Study Reveals How Lungs Age and Offers Targets for Preventing Disease

One of the most comprehensive analyses of human lung aging has found that not all cells age equally.

Aging is associated with increased risk for nearly every lung disease, including acute conditions like pneumonia and chronic diseases like chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer.

Now, a new Nature Communications study has found that certain types of lung cells are especially vulnerable to aging. The findings could inform treatments that target the defective cells, the researchers say.

“This data allows us to start thinking about lung aging not as a passive state that we have to accept, but as something that we may be able to modify with therapies and interventions,” says senior author Naftali Kaminski, MD, Boehringer Ingelheim Pharmaceuticals, Inc. Professor of Medicine (Pulmonary) at Yale School of Medicine and chief of pulmonary, critical care and sleep medicine at Yale.

The study was led by first author Ruben De Man, an MD-PhD student in the cellular and molecular physiology graduate program at YSM.

In the study, the researchers collected data from 60 human lungs from donors ranging from 11 to 80 years old. Using single-cell RNA sequencing and advanced computational methods, they identified all of the cells within each sample. They also looked for age-related changes in cell type proportions, gene expression, as well as in the sequence of the genes that reflects somatic mutations (changes in DNA acquired after birth).

Their analyses revealed that not all the cells in the lung age at a similar rate.

AT2 cells—which produce a substance called surfactant that helps maintain the integrity of the lungs’ air sacs—and endothelial cells that form the lining of the lung vascular system are especially impacted by aging. These cells exhibited the greatest changes in gene expression and number of somatic mutations, as well as other changes associated with age. In AT2 cells, for example, the team observed decreased expression in genes that drive surfactant production, and that gene expression seemed more disordered with age.

“Our analysis shows that aging is accompanied by an increase in transcriptional entropy across many cell types in the lung,” says De Man. “This rising disorder in gene regulation may be a fundamental feature of how our cells lose their organization and stability as we grow older.”

This gene expression entropy seemed to be associated with an increase in somatic mutations, and thus could help scientists pinpoint specific mutations and genetic changes that increase the risk of developing various diseases associated with aging.

“While the role of somatic mutations is well known in conditions such lung cancer, the abundance of such mutations with aging may allow better understanding of the increased predisposition to lung diseases with aging and lead to targeted cell therapies,” Kaminski says.

Ivan O Rosas, MD, section chief of pulmonary, critical care, and sleep medicine at Baylor College of Medicine was also a key contributor to the study.