This new ME/CFS / long-COVID paper, “Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis”, highlights something we’d hoped would occur with COVID-19: new eyes being placed on, and new perspectives being produced on chronic fatigue syndrome (ME/CFS).

The group that wrote this paper is an interesting case in point. Their June 2020 paper, “Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis“, proposed that endothelial dysfunction was a key aspect of COVID – and linked it to high angiotensin II (Ang II) levels. They suggested that the high Ang II levels in COVID-19 had caused “premature vascular senescence”.

That was intriguing given the really interesting place that high Ang II levels, and something called the RAAS or RAS paradox, inhabits in the ME/CFS/POTS universe.

The Paradox in Chronic Fatigue Syndrome (ME/CFS) and POTS

The paradox concerns the renin-angiotensin-aldosterone pathway that’s supposed to kick in when low blood volume levels occur. Even in context of the very low blood volumes found in ME/CFS/POTS, the pathway doesn’t kick in, and its critical endpoint, aldosterone, remains at normal or even low levels. This is despite the fact that the levels of Ang II – found in the middle of the pathway – tend to be very high.

Wirth and Scheibenbogen were the first, to my knowledge, to possibly explain the RAAS paradox. They proposed that balky B2AdR receptors and high bradykinin levels had interfered with two of the three major factors needed to stimulate the RAA pathway; i.e. the signal to increase blood volume in ME/CFS has gotten “annihilate(d)”.

Hypothesis Predicts Major Failure Point in Chronic Fatigue Syndrome (ME/CFS)

The current authors brought a whole new perspective to the high Ang II levels found in ME/CFS/POTS. They proposed that high ANG II levels are knocking out the mitochondria in endothelial cells lining the blood vessels – reducing nitric oxide (N0) levels (inhibiting the blood vessels from dilating properly), and triggering something they called “vascular aging”.

They also believe high Ang II levels in the brain are producing cognitive and other symptoms. Abilify sprang to mind when they proposed that dopamine-enhancing antipsychotic drugs may be protective against the central nervous system effects of COVID-19. The exhausted cytotoxic T and NK cells found in COVID-19 provided another possible touchpoint with ME/CFS.

ME/CFS, however, was never mentioned.

The Gist

  • In June 2020, researchers proposed that the renin-angiotensin-aldosterone system had become discombobulated in COVID-19, and that high Ang II levels were causing damage to the blood vessels and the mitochondria. Despite the fact that high Ang II levels are also found in ME/CFS, they did not mention it.
  • One of the great mysteries in ME/CFS and POTS has been something called the renin-angiotensin-aldosterone (RAAS) paradox. The paradox lies in the fact that despite the very low blood volume levels in the disease, the RAA system – which is designed to increase them – is never activated.
  • One part of the RAA system is, though. Angiotenson II levels are greatly increased. Wirth and Scheibenbogen provided a possible explanation for the paradox. Balky beta-adrenergic receptors and plus a vasodilator called bradykinin were “annihilating” the signal the RAA system needed to proceed.
  • A year later, the long-COVID researchers were back with a hypothesis they believe explains both long COVID and ME/CFS. It was centered squarely on those high Ang II levels found in ME/CFS.
  • Ang II levels, it turns out, can cause more problems than we knew. Besides possibly producing blood vessel and mitochondrial problems, they can damage the gut lining, jack up oxidative stress levels, interfere with cellular cleanup, and even damage telomeres.
  • The authors proposed that the high Ang II levels were causing the guts of both long-COVID and ME/CFS patients to leak bacterial molecules into the bloodstream – triggering an immune reaction reaching all the way to the brain.
  • The authors even believe that the adrenergic autoantibodies that have received so much attention in ME/CFS may have been produced to deal with the bacterial molecules making their way into the gut.
  • The authors outlined a variety of possible treatments not currently being used in ME/CFS that might help.
  • Time will tell whether the current flock of ME/CFS and long-COVID hypotheses will win out, but the fact that most (Systom, Wirth and Scheibenbogen, Fluge/Mella, Patterson, Sfera at. al.) involve problems with the blood vessels, and some are even focusing on the RAA system (which hasn’t gotten much attention in ME/CFS), is nothing if not encouraging.

Endothelial Senescence and Chronic Fatigue Syndrome

Jump forward a year and this group of researchers – hailing from California, Texas, France, and Mexico – have now become fully embedded in ME/CFS research. Their dense, technical paper, “Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis“, attempts to link long COVID and ME/CFS together in several novel ways.

The really fascinating thing, though, is how much of the paper centers on and expands on a key part of ME/CFS – the renin-angiotensin-aldosterone system (RAAS or RAS) paradox, and those high Ang II levels in particular.

Ang II – A Key to ME/CFS and Long Covid?

It’s upon those high Ang II levels that much may hang in ME/CFS and long COVID.

At high levels, Ang II can produce a remarkably wide array of nasty effects. High levels of Ang II produce inflammation, fibrosis, inhibit muscle repair, damage the endothelial cells lining the blood vessels, produce vasoconstriction (narrowing) in the blood vessels, jack up oxidative stress levels – producing peroxynitrite, and reducing the levels of nitric oxide – an important vasodilator.

