Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4.

In nearly every organism studied, reduced caloric intake extends life span. In yeast, span extension from dietary restriction is thought to be mediated by the highly conserved, nutrient-responsive target of rapamycin (TOR), protein kinase A (PKA), and Sch9 kinases. These kinases coordinately regulate various cellular processes including stress responses, protein turnover, cell growth, and ribosome biogenesis. Here we show that a specific reduction of 60S ribosomal subunit levels slows aging in yeast. Deletion of genes encoding 60S subunit proteins or processing factors or treatment with a small molecule, which all inhibit 60S subunit biogenesis, are each sufficient to significantly increase replicative life span. One mechanism by which reduced 60S subunit levels leads to life span extension is through induction of Gcn4, a nutrient-responsive transcription factor. Genetic epistasis analyses suggest that dietary restriction, reduced 60S subunit abundance, and Gcn4 activation extend yeast life span by similar mechanisms.

Quantitative evidence for conserved longevity pathways between divergent eukaryotic species.

Studies in invertebrate model organisms have been a driving force in aging research, leading to the identification of many genes that influence life span. Few of these genes have been examined in the context of mammalian aging, however, and it remains an open question as to whether and to what extent the pathways that modulate longevity are conserved across different eukaryotic species. Using a comparative functional genomics approach, we have performed the first quantitative analysis of the degree to which longevity genes are conserved between two highly divergent eukaryotic species, the yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans. Here, we report the replicative life span phenotypes for single-gene deletions of the yeast orthologs of worm aging genes. We find that 15% of these yeast deletions are long-lived. In contrast, only 3.4% of a random set of deletion mutants are long-lived-a statistically significant difference. These data suggest that genes that modulate aging have been conserved not only in sequence, but also in function, over a billion years of evolution. Among the longevity determining ortholog pairs, we note a substantial enrichment for genes involved in an evolutionarily conserved pathway linking nutrient sensing and protein translation. In addition, we have identified several conserved aging genes that may represent novel longevity pathways. Together, these findings indicate that the genetic component of life span determination is significantly conserved between divergent eukaryotic species, and suggest pathways that are likely to play a similar role in mammalian aging.