A look back at 2024 indicated some surprising progress has been made.
Any year in review immediately brings up the question – what did we want to see happen and what actually did happen.
For me, regarding chronic fatigue syndrome (ME/CFS) research, I wanted to see new findings that generated new hypotheses popping up. Most of all, I wanted to see broad themes emerge which validate past findings, provide an impetus for future research, and suggest we’re getting at core issues. Lastly, I would love to see large studies that give the findings staying power.
THE GIST
- When we look back, 2024 might just be perceived as a year of fundamental progress. In study after study, two general themes popped up again and again. ME/CFS patients’ cells across their bodies are exhausted and exhibit a “failure to respond” when exposed to stress.
- An early study, for instance, found – in what the authors stated constituted a “profound disruption” – that important signaling factors called extracellular vesicles became activated about 1/3rd as much as the healthy controls did after exercise.
- Next, a UK/Australian B-cell study demonstrated that when asked to proliferate – something that happens during an infection – the B-cells of the ME/CFS patients displayed their own kind of “profound disruption”; i.e. they produced fewer mitochondria and turned to a dirty and inefficient fuel – amino acids – to try to produce energy.
- Talk about “profound” … Avindra Nath’s finding that B-cells were stuck in an immature stage bothered him so much that he concluded they were “the primary defect” (in ME/CFS). He believes they produce immune exhaustion and, via activation of innate immune responses, inflammation.
- For his part, Anthony Komaroff spoke of an immune system that seemed to be spinning and spinning – causing it to eventually burn itself out.
- Vishnu Shankar of Stanford agreed. His finding of high rates of reactive oxygen species (free radicals) linked to T-cell hyperproliferation suggested that a chronically activated immune system was using up so much energy that it had created an energy sink for the rest of the body.
- Exhaustion was the linchpin of a metabolomic study that proposed that as their mitochondrial resources were exhausted, females, in particular, became more prone to coming down with ME/CFS.
- Meanwhile, the Simmaron Research Foundation found that low oxygen (i.e. low energy levels) produced a melange of familiar problems (increased oxidative stress, impaired lipid synthesis, problems with tissue repair, and pathogen killing).
- ME/CFS patients’ brains appeared to be in a similar fix as blood oxygen levels suggested that the brain’s voracious appetite for energy was causing it to strip as much oxygen from the blood as possible.
- Another seconded that notion when it showed that instead of adapting to a task and using less energy like the healthy controls did – the ME/CFS patients’ brains actually used more energy to accomplish the same task; i.e. when given a task, their brains appeared to be in a hypermetabolic state that would lead to a crash.
- Cellular exhaustion reared its head again when Younger found elevated lactate levels throughout the brain in a subset of ME/CFS patients, suggesting the brain had exhausted its resources, run out of oxygen, and was burning other fuels to keep it going.
- Nath’s findings of reduced cerebrospinal levels of dopamine metabolites and a serotonin precursor (DHPG) hit at yet another potential metabolic issue – decreased catecholamine biosynthesis – once again suggesting that the brain was running low on vital resources.
- With that, it appeared that both the brains and immune cells of ME/CFS patients had fallen prey to the same problem: both were running out of resources and had resorted to operating anaerobically and/or using inefficient fuels to fuel them.
- An African Green Monkey virus suggested how this may be happening. It found that the energy demands of people with “long-African Monkey virus syndrome” soared in the early stages of the infection, creating a “hypermetabolic state” in their immune cells.
- Patients whose immune cells couldn’t meet the metabolic demands were forced to turn to alternative anaerobic energy pathways (glycolysis/pyruvate metabolism) to generate energy – and were sicker. Indeed, 30 days after the pathogen had apparently been vanquished, an “energy maladjustment” had occurred, leaving them in a state of “metabolic insufficiency”.
- The conclusion – an inability to produce enough energy during the infection overloaded the mitochondria – damaging them – and leaving their cells in a low-energy state.
- An October conference presentation suggested that the hypermetabolic/hypometabolic pattern may be happening in the muscle cells as well. When muscle tissue was exposed to serum from ME/CFS and long-COVID patients, the muscle’s ability to contract or produce force (or generate energy) became “severely compromised”.
