# Conserved Aging Mechanisms Impacting Dopamine Neuron Survival

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $231,000

## Abstract

PROJECT SUMMARY
The single biggest risk factor for developing Parkinson’s disease is age, suggesting that age-related
changes in the brain predispose to loss of dopamine (DA) neuron health and viability. Cell stressors
such as oxidative stress and metabolic dysfunction increase with age in many species including
humans, and DA neurons are particularly vulnerable to oxidative stress because of their high
metabolic demands and intrinsic reactive oxygen species production. Despite a growing body of
evidence linking elevated oxidative stress to aging and DA neuron degeneration, the role of oxidative
stress-responsive signaling pathways in connecting this stress to enhanced DA neuron vulnerability
with age are not well understood. Prior studies link activation of the HIF-1 (hypoxia-inducible factor-1)
pathway to suppression of TOR (target of rapamycin) signaling and recent GWAS studies raise the
possibility that the interaction of these pathways may be important in regulating lifespan, possibly in
response to cellular stress signals. Key components of HIF-1/TOR signaling are also altered in
human Parkinson’s disease substantia nigra DA neurons. The primary goal of this proposal is to
determine whether age-related oxidative stress results in sustained upregulation of specific signaling
mediators in the HIF-1/TOR signaling pathway that promote susceptibility of DA neurons to age-
related death and limit organismal lifespan. Studies from multiple animal models including Drosophila
indicate that TOR deregulation is a feature of nervous system aging and neurodegenerative disease.
We will leverage the natural genetic variation in a collection of Drosophila genetic backgrounds that
we find influences reactive oxygen species production, lifespan and DA neuron viability to achieve
two primary goals: First, we will examine the effects of aging on brain expression of oxidative stress
signaling mediators both in the whole brain as well as in specific vulnerable (i.e. DA) and spared
neuronal populations. Second, we will determine the role of these signaling mediators on age-related
DA neuron death and lifespan. These exploratory studies will pave the way for detailed
characterization of how aging and age-related stress drives upstream regulators of this signaling
pathway, and inform broader studies on the role of these signaling mediators in Parkinson’s disease
neurodegeneration linked to additional genetic and environmental factors.

## Key facts

- **NIH application ID:** 10351123
- **Project number:** 1R21AG075320-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Ian Martin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $231,000
- **Award type:** 1
- **Project period:** 2022-08-04 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10351123

## Citation

> US National Institutes of Health, RePORTER application 10351123, Conserved Aging Mechanisms Impacting Dopamine Neuron Survival (1R21AG075320-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10351123. Licensed CC0.

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