Genetic and Molecular Analysis of Aging and Apoptosis in the Yeast, Saccharomyces (2005 - Present)

Investigator:  Nicanor Austriaco, Providence College
Mentor:  Brian Kennedy, University of Washington School of Medicine 

Abstract:  Cellular aging and apoptosis are two cellular processes that have been implicated in human disease. For instance, it is now clear that both are potent anti-cancer mechanisms. Cells that either escape senescence or bypass apoptosis in response to oncogenic stimuli can undergo malignant transformation. Some have even called the ability to evade programmed cell death a “hallmark of cancer.”  Significantly, there is good evidence that senescence and apoptosis contribute to the anti-tumor activity of many chemotherapeutic drugs and that mutations that disable apoptosis can result in multi-drug resistance. 

The budding yeast Saccharomyces cerevisiae has served as a useful model for complex physiological processes of metazoan cells including aging and apoptotic cell death. Molecular mechanisms of both these processes appear to be conserved and genetic determinants have been identified in yeast with orthologues in higher organisms. Much work has gone into attempting to describe the molecular mechanisms that drive each process.  This research program outlines several genetic strategies to identify molecular links between these two processes in yeast, links that could be conserved in higher organisms.  It will exploit the primary advantage of the yeast system over its mammalian counterpart as a model system for aging – simply, yeast cells are easier to work with because they age and reach senescence within a matter of weeks.  Mammalian cells, on the other hand, take months to undergo senescence, while mammalian organisms take years, if not decades, to age.

Specifically, this research program will determine if yeast cells that undergo both replicative and chronological aging activate the apoptotic pathway in order to die, by examining the lifespan of yeast cells bearing gain-of-function and loss-of-function mutations in key yeast apoptosis genes.  It will also determine if the yeast cells undergoing senescence from the accumulation of extrachromosomal circles activate the apoptotic machinery to die.  Finally, it will determine if the chronological aging process that can be delayed by calorie restriction (CR) functions through the apoptotic pathway by studying the effects of CR on yeast cells bearing loss-of-function mutations in key yeast apoptosis genes.