Control of Yeast Life Span

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Caloric restriction (CR), i.e. the reduction of the daily caloric intake, can prolong the life span of mice and yeast. CR has long been thought to extend life span by reducing the number of reactive oxygen species (ROS) produced by cellular energy metabolism. It is not known if CR only reduces the production of ROS or also induces a state that protects the cell from potential damage from ROS. Our studies on the control of yeast silencing provide novel insights into the molecular mechanisms of CR. Silencing, the reversible repression of gene expression, changes in old yeast and plays a role in the yeast response to CR. We isolated mutations that mimic the silencing phenotype of aged yeast. Remarkably, we found mutations known to increase yeast life span and identified pathways homologous to mouse pathways whose expression changes during CR and aging. 60 percent of our mutants have defective mitochondria, a hallmark of aging in mammalian cells. Thus, our identification of genetic pathways that control silencing has also identified pathways modulated by CR and aging in mice. We have also isolated a second set of mutations that block the silencing phenotype of aged yeast. These mutants identify a chromatin remodeling factor and chromatin components. Changes in chromatin are the likely endpoints of pathways that modulate transcription in response to CR. Thus, our two sets of mutants most likely identify signal generating and signal responding ends of pathways that control life span. The goal of this proposal is to understand how gene silencing and life span are controlled in response to defective mitochondria and CR. We hypothesize that CR and our mutants induce pathways that the cell normally uses to respond to changes in energy source, and to control the rate of aging through specific chromatin components. To test these hypotheses, we will pursue the following specific aims: Aim 1. What life span- and silencing-modulating pathways do our mutants identify? Aim 2. Do our control of silencing mutations delay the appearance of aging phenotypes in the same way as CR? Aim 3. Which life span extending genes are controlled by CR and the pathways identified and characterized in aims 1 and 2? The results of this work will elucidate the molecular mechanisms of CR-mediated life span extension and provide a model for mammalian systems.