- Highly elevated levels of mitochondrial and non-mitochondrial oxygen consumption suggest that the serum had put the muscle cells under huge energy stress. Ultimately, the mitochondria began to break up, fuse, and become dysfunctional, causing the muscle tissues to rely on – you guessed it – an alternative energy source – anaerobic energy production. The authors hypothesized that a “stress-induced hypermetabolic state” resulted in “severe deterioration” in muscle cell functioning.
- Just last month, Hanson’s group published a paper that added a new and potentially significant factor to the cellular exhaustion discussion – epigenetics. Epigenetics refers to how our bodies regulate our gene expression over time. Because infections can be big drivers of epigenetic change, the idea that an epigenetic change triggered by an infection might be causing ME/CFS, long COVID, post-treatment Lyme Disease, etc., has always been an enticing possibility.
- The study found that the T-cells in ME/CFS had become “epigenetically predisposed toward terminal exhaustion“(!). Given the cellular exhaustion found in B, NK, and muscle cells, one wonders if epigenetic reprogramming may be present in them as well. This study has major implications for ME/CFS and will be covered in an upcoming blog.
- At the end of 2024, we’re at a very interesting place! Again and again, we saw studies circling around familiar issues: mitochondrial dysfunction, cellular exhaustion, blood vessel and clotting issues, high levels of oxidative stress, and lipid dysregulation in a variety of cells.
- All these seem to cohere around the idea of a “failure to respond” to a stressor, and suggest that a hypermetabolic state triggered by an infection ultimately produces a hypometabolic state characterized by cellular exhaustion.
- Despite our low funding, this was a good year for ME/CFS as the field seemed to tap into a deep and rich vein associated with reduced energy production.
A Failure to Respond
A failure of ME/CFS patients’ systems to respond in one way or another pervaded the findings of the past year. Not surprisingly, a failure to respond at the level of the immune system led the way.
The Immune System
The 2024 studies suggested that a “failure to respond” permeates ME/CFS patients’ cells.
We started 2024 – with who else but Dr. Maureen Hanson’s NIH-funded Cornell group – which has been knocking it out of the park for quite some time. Hanson’s exercise study suggested that when it comes to exercise, ME/CFS patients exhibited a failure to respond on a molecular level; i.e. exercise increased the levels of 3 x’s more proteins in the healthy controls than in the ME/CFS patients.
Increased levels of proteins associated with coagulation perhaps provided a possible reason why – blood clots triggered by the exercise session were keeping the message from getting through. The authors wrote:
“this suggests that the profound disruption of EV signaling post‐exercise may contribute to the inability of ME/CFS patients to recover from exertion.”
Hanson’s group was quickly back at it with an exercise study using a cell-by-cell technique. The new, more rigorous study raised eyebrows when it suggested that monocytes – an immune cell never before associated with ME/CFS – played the key role in the immune dysfunction found following exercise. A strange pattern of platelet dysregulation pre- and post-exercise suggested that exercise may be producing blood clots.
That same month, a UK/Australian B-cell study demonstrated a different version of the “failure to respond” theme. When asked to proliferate – which is needed during an infection – the B-cells of the ME/CFS patients produced fewer mitochondria and turned to a dirty and inefficient fuel – amino acids – to try to produce energy.
In his intramural study, Avindra Nath found evidence of both immune activation and immune exhaustion. Increased percentages of naïve B-cells and decreased levels of switched-on memory B-cells in the blood also suggested that B-cells were failing to respond as well.
Nath proposed that the increased presence of immature B-cells constitutes “the primary defect” (in ME/CFS) and results in “immune exhaustion and activation of innate immune responses”. In this scenario, the adaptive (later) immune response that the B-cells participate in punks out causing the early and more inflammatory innate immune response to try to compensate. Since the innate immune system wasn’t built to do this, it fails, allowing the pathogen to persist.
The immune system seems to be spinning and spinning – eventually burning itself out.
For his part, Anthony Komaroff spoke of an immune system that seemed to be spinning and spinning – causing it to eventually burn itself out. Komaroff proposed that the immune system seemed to be “engaged in a long war against a foreign microbe, a war it couldn’t completely win and therefore had to continue fighting”.
This has implications for energy production. Activated immune systems take up so much energy that one of the reasons the brain invokes flu-like symptoms (aka “sickness behavior”) when we have a cold is to keep us in bed and not wanting to eat in order to save our energy for the immune response. (Digestion takes an enormous amount of energy) .
