Older people are far more likely to get seriously ill from the flu or the coronavirus, and a new study from the University of California, San Francisco offers an explanation. This study shows that aging of lung cells can trigger an overly aggressive immune response, turning even mild infections into serious conditions.
These findings provide new insights into age-related inflammation and help explain why simple symptoms like cough can lead to hospitalization in older people.
Aging and inflammation of lung cells
To explore what changes occur in the lungs as we age, researchers focused on fibroblasts, structural cells that help maintain lung tissue. Experiments with young mice activated stress signals normally associated with aging. This causes clusters of inflamed cells in the lungs, including those characterized by the GZMK gene, which was first identified in cases of severe COVID-19 infection. Scientists believe that future treatments may be able to target these cells and interrupt the harmful cycle known as inflammation.
“We were surprised to see that fibroblasts in the lungs cooperated with immune cells to cause inflammation,” said Tian Peng, MD, professor of medicine at UCSF and member of the Heart and Vascular Institute and the Bakar Institute on Aging. “This suggests new ways to intervene before patients progress to severe inflammation that requires intubation.”
Peng is the study’s senior author. immunity Nancy Allen, MD, a clinical research associate in the Division of Pulmonary and Critical Care Medicine at UCSF School of Medicine, is the lead author.
Fibroblasts and the NF-kB pathway
Fibroblasts play an important role in keeping the airways and air sacs of the lungs stable and functional. However, they are also known to contribute to inflammation in conditions such as COPD. The research team wanted to see if signals from these cells could destroy healthy lungs.
They looked at a pathway called NF-κB, which is commonly associated with aging-related diseases. Once activated, fibroblasts send signals to macrophages in the lungs that mount an immune response. This reaction draws additional immune cells from the bloodstream, including those marked by GZMK.
Although these GZMK cells were less effective at fighting infection, they were still able to damage lung tissue.
Immune cell clusters and lung damage
Once these clusters of immune cells formed, young mice developed severe symptoms when infected, similar to reactions typically seen in older adults. When researchers used genetic techniques to eliminate GZMK cells, the mice became more resistant to infection.
This finding suggests that aging lung tissue itself may be a major source of harmful inflammation.
The researchers also examined lung tissue from elderly patients hospitalized with coronavirus-related ARDS (acute respiratory distress syndrome). These samples contained clusters of inflammatory cells similar to those observed in mice. Many of these clusters occurred in patients with more severe disease, but no clusters occurred in the lungs of healthy donors.
“We saw during COVID-19 that our most vulnerable patients were no longer infected but still had persistent and devastating lung inflammation,” Penn said. “This dysfunctional circuit between lung cells and immune cells represents a promising new therapeutic target.”
