# Elucidating the role of ER remodeling in aging of C. elegans

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2024 · $53,351

## Abstract

PROJECT SUMMARY/ABSTRACT
An aging human population has revealed the burden of chronic illness and age-related disease, and by
understanding the genetic and environmental factors that drive aging, we will be better suited to develop and
test therapeutics that slow age-related disease. As biological aging is influenced by both genetics and the
environment, our laboratory studies the cellular and molecular drivers of aging, with a particular focus on inter-
organelle communication in disease. Here, we newly describe a dramatic reorganization of endoplasmic
reticulum (ER) subdomains in aging C. elegans. The ER mediates inter- and intracellular signaling through these
sheet and tubule domains, and sheet:tubule balance is critical for cell function. ER tubules store calcium and
lipids, and at specialized membrane contact sites, they regulate mitochondrial dynamics. We find that the aging
ER undergoes a loss of rough ER sheets and expansion of smooth ER tubules, and our data suggest that
modifying ER structure is sufficient to preserve mitochondrial morphology in age, making the ER a potential
target in preventing age-related mitochondrial fragmentation. Though autophagy is seen as cytoprotective in
aging, we show that autophagy is necessary for age-related ER remodeling. This may be explained by ER-
phagy, a form of ER-selective autophagy that has not been studied in the context of aging, as ER-phagy shares
common recycling processes. Finally, we demonstrate that caloric restriction, which extends lifespan, prevents
this age-related loss of ER morphology. Therefore, we hypothesize that dysregulated ER-phagy drives age-
related ER remodeling and that dietary restriction promotes longevity by mitigating this loss of ER form and
function. To discern whether these changes are attributable to selective ER-phagy, rather than general
autophagy, I will use a combination of in vivo imaging, fluorescent reporters, and RNAi to investigate the
molecular mechanisms leading to a change in ER subdomains with age (Aim 1). In Aim 2, I will use dietary
restriction, a robust longevity paradigm, to investigate the cause(s) and consequence(s) of ER remodeling in
healthspan and lifespan regulation. This work will be conducted at Vanderbilt University under the supervision
of Dr. Kristopher Burkewitz, Assistant Professor of Cell & Developmental Biology, who discovered roles for ER
function in lifespan regulation through ER-mitochondrial crosstalk. I will additionally be supported by Dr. David
Miller, Professor of Cell & Developmental Biology, whose lab is experienced in electron microscopy and
pioneered many genetic engineering techniques I will perform in C. elegans. In these studies, I will receive
feedback from a strong advisory committee with expertise including interorganelle signaling, membrane
dynamics, and aging physiology. Successful completion of this project will not only advance our understanding
of cell biology and the role of the ER in aging but also establish ...

## Key facts

- **NIH application ID:** 10909195
- **Project number:** 5F31AG076290-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Eric KF Donahue
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,351
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909195

## Citation

> US National Institutes of Health, RePORTER application 10909195, Elucidating the role of ER remodeling in aging of C. elegans (5F31AG076290-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10909195. Licensed CC0.

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