Ageing lungs turn viruses more dangerous

Ageing lung tissue, rather than age alone, may be a central reason influenza and COVID-19 become far more dangerous for older adults, according to a newly published study that found structural cells in the lung can set off a damaging immune overreaction. The work, led by University of California, San Francisco researchers and published in Immunity on March 27, adds a fresh layer to the medical understanding of why an ordinary respiratory infection can spiral into severe illness in later life.

For years, doctors have known that people over 65 face a sharply higher risk from respiratory viruses. The US Centers for Disease Control and Prevention says older adults bear the greatest burden of severe influenza disease in most seasons, accounting for an estimated 70% to 85% of flu-related deaths and 50% to 70% of hospitalisations. The agency also says more than 81% of COVID-19 deaths occur in people over 65, with risk rising steeply with age. That broad pattern has usually been explained by weakening immune defences and the heavier burden of chronic illness in older populations.

The new research argues that the lungs themselves are active participants in that vulnerability. Investigators focused on fibroblasts, cells best known for maintaining the lung’s structural framework. They found that, with age, these cells can activate an inflammatory pathway known as NF-kB and help reorganise the local immune environment in ways that become harmful rather than protective. In the study, this process promoted the build-up of inflammatory cell clusters and the emergence of granzyme K, or GZMK, positive immune cells associated with severe disease.

Researchers tested the mechanism in young mice by switching on an ageing-linked distress signal in lung fibroblasts. The result was striking: the animals’ lungs began to resemble older lungs, forming inflamed cell clusters and responding to infection with more severe symptoms. When the scientists genetically removed the GZMK-marked cells, the mice tolerated infection better, suggesting those cells were contributing to tissue injury instead of viral control. That finding strengthens the argument that age-related changes in the lung microenvironment can turn a standard immune response into self-inflicted damage.

The human evidence, while narrower, moved the study beyond an animal model. The team examined lung tissue from older patients hospitalised with COVID-related acute respiratory distress syndrome and found similar inflammatory clusters. According to the study summary and follow-on coverage, the sickest patients had the highest number of these clusters, while healthy donor lungs did not show them. That link does not prove the same pathway is solely responsible for severe disease in humans, but it does place the mouse findings in a clinically relevant setting.

Tien Peng, the study’s senior author and a professor of medicine at UCSF, said the team was surprised to see fibroblasts “working hand-in-hand with immune cells to drive inflammaging”, using the term for chronic age-related inflammation. He said the results suggest new ways to intervene before patients develop the kind of runaway inflammation that can lead to intubation. Peng also said clinicians saw during the COVID pandemic that some of the most vulnerable patients no longer had active infection yet still suffered devastating lung inflammation, making this lung-immune circuit a possible therapeutic target.

The findings arrive as influenza continues to impose a heavy burden on older adults. CDC estimates for the 2024-25 flu season show people aged 65 and over accounted for 57% of flu-related hospitalisations and 71% of deaths, even as vaccination was estimated to prevent millions of illnesses and thousands of deaths overall. That matters because the new study does not displace existing public health advice; it reinforces it. Vaccination, early antiviral treatment and tighter protection for older adults remain the main tools now available, while the biology described in Immunity points to what future therapies might target.