# Investigating the interface of NLRX1 and immune aging

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $351,750

## Abstract

Project Summary/Abstract: Alterations in the immune system occur with aging, likely contributing to
infections and malignancies. In T cells, probably the most prominent change with aging is memory T cell
expansion. A possible mechanism for this finding is immune stimulation over a lifetime. The nucleotide binding
domain and leucine-rich-repeat-containing (NLR) protein X1 or NLRX1 located in mitochondria is a negative
regulator of multiple inflammatory pathways including the retinoic acid-inducible gene I (RIG-I), NLR pyrin
domain containing 3 (NLRP3) inflammasome, and NF-κB signaling. Our published and preliminary studies
support the possible implication of NLRX1 in aging. Aging induced the reduction of NLRX1 in murine lungs.
The lungs from whole body NLRX1 null mutant (-/-) or knockout (KO) mice revealed increased lung compliance,
a key feature of the “aging lung”8. Of interest, we found decreased expression of NLRX1 in peripheral blood
mononuclear cells (PBMCs) of older adults, raising the implication of NLRX1 in immune aging. Indeed, the
NLRX1 KO mice have changes in T cell immunity known to occur with aging. These changes include an
expansion of memory CD4+ and CD8+ T cells, decreased naïve T cell survival and IL-2 production, increased T
cell exhaustion molecules and effector cytokine IFN-γ. Our RNA-seq analysis on effector memory (EM) CD4+ T
cells of WT and NLRX1 KO mice highlighted an aging-like change in the global gene expression profile in
NLRX1 KO mice, implying the role of NLRX1 in altering T cell immunity with aging. This point is further
supported by noticing well-known age-associated changes in NLRX1 KO mice, including reduced
mitochondrial mass, nicotinamide adenine dinucleotide (NAD+) and SIRT1 as well as enhanced mitochondrial
reactive oxygen species (ROS), mTOR activation, hypoxia-inducible factor 1-alpha (HIF-1α) expression and
cellular exhaustion which are mechanistically linked. However, our understanding remains poor about how
NLRX1 plays in altering T cell immunity in the context of aging biology and whether such changes can be
restored by increasing NLRX1 in aged hosts. Here we address this question based on the hypotheses that
decreased NLRX1 augments T cell aging by mechanistically affecting a set of aging-associated molecules (i.e.,
mitochondrial ROS, NAD+, SIRT1, and mTOR) and that such aging-associated changes can be improved by
restoring NLRX1 expression in old mice. The goal of our proposal is to test these hypotheses with the following
specific aims: 1) Aim 1. Elucidate the mechanism of how NLRX1 deficiency alters T cell characteristics,
especially ones related to immune aging; 2) Aim 2. Elucidate the implication of mitochondrial ROS and NAD+
in inducing T cell immunity changes via affecting mTOR activity in NLRX1 KO mice; and 3) Aim 3. Elucidate
whether restoration of NLRX1 in vivo can attenuate aging-associated changes in T cell immunity. The results
of our study will reveal a novel mechanism of T cell aging in ...

## Key facts

- **NIH application ID:** 10801956
- **Project number:** 1R01AG082433-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Insoo Kang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $351,750
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801956

## Citation

> US National Institutes of Health, RePORTER application 10801956, Investigating the interface of NLRX1 and immune aging (1R01AG082433-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10801956. Licensed CC0.

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