Ang II also inhibits the phagocytosis or swallowing of damaged and dead cells (efferocytosis) – possibly allowing damaged endothelial cells to accumulate – and the intestinal dysbiosis to worsen.

When phagocytic cells such as macrophages fail to cleanly envelop or swallow damaged cells, the contents of those cells (called damage-associated molecular pattern (DAMP)) can leak into the bloodstream, causing an immune response. High DAMP levels have been associated with unexplained fatigue, chronic pain, exhaustion, and muscle dysfunction in other diseases.

Let’s not forget telomere attrition. Three years after the CDC found telomere attrition in ME/CFS, telomere attrition was linked to high Ang II levels in COVID-19.

To the Gut We Go

In the current paper, the authors move from their focus on the blood vessels to the gut. The epithelial part of the intestinal barrier is a fragile one – a single layer of epithelial cells covered up with mucous.

Besides all the other things it can do, Ang II can apparently trigger the death of that fragile line of intestinal epithelial cells. It also may be able to alter the junction molecules (claudins) that control barrier permeability. Either way, the intestinal barrier breaks down, allowing bad actors like lipopolysaccharides (LPS) to move into the bloodstream – sparking an immune response that may reach all the way to the brain.

The authors write that the fact that:

“… a dysfunctional RAS can trigger barrier disruption, dysbiosis and amino acid malabsorption…(makes it) not surprising that COVID-19 and ME/CFS have been associated with both aberrant immune responses and dysfunctional intestinal permeability.”

Several studies suggest a leaky gut may be present in ME/CFS, including one which concluded that exercise exacerbated it.

The Gut-Wrenching Effects of Exercise: Could Exercise Be Wiping Out the Gut in Chronic Fatigue Syndrome?

One wonders if the authors missed a beat by not including fibromyalgia (FM) in their hypothesis. It’s taken longer to get to the gut connection in FM, but a recent study suggested similar bacterial problems occur in FM.

Gut Pain Connection Emerges in Fibromyalgia


Finally, the authors bring in one of the key actors in the Wirth and Scheibenbogen and Fluge/Mella hypotheses – the autoantibodies directed at the cholinergic and beta 2 adrenergic receptors (B2AdR). Instead of the autoantibodies resulting from molecular mimicry, though, the authors propose these autoantibodies are being produced and aimed at the bacterial molecules escaping from the intestines.

Hope for an ME/CFS Autoimmune Subset: A German Researcher Steps Forward


Possible Treatments

The authors noted that several treatments (escitalopram, coenzyme Q10 and nicotinamide adenine dinucleotide (NAD), mildronate) used in ME/CFS can restore endothelial functioning, and suggested that angiotensin receptor blockers (ARBs) might be helpful.

Factors that improve short-chain fatty acids (SCFAs/fermented dietary fiber) may be able improve intestinal integrity. Fat globule membranes (MFGM) and b-glucan have been shown to do the same in mouse studies. B-glucan may also be able to damp down microglial activation in the brain. Fecal transplants haven’t been studied enough, but the early word on them in ME/CFS is pretty good. Metformin may be able to protect the gut barrier.

The authors also believe that a new field of drugs called senotherapeutics (dasatinib, hyperoside, quercetin, fistein, Navitoclax), which target cell death and aging, may present another as yet untested option.


Time will tell if these authors are right, but the encouraging thing is that the new eyes being focused on ME/CFS as a result of long COVID are already fashioning new hypotheses and adding new potential insights and treatment possibilities to the field.

We didn’t know, for instance, that the high Ang II levels found in ME/CFS/POTS might be damaging the mitochondria. While the connection between Ang II and the blood vessels had been made, the possible connection between Ang II and the intestinal barrier had not. Ditto with efferocytosis, telomere attrition, and the idea that the beta-adrenergic autoantibodies that have aroused so much interest in ME/CFS might be being produced in response to bacterial products that have leaked into the blood. Along with these insights came a new set of treatment possibilities.

Long COVID and ME/CFS hypotheses seem to be merging…Will it keep up?

Perhaps the most striking thing about this and other recent hypotheses, though, is a continuing focus on the blood vessels from different research groups.

Fluge and Mella believe autoantibodies are affecting blood vessel functioning via endothelial cell dysfunction. Wirth and Scheibenbogen believe the same, and add in vasodilators, and then potentially link the autoantibodies and the vasodilators to the RAAS paradox.

Systrom’s invasive ME/CFS exercise tests suggest blood vessel problems occur in different subsets of ME/CFS: just before the blood gets to the muscles, and in the veins after it’s left the muscles, something is hampering blood flows. Even Bruce Patterson, who is at this point fully focused on long COVID, believes blood vessel problems are at the very core of that condition.

Has Bruce Patterson Cracked Long COVID?

Time will tell whether nature will, as Robert Phair puts it, brush aside these “beautiful hypotheses” or whether they will stand up to the test of time. It’s encouraging though, to see common themes emerge so very early in the hunt for the cause of long COVID.


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