Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

[Cheesus]

Hi @Anne

Ron Davis talks about it in his most recent video: http://forums.phoenixrising.me/inde...e-cfs-research-with-ronald-w-davis-phd.49408/

I originally read about it in an article on Health Rising, but I am having trouble finding it now. The Ron Davis video gives you the most recent insight anyway.

 

[Snow Leopard]

Is this trying to imply that elevated mTor localized to B cells could be an issue? This isn't the first time localization questions or "paradox" about mTor comes up but it's the first time it's sounded relevant... Or is this invoking the other "paradox" where the B cells in CFS might behave opposite to those in autoimmunity?... Or...? (I can't post a lot and very tired so just trying to get the point)

I can't really say.

I will say however that we should not read too much into undemonstrated speculations (at least not to the point of taking potentially dangerous medications).

 

[alex3619]

I can't really say.

I will say however that we should not read too much into undemonstrated speculations (at least not to the point of taking potentially dangerous medications).

This is nearly ALL in early stage research. None of it is suitable for advocating serious medical approaches. The only exceptions in the near future are likely to be Rituximab and Ampligen.

The other "problem" is that Ron Davis and those he is cooperating with are moving toward an open data and fast research approach. This is a good thing. However it means that preliminary findings are probably less reliable early on. False positives will be higher, as will false negatives. Yet in time this is probably the fastest way to make progress. Its a departure from traditional methods, and we need to consider that in interpreting data.

Historically good medical science has started with an hypothesis or exploratory reseach proposal, a grant application, a grant, then the study, then analysis, then write-up, then publication review, possible rewrite, then publication, then widespread review by other scientists.

For clinical application you then repeat those steps, first with phase 1 trials, then phase 2, then phase 3, then ongoing drug or treatment monitoring. Its a long slow road. All of this can take upwards of 20 years if a new drug has to be invented. It can cost over a billion dollars.

The Ron Davis approach is similar to the concept of rapid prototyping in programming. He is doing one experiment a week, not per several years, and wants to increase that to multiple studies a week. Eventually these will form a pattern, and the combination may be published formally, but I am not sure that is an intention. Immediate scientific release of data changes the whole picture. Traditional ways of looking at scientific results will not completely apply. Any scientist can get the raw data and run their own analysis.

This is open research at its most cutting edge. There will be mistakes. There will be corrections. There will be experiments to test previous conclusions. Eventually there may be a phase 3 trial of something, I am not sure how open medical research can currently get around that.

 

[Aroa]

All of this can take upwards of 20 years if a new drug has to be invented. It can cost over a billion dollars.

I don´t know anything about how science works, but it seems to me aberrant

This is open research at its most cutting edge. There will be mistakes. There will be corrections. There will be experiments to test previous conclusions. Eventually there may be a phase 3 trial of something, I am not sure how open medical research can currently get around that.

I hope this approach will mean a shift in how research is being developed for the sake of all kind of patients , which ultimately should be the goal

 

[alex3619]

I don´t know anything about how science works, but it seems to me aberrant

This is why President Donald Trump is talking of scrapping the current approval process, and moving to early access and constant monitoring. It will get drugs out many years sooner, at much lower cost, but means they will be less reliable and patients will be guinea pigs far more often.

 

[adreno]

It will get drugs out many years sooner, at much lower cost, but means they will be less reliable and patients will be guinea pigs far more often.

If there is informed consent from the patient, I am fine with this.

 

[alex3619]

If there is informed consent from the patient, I am fine with this.

Yes, emphasis on informed. Yet they will not know about most side effects, long term issues, proper dosing schedules, cormorbidity effects etc. for many years, as these are often discovered later in the trial process. So when is informed actually informed? Making experimental treatments available I think is a good thing. If they get marketed as just new drugs, and not experimental, that is something else.

 

[Snow Leopard]

This is nearly ALL in early stage research. None of it is suitable for advocating serious medical approaches. The only exceptions in the near future are likely to be Rituximab and Ampligen.

