# Dissecting the aging-associated decline in cellular proteostasis - Project 1

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2020 · $371,303

## Abstract

Project 1 – Frydman - Dissecting the aging-associated decline in cellular proteostasis
Project Summary:
The ability to maintain a functional proteome by preserving protein homeostasis, or proteostasis, is essential
for cell viability. Yet, this ability declines during the process of aging. Such a collapse in proteostasis results in
the accumulation of misfolded and aggregated proteins that are a hallmark of late-onset diseases including,
most notably, a wide range of neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s
Diseases. However, it remains largely unknown what cellular changes are responsible for the loss of protein
homeostasis and the accumulation of damaged proteins during aging. We propose to define the mechanisms
and consequences of this proteostasis decline in order to better understand what cellular interventions could
improve the aging process and ameliorate age-related diseases.
Proteostasis is maintained through the interplay of molecular chaperones, which are essential for protein
folding and function, and quality control factors, including the ubiquitin-proteasome system and autophagy,
which target misfolded proteins for elimination. Accumulating evidence suggests that the proteostasis balance
is disrupted during aging. Yet, our understanding of how aging alters the interplay of proteostasis regulators is
far from complete. This Project will examine several phases that regulate the life cycle of a protein, including
translational fidelity, chaperone function, and misfolded protein management, to determine what cellular
changes dictate the widespread proteostasis collapse associated with aging. Importantly, we will examine how
the presence of aggregation-prone disease-linked proteins such as A-beta, tau and polyQ-expanded Huntingtin
exon1 affect the interplay between proteostasis disfunction and aging. This will provide substantial insight into
how age-dependent modulation of these processes might contribute to the decline in proteostasis, and
associated decline in cell viability, that is a primary hallmark of aging and several late-onset human
neurodegenerative diseases.
In order to elucidate at a molecular level how aging affects the folding of newly translated proteins and the
management of misfolded and stress-denatured proteins, we plan to exploit our collective expertise across a
variety of models of aging to: (i) Examine how aging affects biogenesis and folding of newly made
proteins and (ii) Determine how aging affects the management of misfolded and aggregation-prone
proteins

## Key facts

- **NIH application ID:** 9962256
- **Project number:** 5P01AG054407-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Judith Frydman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,303
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962256

## Citation

> US National Institutes of Health, RePORTER application 9962256, Dissecting the aging-associated decline in cellular proteostasis - Project 1 (5P01AG054407-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9962256. Licensed CC0.

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