The Collapse of Proteostasis during Aging is Mediated by Cytoskeletal Actin Functions

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The conserved heat shock transcription factor-1 (HSF-1) is essential to cellular stress resistance and life-span determination. The canonical function of HSF-1 is to regulate a network of genes encoding molecular chaperones that protect proteins from damage caused by extrinsic environmental stress or intrinsic age-related deterioration. In Caenorhabditis elegans, we discovered a modified HSF-1 strain that increased stress resistance and longevity without enhanced chaperone induction. Intriguingly, both modified HSF-1 and wild type HSF-1 were instead capable of increasing expression of an array of actin regulating genes. These data suggest that HSF-1 has a prominent role in actin cytoskeletal integrity. Surpassingly, upregulation of at least one of these actin components was alone sufficient to increase stress resistance and life span. We hypothesize that a loss in actin homeostasis occurs during the aging process, and that this loss is driven by the inability for HSF-1 to normally mount a response to protect actin from stress in aging cells. In this proposal, we will explore how actin homeostasis becomes compromised during normal aging, and whether the activity of HSF-1 will protect the cells from age-onset declines in function. We will use state-of-the-art, in vivo imaging techniques alongside innovative biochemical analyses to monitor changes in actin structure and dynamics both spatial and temporally. We predict that forced expression of hsf-1 in geriatric animals will restore the function of the actin cytoskeleton, protecting the cell from age-onset damage and extending lifespan. We will further explore the possibility that hsf-1 works as a part of a team of additional stress-responsive proteins designed to manage a “actin cytoskeletal stress response” that be compromised with age, and propose a series of genetic screens to identify other actin-regulatory factors. Finally, we will explore the idea that changes in actin dynamics must be coordinated across tissues and cells, suggesting a role for hsf-1 in the endocrine mediated regulation of actin dynamics. We will leave this work with a newfound understanding of the role of actin homeostasis plays in many of the destructive diseases seen in older individuals.