Millions of people who recover from infections such as COVID-19, influenza, and glandular fever experience long-lasting symptoms. These persistent symptoms can include chronic fatigue, brain fog, exercise intolerance, dizziness, muscle or joint pain, and gut problems. Notably, many individuals find that their symptoms worsen after exercise—a condition known as post-exertional malaise. Medically, these symptoms are classified as myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). The World Health Organization (WHO) recognizes this condition as a post-viral fatigue syndrome, and it is also acknowledged by the United States Centers for Disease Control and Prevention as a brain disorder.
Experiencing prolonged illness after an infection is not a new phenomenon; patients have reported such symptoms for decades. However, the COVID-19 pandemic has exacerbated these issues on a global scale. Recent estimates suggest that nearly half of those suffering from ongoing post-COVID symptoms, known as long-COVID, meet the criteria for ME/CFS. Since the pandemic began in 2020, over 400 million people worldwide are believed to have developed long-COVID.
Despite extensive research, no widely accepted and testable mechanism has fully explained the biological processes underlying long-COVID and ME/CFS. Our research group, focused on studying blood and the cardiovascular system in inflammatory diseases and post-viral conditions, aims to bridge this gap. We examine key factors such as coagulation, inflammation, and endothelial cells. These cells form the inner layer of blood vessels and play crucial roles in regulating blood clotting, vessel dilation, and inflammation.
In our latest review, our international team proposes that certain viruses induce endothelial cells to enter a state of dysfunction known as cellular senescence. These senescent endothelial cells stop dividing but continue to release molecules that can disrupt and confuse the immune system. This results in increased blood clot formation and impairs the breakdown of existing clots, potentially leading to restricted blood flow and vessel constriction. By placing these “zombie” blood-vessel cells at the core of post-viral diseases, our hypothesis connects microclots, oxygen debt, brain fog, dizziness, gut leakiness, and immune dysfunction into a cohesive narrative.
Viruses such as SARS-CoV-2, Epstein–Barr virus, HHV-6, and influenza A have been shown to infect endothelial cells directly. Research indicates that these viruses can trigger endothelial senescence. For instance, studies have demonstrated that SARS-CoV-2 can induce senescence across various cell types, including endothelial cells. The viral proteins from SARS-CoV-2 disrupt DNA-repair pathways, pushing host cells toward a senescent state, thereby increasing their susceptibility to further viral entry.
We hypothesize that when blood-vessel cells transition into “zombies,” they release substances that thicken the blood and promote the formation of tiny clots, slowing circulation and depriving muscles and organs of oxygen. This could explain the profound fatigue experienced by patients. During physical exertion, the situation worsens; rather than allowing vessels to relax for adequate blood flow, they constrict further, leading to muscle oxygen deprivation and subsequent crashes after exercise. In the brain, faulty endothelial cells can reduce blood flow and cause leaks, contributing to brain fog and dizziness. In the gut, these cells can weaken the intestinal lining, allowing toxins to enter the bloodstream and trigger further inflammation.
Some components of the immune system, such as natural-killer cells, macrophages, and complement proteins, are responsible for eliminating senescent cells. However, individuals with long-COVID and ME/CFS often experience impaired natural-killer cell function, sluggish macrophage activity, and complement dysfunction. Additionally, senescent endothelial cells may emit signals that repel immune responses, creating a cycle of vascular and immune dysfunction where these “zombie cells” persist. In healthy individuals, these senescent cells would typically be cleared; however, significant immune dysfunction in ME/CFS and long-COVID allows these cells to survive and the disease to progress.
Currently, a registered clinical trial in the US is investigating the role of senescence in long-COVID. Our consortium is exploring innovative methods to detect signs of aging in endothelial cells. In laboratory settings, we expose healthy endothelial cells to blood samples from patients to determine if this exposure induces a senescent state. Concurrently, we are testing non-invasive imaging techniques and fluorescent probes that could potentially reveal these aging cells within the body. In select cases, tissue biopsies may later confirm these findings. Together, these methodologies aim to clarify how substances in the blood drive cellular aging, fueling disease progression.
Our ultimate goal is straightforward: identify aging endothelial cells in real patients. By pinpointing these cells, we hope to inform future clinical trials and pave the way for therapies that specifically target senescent cells. This approach could lead to healthier blood vessels and, ultimately, alleviate the burden of disease in individuals suffering from ME/CFS and long-COVID.
