# Mechanisms of regenerative decline in aged alveolar type 2 cells

> **NIH NIH F31** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2024 · $36,138

## Abstract

Abstract
The delicate gas-exchange surface of the lung is the site of many burdensome diseases, including COVID-19-
induced acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and
interstitial lung diseases (ILDs). Old age is a well-established predictor of the incidence and severity of these
diseases. Alveolar type 2 (AT2) cells, which acts as the guardian of the gas exchange surface against injury and
natural turnover via their progenitor cell activity, are detrimentally impacted by aging. AT2 cell self-renewal and
differentiation to produce new alveolar type 1 (AT1) cells, the cells that exchange gas with the capillaries, is
compromised in old age. In contrast, other progenitor cell populations in the airways of the lung show little
evidence of age-related stem cell exhaustion. Why AT2 cell regenerative capacity is reduced in old age is still
an open question. Our preliminary studies in mice supported by a single nuclear RNA and ATAC sequencing
dataset demonstrated that old AT2 cells have an IFNγ-inducible transcriptional signature, a cytokine critical for
many functions in innate and adaptive immunity. IFNγ is elevated in the aged mouse lung, and evidence exists
that IFNγ represses AT2 cell growth in human alveolar organoids and mouse disease models. Resident and
infiltrating lymphocytes, which act to surveil the lung epithelium for infectious cells, are often the main source of
IFNγ during an immune response. Additional preliminary studies demonstrate that there is an enrichment of
resident lymphocytes and resident natural killer cells in aged mouse lungs, indicative of more interactions and/or
paracrine signaling within the aged lung parenchyma. It is not known whether elevated IFNγ and/or the changes
in lymphocyte populations observed in the healthy aging lung influence AT2 cell regenerative decline. We
hypothesize that resident natural killer cells contribute to elevated IFNγ in the aging lung which induces AT2 cell-
specific regenerative decline. A variety of approaches will be taken to determine if elevated IFNγ or aging
lymphocyte populations are 1) necessary for aging AT2 cell regenerative decline and 2) whether they are
sufficient to block AT2 cell regeneration. In vivo alveolar injury from bleomycin, alveolar organoid forming assays,
and BH3 profiling will be used to assess AT2 cell regenerative capacity and apoptotic potential. Additionally, flow
cytometry and multiple imaging techniques, such as RNA in situ hybridization and immunofluorescent staining,
will be used to quantitate and localize lymphocytes or cells releasing IFNγ in the aging lung. Using these
strategies, this proposal will answer pertinent questions about shifts in aged AT2 cell-immune interactions, the
origins of aging AT2 cell exhaustion, and the role of the aging microenvironment in the causation of age-related
disease. This knowledge could prove crucial for proper preventative care and targeted therapies in individuals
with ...

## Key facts

- **NIH application ID:** 10995145
- **Project number:** 1F31HL168966-01A1
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Jake Jensen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,138
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995145

## Citation

> US National Institutes of Health, RePORTER application 10995145, Mechanisms of regenerative decline in aged alveolar type 2 cells (1F31HL168966-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10995145. Licensed CC0.

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