New Genes Tied to Endocrine, Metabolic, and Dietary Regulation of Lifespan from a Caenorhabditis elegans Genomic RNAi Screen

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Abstract
Most of our knowledge about the regulation of aging comes from mutants originally isolated for other phenotypes. To ask whether our current view of aging has been affected by selection bias, and to deepen our understanding of known longevity pathways, we screened a genomic Caenorhabditis elegans RNAi library for clones that extend lifespan. We identified 23 new longevity genes affecting signal transduction, the stress response, gene expression, and metabolism and assigned these genes to specific longevity pathways. Our most important findings are (i) that dietary restriction extends C. elegans' lifespan by down-regulating expression of key genes, including a gene required for methylation of many macromolecules, (ii) that integrin signaling is likely to play a general, evolutionarily conserved role in lifespan regulation, and (iii) that specific lipophilic hormones may influence lifespan in a DAF-16/FOXO-dependent fashion. Surprisingly, of the new genes that have conserved sequence domains, only one could not be associated with a known longevity pathway. Thus, our current view of the genetics of aging has probably not been distorted substantially by selection bias. Lifespan in C. elegans is influenced by several genetic pathways and processes; a great deal of the information about this regulation of aging comes from genetic mutants originally identified because of other phenotypes. Therefore, to ask whether the current view of the genetics of aging has been significantly affected by selection bias, and to deepen the understanding of known longevity pathways, Hansen et al. screened a genome-wide RNAi library for bacterial clones that extend lifespan when fed to the nematode Caenorhabditis elegans. The investigators identified 23 new longevity genes affecting signal transduction, the stress response, gene expression, and metabolism and assigned these genes to specific longevity pathways. Their most important findings were (i) that dietary restriction extended C. elegans' lifespan by down-regulating expression of key genes, including a gene required for methylation of many macromolecules, (ii) that integrin signaling is likely to play a general, evolutionarily conserved role in lifespan regulation, and (iii) that specific lipophilic hormones may influence lifespan through the conserved insulin/IGF-1 signaling pathway. Surprisingly, the authors found that of the new genes that have conserved sequence domains, only one could not be associated with a known longevity pathway. Thus, the current view of the genetics of aging has probably not been distorted substantially by selection bias. The authors expect the further study of these genes to provide valuable information about the mechanisms of aging, not only in C. elegans but also in higher organisms.