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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $321,850

## Abstract

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.

## Key facts

- **NIH application ID:** 9902275
- **Project number:** 5R01AG055891-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Andrew G Dillin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $321,850
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902275

## Citation

> US National Institutes of Health, RePORTER application 9902275, The Collapse of Proteostasis during Aging is Mediated by Cytoskeletal Actin Functions (5R01AG055891-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9902275. Licensed CC0.

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