Cellular and Transcriptional Changes in Lung Aging

Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular and Molecular Physiology

First Advisor

Kaminski, Naftali

Abstract

Age is a major risk factor for lung disease. Diseases such as pneumonia, lung cancer, chronic obstructive lung disease (COPD), and idiopathic pulmonary fibrosis (IPF) are both more common and more lethal in aged individuals. While there has been significant progress in understanding the role of aging-related mechanisms in advanced lung disease and in describing the physiological effects of aging in the lung, the cellular and molecular mechanisms that underlie the lung's aging response remain poorly understood. The goals of this dissertation are threefold: 1) to characterize signatures of aging and cellular senescence in the lung at cell type resolution, 2) to identify cellular and molecular basis for age-related lung and pulmonary vascular dysfunction, and 3) to develop a model for studying the effect of induced senescence on lung aging. Overall, our results suggests that lung cellular aging is dyssynchronous, with alveolar epithelial and endothelial cells exhibiting the greatest changes with aging. Transcriptional changes show a decline in surfactant-producing AT2 cells and capillary endothelial cell hypofunction. Somatic mutations called from scRNA-seq data increase with aging, with alveolar epithelial and endothelial cell types exhibiting greater mutation burdens. Using well-validated senescence signatures, we identified and characterized the heterogeneity of cells expressing senescence signatures, and showed that they did not increase with age. In the pulmonary vasculature, we identified cellular and molecular signatures of pulmonary artery aging. We showed that these reflect hallmarks of aging, with evidence showing changes in proteostasis, intercellular signaling, and senescence in aged arteries. These changes were associated with pulmonary vascular stiffening, offering insights on the molecular basis for age-related phenotypes and downstream effects on lung aging. Finally, to better characterize the findings of parts 1 and 2, we developed an ex vivo model of accelerated lung aging. We showed that this model can used to study perturbations such as oxidative stress-induced senescence. This approach allowed us to study and culture human lung tissue, while retaining the structure and organization of the lung parenchyma. The model was used to show age-associated differences in response to senescence induction, and to differentiate between aging and senescence signatures.

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