Next, enter Vishnu Shankar, a Stanford graduate student who, struck by the idea that ME/CFS is an energy depletion disease, took a new approach to the mitochondria and the immune system. Recognizing that damaged mitochondria produce oodles of free reactive oxygen species (ROS) (free radicals) which can then damage the mitochondria, Shankar assessed the ROS in immune cells.
Shankar found high rates of ROS and linked them to a chronically activated immune system. He proposed that an immune system that was spinning its wheels was producing high levels of reactive oxygen species (free radicals) that were damaging the mitochondria.
His results suggested that the free radicals had triggered a vicious circle in the immune system. High levels of reactivated oxygen species caused the T-cells in women to hyperproliferate – which, in turn, produced more oxidative stress – and more hyperproliferation, etc. Shankar proposed that this ongoing hyperproliferation was using up so much energy that it was creating an energy sink for the rest of the body.
- See The Vampire in ME/CFS for more.
Shankar’s conclusion that reactive oxygen species (free radicals) – possibly produced by damaged mitochondria – may play a major role in ME/CFS was echoed in a metabolomic study which found indications in lipid markers that low mitochondrial output was present and that oxidative stress was damaging cellular membranes.
Next, a metabolomic study suggested that the mitochondria in females are built in such a way as to make them more susceptible to coming down with ME/CFS when one’s mitochondrial resources become exhausted.
Meanwhile, in a small study with major implications, Simmaron researchers found evidence that low oxygen levels in the cells of ME/CFS patients produced a melange of familiar problems (increased oxidative stress, impaired lipid synthesis, problems with tissue repair, and pathogen killing). Plus,. high levels of BH2 could be narrowing blood vessels down, producing inflammation, clotting, oxidative stress, and mitochondrial dysfunction
An Exhausted Brain
The immune system may not be the only energy sink present in ME/CFS. Speaking at the NIH ME/CFS Conference, Xiang Xu of Dr. Natelson’s Mt. Sinai, proposed the ME/CFS brain was another.
Xu found increased blood oxygen levels in the arteries but decreased blood oxygen levels in the venous blood flows flows leaving the brain. That suggested that ME/CFS patients’ brains’ voracious appetite for energy was causing it to strip as much oxygen from the blood as possible.
An Australian/Swiss and US study seconded that notion when it showed that instead of adapting to a task and using less energy like the healthy controls did – the ME/CFS patients’ brains actually used more energy to accomplish the same task; i.e. when given a task, their brains appeared to be in a hypermetabolic state that would lead to a crash.
The authors proposed that an inability to direct blood (i.e. oxygen or energy) flows to different parts of the brain was the cause, and pointed to problems with calcium mobilization. That was intriguing given that Wirth and Scheibenbogen believe that calcium mobilization is at the heart of the mitochondrial problems in ME/CFS.
Nath’s findings of reduced cerebrospinal levels of dopamine metabolites and a serotonin precursor (DHPG) hit at yet another potential metabolic issue – decreased catecholamine biosynthesis – again suggesting that the brain was running low on vital resources.
Speaking at an NIH conference, Jarred Younger outlined a possible reason ME/CFS patients’ brains were using up so much energy: activated microglia and neuroinflammation. Cellular exhaustion reared its head again when the elevated lactate levels Younger’s work found throughout the brain in a subset of ME/CFS patients suggested the brain had exhausted its resources, run out of oxygen, and was burning other fuels to keep it going.
With that, it appeared that both the brains and immune cells of ME/CFS patients had fallen prey to the same problem: both were running out of resources and had resorted to operating anaerobically and/or using inefficient fuels to fuel them.
The Hyper-Hypometabolic Switch
A series of studies illuminated how cellular exhaustion may be being produced in the immune system and in muscle cells.
First, one of the year’s most intriguing and timely pathogenic studies was not on ME/CFS, the coronavirus, or a herpes virus but in a study on people suffering long-term consequences from the African Green Monkey virus. The study found that the energy demands of people with “long-African Monkey virus syndrome” soared in the early stages of the infection, creating a “hypermetabolic state” in their immune cells.
ME/CFS patients’ cells may be switching from really on to really off.
Patients whose immune cells couldn’t meet the metabolic demands were forced to turn to alternative anaerobic energy pathways (glycolysis/pyruvate metabolism) to generate energy. This indicates how crucial it is to produce ample supplies of energy during an infection.
