Genetic analysis of longevity in Saccharomyces cerevisiae

Abstract

Aging is a universal process that affects organisms from yeast to humans. Replicative life span in the budding yeast, Saccharomyces cerevisiae is defined as the number of daughter cells produced by a mother cell prior to senescence. The isolation and characterization of genes and interventions that extend mother cell life span can provide insight into the mechanisms of aging. One cause of aging in yeast is the accumulation of extrachromosomal ribosomal DNA circles (ERCs) in the mother cell nucleus. ERCs are formed by homologous recombination within the ribosomal DNA (rDNA) caused by the presence of a stalled replication fork. Mutation of the replication fork block protein Foblp dramatically reduces ERCs and extends life span. A central regulator of longevity in yeast is the silencing protein Sir2p. Deletion of SIR2 shortens life span and overexpression of SIR2 extends life span. Sir2p promotes silenced chromatin at the rDNA by catalyzing a novel NAD-dependent histone deacetylation reaction. This rDNA silencing function is likely to promote long life span by inhibiting rDNA recombination and, hence, the formation of ERCs. Sir2p is required for life span extension by caloric restriction (CR), demonstrating the important role that this protein plays in the aging process. CR is thought to activate Sir2p by increasing the amount of NAD that is available as a substrate for Sir2p. The finding that osmotic stress extends life span by a mechanism that genetically mimics CR supports this. High osmolarity causes a metabolic shift from fermentation to an NAD-generating glycerol biosynthesis pathway.

(cont.) Life span extension by high osmolarity requires both Sir2p and glycerol biosynthesis. SSD1-V defines the only known Sir2p independent pathway that promotes long life span. SSD1-V functions in many different cellular processes and the mechanism(s) by which it extends life span is not known. SSDI-V functions in a pathway parallel to the longevity promoting protein Mpt5p for cell integrity and interacts genetically with the aging gene UTH1 in several, apparently unrelated, cellular processes. Further defining the molecular nature of this Sir2p-independent longevity pathway will provide insight into the aging process in yeast and, perhaps, higher organisms as well.