Yeasts are powerful model systems to examine the evolutionarily conserved aspects of eukaryotic aging because they maintain many of the same core cellular signaling pathways and essential organelles as human cells. We constructed a strain of the budding yeast Saccharomyces cerevisiae that could monitor the distribution of proteins involved in heterochromatic silencing and aging, and isolated mutants that alter this distribution. The largest class of such mutants cause defects in mitochondrial function, and appear to cause changes in nuclear silencing separate from the well-known Rtg2p-dependent pathway that alters nuclear transcription in response to the loss of the mitochondrial genome. Mutants that inactivate the ATP2 gene, which encodes the ATPase subunit of the mitochondrial F(1)F(0)-ATPase, were isolated twice in our screen and identify a lifespan extending pathway in a gene that is conserved in both prokaryotes and eukaryotes. The budding yeast S. cerevisiae S. cerevisiae has been used with great success to identify other lifespan-extending pathways in screens using surrogate phenotypes such as stress resistance or silencing to identify random mutants, or in high throughput screens that utilize the deletion strain set resource. However, the direct selection of long-lived mutants from a pool of random mutants is more challenging. We have established a new chronological aging assay for the evolutionarily distant fission yeast Schizosaccharomyces pombe that recapitulates aspects of aging conserved in all eukaryotes. We have constructed a novel S. pombe S. pombe DNA insertion mutant bank, and used it to show that we can directly select for a long-lived mutant. The use of both the budding and fission yeast systems should continue to facilitate the identification and validation of lifespan extending pathways that are conserved in humans.
