New data comes in – and new models of ME/CFS and long COVID pop up. That’s, of course, how it should work and that’s what happened in “Chronic inflammation, neuroglia dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome“.
The nice thing about this model is that it takes the same two, possibly key, factors – inflammation and microglial activation – that we’ve been talking about, it seems for ages, and adds a third, more recent one – plasmalogen deficiency – to it. In other words, the research seems to be building on itself, the pieces seem to be fitting together, and it’s producing more than the sum of its parts. We will see whether the model will stand the test of time, but it’s nice to see research findings cohere together in this way.
It’s also nice to see distinguished researchers get pulled into the ME/CFS/long-COVID orbit. If anyone knows the neuroglia or the microglia, it’s the senior author of this paper, Marie-Eve Tremblay. (Microglia are a form of neuroglia). Hailing from the University of Victoria in British Columbia (Canadians, note – this paper was entirely a BC effort), Tremblay has managed to publish over 100 papers on the microglia and the central nervous system over the past 13 years. This is actually her second shot at ME/CFS. Last year, she co-authored Herbert Renz-Polster’s neuroglial (microglial) hypothesis paper “The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome:The Case for Neuroglial Failure“.
As with so many other hypotheses, this one starts off with inflammation; i.e. chronic immune activation that just won’t quit. The authors note that many things could be causing neuroinflammation, or an “inflamed brain” – viral invasion, inflammation in the body, an autoimmune reaction, vagus nerve, and autonomic nervous system problems, and interestingly, angiotensin II overload.
The great question that any legitimate hypothesis must be able to answer is how to account for the many different triggers that can spark the ME/CFS spectrum of diseases (which includes, of course, long COVID). That clearly means getting at some core, or fundamental, physiological factors that have the capability of undermining a person’s physiology at a deep level.
In that vein, the authors brought in Angus Mackay’s ME/CFS hypothesis that a key stress integrator in the brain called the hypothalamic paraventricular nucleus (PVN) has been damaged. Stressors of all kinds (infections, pain, emotional distress, exercise) all converge on the little PVN. (Note that two published hypotheses from two people with ME/CFS – Herbert Renz Polster and Angus Mackay – have already made it into this paper :)).
The authors posit that inflammation “primes” the immune cells of the brain – the microglia – putting them in a hyperexcitable (could we say catastrophizing-like) state where they see danger everywhere. The slightest hint that something’s wrong causes them to jump into action and start pounding the area with “bullets”; i.e. pro-inflammatory cytokines. Maybe think of them like jumpy soldiers who, hearing a branch crack, unload with their guns – destroying the forest around them – clearly an exhausting and destructive process.
Since the microglia or neuroglia in the brain could conceivably play a role in so many of the issues found in long COVID and ME/CFS (movement, autonomic nervous system, sleep, homeostasis, sensory gating, memory, mood, and cognition), these amped up, twitchy immune cells could explain much of what’s going on.
This is all pretty much old hat, but a couple of studies from NIH-funded ME/CFS research centers run by Ian Lipkin and Maureen Hanson have opened up a whole new slant on how this may all have started. Enter the lipids and the cellular membranes.
Could Damaged Lipids and Cellular Membranes Be a Core Feature of ME/CFS?
Talk about a core factor – the membranes, that cover our cells protect them from pathogens, toxins, and free radicals, and allow them to communicate with other cells, present the conduit through which all signals to the cells must pass. If the signal can’t get through to the cell, it can’t react to anything properly. It might as well be inert.
Plasmalogens are one the building blocks of the cell membranes that protect the cell. They contain polyunsaturated fatty acids (PUFAs), are powerful antioxidants, support cholesterol synthesis and transport, provide structural support for the cellular membranes, and play a key role in the “lipid rafts” that play a role in cellular signaling. They also appear to be low in ME/CFS.
Since plasmalogens (PLs) are synthesized in little organelles in the cells called peroxisomes, the low plasmalogen levels found in ME/CFS suggest peroxisomal dysfunction is present. The authors believe the plasmalogens in ME/CFS are getting beaten up by high amounts of oxidative stress – an intriguing idea given that damaged mitochondria emit enormous numbers of free radicals.
