# The reduction of NLRX1 and its role in pulmonary aging

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $343,375

## Abstract

PROJECT SUMMARY
Biological aging of the pulmonary system is associated with structural changes that lead to a progressive
decline in function, and the term “aging lung” is used to describe the organ in this stage of decline. With
population rapidly aging, a thorough understanding of physiologic aging-related changes in the lung is
imperative. We recently demonstrated a mitochondrial molecule, nucleotide-binding domain and leucine-rich-
repeat-containing protein X1 (NLRX1) which has been identified as a negative regulator of mitochondrial
antiviral signaling molecule (MAVS), plays a critical role in the pathogenesis of chronic obstructive pulmonary
disease (COPD). Because aging is a common risk factor for COPD, studies were undertaken to determine if
NLRX1 is an important player in “aging lung.” Our preliminary studies revealed that (i) aging itself induced the
reduction of NLRX1 at the level of gene and protein in murine lungs; (ii) the site of major reduction was in
macrophages; and (iii) the lungs from 12-month-old (mo) NLRX1 null mutant (-/-) mice manifested enhanced
characteristics of the “aging lung.” These features observed from NLRX1-/- mice included (a) activation of the
inflammasome, (b) increased p53 signaling and its target molecule promyelocytic leukemia (PML; a well-known
marker of cellular senescence), (c) decreased production of vascular endothelial growth factor (VEGF), a key
regulator of pulmonary vasculature and cytoprotection and (d) enhancement of senile emphysema-like alveolar
remodeling, all of which were modestly observed in lungs from wild type (WT) controls. In addition, we
identified an unprecedented function of NLRX1 as an interacting molecule with PTEN-induced kinase 1
(PINK1), an essential regulator of mitochondrial quality control. The importance of NLRX1 in aging studies was
evident in humans, revealing the expression of NLRX1 was significantly reduced in peripheral blood
mononuclear cells from the elderly (age>65) compared to those from young controls (age<40). This
constellation of findings led us to hypothesize that aging-induced reduction of NLRX1 plays a critical role
in the aging of pulmonary system via, at least, mitochondrial dysfunction/molecular dysregulation. To
test the hypothesis, we will utilize newly generated mice in which the NLRX1 gene can be null mutated or
induced, respectively, in a temporospatial manner. Proposed aims driven by specific hypotheses are: Aim #1.
Define the alteration of NLRX1 and its role(s) in pulmonary aging in vivo; Aim #2. Determine if restoring the
expression of NLRX1 in vivo attenuates aging-related alterations in the pulmonary system; Aim #3.
Characterize the mitochondrial dysfunction/molecular dysregulation in the lung with aging and define the role
that NLRX1 plays in aging-related mitochondrial dysfunction/molecular dysregulation. To our best knowledge,
NLRX1, an innate immune regulator, has never been studied in the context of aging. Its specific function(s) in
macroph...

## Key facts

- **NIH application ID:** 9936123
- **Project number:** 5R01AG053495-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Min-Jong Kang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,375
- **Award type:** 5
- **Project period:** 2016-08-15 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936123

## Citation

> US National Institutes of Health, RePORTER application 9936123, The reduction of NLRX1 and its role in pulmonary aging (5R01AG053495-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9936123. Licensed CC0.

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