Thirty days after the pathogen had apparently been vanquished, the long African Monkey virus syndrome patients were still in bad shape metabolically (and symptomatically). The energy production (glycolysis, TCA cycle, OXPHOS) of their immune cells had fallen so much that the researchers concluded that an “energy maladjustment” had occurred and they were in a state of “metabolic insufficiency” or hypometabolism.
The conclusion – an inability to produce enough energy during the infection overloaded the mitochondria – damaging them – leaving their cells in a low-energy state.
“Severely Compromised Muscles”
An October Neuromuscular Disorders conference presentation suggested that the hypermetabolic/hypometabolic pattern may not be confined to the immune cells. When Spanish researchers exposed muscle tissue to serum from ME/CFS and long-COVID patients, the muscles’ ability to contract or produce force (or generate energy) became “severely compromised”.
Highly elevated levels of mitochondrial and non-mitochondrial oxygen consumption suggest that the serum had put the muscle cells under huge energy stress. Ultimately, the mitochondria began to break up, fuse, and become dysfunctional, causing the muscle tissues to rely on – you guessed it – an alternative energy source – anaerobic energy production.
Mirroring the immune cell findings, the authors hypothesized that a “stress-induced hypermetabolic state” resulted in “severe deterioration” in muscle cell functioning. In both tissues, cellular exhaustion was the theme.
When Bob Naviaux, the author of the Cell Danger Response hypothesis, was asked whether this hypermetabolic to hypometabolic switch fit his hypothesis, he said it did.
“While everyone experiences a transient hypermetabolic state with the beginning of CDR1 and fever during an acute infection. Most people experience this dozens of times in a lifetime. Ninety percent of the time this resolves without any consequences after a few days to weeks, and we recover completely.”
“Only about 10% of patients have lingering symptoms that last for more than 6 months. In the patients who develop ME/CFS, Long-COVID, and many other hypometabolic, multi-system, chronic fatigue syndromes, mitochondria and cells enter a chronic, but reversible physiologic state that protects the patient and cells from new injuries and chronic threat, but at the expense of a dramatic decrease in functional capacity.”
Then he spoke of yet another, more basic kind of energy sink – one focused on cellular defense.
“This occurs because the chronic response to danger (the 3 phases of the CDR) siphons energy and resources away from baseline health for purposes of cellular defense.”
Stress and exertion play a key role, Naviaux believes. Naviaux stated that “very small stresses” trigger setbacks due to an enhanced sensitivity to the eATP that cells release when they are under stress. He hopes that drugs like Suramin will be able to reverse the process.
Predisposed to Exhaustion…
Epigenetic modification from DNA methyl transferase I (blue). An epigenetic change put the T-cells on the road to exhaustion in ME/CFS.
This blog started with Hanson and ended with Hanson. Using the single-cell approach that produced such dividends in the monocyte study, just last month Hanson’s group published a paper that added a new and potentially significant factor to the cellular exhaustion discussion – epigenetics.
Epigenetics refers to how our bodies regulate our gene expression over time. By turning on and off genes, cells adapt – hopefully effectively but sometimes negatively – to the changes in our bodies and the environment over time.
Because infections can be big drivers of epigenetic change, the idea that an epigenetic change triggered by an infection might be causing ME/CFS, long COVID, post-treatment Lyme Disease, etc., has always been a very enticing possibility. Thus far, the epigenetic studies in ME/CFS have not been particularly enlightening but this study was.
Rather amazingly, the study found that the T-cells in ME/CFS had become “epigenetically predisposed toward terminal exhaustion“(!). Given the cellular exhaustion found in B, NK, and muscle cells, one wonders if epigenetic reprogramming is present in them as well.
This study has major implications for ME/CFS and will be covered in an upcoming blog.
Conclusion
With the ample findings from 2024, the ME/CFS field – given enough funding – is primed to move forward.
At the end of 2024, we’re at a very interesting place! Again and again, we saw studies circling around familiar issues: mitochondrial dysfunction, cellular exhaustion, blood vessel and clotting issues, high levels of oxidative stress, and lipid dysregulation. These problems appear to be showing up in multiple areas – the immune cells, the muscles, and the brain.
All these seem to cohere around the idea that a “failure to respond” to a stressor is present at many levels. They suggest that a hypermetabolic state triggered by an infection may become chronic, ultimately producing a hypometabolic state characterized by cellular exhaustion in multiple tissues. Problems with blood flows, low oxygen states, and oxidative stress are implicated.
