# Alveolar Macrophages as Age-Related Drivers of Disordered Tissue Repair

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2022 · $399,053

## Abstract

Abstract
One of the most important clinical manifestations of age-related immune dysfunction is an enhanced
susceptibility to and mortality from pneumonia, the most common cause of death from an infectious disease
worldwide. In the year after hospital discharge older pneumonia survivors have an increased risk of developing
age-related disorders including persistent lung injury, skeletal muscle dysfunction leading to immobility,
myocardial infarction, chronic kidney disease, dementia and cognitive impairment. As such, pneumonia is a
gateway for the compounding morbidity that limits healthspan at the end of life. Alveolar macrophages are the
most abundant resident immune population in the alveolar space, where they serve as sentinel and effector cells
that respond to inhaled particles, toxins and pathogens in the ambient air. We used a combination of causal
genetic experiments targeting macrophages and unbiased transcriptomic and proteomic analyses of flow-sorted
cell populations from the lungs of influenza A infected mice to suggest that the reparative function of alveolar
macrophages is reduced during aging. These findings converge with the concept of mitochondrial hormesis that
emerged from Dr. Morimoto and Dr. Chandel's work (Project 2). They found that low level inhibition of
mitochondrial electron transport in C. elegans induced a proteostasis-protective response that enhanced the
resilience of aging animals, while more dramatic inhibition of electron transport was toxic. In mice, we found
that metformin inhibits mitochondrial electron transport at complex I in alveolar macrophages to induce the
expression of proteostasis protective genes in response to environmental stress. Mitochondrial electron
transport is linked with proteostasis through the integrated stress response and activation of the transcription
factor ATF4. Consistently, we found a small molecule inhibitor of the integrated stress response, ISRIB,
accelerated lung repair after influenza A infection in aged mice. These data support our hypothesis that age-
related impairments in the reparative function of alveolar macrophages can be reversed by transient low level
inhibition of electron transport with complex I inhibitors via the ISR and ATF4, while smoldering activation of
these pathways during aging precludes normal repair. We will test this hypothesis in three interrelated Specific
Aims:
Aim 1. To determine whether deficiency of the scavenger receptor Mertk in aged alveolar macrophages
impairs lung repair after influenza A-induced injury.
Aim 2. To determine whether metformin can restore the reparative function of alveolar macrophages via
inhibition of complex I of mitochondrial electron transport during aging.
Aim 3. To determine whether mitochondrial activation of proteostasis through eIF2?-mediated
translational inhibition and/or ATF4 improves lung repair after injury during aging.

## Key facts

- **NIH application ID:** 10417059
- **Project number:** 5P01AG049665-08
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** GR Scott Budinger
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $399,053
- **Award type:** 5
- **Project period:** 2015-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417059

## Citation

> US National Institutes of Health, RePORTER application 10417059, Alveolar Macrophages as Age-Related Drivers of Disordered Tissue Repair (5P01AG049665-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10417059. Licensed CC0.

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