A study led by researchers at UC San Francisco announced on March 27 finds that older adults are more likely to become seriously ill from flu or COVID because aging lung cells can drive excessive immune responses. The research, published in the journal Immunity, highlights how age-related changes in lung tissue contribute to severe inflammation, which can turn a minor cough into a life-threatening condition for elderly individuals.
The findings are important as they help explain why older people face higher risks of hospitalization from respiratory infections. Understanding these mechanisms may lead to new therapies that target the root causes of inflammaging—chronic inflammation associated with aging.
Researchers engineered structural lung cells called fibroblasts in young mice to activate an age-related distress signal. This triggered clusters of inflamed cells similar to those observed in severe COVID-19 cases, including some marked by the GZMK gene. "We were surprised to see lung fibroblasts working hand-in-hand with immune cells to drive inflammaging," said Tien Peng, MD, professor of Medicine and member of both 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 senior author of the paper; Nancy Allen MD, PhD is first author.
Fibroblasts normally help maintain healthy lung structure but can also promote inflammation seen in diseases like chronic obstructive pulmonary disease (COPD). The study found that when fibroblasts send out signals through a pathway known as NF-kB—a pathway commonly active in aging—they prompt immune system macrophages and other inflammatory cells marked by GZMK into action. These recruited immune clusters did not fight disease effectively but caused further damage within the lungs.
When scientists eliminated GZMK-marked immune cells from mice with engineered lungs, those animals were better able to withstand infection. This points toward potential therapies targeting specific cell types or pathways involved in inflammaging.
The team also examined lung tissue from older patients hospitalized with COVID-related acute respiratory distress syndrome (ARDS) and found similar clusters of inflamed cells as seen in their mouse models—the sicker the patient, the more pronounced these clusters appeared. Healthy donor lungs showed none of these features. "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."
