# Role of Mitochondrial Homeostasis in Animal Aging

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $554,549

## Abstract

Project Summary
As advanced age is the most significant risk factor for Alzheimer’s disease (AD), targeting detrimental
age-related processes may lead to effective therapies. Mitochondrial dysfunction and pro-inflammatory
signaling are each thought to be key drivers of aging and AD. However, a clear understanding of the
connections between mitochondrial homeostasis, immune signaling and aging remains elusive. Mitochondrial
DNA (mtDNA) is normally kept within the mitochondria. However, under conditions of mitochondrial stress or
damage, mtDNA can be released into the cytosol thus encountering cytosolic DNA sensors and activating pro-
inflammatory responses. Cytosolic mtDNA has been reported in the brains of AD patients and cellular models
of AD, but, whether cytosolic mtDNA can be targeted for therapeutic intervention in AD has not been
determined. Moreover, fundamental questions remain regarding the occurrence and role of cytosolic mtDNA in
aging and age-related health decline.
In preliminary work, we find that aging leads to a striking decline in mitochondrial autophagy and a
concurrent accumulation of cytosolic mtDNA, which is linked to pro-inflammatory signaling in different organ
systems of Drosophila including the brain. Critically, we have discovered that adult-onset, neuron-specific
silencing of EYA, a molecule involved in sensing cytosolic DNA, dampens inflammatory signaling in the aged
brain and extends lifespan. In addition, we have developed genetic approaches to reduce cytosolic mtDNA,
via increased lysosomal DNase activity, in aged flies. These findings provide an important first step towards
understanding the mechanistic interplay between cytosolic mtDNA, immune signaling and healthspan.
Here, we propose to build upon these groundbreaking findings by exploring three broad questions:
1) What are the mechanistic relationships between mitochondrial homeostasis, cytosolic mtDNA, and
aging?
2) Does cytosolic mtDNA and associated pro-inflammatory signaling drive aging and age-related health
decline?
3) Can modulating cytosolic mtDNA and associated pro-inflammatory signaling counteract Alzheimer’s
disease pathogenesis?
 The work described herein will bring about fundamental knowledge towards our understanding of the
mechanisms of aging and AD-related pathology. Our findings may also lead to novel therapeutic approaches
to counteract aging, AD and related dementias.

## Key facts

- **NIH application ID:** 10756521
- **Project number:** 5R01AG037514-12
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** David W Walker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $554,549
- **Award type:** 5
- **Project period:** 2010-07-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756521

## Citation

> US National Institutes of Health, RePORTER application 10756521, Role of Mitochondrial Homeostasis in Animal Aging (5R01AG037514-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10756521. Licensed CC0.

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