简介

B.S. University of Redlands Ph.D. University of California, Los Angeles Research Description: Some people grow old yet show few signs of aging, while others show signs of aging long before they grow old. How can this be? We are trying to identify and understand the signal transduction pathways and cellular processes that control the rate of biological aging and lifespan. We use the common baker’s yeast Saccharomyces cerevisiae as a model eukaryote because it has a short lifespan that can be analyzed by genetic and biochemical techniques. Furthermore, the first gene that regulates lifespan was identified in this organism and it continues to yield new insights into the molecular mechanisms of aging. A striking outcome of studies in model organisms is that similar proteins and signaling pathways regulate lifespan. Glucose in yeast and insulin or insulin-like growth factor in other organisms regulates a signal transduction pathway that limits or down-regulates lifespan, shown experimentally by deleting a component of the pathway and seeing an increase in lifespan. Protein kinases are a well-conserved feature of these signaling pathways. The Akt/PKB protein kinases are found in organisms ranging from baker’s yeast, where the protein is called Sch9, to worms and man where these kinases play roles in insulin signaling, apoptosis and cell proliferation, all of which play roles in aging and lifespan. One focus of research in my laboratory is the Sch9 protein kinase that regulates lifespan as measured by how many times a cell can divide (Replicative lifespan) and by how long a cell can survive in stationary phase after it stops dividing (Chronological lifespan). To understand how Sch9 regulates lifespan we are examining how nutrients (such as glucose) control production of the sphingolipid called PHS (phytosphingosine), and how PHS turns on the kinase activity of the Pkh1 protein kinase that is needed to activate Sch9 kinase activity. In addition, nutrients control another protein kinase called TORC1 (Target of Rapamycin Complex 1) that is also needed to turn on Sch9 kinase activity. We are also trying to identify proteins that are phosphorylated by Sch9. Once these substrate proteins are identified we determine if they play roles in lifespan, and if they do, we determine the molecular mechanism by which they regulate lifespan. Since there is conservation of function between yeast and mammals, the insight gained from these studies will advance our knowledge of normal cellular functions involved in aging and longevity and abnormal states including cancers, cardiovascular disease and neurological disorders.