Add in a recent finding that plasmalogens also play a role in mitochondrial health, and you potentially have quite a vicious circle forming – low plasmalogens impair mitochondrial health, leading to high levels of oxidative stress that further whack the plasmalogens, damage the cell membrane, and so on.
There’s also a peroxisome-mitochondria connection. The small, ubiquitous peroxisomes appear to punch far above their weight. Not only do they supply the building blocks for the cellular membranes, have anti-inflammatory properties, and reduce oxidative stress, they also break down crucial energy substrates for the mitochondria called long chain fatty acids. Recently peroxisomes have also been found to contain the “mitochondrial antiviral signaling protein (MAVS)” that plays a role in the innate or early immune response.
Peroxisomes are so effective at tamping down inflammation that dysfunctional peroxisomes in the brain have been associated with the accumulation of toxic byproducts and microglial activation.
Damaged peroxisomes in ME/CFS, then, could impair a host of core factors – the cell membranes, energy production, inflammation and protection from pathogens; i.e. it seems like just the kind of fundamental factor we’re looking for to explain complex, multisystemic diseases like ME/CFS, long COVID and similar diseases.
Several metabolomic studies have now found abnormalities across the range of lipids or fats found in cellular membranes. The authors noted that the big breakthrough for ME/CFS in this area may have come in a paper from Ian Lipkin’s group, which found disturbed peroxisomal lipid metabolism, reduced levels of the energy factor carnitine, and evidence of impaired mitochondrial functioning – and tied everything together in a nice bow.
The carnitine depletion does more than impair energy production. When peroxisomes are unable to process long-chain fatty acids, they leave behind long-chain triglycerides behind that are vulnerable to free radical attack – thus causing further peroxisome and mitochondrial damage; i.e. potentially producing a hot mess.
Given that, it was no surprise the Lipkin group study found that the peroxisome-related metabolites in ME/CFS were associated with increased fatigue scores.
Immune Exhaustion Too?
Health Rising recently published a blog suggesting that poor energy production in ME/CFS may be hobbling the innate immune system’s reaction to pathogens and toxins. That was intriguing given this interesting statement: “A disturbed mitochondria-peroxisome interaction could be the underlying factor for the suggested immune system exhaustion in ME/CFS patients.”
Evidence for that immune exhaustion in ME/CFS extends all the way from the T-cells of humoral or late immune response to the macrophages in the early or innate immune response. (Liisa Selin currently has an NIH grant to study T-cell exhaustion in ME/CFS.) Again, we see how a really fundamental factor – low plasmalogen levels and peroxisome dysfunction – could produce a wide array of effects.
Next, the authors go through the many ways that viruses interact with cell membranes, the possibility that the SARS-CoV-2 virus may be depleting plasmalogens, and the increasing evidence for fatty acid and plasmalogen depletion and mitochondrial issues in COVID-19 and long COVID.
Then it was onto – what else? – a possible gut connection to all of this that involves a reduction in butyrate-producing gut bacteria in ME/CFS and long COVID that, in turn, impacts plasmalogen production.
Next came the brain – Dr. Tremblay’s research focus – and a big hypothesis – that plasmalogen depletion plays a key role in many brain disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), Multiple Sclerosis (MS), depression, autism and Niemann-Pick type C disease, plus a new and intriguing possible connection – platelet-activating factor.
Dr. Tremblay recently wrote a review paper on the interactions between plasmalogens and platelet-activating factor (PAF) – an important player in the clotting process. That paper proposed that low plasmalogens trigger an increase in PAF and clotting and histamine release (!). The paper noted that increased PAF levels have been found in neuroinflammation, brain ischemia, and neurodegenerative diseases.
Next in this long, long paper came a detailed examination of the intersection between plasmalogens and estrogens, and the role low plasmalogens might play in the decidedly increased risk of ME/CFS in menopausal women. More sections covered the evidence that low plasmalogen levels play in neurodegenerative diseases.
- It’s always nice to see distinguished researchers get pulled into the ME/CFS/long-COVID orbit! In this case, it’s extra nice because in this case, it’s a microglial expert – Dr. Marie-Eve Tremblay.
