It has not been determined yet whether the ERK-MAPK pathway regulates longevity of metazoans. Here, we show that the Caenorhabditis elegans ERK cascade promotes longevity through the two longevity-promoting transcription factors, SKN-1 and DAF-16. We find that RNAi of three genes, which constitute the ERK cascade (lin-45/RAF1, mek-2/MEK1/2, and mpk-1/ERK1/2), results in reduction of life span. Moreover, RNAi of lip-1, the gene encoding a MAPK phosphatase that inactivates MPK-1, increases life span. Epistasis analyses show that the ERK (MPK-1) cascade-mediated life span extension requires SKN-1, whose function is mediated, at least partly, through DAF-2/DAF-16 insulin-like signaling. MPK-1 phosphorylates SKN-1 on the key sites that are required for SKN-1 nuclear accumulation. Our results also show that one mechanism by which SKN-1 regulates insulin-like signaling is through the regulation of expression of insulin-like peptides. Our findings thus identify a novel ERK-MAPK-mediated signaling pathway that promotes longevity.Recent genetic studies in a variety of model organisms are beginning to reveal the signal transduction networks capable of regulating life span. The insulin-like signaling pathway plays a central role in these networks. In Caenorhabditis elegans, the FOXO transcription factor DAF-16 is required for life span extension by a mutation in daf-2, the insulin-like receptor (1-3). Recently, the longevity-promoting transcription factor SKN-1 has been shown to be inhibited by the insulin-like signaling pathway (4). However, it has not been fully elucidated how the insulin-like signaling pathway interacts with the other distinct signaling pathways to regulate longevity.The ERK-MAPK cascades are evolutionarily conserved signaling modules in eukaryotic cells and transduce signals from the cell surface to the nucleus. These cascades control diverse cellular processes, such as cell proliferation and differentiation (5-8). It has also been demonstrated that increasing nuclear ERK activity can extend replicative life span of diploid human cells (9). Furthermore, a recent report has shown that the increase in life span in mice lacking type 5 adenylyl cyclase correlates with increased ERK-MAPK signaling and that overexpression of mammalian ERK2 increases the chronological life span of yeast (10). However, it has not been determined yet whether the ERK-MAPK cascade promotes longevity of metazoans. In addition, molecular mechanisms by which ERK signaling regulates longevity have remained unclear. Here, we show that the ERK (MPK-1) cascade functions to extend life span in C. elegans. Our analyses show that ERK signaling acts through SKN-1 to regulate the DAF-2/DAF-16 insulin-like signaling and that MPK-1 phosphorylates SKN-1 on the key sites that are required for SKN-1 nuclear accumulation. Moreover, our data suggest that SKN-1 is involved in the regulation of life span through repression of expression of insulin-like peptides. Thus, our results demonstrate a role of the ERK signaling pathway in extending longevity a...

Lifespan is regulated by a complex combination of environmental and genetic factors. Autophagy, which is a bulk degradation system of macromolecules and organelles, has an important role in various biological events. In Caenorhabditis elegans, several autophagy genes have been shown to have a role in promoting longevity, but many other autophagy genes have not been examined for their role in the lifespan regulation. Here we have systematically examined the effect of RNAi suppression of 14 autophagy genes on lifespan. While maternal RNAi of autophagy genes in wild-type worms tended to reduce lifespan, maternal RNAi of each of seven autophagy genes in the insulin/IGF-1 receptor daf-2 mutants extended lifespan. Remarkably, RNAi of unc-51/atg-1, bec-1/atg-6 or atg-9, from young adult, i.e. after development, extended lifespan in both wild-type animals and daf-2 mutants, although RNAi of one or two genes shortened it. Moreover, our analysis suggests that the lifespan extension, which is induced by RNAi of unc-51, bec-1 or atg-9 after development, does not require the transcription factor daf-16, the NAD + -dependent protein deacetylase sir-2.1 or the genes related to mitochondrial functions. Collectively, our results suggest that autophagy may not always be beneficial to longevity, but may also function to restrict lifespan in C. elegans.

In Caenorhabditis elegans, an insulin-like signaling pathway, which includes the daf-2 and age-1 genes, controls longevity and stress resistance. Downregulation of this pathway activates the forkhead transcription factor DAF-16, whose transcriptional targets are suggested to play an essential role in controlling the phenotypes governed by this pathway. We have surveyed the genes that have the DAF-16 consensus binding element (DBE) within putative regulatory regions. Here, we show that one such gene, termed scl-1, is a positive regulator of longevity and stress resistance. Expression of scl-1 is upregulated in long-lived daf-2 and age-1 mutants and is undetectable in a short-lived daf-16 mutant. SCL-1 is a putative secretory protein with an SCP domain and is homologous to the mammalian cysteine-rich secretory protein (CRISP) family. scl-1 is required for the extension of the life span of daf-2 and age-1 mutants, and downregulation of scl-1 reduces both life span and stress resistance of this animal. SCL-1, whose expression is dependent on DAF-16, is the first example of a putative secretory protein that positively regulates longevity and stress resistance.