Aging Lung Cells Drive Severe Flu, COVID in Older Adults
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- UCSF researchers published a study in Immunity on March 27, 2026, showing that aging lung fibroblasts activate the NF-κB pathway, which signals macrophages to recruit immune cells marked by the GZMK gene.
- GZMK-marked cells, first identified in severe COVID-19 cases, damage lung tissue without effectively fighting infection, forming harmful inflammatory clusters rather than protective immune responses.
- Tien Peng, MD, senior author and UCSF professor of Medicine, said the team was 'surprised to see lung fibroblasts working hand-in-hand with immune cells to drive inflammaging,' calling it a promising new therapeutic target.
- In mouse experiments, activating the aging-related stress signal in young mice caused their lungs to develop inflammation clusters and severe illness resembling the response typically seen in older adults.
- Genetically removing GZMK cells in mice allowed them to better tolerate infection, suggesting the cells are key drivers of severity rather than bystanders.
- Lung tissue samples from older COVID-ARDS patients contained the same inflammatory cell clusters seen in mice, with cluster counts correlating to illness severity — healthy donor lungs showed none.
- First author Nancy Allen, MD, PhD, a clinical fellow in Pulmonary and Critical Care at UCSF, helped lead the work identifying a druggable circuit before patients progress to intubation.
Why it matters: Older adults account for the majority of severe flu and COVID hospitalizations, and current vaccines don't fully prevent dangerous outcomes in aging immune systems. This study pinpoints a specific fibroblast-to-immune-cell signaling circuit — NF-κB activation in fibroblasts recruiting tissue-damaging GZMK cells — as a druggable target to interrupt the 'inflammaging' cycle before patients require intubation.
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