# Impact of Aging on Oxysterol Regulation of Alveolar Macrophage Function during S. pneumoniae

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $642,501

## Abstract

Project Abstract
Normal lung aging is associated with multiple structural and functional changes in the respiratory tract. Alveolar
macrophages (AM) are long-lived tissue resident innate immune cells of the airways and during steady state
conditions, adopt a pro-healing, anti-inflammatory phenotype to maintain lung integrity. AM are key effectors of
recognition, initiation, and resolution of the host defense against microbes and play an essential role in mediating
host responses to Streptococcus pneumoniae (S. pne). Cell
essential
and
macrophage
aged
death and the effective clearance of dying cells are
processes t hat maintain tissue homeostasis. When efferocytosis is defective, increased tissue injury
 development of acute respiratory distress syndrome (ARDS) can occur. Despite defects in alveolar
phagocytosis being prevalent i n aging, very little is known on how the process of aging and the
 lung microenvironment contribute to these changes.Our published findings illustrate that an age-
associated increase in mitochondrial and endoplasmic reticulum stress during S. pne contributed to dysregulated,
overly heightened pro-inflammatory immune responses in AM and lung. To better understand the metabolic
factors that might contribute to this phenotype, we examined changes in lipid metabolism in young and aged
lung. We observed a molecular reprogramming in response to dysregulated cholesterol homeostasis. Given
these findings, we hypothesize that an age-associated increase in lipid metabolism alters innate immune
responsiveness and efferocytosis by AMs, thereby contributing to heightened inflammation and prolonged tissue
injury in response to S. pne. To test this hypothesis, we have designed three specific aims that will utilize
innovative techniques to spatially
landscape
landscape
the
mediated
utilize
the
will
the
resolve single-cell data that will allow us to develop a biologically interpretable
of lung pathology from a structural, immunological, and clinical standpoint. This spatial single-cell
will enable the pathophysiological characterization of the lung from its macroscopic presentation to
single-cell, providing an important basis for the understanding of lipid metabolism on alveolar macrophage
process and will provide insights into age-associated changes in lung pathology. In addition, we will
metagenomic sequencing of human plasma to distinguish infection and infectious disease, and to assess
severity of pneumococcal disease. We firmly believe that fundamental insights gained from this novel assay
be applicable to other infection models and will help clarify many of the long-outstanding questions regarding
role of aging on specific tissue responses.

## Key facts

- **NIH application ID:** 10912753
- **Project number:** 5R01AG079937-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Heather Winona Stout Delgado
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $642,501
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912753

## Citation

> US National Institutes of Health, RePORTER application 10912753, Impact of Aging on Oxysterol Regulation of Alveolar Macrophage Function during S. pneumoniae (5R01AG079937-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10912753. Licensed CC0.

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