Aging Lung Cells Trigger Dangerous Immune Overresponse to Flu and COVID in Older Adults, Study Finds
Researchers at the University of California, San Francisco, led by Dr. Tien Peng, published a study on March 27, 2026, in the journal *Immunity* showing that aging lung cells trigger dangerous immune overresponses to flu and COVID-19 in older adults. The study found that aging lung fibroblasts activate a distress signal that causes immune cells to form inflamed clusters, damaging lung tissue and worsening infections, according to the researchers.
Published on March 27, 2026, in the journal *Immunity*, the research demonstrated that these fibroblasts activate the NF-kB pathway, a distress signal associated with aging, which in turn prompts macrophages to mount a heightened immune reaction in the lungs, according to Peng and colleagues.
The study led by Dr. Tien Peng, a professor of medicine at the University of California, San Francisco (UCSF), identified aging lung fibroblasts as the key cells responsible for triggering an excessive immune response in older adults infected with influenza and COVID-19.
This immune overresponse leads to the formation of inflamed cell clusters marked by the gene GZMK, which was previously linked to severe COVID-19 cases. The presence of GZMK-positive cells damages lung tissue despite their ineffectiveness in clearing the infection, the study found. The researchers described this process as “inflammaging,” a condition in which normally mild infections cause severe illness in older adults by triggering runaway inflammation that harms lung tissue.
To investigate the mechanism further, the team engineered young mice to express the age-related distress signals found in aging fibroblasts. These mice developed lung inflammation characteristic of older animals, including the formation of GZMK-marked immune cell clusters. When infected, the engineered mice exhibited severe symptoms similar to those seen in elderly patients. Genetic elimination of GZMK-positive cells in these mice allowed their lungs to better withstand infection, demonstrating that aging lung tissue alone can drive harmful inflammation independently of other age-related factors, according to the study.
Human lung tissue samples from older COVID-19 patients confirmed the presence of these inflamed cell clusters, with the sickest patients showing the highest density of such clusters, the researchers reported. Persistent lung inflammation was observed even after the infection had cleared. Additional analyses revealed elevated levels of interferon-alpha 2 (IFN-α2) and transforming growth factor-beta (TGF-β) in the lungs of elderly COVID-19 patients compared to younger adults, along with reduced densities of CD20-positive B cells and increased pro-fibrotic responses, which contribute to lung scarring and impaired function.
Dr. Peng emphasized that lung fibroblasts work in close coordination with immune cells to drive this age-related inflammation. “The circuit of dysfunction between lung and immune cells is a promising therapeutic target,” Peng said. He noted that the findings open avenues for interventions aimed at preventing severe lung inflammation before patients require intubation. Peng also highlighted that vulnerable patients exhibit persistent, devastating lung inflammation even after recovering from COVID-19.
The study sheds light on why older adults are more susceptible to severe illness from respiratory infections such as flu and COVID-19. According to the researchers, aging lungs trigger a runaway inflammatory response that damages tissue rather than protecting it, making even mild infections potentially serious or requiring hospitalization. Persistent lung damage following infection can lead to serious or fatal outcomes, with age-related changes in lung tissue predisposing elderly patients to faster progression of lung injury.
The research team plans to continue investigating the mechanisms by which aging fibroblasts trigger immune overresponses and to develop therapies targeting GZMK-positive cells to halt the process of inflammaging. The goal is to protect older adults from severe outcomes of flu, COVID-19, and other respiratory infections by disrupting the dysfunctional interaction between lung fibroblasts and immune cells before disease progression necessitates intensive care.
This study builds on previous findings that aging is associated with altered immune responses and increased susceptibility to respiratory diseases. It provides a cellular and molecular explanation for the increased risk of severe lung inflammation and injury in older adults, highlighting potential targets for future therapeutic development.
