40 nature genetics · volume 33 · january 2003
A systematic RNAi screen identifies
a critical role for mitochondria in
C. elegans longevity
Siu Sylvia Lee1, Raymond Y. N. Lee1,3, Andrew G. Fraser2, Ravi S. Kamath2, Julie Ahringer2 & Gary Ruvkun1
Published online 25 November 2002; doi:10.1038/ng1056
We report a systematic RNA interference (RNAi) screen of 5,690 Caenorhabditis elegans genes for gene inactiva-
tions that increase lifespan. We found that genes important for mitochondrial function stand out as a principal
group of genes affecting C. elegans lifespan. A classical genetic screen identified a mutation in the mitochondrial
leucyl-tRNA synthetase gene (lrs-2) that impaired mitochondrial function and was associated with longer-lifespan.
The long-lived worms with impaired mitochondria had lower ATP content and oxygen consumption, but differen-
tial responses to free-radical and other stresses. These data suggest that the longer lifespan of C. elegans with
compromised mitochrondria cannot simply be assigned to lower free radical production and suggest a more com-
plex coupling of metabolism and longevity.
1Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114,
USA. 2Wellcome Trust/Cancer Research UK Institute, University of Cambridge, Cambridge, UK. 3Present address: WormBase, Division of Biology, California
Institute of Technology, Pasadena, California, USA. Correspondence should be addressed to G.R. (e-mail: firstname.lastname@example.org).
Genetic and environmental factors that affect metabolism and