How can we "stimulate" mTOR?

[Tunguska]

@Rose49 After nandixon's ideas the next most interesting thing posted was this study:
http://forums.phoenixrising.me/inde...s-of-pdh-impairement.48742/page-2#post-821122 -> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270830/ (it's a feedback downregulation of mTor through PD-1 -> FoxO1 -> PD-1 extracellular signaling, in immune cell population)
Whether it were proved or ruled out would be just as interesting (well, almost!). Maybe he already knows...

(My personal experiences with these self-therapies are not the best reference because although very good results I focus on brain activity and stay mostly sedentary)

 

[A.B.]

@Rose49 the Australian TRPM3 ion channel findings could tie in with Naviaux' research because this channel is activated by spingosine, and this is unusual.

Sphingolipids, including sphingosine, are known to have inhibitory effects on a variety of ion channels. Thus, TRPM3 is the first ion channel activated by sphingolipids.

https://www.ncbi.nlm.nih.gov/pubmed/15550678

Not that I can make sense of anything here, but it might be more than mere coincidence.

 

[Hip]

Any reason why you stopped?

I was in the middle of testing another treatment, so it was just a quick short term test to see if there might be any immediate benefits from these mTOR boosters.

If fact I am always in the middle of testing some treatment or another, so it's a perennial problem for me to schedule new treatment tests. Trying two or more new treatments at the same makes it difficult to know which one is providing any benefits (or side effects) should these appear. I always say that I would like 10 of me to test things on!

 

[nandixon]

@nandixon, if you want to summarise your theory for Ron to read, this is your chance.

I’d already mentioned mTOR (mTORC1) to Dr Davis a while back, but this post here that I link to in my signature gives an updated graphical representation of what I think are two possible ways to fit the Fluge & Mella and Naviaux studies together via mTORC1. Excerpt:

...
1. ???--> Low ceramides--> Low S1P--> [S1PR1]--> Under-activated Akt/mTOR (mTORC1)--> Inhibited PDH complex

2. ???--> Under-activated Akt/mTOR (mTORC1)--> Inhibited PDH complex--> Low acetyl-CoA--> [Low palmitoyl-CoA]--> Low ceramides--> Low S1P
...
Option #2 might be more preferred now that Dr Davis has indicated that there seems to be something present in ME/CFS blood that shouldn't be there…

 

[Jesse2233]

Going to try an 8 mg ketamine IM injection from a doctor today

 

[nandixon]

@Rose49 After nandixon's ideas the next most interesting thing posted was this study:
http://forums.phoenixrising.me/inde...s-of-pdh-impairement.48742/page-2#post-821122 -> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270830/ (it's a feedback downregulation of mTor through PD-1 -> FoxO1 -> PD-1 extracellular signaling, in immune cell population)
Whether it were proved or ruled out would be just as interesting (well, almost!). Maybe he already knows...

@Rose49 That idea of @halcyon that @Tunguska linked to can be tested with Dr Davis’s testing chip and ME/CFS serum using either or both of an anti-PD-1 (e.g., Keytruda) or anti-PD-L1 monoclonal antibody. That's a great one to rule out or in because PBMCs can be used, unlike some other drugs that it might be nice to test and that unfortunately probably require other types of cells for testing.

 

[necessary8]

@nandixon, one thing just clicked for me. It would make the most sense to me for there to be a feedback loop, that keeps the blockage blocked, because otherwise we would probably see more spontaneous remissions. And you're saying that there are two ways...

What if it's actually:

Low ceramides--> Low S1P--> [S1PR1]--> Under-activated Akt/mTOR (mTORC1)--> Inhibited PDH complex --> Low acetyl-CoA--> [Low palmitoyl-CoA]--> Low ceramides

...and it's a feedback loop?

Once something kicks it into place, like a viral infection while having already inhibited mTORC1 by antibiotic use, it stays in place by this mechanism. Obviously, there are probably more variables to it. It might be one loop of many. But it's an idea.

 

[A.B.]

The feedback loop probably passes through B cells. It would be difficult to explain the Rituximab results otherwise. Remember that Fluge and Mella found problems with PDH in their patients, although it hasn't been confirmed that Rituximab responders also have a PDH impairment (or that response to Rituximab normalises PDH).

Alternatively, the alterations produced by the illness could be fertile ground for developing some B cell dependent autoimmune disease.

I'm not sure if we can exclude the "multiple different diseases in the same patient sample" hypothesis either.

 

[necessary8]

The feedback loop probably passes through B cells. It would be difficult to explain the Rituximab results otherwise.

Not true. In the last Q&A Ron said that Rituximab, like any other drug, affects also other things than just its primary target (B cells), and that this secondary action might be the reason why it helps.

So it might pass through B cells, but it most certainly doesn't have to.

 

[A.B.]

Not true. In the last Q&A Ron said that Rituximab, like any other drug, affects also other things than just its primary target (B cells), and that this secondary action might be the reason why it helps.

So it might pass through B cells, but it most certainly doesn't have to.

The response to Rituximab is delayed in a manner that is consistent with a B cell dependent autoimmune disease.

And this autoimmune process doesn't appear to involve inflammation. There are some autoimmune diseases where there is no meaningful inflammation and tissue destruction, but instead there are antibodies that bind to receptors and mess up the normal signalling going in the body. ME/CFS does seem to involve a lot of dysregulation.

The psychiatrists calling this a "functional disorder" might be right, just not in the way they think are.

PS: one such antibody-to-receptor disease is Grave's disease, where antibodies bind to the TSH receptor and chronically stimulate it, causing hyperthyroidism. It was once considered a psychosomatic illness.

