# Metabolic alterations in age-associated dendritic cell dysfunction

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $494,954

## Abstract

Aging is associated with progressive immune dysfunction, resulting in blunted effector responses and
increased susceptibility to infectious disease and cancers. A significant contributor to this decreased
responsiveness is the impaired functionality of the most potent Ag-presenting cells, the dendritic cells (DCs). A
key aspect of DC function is their capacity to “cross-present” cell-associated Ag to CD8+T cells, a process that
is required to cross-prime CD8+T cell responses against tumors or intra-cellular pathogens. However, the effect
of aging on the acquisition, processing, and presentation of cell-associated Ags by primary DCs has barely
been studied.
We recently uncovered that aging significantly reduced the cross-presenting and cross-priming capacity of the
DC subsets the most efficient at carrying out this important task (CD8αDCs and merocytic DCs). Aged DCs
expressed normal MHC class I levels and were able to prime CD8+T cells to soluble peptides, but they were
strikingly impaired in terms of phagocytosis of cell-associated materials.
Mechanistically, the bio-energetic status, notably mitochondrial activity and membrane potential (Δψm), has
been shown to regulate DC phagocytic capacity. Mitochondrial function was profoundly affected in murine
CD8α or mcDCs, as shown by lower Δψm, reduced ATP turnover and coupling efficiency, decreased baseline
oxidative phosphorylation, and greater proton leak and ROS production. Old macaque CD1c+ DCs displayed
similar defects, demonstrating dysfunction across species. Pharmacologic manipulation of young DCs to mimic
the aged metabolic phenotype significantly impeded their phagocytic and cross-priming capacity, but in vitro
scavenging of ROS by NAC significantly reversed the cross-presentation defect of aged! DCs. Our inter-related
hypotheses are: (1) age-related changes in mitochondrial activity diminish the phagocytic and cross-presenting
activity of murine DCs; and (2) improving mitochondrial activity will boost DC functionality and their potential as
anti-tumor therapeutics in the elderly.
These hypotheses will be tested in the following 3 aims. Aim 1 will identify the mechanisms underlying
decreased mitochondrial fitness in aged murine DCs. We will dissect the effect of aging on DC use of, and
dependence on, specific carbon sources and metabolic pathways to meet their energy needs. Moreover, we
will assess whether the observed metabolic changes result from defects in the DC precursor, the aged
environment in which they differentiate, or a combination of both. Aim 2 will determine whether improving
mitochondrial activity of aged murine DCs increases their capacity to induce more vigorous T cell responses to
cell-associated Ags in vitro, while Aim 3 will study the effect of improving mitochondrial function on their
capacity to induce anti-tumor responses using well-established in vivo models of cross-presentation.
!

## Key facts

- **NIH application ID:** 9869827
- **Project number:** 5R01AG053498-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** CLAIRE A. CHOUGNET
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $494,954
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869827

## Citation

> US National Institutes of Health, RePORTER application 9869827, Metabolic alterations in age-associated dendritic cell dysfunction (5R01AG053498-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869827. Licensed CC0.

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