MUTATION IN THE SILENCING GENE SIR4 CAN DELAY AGING IN SACCHAROMYCES-CEREVISIAE

Aging in S. cerevisiae is exemplified by the fixed number of cell divi sions that mother cells undergo (termed their life span). We have expl oited a correlation between life span and stress resistance to identif y mutations in four genes that extend life span. One of these, SIR4, e ncodes a component of the silencing apparatus at HM loci and telomeres . The sir4-42 mutation extends life span by more than 30% and is semid ominant. Our findings suggest that sir4-42 extends life span by preven ting recruitment of the SIR proteins to HM loci and telomeres, thereby increasing their concentration at other chromosomal regions. Maintain ing silencing at these other regions may be critical in preventing agi ng. Consistent with this view, expression of only the carboxyl terminu s of SIR4 interferes with silencing at HM loci and telomeres, which al so extends life span. Possible links among silencing, telomere mainten ance, and aging in other organisms are discussed.