“Your tests are normal.” For people with post-COVID or ME/CFS, this is a familiar phrase. Yet the symptoms can feel anything but normal. Exhaustion that does not improve with rest. Post-exertional malaise (PEM) after even minor activity. Brain fog, dizziness, palpitations, and sensitivity to stimuli. The gap between what patients experience and what routine tests show is one of the reasons these diseases remain so difficult to understand.
In January 2026, an extensive review published in Cell Death & Disease brought a possible explanation into sharper focus. In this review, researchers bring together evidence for a central idea: after a viral infection, blood vessels may remain dysregulated for a long time because endothelial cells become senescent—a kind of accelerated cellular aging. NMCB researchers Rob Wüst and Anouk Slaghekke are co-authors of this publication.
The endothelium as the “control center” of blood flow
The endothelium is the thin layer of cells lining the inside of blood vessels. It can be thought of as an active organ that constantly decides where blood should go and how easily oxygen and nutrients reach tissues. Among other things, the endothelium regulates:
- dilation and constriction of blood vessels
- barrier functions, such as those in the blood–brain barrier
- interactions with immune cells
- the balance between blood clotting and clot breakdown
When this system becomes disrupted, it may not show up in a standard blood test. But it can have major consequences for energy levels, exercise tolerance, and brain function.
Senescence as a persistent “alarm state”
The word senescence is often translated as cellular aging. However, it does not simply mean that a cell is “older.” Instead, the cell enters a kind of persistent alarm state. The cell no longer divides normally, alters its metabolism, and begins producing a package of signaling molecules known as the senescence-associated secretory phenotype (SASP).
According to the review, an acute viral infection can push endothelial cells toward senescence, either directly or indirectly. This does not always require direct infection of endothelial cells; inflammatory signals, oxidative stress, and specific molecules can also drive this process.
Why these cells may persist
In a healthy system, senescent cells are usually cleared by the immune system. The review points out that in ME/CFS and post-COVID, abnormalities are often seen in immune functions that are important for removing damaged cells. These include changes in natural killer cells, T cells, macrophages, and complement pathways. As a result, the “unhealthy” endothelial cells may not disappear on their own.
This can lead to a vicious cycle:
- endothelial cells become senescent and release SASP signals
- these signals maintain inflammation, clotting tendency, and vessel constriction
- the immune system becomes dysregulated or exhausted
- clearance of senescent endothelial cells becomes less effective
- senescence and immune dysregulation reinforce each other
The authors also describe that these damaged cells may produce signals that suppress immune activity, allowing them to persist and continue driving symptoms.
What this could mean for symptoms
The review links endothelial senescence to several symptom clusters seen in ME/CFS and post-COVID.
Reduced blood flow and oxygen delivery
If blood vessels cannot adequately respond to the body’s demands, the supply of oxygen and glucose may fall short. In ME/CFS and post-COVID, several studies have reported abnormalities in blood flow and perfusion, including in the brain. In the proposed model, endothelial senescence may contribute to a situation in which vessel dilation becomes less effective and constricting signals dominate.
Brain fog and neurological symptoms
The blood–brain barrier is partly formed by specialized endothelial cells. If this barrier becomes less effective at controlling what enters and leaves the brain, it can affect neuroinflammation, sensory processing, and cognitive performance. The review discusses how senescent endothelial cells in the brain’s microvasculature could theoretically contribute to increased permeability and dysregulation of local inflammatory processes.
PEM and exercise intolerance
During physical activity, blood flow to muscles must increase rapidly and waste products must be cleared efficiently. If endothelial cells are in a senescent state, this dynamic regulation may not function properly. The review links this to a plausible mechanism for PEM: not only “too little energy,” but also a vascular and immune environment that reacts slowly or excessively after exertion.
Clotting and microcirculation
The authors also pay considerable attention to clotting processes and the role of the endothelium in signals that promote coagulation. In this model, SASP factors may contribute to an environment in which clotting occurs more easily and blood clots are less efficiently cleared. This could further impair the microcirculation.
An important point for patients and healthcare professionals
This review is not proof that a single mechanism explains everything, nor is it a clinical guideline. However, it is an important step in recognizing a biologically coherent explanation that aligns with what many patients experience: symptoms that are not simply the result of reduced fitness due to inactivity.
The implication is also practical: if the body already struggles to regulate blood flow, recovery, and immune balance, certain interventions may backfire. This underlines the importance of safe approaches that take PEM and limits in exertion into account.
What are the next steps?
The review concludes with a clear research agenda. If endothelial senescence plays a role, three avenues could accelerate progress:
- improved measurement methods and biomarkers that specifically reflect endothelial status and senescence
- studies that more directly map where and how many senescent cells are present
- targeted therapeutic strategies that protect the endothelium, improve immune clearance, or modulate senescent cells
Read the full scientific review here:
👉 https://lnkd.in/ePNJ2aAa