Why flu and COVID-19 are so dangerous for older people
New research from the University of California, San Francisco opens up an important piece of the puzzle that was repeatedly confirmed in hospitals during the pandemic and flu seasons: older people develop severe forms of respiratory infections significantly more often, but the reason is not only that their immune system is “weaker.” According to a paper published on March 27, 2026 in the prestigious journal
Immunity, the problem may also lie in the lung tissue itself, which changes with age in the way it communicates with defensive cells. Researchers from UC San Francisco showed that fibroblasts, connective tissue cells that maintain the structure and stability of the lungs, can in older age trigger a chain of events that ends in excessive inflammation potentially fatal for the patient. This is especially important because precisely such an excessive immune reaction is often associated with severe courses of flu, COVID-19, and similar viral diseases of the respiratory system. The finding does not mean that a ready-made cure has been found, but it provides a convincing explanation of why, in some older patients, an infection turns into an inflammatory collapse that requires hospital treatment, oxygen, and even mechanical ventilation.
What scientists actually discovered
The center of the story is not viruses but cells that normally play a supporting role. Fibroblasts maintain the structure of the pulmonary alveoli and airways, help in tissue repair, and participate in keeping the lungs functional and elastic. However, the team of Professor Tien Peng determined that fibroblasts in aged lung tissue can activate the NF-kB signaling pathway, a well-known mechanism associated with chronic inflammation and diseases of aging. When that signal is amplified, fibroblasts are no longer merely “construction” cells, but become active organizers of the inflammatory response. In experiments on mice, researchers artificially switched on such a signal in young lungs and thereby induced a state resembling older lung tissue. The consequence was the formation of clusters of immune cells that behaved as if the organism were going through a severe inflammatory crisis.
Especially important is the appearance of cells carrying the GZMK marker. This is a subset of immune cells that appeared in earlier research in severe forms of COVID-19, and it has now been shown that the aged lung environment can actively attract and sustain them. According to the description of the study, those cells do not act effectively against the disease itself, but they can still inflict damage on lung tissue. In other words, the defense system arrives at the site of infection, but some of its actors do not contribute to calming the disease and instead further intensify the damage. In the laboratory model, when researchers genetically removed those GZMK cells, the lungs tolerated the infection better. This points to the conclusion that the problem is not only in the virus but also in how aging reshapes the local tissue response.
Why this finding is important for understanding severe infections
It has been known for years that age strongly increases the risk of complications from flu and COVID-19. The American CDC states that people aged 65 and older bear the greatest burden of severe flu: in recent seasons, this age group accounted for between 70 and 85 percent of flu-related deaths and between 50 and 70 percent of hospitalizations. The U.S. federal health department, in an information sheet for older adults, also states that people aged 65 and over make up approximately three quarters of flu-related deaths and nearly nine out of ten COVID-19-related deaths. Those data do not by themselves prove the cause, but they clearly show the scale of the problem. The new research now provides a biologically convincing mechanism that can explain why infections in older age more often turn into life-threatening conditions.
Until now, the vulnerability of older people has most often been explained by the general weakening of immune defenses, a higher number of chronic diseases, and slower recovery. All of that remains true, but the new study adds another layer: aged lung tissue may not be only a passive victim of infection, but an active participant that drives an inappropriately strong inflammatory response. In that sense, the research speaks of “inflammaging,” a term describing chronic, low-grade inflammation associated with aging. When a respiratory infection is superimposed on such a background, the consequence can be a sudden and destructive escalation of inflammation. Precisely such a pattern was familiar to physicians during the most severe waves of the pandemic, when some older patients ended up in intensive care units even though active viral replication itself was no longer the dominant problem.
How the research was conducted
The authors did not stop at the animal model. After they artificially induced “old” inflammatory lung behavior in young mice, they also analyzed lung tissue from older patients hospitalized because of COVID-19-related ARDS, that is, acute respiratory distress syndrome. This is a severe condition in which the lungs, because of intense inflammation and fluid accumulation, can no longer supply the body with oxygen effectively enough. The American National Heart, Lung, and Blood Institute explains that ARDS causes a drop in blood oxygen levels, along with a buildup of fluid in the small air sacs of the lungs, and that it can develop quickly and follow a life-threatening course. In samples from older patients, researchers found cell clusters similar to those seen in experimental models. The more severe the clinical condition was, the more pronounced the inflammatory clusters were. In healthy donor lung tissue, there were no such findings.
Such agreement between the experimental model and human tissue is one of the stronger elements of the study. It does not automatically prove that the entire mechanism is already ready for clinical application, but it significantly increases the plausibility of the conclusion that older lung tissue really can create conditions for excessive inflammation. The first author of the paper, Nancy Allen, a physician and clinical researcher from the pulmonary and critical care division at UCSF, signed the study together with a larger team of researchers from several laboratories and clinical programs. Funding was provided, according to the UCSF announcement, by the U.S. National Institutes of Health and the Bakar Aging Research Institute, which further indicates that this is research integrated into a broader effort to understand the biology of aging.