Most intriguingly, Hanson’s latest study suggests that ME/CFS patients’ T-cells may have been epigenetically reprogrammed by an infection to become exhausted.
The fly in the ointment is the presence of quite a few small studies, but with so many study results seeming to cohere, the ME/CFS field appears to have hit a rich vein to mine. Rather remarkably, it outstrips the long-COVID field in its understanding of the role metabolomics, cellular energy production and exhaustion, and oxidative stress play in these diseases.
While ME/CFS lost one NIH-funded ME/CFS research center, Hanson’s and Lipkin’s remain, and the NIH is going to produce a grant package for ME/CFS that should produce some of the large, rigorously produced research studies we need. One extensive large study (n=288) examining neurovascular coupling in ME/CFS underway should help us understand what’s going on in the brain.
One hopes that if the RECOVER Initiative, with its immense funding, ever seriously digs into long-COVID pathophysiology, it’s taking note.
The year-end review suggested that our researchers may be slowly but surely hitting the mark.
Health Rising’s BIG (little) End of the Year (Beginning of the Year) Donation Drive
Thanks to everyone who’s supported HR to the tune of about $52,000 as we round into the last week of the drive.
Year-end summaries take a lot of work, but this one was worth it as even I was surprised – and impressed – at how far this little field progressed this year.
Seeing findings from different studies pointing to the same general problem suggests that the ME/CFS field is zeroing into some core areas. Determining if that’s happening is one reason we do these major overviews. If that kind of work supports you – please support us!
Wow! Just read “The Gist” and it’s an excellent, easy to process summary of what I consider was a good year for giving hope to ME/CFS sufferers. Thanks Cort, for all your work! (I’ll get to the entire article on a day I’ve got more brain power working.)
Thanks! Whenever I need to go back to an article I go back to the GIST 🙂
I’ve always thought that my ‘chronically activated immune system’ was a big part of my energy deficits in my ME/CFS – as well as the reason that I never seemed to get things like colds, even when utterly exhausted.
Even more interesting: husband and I just got Covid for the first time this past December – we’ve had all the shots, isolated, masked – but his case was MUCH worse than mine. I was completely wiped out, but started pretty close to that. He was healthy, doing cardiac rehab, and brought us the virus home (probably) from the hospital he was doing it at – but had a lot more new symptoms and general misery than I did. His immune system is more ‘normal.’ He did acquire a better understanding of MY life, though.
It costs a lot of energy to keep an immune system on all the time.
This is what confuses me about the immune system in ME/CFS! Signs that it is activated, and signs that it is under activated ie. exhausted.
Mady Hornig and her team showed, a number of years ago, immune activation early in the illness (first three years) followed by under activation later on (after 3 years).
Yet my understanding is you have had the illness for many years?
I have had ME/CFS since 1989 – thirty-five years ago now. But during that time, I’ve had few illnesses like colds. I’ve always wondered if that was connected.
Part of the effect may have been that, during the first twenty years or so I homeschooled our three children – and they thus brought far fewer germs into our home (although they had a reasonable amount of activities such as sports, Scouts, music, and dance.
I found, in the first year sick, that dealing with schools with two, then three little ones was far more exhausting than I ever expected, because schools have so many demands. Complicating that was that our three were reading well by three, and none of the accessible schools had much accommodation for THEIR needs.
When asked how we managed, I found that schools also waste a lot of the time they have the kids, and we could do more in a couple of hours – and much of that one-on-one – than a school which had a lot of children for a longer period. I called it ‘accidental homeschooling,’ because, as a working plasma physicist at Princeton, I had NO plans to stay home and teach. With computers and books, their time seemed well spent. It was a struggle, but each of them also had a chance to try schools the year my husband had a heart attack, which he didn’t turn out to need my help recovering from, and the kids came home the next year.
Like Alicia, I rarely caught any colds or flus, in spite of teaching post secondary – where many students would go home to communities far and wide on weekends, and then bring back any circulating bugs from their communities to share with the rest of us. I had to walk through crowded hallways several times daily, but often went years without catching a bug, even though most students and other staff caught them. This always suggested some kind (or portion) of immune system upregulation to me.
I hadn’t thought about that but it seems to fit – immune activation followed by immune exhaustion.
Remember the big study Hornig led, Cort? I think 2017.
