Abstract
Calorie restriction slows aging and increases life span in many organisms. In yeast, a mechanistic explanation has been proposed whereby calorie restriction slows aging by activating Sir2. Here we report the identification of a Sir2-independent pathway responsible for a majority of the longevity benefit associated with calorie restriction. Deletion of FOB1 and overexpression of SIR2 have been previously found to increase life span by reducing the levels of toxic rDNA circles in aged mother cells. We find that combining calorie restriction with either of these genetic interventions dramatically enhances longevity, resulting in the longest-lived yeast strain reported thus far. Further, calorie restriction results in a greater life span extension in cells lacking both Sir2 and Fob1 than in cells where Sir2 is present. These findings indicate that Sir2 and calorie restriction act in parallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes.
Highlights
The budding yeast Saccharomyces cerevisiae has served as a useful model for aging research, leading to the identification of new longevity genes and pathways whose counterparts can be examined in higher eukaryotes (Kaeberlein et al 2001)
Replicative aging of yeast can be caused by the accumulation of extrachromosomal rDNA circles (ERCs) in the mother cell nucleus (Sinclair and Guarente 1997), and mutations that decrease ERC formation correlate with increased life span
Since both Calorie restriction (CR) and deletion of FOB1 increased life span individually in BY4742, we examined the effect of CR combined with deletion of FOB1
Summary
The budding yeast Saccharomyces cerevisiae has served as a useful model for aging research, leading to the identification of new longevity genes and pathways whose counterparts can be examined in higher eukaryotes (Kaeberlein et al 2001). The survival of nondividing yeast cells over time can be monitored and has been termed chronological aging (Fabrizio and Longo 2003). Replicative aging of yeast can be caused by the accumulation of extrachromosomal rDNA circles (ERCs) in the mother cell nucleus (Sinclair and Guarente 1997), and mutations that decrease ERC formation correlate with increased life span. One example of such a mutation is deletion of the gene encoding the rDNA replication fork barrier protein Fob, which results in a dramatic decrease in ERC levels accompanied by a 30%–40% increase in mean and maximum RLS (Defossez et al 1999)
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