Cell polarity and aging

DESCRIPTION (provided by applicant): Mitochondria have emerged as central regulators of lifespan, through their functions in aerobic energy mobilization, cellular metabolic control, and reactive oxygen species (ROS) production. Moreover, there are numerous descriptions of age-associated degeneration in actin organization and function in epithelia, fibroblasts, and T cells. Equally important, recent studies support a role for Cdc42, a Rho GTPase family member that regulates actin cytoskeleton organization, polarity and growth, in regulating mammalian genomic stability and aging-related physiology. Specifically, Cdc42 undergoes an age-associated increase in activity in multiple tissues in mice, and constitutive activation of Cdc42 results in p53-dependent shortened life span, and multiple premature aging phenotypes in mice. In budding yeast, mitochondria use actin cables, bundles of F-actin that align along the mother-bud axis, as tracks for polarized movement. We find that the actin cytoskeleton undergoes age-associated loss in polarization, and increase in abundance. Moreover, we find that actin undergoes an age-associated decline in its function in control of mitochondrial distribution and inheritance. Finally, other studies support a role for SIR2, a conserved lifespan regulator and the actin cytoskeleton in the localization of oxidatively-damaged proteins, and indicate that perturbation of the actin cytoskeleton results in decreased lifespan, increased mitochondrial ROS production, and reduced mitochondrial membrane potential. Here, I propose to use yeast as a model system to understand how age-associated changes in actin organization contribute to lifespan control. I will work towards identifying the mechanism responsible for this decline through evaluation of several pathways known to regulate cell polarity in budding yeast. Additionally, I will assess the presence and effect of post-translational modifications to the actin monomer with age. Finally, 1 will detemnine if these changes are a downstream consequence of the aging process or direct determinants of aging, through genetic manipulation of the actin cytoskeletal machinery. Increased life expectancy over the last hundred years has increased the incidence of age-associated diseases. Our studies will provide clues into the conserved mechanisms of cellular and tissue degeneration, and insights into possible treatment strategies.