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.

Public Health Relevance

Aging organisms lose the capacity to activate stress-responsive genes, diminishing their ability to respond to damage and shortening lifespan. We have identified a stress-response pathway that is capable of maintaining the health of a structural component of the cell, the actin cytoskeleton, during old age, protecting the cell against environmental stress, and extending lifespan. We propose a multipronged approach to understand how this network is regulated and how the aging process might compromise its function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG055891-04
Application #
9902275
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94710