Older adults are significantly more likely to develop severe illness from influenza or COVID-19, and new research suggests that ageing lung cells may play a central role in this vulnerability. A study led by scientists at the University of California, San Francisco, has found that structural cells in the lungs can trigger exaggerated immune responses as people age. These findings offer new insight into why infections that might cause only mild symptoms in younger individuals can escalate into serious, even life-threatening conditions in older adults.
The research sheds light on the broader phenomenon of age-related inflammation, often referred to as “inflammaging.” This process helps explain how what begins as a relatively minor respiratory symptom, such as a cough, can rapidly progress into a condition requiring hospital care in older individuals. Rather than simply being a consequence of weaker immunity, the study suggests that ageing lungs may actively contribute to harmful inflammatory responses.
To investigate what goes wrong in ageing lungs, the research team focused on fibroblasts—structural cells responsible for maintaining the integrity of lung tissue. In laboratory experiments, scientists engineered these cells in young mice to activate an age-associated distress signal. This manipulation caused the lungs to develop clusters of inflamed cells, mimicking patterns typically seen in older individuals. Among these were immune cells marked by the GZMK gene, previously identified in severe cases of COVID-19.
The study revealed that these fibroblasts do not act in isolation. Instead, they appear to work closely with immune cells, amplifying inflammatory processes. According to senior author Tien Peng, this interaction was unexpected and suggests new possibilities for early intervention. By identifying how these cells collaborate to drive inflammation, researchers may be able to develop therapies that interrupt this process before it escalates to severe disease requiring interventions such as mechanical ventilation.
At the molecular level, the distress signal observed in the study is linked to the NF-κB pathway, a well-known regulator of inflammation that becomes more active with age. Activation of this pathway prompted macrophages—key immune cells in the lungs—to initiate a broader immune response. This, in turn, attracted additional immune cells from the bloodstream, including those expressing GZMK. Although these cells were not effective at combating infection, they contributed to tissue damage and worsened lung function.
When these inflammatory cell clusters formed, the lungs of otherwise young and healthy mice began to respond to infection as though they were much older. However, when researchers removed the GZMK-marked cells using genetic techniques, the mice showed a markedly improved ability to withstand infection. This finding suggests that the ageing lung environment itself, rather than infection alone, plays a decisive role in driving severe inflammatory responses.
To validate these findings in humans, the team analysed lung tissue from older patients hospitalised with COVID-related acute respiratory distress syndrome (ARDS). They observed similar clusters of inflamed cells, with more extensive clustering associated with more severe illness. In contrast, lung tissue from healthy individuals showed no such patterns. These results point to a self-reinforcing cycle between ageing lung tissue and the immune system, highlighting a potential target for future therapies aimed at reducing harmful inflammation in older adults.
More information: Nancy Allen et al, NF-κB-activated fibroblasts orchestrate inflammaging and emergence of pro-inflammatory granzyme K+ T cells, Immunity. DOI: 10.1016/j.immuni.2026.02.016
Journal information: Immunity Provided by University of California – San Francisco