Nothing new about early activation-leading eventually to exhaustion
I agree Cort!, … (chronic) immune activation followed by immune exhaustion (accompanied by ANS exhaustion (chronic activation of the sympathetic phase activation), adrenal exhaustion, thyroid exhaustion or excessive RT3, and a general cellular energy deficiency for all non-immune purposes – causing no end of challenges from PEM to digestion to brain fog).
Hoi Cort, interessant om dit te lezen! Ik heb ME gekregen toen ik ong anderhalf jaar bezig was met Eén desensibilisatie injectie kuur voor pollen en huisstofmijt. Zou dit kunnen verklaren dat er eerst een overreactie van het immuunsysteem ontstaat en daarna de uitputting van hetzelfde systeem?
Dankjewel voor al je werk en begrijpelijk maken van deze complexe ziekte!
Hoi Cort, ik heb ME gekregen ( 2016) toen ik voor ongeveer anderhalf jaar bezig was met een desensibilisatie kuur voor pollen en huisstofmijt. Zelf heb ik altijd het idee gehad dat daardoor mijn immuunsysteem overbelast/overwerkt is geworden en daardoor/daarna ingestort is. Dankjewel voor al je werk om wetenschappelijke artikelen voor ons begrijpelijk te maken.
Interesting comment. I taught in the public schools for 37 years, and I had fibromyalgia for the second half of that time. I didn’t get the flu shot in those days and never got the flu. Schools are a petri dish. I’ve been sneezed and coughed on and once was vomited on, but I rarely even got a cold.
I have a difficult time trying to understand exactly when I became ill with ME. When I was in grade 11 I contracted a virus of some sort that kept me exhausted and weak for a few months but got better. Same thing happened after the birth of my third child. I was weak and exhausted for months and months. Got better again. I picked up every virus around, Epstein Barr, c-pneumonia and HHV6 for decades if it was caused by roseola. Then I completely “crashed” after a bad skiing accident and a very stressful time taking a patient to Myanmar. So what was the cause of my ME when there are so many factors in place? Was I bombarded by one too many events? Did my epigenetics change? If that’s the correct term? Yes I have PTSD but too many times my condition is dismissed as psychological. Thank goodness I now have Dr. Ric Arseneau as my specialist and we’re trying different meds.
The one pattern that stands out for me is your body struggling to bounce back from stressors. I imagine there’s a root cause for all of that. Good luck with Dr. Aresenau. I think you are in good hands 🙂
Hi Alicia, I made the same experience : after various infections in 2023 (varicella Zoster, corona and others) I don’ t get colds or corona, even if my family gets It, but energy never returns.
This shows that there is something wrong with the immune system. Hope it will be found soon.
Thanks Cort for all the informations !
Nice summary.
Study after study has shown immune exhaustion. It’s indisputable.
I think a key question is whether it is driving symptoms, or is secondary.
My money is still ( as it has been for more than 15 years) on the brain being the key driver of symptomology, hence I found Nath et al’s findings interesting.
I am curious to see the results of Simmaron’s rapamycin trial. Roy was quoted as saying the results look ‘very promising’, so let’s see.
Will also be interesting to see how PolyBio’s antiviral trial for viral reactivation goes. I’m still not 100% convinced on viral reactivation, but the theory does jive quite nicely with the immune exhaustion.
The other brain studies you highlighted are interesting too! While I do think the brain is the primary driver of symptoms, I definitely think there is some sort of inter/ relationship with the immune system.
Understanding the brain-immune system relationship in this disease is going to be fascinating 🙂
I was so struck by Clauw’s study where he was able to trigger small fiber neuropathy in an animal model by targeting the brain. That was a eye-opener…
Ok, I went down a rabbit hole with neurovascular coupling, and interestingly found a 2021 study that found that rapamycin could correct abnormalities in neurovascular coupling! Interesting! I don’t think that is the basis for Simmaron’s theory on rapamycin’s utility in ME/CFS, but it might potentially be meaningful:
https://pubmed.ncbi.nlm.nih.gov/33888602/
Amazed to read The Gist and to discover that the hypothesis of the Gupta Program matches the overview you provided. I’ve only been on it for a couple of months but it’s explained (which nobody else has until now) why I don’t get colds which my husband constantly goes down with. A while back I was in A&E (ER) over an infected insect bite and the doctor who treated me said “You must have an excellent immune system.” I made him repeat what he said because I was so gobsmacked that being so ill I could hear positive feedback from a medic.
