The actin cytoskeleton has essential roles in cellular functions including intracellular and cellular movement, establishment and maintenance of cell polarity, junctions and shape, muscle contraction, cell signaling and cytokinesis. While it is clea that actin function undergoes an age-associated decline in all systems studied including skeletal and cardiac muscle and the immune system, remarkably little is known about the role of the cytoskeleton in the normal aging process. Indeed, it is not clear whether modulation of the actin cytoskeleton can extend lifespan in mammalian cells. We obtained the first evidence that modulation of the actin cytoskeleton can extend lifespan using yeast as a model system. Previous studies from our laboratory revealed a role for the actin cytoskeleton in control of mitochondrial movement and promoting inheritance of fitter mitochondria by yeast daughter cells, and uncovered the mechanism underlying that process. Equally important, we found that promoting actin dynamics and function extends yeast lifespan and healthspan by a mitochondria-dependent mechanism. Finally, we obtained evidence that the actin cytoskeleton undergoes a decline in structure, polarization and function in yeast as they age, and that the defects in actin observed in old cells are similar to those observed upon deletion of Sir2p, the founding member of the Sirtuin family of lifespan regulators. In the R21 phase, we will study the mechanisms underlying age-linked declines in function of the actin cytoskeleton using yeast as a model system. Specifically, we will test whether there are age-linked declines in the stability o assembly of the actin cytoskeleton, and whether similar changes are observed in yeast in which lifespan has been extended or reduced by modulation of Sir2p. We obtained evidence that actin undergoes age-linked post- translational modifications (PTMs), and will determine the nature of those PTMs and the sites on actin where they occur. Finally, we will test whether the age-associated decline in actin polarization is due to defects in the polarization or activity of Cdc42 (a conserved Rho protein and actin regulator) and/or formins (which mediate actin polymerization and assembly at sites of polarized cell surface growth and are recruited to those sites by Cdc42). In the R33 phase, we will determine whether interventions that promote the structure, polarization and function of the actin cytoskeleton or prevent age-linked PTM of actin protein extend lifespan and/or healthspan. Moreover, we identified genes, including previously uncharacterized open reading frames, which enhance actin structure and polarity in a yeast genetic screen. We will test whether modulation of these genes and other actin-associated proteins can extend lifespan (R21 phase), and the mechanism underlying actin regulation by lifespan-extending genes (R33 phase). Since declines in actin function occur in aging mammalian cells, tissues and organs, and stabilizing actin extends lifespan in C. elegans, these studies will provide a foundation for understanding age-associated declines in the actin cytoskeleton, and may reveal interventions to promote actin function in lifespan and healthspan control in yeast and other eukaryotes.
The actin cytoskeleton, a component of the cellular scaffolding system, controls cell size, shape and stability as well as cellular and intracellular movement. The actin cytoskeleton undergoes an age-associated decline and this process contributes to age-linked declines in processes including wound healing, the immune response and muscle contraction. Important goals of the proposed studies are to understand the mechanism underlying aging of the actin cytoskeleton and whether interventions that slow or prevent age-associated declines in the actin cytoskeleton can extend lifespan and healthspan.
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