These findings provide new insight into age-related inflammation and help explain why something as simple as a cough can sometimes lead to hospitalization in older individuals.

Aging Lung Cells and Inflammation

To explore what changes in older lungs, researchers focused on fibroblasts, the structural cells that help maintain lung tissue. In experiments with young mice, they activated a stress signal typically linked to aging. This caused the lungs to develop clusters of inflamed cells, including some marked by the GZMK gene, which was first identified in severe COVID-19 cases. Scientists believe future treatments could target these cells to interrupt the harmful cycle known as inflammaging.

“We were surprised to see lung fibroblasts working hand-in-hand with immune cells to drive inflammaging,” said Tien Peng, MD, a professor of Medicine and a member of the Cardiovascular Research Institute and Bakar Aging Research Institute at UCSF. “It suggests new ways to intervene before patients progress to severe inflammation that can require intubation.”

Peng is the senior author of the study, published in Immunity on March 27. Nancy Allen MD, PhD, a clinical fellow in the Pulmonary and Critical Care Division in the UCSF Department of Medicine, is the first author.

Fibroblasts and the NF-kB Pathway

Fibroblasts play a key role in keeping the lungs’ airways and air sacs stable and functional. However, they are also known to contribute to inflammation in conditions such as COPD. The research team wanted to determine whether signals from these cells could disrupt otherwise healthy lungs.

They examined a pathway called NF-kB, which is commonly associated with aging-related diseases. When activated, fibroblasts signaled macrophages in the lungs to initiate an immune response. This response then drew additional immune cells from the bloodstream, including those marked by GZMK.

Although these GZMK cells were not effective at fighting infection, they were still able to damage lung tissue.

Immune Cell Clusters and Lung Damage

After these clusters of immune cells formed, the young mice developed severe symptoms when infected, resembling the response typically seen in older adults. When researchers used a genetic method to remove the GZMK cells, the mice were better able to tolerate the infection.

This finding suggests that aging lung tissue itself may be a major driver of harmful inflammation.

The researchers also examined lung tissue from older patients hospitalized with COVID-related ARDS (acute respiratory distress syndrome). These samples contained similar clusters of inflamed cells to those observed in the mice. Patients with more severe illness had a greater number of these clusters, while healthy donor lungs showed none.

“We saw during COVID that our most vulnerable patients no longer had the infection but still had persistent and devastating lung inflammation,” Peng said. “This circuit of dysfunction between lung and immune cells makes for a promising new therapeutic target.”