I am more than ever convinced that 2025 is my year…..
Monthly donation activated.
Excellent summary! How things have moved along and progress made in identifying what is actually happening to our bodies. Who can refute this evidence?!!
Thank you, Cort!!!!!
Thanks, Sue! Appreciate it!
Interesting! At some point – actually I think we’re at that point already – we’re going to understand physiologically why it makes sense that programs like Gupta’s and Neuffer’s ANS rewired can work in some people.
If you’d like to do an update on Stellate Ganglion Blocks in 2025, I’d be very interested in reading it. I am interested in this procedure.
Happy New Year!
I welcome epigenetics research for ME/CFS – here’s an input I made on the topic:
“To me as a patient, it seems quite likely that ME/CFS is a both epigenetically triggered and epigenetically mediated disease – for the following reasons:
Its known genetic predisposition in some families*, and range of known environmental immune triggers for initial onset of ME/CFS (including infection, operation, stress, chemical exposure etc.) seem to correspond well to the epigenetic disease model of “genetic predisposition” and “epigenetic activation of existing predisposition triggers outbreak of disease”. As far I know, this model is state of the art for many diseases including e.g. diabetes.
ME/CFS seems to be at heart a complex (and in some patients reversible) dysregulation problem (rather than an irreversible degradation of tissues), as evidenced e.g. by: the waxing/waning nature of PEM cycles, and the fact some patients have experienced either full remission, or temporary remission before relapsing: Flexible up- and downregulation in the body are epigenetically mediated processes.”
*though I would not exclude that “inheritance” of e.g. HHV6 virus with germ cells might possibly also play a role with family predisposition
I think some of ME/CFS research (like Prusty’s miRNA researcher) is actually epigenetics, but I’d be happy to see more epigenetics research for ME/CFS and dialogue between this field and the other existing body of ME/CFS research, such as including epigenetics specialists into conferences and ideally the Stanford Working Group! Looking forward to exciting ME/CFS research findings in 2025 and your wonderful reporting of them, Cort!
On the topic of family predisposition, I was wondering if anyone else had a mother or father that contracted polio in the late 1940s / early 1950s? Polio epidemics were common on western countries during this time period.
My mother had polio in the late 1940s. She then had ME/CFS for a few years in the mid to late 1970s when I was a young child. She eventually got Parkinsons in her late 60s.
I have sometimes wondered if my own CFS was related to her having polio as a child. Keen to know if anyone else with ME/CFS had a parent who contracted polio
Hi Matthias, I have not, but I know that “post-polio syndrome” is a recognized thing in Germany, because an acquaintance was diagnosed with it in one of the couple of Polio clinics that exist in Germany. My older acquaintance had Polio as a child and has ME/CFS-like symtoms today (including sensory hypersensitivity, fatigue, PEM, gait problems and – interestingly similar to my own ME/CFS – for her just like for myself, cleaning-type hand and arm movements are particularly taxing.
I don’t know if “post-polio” is just another name for a subtype of ME/CFS, but I guess there’s probably more to it because I think the polio virus can also leave behind real organic damage to nerves/tissue etc.? (…or ME/CFS could be one subset of post-polio syndrom just as it is one subset of post-Covid; or my acquaintance could have both post-polio and ME/CFS, with only the post-polio diagnosed?).
Regarding your idea of a relation between polio in a parent and ME/CFS in a child, I supppose that either you could have inherited a family predisposition for ME/CFS independent of your mother’s polio, or I guess one question would be whether either the polio virus itself, or rather the “stressful” conditions in the body resulting from both the infection and its subsequent health problems are able to promote an ME/CFS predisposition in a child via epigenetic imprints during germ cell development and gestation. I guess indirect effects could also be involved that promote a vulnerability to ME/CFS, e.g. I think that I’ve once read in a book on generational epigenetics research that when the parent is stressed/traumatised, the children may have problems with their cortisol system, too.
Maybe you could ask polio patient organisations too if their children developed ME/CFS.
A great summary. Lots of promising research avenues ahead. Thank you Cort. We’re so blessed to have you do what you do. Wishing you a happy new year!
Thanks!
Hey Cort. The list of research in your Gist is absolutely terrific. Thanks.
