# Glial regulation of longevity through a transcellular unfolded protein response

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $392,500

## Abstract

Cells are repeatedly exposed to various stressors that disrupt protein homeostasis (such as infection,
excess nutrients, heat, genetic mutations), resulting in protein misfolding and aggregation. To maintain protein
homeostasis (proteostasis), cells have evolved compartment specific stress responses such as the Unfolded
Protein Response of the endoplasmic reticulum (UPRER). In times of ER stress when the load of misfolded or
unfolded proteins overwhelms the ER, the UPRER is initiated to restore proteostasis.
Unfortunately, the ability to mount an effective UPRER is impaired with age, which likely contributes to the
accumulation of misfolded proteins - a central molecular hallmark of aging and many degenerative diseases.
Our laboratory discovered that ectopic expression of the UPRER transcription factor xbp-1s in neurons is sufficient
to prevent age-onset loss of UPRER throughout the organism. Surprisingly, neuronal expression of xbp-1s leads
to cell non-autonomous activation of the UPRER in distal, intestinal cells and extends lifespan in C. elegans.
Initially this phenomenon was ascribed only to neurons, however recent data from our lab suggests glial
cells are more potent cell non-autonomous regulators of ER stress resistance and longevity. Animals lacking a
subtype of glial cell are more susceptible to chronic ER stress. Conversely, expressing xbp-1s in glia results in
robust ER stress resistance and lifespan extension in a mechanism that is distinct from that initiated by neuronal
xbp-1s. Therefore, we hypothesize that glial cells play a central role in coordinating organismal ER stress
resistance and longevity. In this proposal, we outline our strategy to pinpoint the origin and identity of the glial
cell non-autonomous signal (Aim 1) and to uncover the mechanism by which the signal is perceived in distal
tissues (Aim 2). Our approach utilizes techniques which combine the traditional advantages of using C. elegans
as a model system (genetic tractability, transparency, short lifespan), with advanced technologies (large particle
flow cytometry and tissue-specific ribosomal profiling) to study cell non-autonomous signaling between tissues
in the context of aging. Data generated through this proposal will implicate glia as cell non-autonomous
regulators of aging and open new avenues for metabolic and neurodegenerative disease therapeutics.

## Key facts

- **NIH application ID:** 9902280
- **Project number:** 5R01AG059566-03
- **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:** $392,500
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902280

## Citation

> US National Institutes of Health, RePORTER application 9902280, Glial regulation of longevity through a transcellular unfolded protein response (5R01AG059566-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9902280. Licensed CC0.

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