- Her hypothesis paper takes the same two possibly key factors – inflammation and microglial activation – that we’ve been talking about, it seems for ages, and adds a third, more recent one – plasmalogen deficiency – to it, and comes up with a new hypothesis and a new (if expensive) treatment option.
- Tremblay and her British Columbia crew posit that inflammation “primes” the immune cells of the brain – the microglia – putting them in a hyperexcitable (could we say catastrophizing-like) state where they see danger everywhere. The slightest hint that something’s wrong causes them to jump into action and start pounding the area with “bullets”; i.e. pro-inflammatory cytokines.
- Plasmalogens are one of the building blocks of the cell membranes that protect the cell. They are also present in the organelles in our cells. Tremblay posits that low plasmalogen levels in the membranes of our cells are behind this mischief. Without healthy membranes to protect our cells from pathogens, toxins, and free radicals, and allow them to communicate with each other, our cells are pretty much toast.
- Plu,s the peroxisomes that produce the plasmalogens in the first place play a critical role in mitochondrial production. If both the peroxisomes and plasmalogens have gotten hit in ME/CFS and long COVID – and the latest research suggests they may have – that could explain much.
- The authors noted that the big breakthrough for ME/CFS in this area may have come in a paper from Ian Lipkin’s group, which found evidence of plasmalogen deficiency, balky peroxisome functioning, reduced levels of the energy factor carnitine, and impaired mitochondrial functioning – thus tying everything together in a nice bow.
- That plasmalogen deficiency could also explain the immune exhaustion found in ME/CFS. Plasmalogen deficiency has also been found in neurodegenerative diseases such as multiple sclerosis, Parkinson’s, and Alzheimer’s Disease.
- Plasma Replacement Therapy (PRT) has not yet been tested in ME/CFS or long COVID, but the authors believe it “could represent a valuable therapeutic tool against this emerging health condition (long COVID) affecting millions worldwide.” They suggest that “therapeutic plasmalogen” replacement may be key in treating these disorders.
- No PRT drugs, unfortunately, have been FDA-approved. Some plasmalogen-enhancing supplements are available. Dr. Goodenowe, a researcher/doctor who has been studying plasmalogens for over a decade, has created plasmalogen supplements that he says are 100-900 x’s more effective than others. At $199 and/or $99 per bottle, though, and with an early loading regimen required, the first month or couple of months would cost from $200-$400 a month.
- Whether plasmalogen supplements are the latest “wonder supplement”, or whether they could get at a core problem in ME/CFS and long COVID, is unclear.
- With academics like Dr. Tremblay proposing that plasmalogens play a key role in ME/CFS and long COVID, plasmalogen supplementation, and ultimately plasmalogen drugs, seems like something to keep an eye on.
The treatment section noted the “compelling literature” suggested that low plasmalogen levels are common in metabolic and neurodegenerative disorders such as ME/CFS and long COVID as well as many others.
What to do? Boost plasmalogen levels with – what else – “plasmalogen replacement therapy” (PRT). The authors state that both in vitro (animal) and in vivo (lab) studies provide (again) “compelling” evidence that PRT that utilizes purified plasmalogens is able to dramatically increase plasmalogen levels in a variety of tissues and, most importantly, protect the neurons and glial cells against multiple kinds of injury – and therefore possibly reduce neuroinflammation. The authors also believe that PRT may help with aging, and chronic stress, and enhance responses to bacterial-produced toxins.
PRT has not yet been tested in ME/CFS or long COVID, but the authors believe it “could represent a valuable therapeutic tool against this emerging health condition (long COVID) affecting millions worldwide.” They suggest that “therapeutic plasmalogen” replacement may be key in treating these disorders.
They propose that the use of “naturally derived and synthetic analogs of PLs in combination with other nutraceuticals, such as dietary antioxidants and multimodal lifestyle interventions (e.g., acting on stress resilience, thermoregulation, metabolism) will be critical for the prevention, management, and treatment of multifactorial diseases including ME/CFS and post-COVID-19 syndromes.”
