Reducing the function of these loci extended mean lifespan anywhere between 15-80%. The lifespan extension observed with 7 of these clones was dependent on
daf-16, suggesting that they might encode new components in the DAF-2 insulin/IGF-1 signaling pathway, or, potentially,
daf-2-independent,
daf-16-dependent genes. We are currently characterizing these genes further. In contrast, the lifespan extension observed with the remaining 21 genes, including components of the mitochondrial respiratory chain (see 2), was not dependent on
daf-16. We are continuing to analyze these genes to determine their involvement, if any, in other known aging pathways. We expect the study of these genes to provide valuable information about the mechanism of aging, and possibly to define new aging pathways. Keywords: lifespan, screeen, RNAi,
daf-16 (1) Tatar et al., Science, 2003 (2) Dillin et al., Science, 2002 (3) Lee et al., Nature Genetics, 2002 (4) Arantes-Oliveira et al., Science, 2003 (5) Houthoofd et al., Exp Geron, 2003 (6) Lakowski and Hekimi, PNAS, 1998