# Role of Mitochondrial Homeostasis in Animal Aging

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $33,604

## Abstract

Summary/Abstract of Parent Grant
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 proinflammatory 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:** 11078092
- **Project number:** 3R01AG037514-12S1
- **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:** $33,604
- **Award type:** 3
- **Project period:** 2010-07-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11078092

## Citation

> US National Institutes of Health, RePORTER application 11078092, Role of Mitochondrial Homeostasis in Animal Aging (3R01AG037514-12S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11078092. Licensed CC0.

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