Even more useful, however, is the interpretation of an expert. I have no idea on my own how to assess 2024. My takeaway of your takeaway–it was a pretty successful year regarding research?
I know your focus in the article was on research, but that a year-end review didn’t include significant progress in treatment or government support for sufferers (at least in U.S.) is suggestive.
I think 2025 will bring more news on treatments, as there are at least a couple of clinical trials that should be finished this year. I am praying that the rapamycin trials are positive. Will be interesting to see how PolyBio’s antiviral trials go too, but I suspect they won’t be finalised until 2026.
I also have an idea on a treatment, but I need to do some more research on it before I mention it
Bravo to those that have tried and got great results with my unconventional ldn and caffiene protocol.
I don’t claim it to be a cure but it is a very affective treatment.
To go from severe to be able to dance, walk, shop, travel, lug 50kgs of luggage on trains and buses, cook, clean, have zero pain, no pem, and extremely reduced fatigue, it only returns before the next dose, So you must keep it up regularly!
To find my abstract and protocol go to face book page, Multi – dosing Naltrexone for cfs/ME.
To Cort Johnson: I have a 25 year history of lupus, Graves, pseudotumor cerebri. I’ve had symptoms of limb weakness, ataxia, ptosis, high BP, heart problems and extreme fatigue with brain fog 25 years. I recently read an article about Wernickes encephalopathy caused by B1 deficiency. I started benfotiamine on 12/24 at 300mg twice daily. I bought it from Amazon. My neuropathy in hands/ feet mostly has disappeared in the first 4 days. Limb weakness is nearly gone and strength is coming back. Balance is better and brain fog is 80% improved. Energy level is amazing. Not one of 7 neurologists nor 3 neuro-ophthalmologists ever checked my B1 levels in the 25 yr period. I even stopped lisinopril 20mg daily and blood pressure is normal at 120/80. Im 55 years old and have suffered from these symptoms since my mid 30’s. I’ve always taken a daily multivitamin but never additional B1. I hope this helps someone out there.
That is amazing- congratulations and thanks so much for sharing that. It’s just so great when something simple can help. I’m going to try B1 again 🙂
There is a an area of research that our organization has worked in for many years that has not been addressed in ME/CFS studies.
The Developmental Origins of Health and Disease
The Developmental Origins of Health and Disease (DOHaD) theory is a multidisciplinary field of medical research that explores how environmental factors and genetics interact to affect health later in life:
DOHaD suggests that exposures to environmental factors during early life, particularly in the womb, can increase the risk of disease later in life. These risks can sometimes be passed on to future generations.
Factors
Environmental factors that may contribute to disease risk include:
Nutrition
Stress
Environmental pollutants
Environmental chemicals
Infections
The microbiome
Drugs
Diseases
Some diseases and conditions that may be linked to early life exposures include:
Obesity
Type 2 diabetes
Insulin resistance
Asthma
Cardiovascular diseases
Behavioral disorders
Neurodegenerative diseases
Reproductive disorders
Some cancers
Research on ME/CFS and Long Covid needs to start much earlier in the life of the affected person.
Our research looks at both male and female preconceptual and pregnancy exposures. We have found a notable increase in ME/CFS in the children of male Vietnam veterans which we believe is caused by the epigenetic effects of dioxin on sperm resulting in a deficient immune system in the veterans’ children.
Our organization sponsors the National Birth Defect Registry http://www.birth defects.org , a comprehensive online data collection project. Since we have already found an increase in cases of ME/CFS, we would like to see more cases followed through to possible developmental origins.
As the new year begins and you are hoping for long awaited help to emerge from research, read the story of a 12 year old boy who developed Long Covid in 2022.
It is easy reading even if you are “brain fogged”.
https://www.who.int/europe/news-room/feature-stories/item/unable-to-walk-and-housebound-at-the-age-of-12—the-extreme-consequences-of-long-covid
The Omicron variety is the same Covid that I got in 2022 and the symptoms from this are much more severe and life-threatening that the ME/CFS I have had since 1984.
I now have A-fib, high blood pressure, increased hearing loss, dizziness, constant back pain and can barely walk.
I am tired of researchers constantly re-inventing the wheel to keep the funding flowing.
According to an article in a major newspaper, one in four people who had Omicron in 2022 now have Long Covid.
Do the politicians in either party understand the cost of this to our healthcare system, our country, our future? Do they even give it a thought?