One review paper noted that three kinds of PRT exist. They include using metabolic precursors of plasmalogens, using plasmalogens derived from natural sources, and finally, and likely most effective, using synthetic analogs of plasmalogens. One synthetic plasmalogen-enhancing drug called PPI-1040 was given Orphan Drug Designation (giving it a leg up on the approval process) by the FDA for the treatment of Rhizomelic Chondrodysplasia Punctata (RCDP). I don’t know of any FDA approved plasmalogen drugs.
Neither of these papers mentioned plasmalogen supplements, but some are available.
According to the Top Supplements webpage, the ProdomeNeuro Plasmalogen supplement is designed to maximize absorption in the gut, thus producing plasmalogens that can cross the blood-brain barrier. Its producer, Dr. Dayan Goodenowe Ph.D., states it’s 100-900 times more potent than other supplements.
Goodenowe is a bit different from other functional medicine practitioners in that he actually does have a research background. He first proposed that plasmalogen deficiency played a role in Alzheimer’s Disease back in 2007, and over time, produced a dozen or so plasmalogen papers. A small 2010 study found that low plasmalogen levels were associated with reduced functioning in Alzheimer’s. His 2011 study found that an oil-derived plasmalogen precursor supplement was able to cross the blood-brain barrier and increase plasmalogen levels in rabbits.
His 2022 study of elderly people did not find that levels of amyloid plaques or neurofibrillary tangles were associated with reduced cognition, but reductions in some types of plasmalogens were. Only high brain levels of one type of plasmalogen were predictive of normal cognition in the elderly. A small Japanese study had a similar reduction, and plasmalogen levels are being actively studied in dementia.
In an interview, Goodenowe said he’d seen rapid results with plasmalogen therapy in dementia and even autism because, he thinks, plasmalogens are an incredibly basic molecule. Neuroinflammation, he believes, is having more fundamental effects than we think.
So far, so good. The supplement ProdomeNeuro his company Prodome Sciences produces has 900 mg of omega-3 plasmalogen oil per serving, but at $199 for sixty tablets with a recommended 1-3 month loading dose of 4-8 tablets a day, you’re looking at a minimum of $400 for the first month. The omega-3 plasmalogens are targeted at improving nerve functioning at the synapse and cognition.
At $99, another plasmogen supplement called ProdomeGlia Protector Plasmologen supplement with Omega-9 Plasmalogen Oil (ProdromeGlia™) and the same dosing regimen is less expensive ($200 for the 1st month or so) but still hardly cheap. Omega 9 plasmalogens are aimed at the white matter covering the nerves in the brain. They’re designed to tune your nervous system both inside the brain and in the body to ensure that your nerve conduction rates are fast and clear, and he referenced white matter degradation. This might be the one to try for ME/CFS and long COVID.
A less expensive supplement called LABO Nutrition NeuroRegain is derived from scallops. Another supplement called AKG, which contains a part of the amino acid glutamine (AKG), has been shown in animal studies to increase endogenous plasmalogen levels. It’s traditionally been used to increase muscle mass, and it may help with aging and cognition.
It was nice to see a distinguished researcher get excited enough at the latest ME/CFS and long-COVID findings to pen a paper proposing that researchers may be getting at the core aspects of the disease. Time, of course, will tell whether they’ve lit upon a really core part of these diseases.
Because plasmalogens play such a fundamental role in our cellular membranes, plasmalogen deficiency and problems with the peroxisomes which produce them have the potential to affect many systems and could cause many symptoms. While we don’t know the cause of the possible plasmalogen deficiency in ME/CF,S it may be possible to raise plasmalogen levels.
While plasmalogen drugs are not available, plasmalogen supplements – some of which are quite expensive – are. Are plasmalogen supplements simply the latest “wonder supplement” that’s being touted to be able to reverse all sorts of conditions, or could it really get at a core problem in ME/CFS and long COVID? For me, I would be shocked if any one supplement is enough, but with academics like Dr. Tremblay proposing that plasmalogens play a key role in ME/CFS and long COVID, plasmalogen supplementation seems like an intriguing, albeit expensive, idea.