EAGER: Discovery of an Extracellular Mediator of Glucose Restriction in Yeast

University Of Iowa, Iowa City IA

Investigators

Abstract

Intellectual Merit: All organisms tune their gene expression and phenotypic programs to current conditions. Budding yeast, which has long been cultivated for making bread, wine and beer, is adapted to high concentrations of simple carbohydrates, such as glucose. Growth at lower glucose levels extends the number of times that a yeast mother cell can produced daughter cells (replicative longevity). Associated with lower glucose, there are a variety of known gene expression and epigenetic changes and a known set of enzymes, which are required for the lifespan extension due to glucose restriction. Among these enzymes are Sir2, a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, and enzymes that perform NAD salvage biosynthesis. Earlier investigators in this field hypothesized that lower glucose would alter the levels of intracellular NAD metabolites in a manner that would tune Sir2 activity. However, recent work has indicated that, while increasing intracellular NAD can extend yeast lifespan, glucose restriction does not substantively alter the levels of intracellular NAD metabolites. Rather, the extracellular metabolome of glucose restricted yeast cells is required for lifespan extension and an extracellular fraction has been obtained, which contains a metabolite 300-fold induced by glucose restriction. The goal of this EAGER proposal is to use a combination of mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy to identify the molecule and initiate characterization of its mechanism of action. Given that yeast cells live as communities, the research has the potential to reveal new insights about how a diffusible factor that extends lifespan might act to extend the lifespan of a community and not simply for the benefit of the metabolite-exporting cell. Broader Impacts: The project will contribute to training of a graduate student and a postdoctoral associate, who will directly carry out the research and also participate in outreach a local high school.