# Targeting mechanisms of inter-organelle communication to promote healthy aging

> **NIH NIH R00** · VANDERBILT UNIVERSITY · 2021 · $234,718

## Abstract

Project Summary/Abstract
Age-onset diseases including cancer, neurodegenerative disease, diabetes, cardiovascular disease, stroke,
and osteoporosis are generating a public health burden that is quickly becoming insurmountable. Exacerbating
this problem, co-morbidities are common among the elderly. The ideal therapeutic strategy to confront this
crisis is to target a unifying risk factor, but patient age is the only risk factor common to all these diseases.
Fortunately, it is increasingly clear that the biological processes of aging are malleable, thus the rate and
quality of aging may be improved. Genetic and nutritional interventions causing real or perceived energy-
depletion are robust, conserved mechanisms to promote healthier aging. Unfortunately these interventions,
e.g. activation of the molecular low-energy sensor AMPK, also carry clinically unacceptable side effects, such
as suppressed immunity and fertility. Translating these findings into therapeutics thus requires identification of
downstream mechanisms that are sufficient for healthier aging. Through a genetic model of longevity in C.
elegans via activation of AMPK, we demonstrated that the negative side-effects of energy-depletion can be
uncoupled from the positive effects on healthy aging. Using unbiased, systems-level approaches, we found
that the longevity-specific mechanism involves downstream regulation of mitochondrial dynamics and
metabolic functions, and we now demonstrate that regulation of mitochondrial dynamics is causal to AMPK
longevity. New data indicate that perturbing the unfolded protein response (UPR), which mediates homeostasis
of the endoplasmic reticulum (ER), interacts with the AMPK pathway to extend lifespan through a mechanism
that also requires mitochondrial remodeling. Given recent studies showing that the ER physically interacts with
mitochondria to regulate organelle morphology and metabolic signaling, these data suggest a new paradigm in
aging: ER/mitochondrial regulation of longevity occurs through an integrated metabolic mechanism. Physical
changes in mitochondrial networks are a hallmark of aging, but how organelle dynamics are mechanistically
involved in longevity is unknown. By genetically inactivating mediators of mitochondrial remodeling
(fission/fusion), Aim 1 will define how mitochondrial dynamics drive the changes in mitochondrial metabolism
associated with low-energy longevity. Through novel transgenics and training in high-resolution microscopy in
Aim 2, I will test the hypothesis that UPRER perturbations promote altered mitochondrial morphology and
signaling between organelles. Finally in the R00 phase, Aim 3 will build on the tools and insights developed in
Aims 1 and 2 to identify genetic mechanisms in C. elegans by which ER-mitochondrial inter-organelle
communication can be directly targeted to extend healthy lifespan and protect metabolic homeostasis. Taken
together, the goal of this proposal is to identify how evolutionarily conserved e...

## Key facts

- **NIH application ID:** 10086359
- **Project number:** 5R00AG052666-05
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Kristopher Burkewitz
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $234,718
- **Award type:** 5
- **Project period:** 2016-09-30 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086359

## Citation

> US National Institutes of Health, RePORTER application 10086359, Targeting mechanisms of inter-organelle communication to promote healthy aging (5R00AG052666-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10086359. Licensed CC0.

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