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.
Editor: Stuart Kim, Stanford University School of Medicine, United States of America
Received: February 24, 2005; Accepted: June 9, 2005; Published: July 25, 2005
DOI: 10.1371/journal.pgen.0010017
Copyright: © 2005 Hansen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abbreviations: DR, dietary restriction; RNAi, RNA interference; TPR, tetratrico-peptide-repeat
*To whom correspondence should be addressed. E-mail: ckenyon@biochem.ucsf.edu
☯These authors contributed equally to this work.
¤a Current address: Department of Internal Medicine and Geriatrics Center, University of Michigan, Ann Arbor, Michigan, United States of America
¤b Current address: Molecular and Cell Biology Laboratory, The Salk Institute, La Jolla, California, United States of America
Citation: Hansen M, Hsu A, Dillin A, Kenyon C (2005) New Genes Tied to Endocrine, Metabolic, and Dietary Regulation of Lifespan from a Caenorhabditis elegans Genomic RNAi Screen. PLoS Genet 1(1): e17