There is a big difference between testing hypotheses in controlled (ideally unbiased) studies and clinical trials and pretending those hypotheses are fact, based on educated guesses from scientific literature (or intuition) and experimenting with drugs (without clinical supervision) as a result.

 

[Aroa]

Yes, emphasis on informed. Yet they will not know about most side effects, long term issues, proper dosing schedules, cormorbidity effects etc. for many years, as these are often discovered later in the trial process. So when is informed actually informed? Making experimental treatments available I think is a good thing. If they get marketed as just new drugs, and not experimental, that is something else.

I guess there are some drugs on the market, which followed the whole research procedure , and whose studies are quite biased by pharmaceutical interests....

 

[alex3619]

I guess there are some drugs on the market, which followed the whole research procedure , and whose studies are quite biased by pharmaceutical interests....

This is well known.

 

[Tunguska]

If there is informed consent from the patient, I am fine with this.

Yeah the informed part is everything. As someone who's been damaged this way you might think I'd be more careful, and while I actually am to some extent (usually avoid herbals, high dose steroids, and weird stuff), the flip side is, I can try a thousand substances and none of it could do even a quarter of the damage the doctor-/pharmacy-dispensed pills did, that had no legal requirement to list any of their known severe sides (this isn't the USA).

Anyhow that B cell question is of course because if there's a possibility that increasing mTor indiscriminately could worsen the immune state somehow then that would alter my excitement for long term band-aids. But I don't research immune systems for a living so I can't even guess if that effect would be measurably harmful or even apply or matter at all.

Anyhow (2) at the moment I'm trying to figure out the viability of the steroids. These are extremely helpful (to me) at certain times of day, and traditionally in research quite a benefit against neurodegeneration, but it's difficult to say whether they interfere with or benefit mTor. Only androsterone seems pretty certain to side as pro-mTor. (these are largely the ones sold via another forum of relatively careful people that's been linked) edit: and the DHEA, sorry.

 

[soulfeast]

The energy boost I got from leucine was only quite mild; useful, but nothing major.



Having read this Fluge and Mella paper about the pyruvate defect, one thing I may look into is getting hold of the new supplement called KetoForce®, which contains beta hydroxybutyrate.

Beta hydroxybutyrate is one of the ketone bodies produced by a ketogenic diet, and thus I think this supplement may get you into ketosis (fat burning using ketone bodies) without necessarily needing to go on a ketogenic diet (these diets can be hard to do). The only problem is that it is pretty expensive.

I suspect that if you can stoke up fat burning on the mitochondria, this may give you larger energy gains than anything you can do with amino acid burning.

I was low carb, high fat and not in keto range (or at least I didn't think so) and had high beta hydroxybutyrate. The low carb, high fat diet didn't really help me that much. I then read Ray Peat info and went high carb. I can't tell a difference. I will up my protein now, though. Won't high protein put you out of keto?

 

[JES]

I don´t know anything about how science works, but it seems to me aberrant

20 years for developing a new ME/CFS drug does unfortunately seem quite realistic to me. The whole pharma business is a bit dysfunctional at the moment, as there are few big players on the market holding most of the patents. The big companies are unwilling to take big risks in creating new types of drugs as long as they get their money from patents, one reason is the fear of getting sued. For example, drugs for depression today are basically no more effective than the original antidepressants created 40 years ago, and depression gets way more research money than ME/CFS.

IMO the best bet lies in finding existing approved drugs on the market such as Rituximab and re-purposing them for ME/CFS treatment. This is an approach that is very much investigated at moment among all diseases.

 

[Aroa]

Yes I ignore how science works BUT one thing I am sure of "it is not patient oriented"

I am glad Ron Davis is starting to change things like the time it takes for studies to be published and
developing innovative technologies to cut healthcare costs . He said “We note this is not a very high priority for the NIH “

 

[Aroa]

For example, drugs for depression today are basically no more effective than the original antidepressants created 40 years ago, and depression gets way more research money than ME/CFS.