What the role of fibroblasts means, and what the role of immune cells means
In public discussion, the role of connective tissue in infections is rarely mentioned, because attention is almost always directed at the virus, the bacterium, or classic immune cells such as lymphocytes and macrophages. But fibroblasts are much more than passive support. They determine the local tissue environment, send chemical signals, participate in healing, and can recruit other cells when they sense danger. According to the researchers’ description, activated fibroblasts in older lungs alert macrophages, and then an additional wave of immune cells arrives from the bloodstream, including those carrying the GZMK marker. This creates a vicious circle in which tissue and the immune system mutually amplify inflammation.
It is important to emphasize that such a response is not the same as effective antiviral defense. In clinical practice, physicians have long distinguished situations in which the body cannot suppress the pathogen from those in which the defensive reaction itself becomes part of the problem. In severe forms of COVID-19 and flu, excessive inflammation is precisely one of the reasons for rapid deterioration, and in some patients the greatest damage develops in a phase when the virus is no longer the only or main driver of the clinical picture. The UCSF team now suggests that one part of that story may begin earlier than previously thought, in the very architecture and biological age of lung tissue. This is an important shift, because the therapeutic target would then not be only the virus but also the misdirected host response.
Can this lead to new therapies
The most cautious and most important part of announcements like this is the question of application. The study does not claim that there is a ready-made drug that will protect older people from severe COVID-19 or flu, nor does it suggest that classical prevention is less important. But its value lies in showing more precisely where future therapies might intervene. If it is further confirmed that GZMK-positive cells and the signaling pathways activated by fibroblasts play a key role in the inflammatory spiral, it is possible to imagine drugs that would calm that cycle before the patient develops respiratory failure. That is precisely why Professor Peng, in the UCSF announcement, speaks of a promising new therapeutic target.
This is especially relevant for older and chronically ill patients, in whom the window for action is often short. Today’s treatment of severe viral respiratory infections already combines several approaches: antiviral drugs when given early enough, breathing support, monitoring of complications, and, in certain situations, anti-inflammatory therapy. Still, medicine does not yet have sufficiently precise tools to distinguish in advance patients in whom inflammation will remain under control from those in whom it will turn into ARDS and multisystem deterioration. If it is confirmed that fibroblast aging and the appearance of GZMK cells serve as early biological indicators, that could also help in earlier identification of at-risk patients.
Broader context: why older people remain the highest-risk group
Even regardless of new laboratory discoveries, the epidemiological picture remains clear. Older age in itself increases the risk of a severe course of flu and COVID-19, and that risk is further increased by heart disease, diabetes, obesity, chronic lung diseases, and a weakened immune system. In a current information sheet for older adults, the American HHS explicitly warns that people aged 65 and over are in the high-risk group for severe flu or COVID-19, while for flu the CDC also emphasizes the importance of the rapid start of antiviral treatment when symptoms appear in that age group. This means that the new research does not change the basic public health message, but complements it with a deeper explanation. Vaccines, early recognition of symptoms, and timely therapy remain the first line of defense.
Likewise, one should be cautious with the simplified interpretation that only old lungs are “to blame.” Aging is a complex process that encompasses the entire body: from changes in the functioning of the immune system to weaker tissue regeneration, a higher frequency of comorbidities, and a different response to drugs. But that is precisely why studies like this are important. They help separate general claims from concrete mechanisms. Instead of the abstract formulation that “immunity is weaker,” it is now seen more precisely how local communication between fibroblasts, macrophages, and specific T cells can turn an infection into an extremely dangerous condition. For clinicians, this is a potentially important clue, and for the public, a reminder that behind the increased risk in older age stand very real and measurable biological changes.
What is still not clear for now
As with any early biomedical discovery, there is a series of open questions. It is not yet known to what extent the same mechanism occurs in all respiratory viruses, how much it depends on previous lung diseases, and whether it can be blocked safely enough without impairing normal defense against infection. It is also not clear whether future therapy will be directed directly at fibroblasts, at the NF-kB signaling pathway, or at the GZMK-positive cells themselves. Additional research will also have to show whether this biological pattern can be recognized early enough, before a sudden drop in oxygenation and the need for intensive treatment occur.
Despite these limitations, the study published at the end of March 2026 comes at a time when the need for a more precise understanding of respiratory risk in older age remains great. COVID-19 is no longer in the same phase as in 2020, but it still represents a serious problem for older and chronically ill patients, just like seasonal flu and other respiratory infections. That is why every finding that can explain why in some patients the disease does not stop at the usual symptoms but progresses to lung failure is important from both a scientific and a public health perspective. The UCSF research can therefore be read as more than a laboratory curiosity: it offers a convincing framework for understanding how the aging of lung tissue itself can turn an infection into a dangerous immune storm and why future treatment may have to target not only the cause of the disease but also the way older lungs react to the attack.
Sources:- UC San Francisco – announcement on the research and statements by the authors: UCSF News- Immunity / Cell Press – summary of the paper on NF-kB-activated fibroblasts and GZMK+ T cells: Cell Press- CDC – official data on the risk and burden of flu in the 65+ group: CDC- U.S. Department of Health and Human Services – information sheet for older adults on flu, COVID-19, and RSV: HHS- NHLBI / NIH – official explanation of acute respiratory distress syndrome (ARDS): NHLBI- UCSF Department of Medicine – profile of Professor Tien Peng and the research focus of the laboratory: UCSF Department of Medicine
Find accommodation nearby
Creation time: 2 hours ago