Nutritional Control of Chronological Aging and Heterochromatin in Saccharomyces cerevisiae

Calorie restriction extends life span in organisms as diverse as yeast and mammals through incompletely understood mechanisms. The role of NAD(+)-dependent deacetylases known as Sirtuins in this process, particularly in the yeast Saccharomyces cerevisiae, is controversial. We measured chronological life span of wild-type and sir2 Delta strains over a higher glucose range than typically used for studying yeast calorie restriction. sir2D extended life span in high glucose complete minimal medium and had little effect in low glucose medium, revealing a partial role for Sir2 in the calorie-restriction response under these conditions. Experiments performed on cells grown in rich medium with a newly developed genetic strategy revealed that sir2D shortened life span in low glucose while having little effect in high glucose, again revealing a partial role for Sir2. In complete minimal media, Sir2 shortened life span as glucose levels increased; whereas in rich media, Sir2 extended life span as glucose levels decreased. Using a genetic strategy to measure the strength of gene silencing at HML, we determined increasing glucose stabilized Sir2-based silencing during growth on complete minimal media. Conversely, increasing glucose destabilized Sir-based silencing during growth on rich media, specifically during late cell divisions. In rich medium, silencing was far less stable in high glucose than in low glucose during stationary phase. Therefore, Sir2 was involved in a response to nutrient cues including glucose that regulates chronological aging, possibly through Sir-2dependent modification of chromatin or deacetylation of a nonhistone protein.