What a WASTE of MONEY !!!!!! This is Nonsense .

Does it has to do with what Dr Davis was saying ??

"The Grants were both turned down because we were trying to discovery, and they wanted us to only do hypothesis testing, and as I said to them: the scientific method is first observation, then
hypothesis. And if you have virtually no observations you can’t generate a good hypothesis"

 

[Tunguska]

I took my first sodium dichloroacetate 200 mg oral dose yesterday. It seemed to make me sleepy for a few hours (increased fatigue is apparently one of the side effects of DCA), rather than boosting energy.

Sorry this is 15 pages late: did you try it with caffeine, after all (smallish dose I mean)?

Feels like there's more to that story. If you go through the DCA studies, a lot of them mention it's not strictly a PDK4 inhibitor but also a FoxO1 inhibitor, which in turn is a PDK4 activator (this was mentioned in @Snow Leopard 's post on page 2). Caffeine is a well-known FoxO1 activator so maybe they counteract that way?

I hadn't read about FoxO1 in awhile (since the accutane stuff) so I had to brush up, but it seems to be more powerful and broad-sensing than anything I remembered/understood (you'd have to read this whole thing: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031984/ ; title's just a hint). Including that too much inhibition could account for increased fatigue.

Not my idea, it seems to be catching on (but I do like blunt weapons):
https://www.ncbi.nlm.nih.gov/pubmed/26239835 (FoxO1 Inhibitors: The Future Medicine for Metabolic Disorders?) (2016)
https://www.ncbi.nlm.nih.gov/pubmed/25483084
https://www.ncbi.nlm.nih.gov/pubmed/20736318

 

[Hip]

Sorry this is 15 pages late: did you try it with caffeine, after all (smallish dose I mean)?

I have not tried DCA again, only tried it once. Will try it again at some point.

 

[SherDa]

I was low carb, high fat and not in keto range (or at least I didn't think so) and had high beta hydroxybutyrate. The low carb, high fat diet didn't really help me that much. I then read Ray Peat info and went high carb. I can't tell a difference. I will up my protein now, though. Won't high protein put you out of keto?

I don't think a low carb/high fat diet will work very well if one is trying to burn longer chain fats. It may be true that only amino acids and ketones are burned very well for energy.

So I believe the point of using the beta hydroxybutyrate is that it is already a ketone. Most ketogenic diets rely on the body's ability to create ketones from longer chain fats, but that is likely an impaired process in this scenario.

High protein intake won't put you out of keto if you're converting the aminos to ketones but could put you out of keto if they are converting to glucose. (I think it is stated elsewhere in this thread, but leucine and lysine are the 2 aminos that only convert to ketones and not glucose.)

 

[adreno]

@nandixon

As far as I can tell, pathogens activate the Akt/mTOR pathway:

The Battle over mTOR: An Emerging Theatre in Host–Pathogen Immunity

Another indication perhaps that ME/CFS isn't caused by an ongoing infection.

 

[ljimbo423]

As far as I can tell, pathogens activate the Akt/mTOR pathway:

Could it be that in the short term the mTOR pathway is activated by pathogens but in the long term, the oxidative stress from chronic immune activation inhibits mTOR? High levels of oxidative stress are very common in cfs.

As a central cell growth controller, mTORC1 is potently inhibited by stress conditions such as hypoxia, oxidative stress, and hyperosmotic stress. Under physiological condition, ∼1%–3% of the oxygen consumed by cells is metabolized to reactive oxygen species (ROS), which generates oxidative stress in the cell. Oxidative stress potently and rapidly inhibits mTORC1, possibly through activating AMPK kinase (Chen et al. 2010).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691891/

If 1-3% of oxygen consumed is metabolized to reactive oxygen species (ROS) in healthy people. How much would that percentage go up in people with cfs and dysfunctional mitochondria? It seems like it would be a lot!