 

[eljefe19]

From my personal experience, mTOR activators help mainly with PEM severity and likelihood of being triggered. As @Sushi pointed out to me, and as Prof Davis said in his last video, avoiding or even minimizing PEM may be protecting us from further damage that PEM causes. It does seem like it throws a bit of a wrench in that feedback loop you guys are talking about.

 

[Tunguska]

Sorry I don't want to divert from more important things, but for the sake of information, it turns out caffeine is probably not a significant mTor inhibitor in muscle in vivo (brand new 2017): https://www.ncbi.nlm.nih.gov/pubmed/28177708

recent in vitro findings have suggested that caffeine may block skeletal muscle anabolic signaling through AMP-activated protein kinase (AMPK)-mediated inhibition of mechanistic target of rapamycin (mTOR) signaling pathway. This could negatively affect protein synthesis and the capacity for muscle growth. [...]
We found that caffeine administration to mice did not significantly enhance the phosphorylation of AMPK or inhibit signaling proteins downstream of mTOR [...]
In conclusion, caffeine administration does not impair skeletal muscle load-induced mTOR signaling, protein synthesis or muscle hypertrophy.

(other factors might get involved but you get the gist)

 

[eljefe19]

Sorry I don't want to divert from more important things, but for the sake of information, it turns out caffeine is probably not a significant mTor inhibitor in muscle in vivo (brand new 2017): https://www.ncbi.nlm.nih.gov/pubmed/28177708

(other factors might get involved but you get the gist)

To continue this divergence, I found out that Cannabidiol (CBD) activates mTOR.
https://medicalxpress.com/news/2016-08-antipsychotic-mechanism-action-cannabidiol.html

Hypothesizes that it's action on mTOR may contribute to it's antipsychotic effect.

 

[Alvin2]

Please be cautious! I try to tell him or read him people's ideas and things they try. He's very interested in your ideas

That leads to something i have been wondering, how much is he reading research done in the past and buried in medical journals (for example someone in another thread posited a theory that excess ACh is the cause of ME/CFS, doubtful but there is some circumstantial evidence). Also i read a paper about high homocysteine found in the cerebrospinal fluid of ME/CFS patients and a followup study where they successfully lowered it with B12 combined with folic acid. Its something i actually tried when i could afford it (substituting methylfolate which is safer/more potent), it cut my headache/throbbing/fluid draining from the brain sensation and reduced my recovery by a couple days (from 2 weeks on a bad overload to 10-12 days).
Also i was wondering what you give your son as supplements/medication, if there is anything we have missed, i noticed B12 injections in one of the videos.

 

[Murph]

Sorry I don't want to divert from more important things, but for the sake of information, it turns out caffeine is probably not a significant mTor inhibitor in muscle in vivo (brand new 2017): https://www.ncbi.nlm.nih.gov/pubmed/28177708

(other factors might get involved but you get the gist)

This mentions the role of AMPK. AMPK, which is upstream of mTor, needs a more prominent role in all this, IMO. It shoots up during exercise, inhibiting mTor, as these papers show.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1890364/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779044/

It is supposed to go back down afterward. Perhaps it doesn't do that effectively?

(the amp in ampk is adenosine monophosphate. ampk depends on amp/atp ratios. If the Myhill school of thought is right and atp is eliminated dramatically during exercise (rather than merely recycled), then ampk might be elevated for a long time, inhibiting mtor and possibly helping explain PEM.)

 

[eljefe19]

This mentions the role of AMPK. AMPK, which is upstream of mTor, needs a more prominent role in all this, IMO. It shoots up during exercise, inhibiting mTor, as these papers show.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1890364/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779044/

It is supposed to go back down afterward. Perhaps it doesn't do that effectively?

(the amp in ampk is adenosine monophosphate. ampk depends on amp/atp ratios. If the Myhill school of thought is right and atp is eliminated dramatically during exercise (rather than merely recycled), then ampk might be elevated for a long time, inhibiting mtor and possibly helping explain PEM.)

Does anything inhibit AMPK? Also, a few agents activate both AMPK and mTOR. How do you explain this?

 

[Murph]

Does anything inhibit AMPK? Also, a few agents activate both AMPK and mTOR. How do you explain this?

This paper lists lipids, glucose, glycogen, amino acids, insulin, compound C, (nb this is dubious) and certain inflammatory signals as AMPK inhibitors. But as far as I can tell the only thing that reliably inhibits ampk is having ample atp. Which, as we know, cant be taken as a supplement. (But can probably be obtained/maintained by pacing).

As for things that activate both ampk and mTor, the chemistry is beyond me but at a purely logical level I can imagine compounds that elevate both, even though one then inhibits the other....

EDITS:
1. I added in a bunch of AMPK inhibitors after I tracked them down.

2. Interestingly, ampk is also raised by high calcium in cells. A possible link between the mTor hypothesis and the NCNED resarch?

"In addition, Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) has also been identified as a separate AMPK kinase (Hawley et al., 2005; Hurley et al., 2005; Woods et al., 2005), that phosphorylates and activates AMPK in response to elevated intracellular Ca2+ concentrations, independent of any change in cellular AMP/ATP ratio."

 

[eljefe19]

So I did a little research into AMPK suppressors and found Palmitoylethanolamide (PEA).
It activates AMPK in fat tissue but decreases it in the hypothalamus (Reference).
It also disrupts the PERK-eIF2α pathway and may disinhibit mTOR this way. (Reference)
Furthermore, it activates PPAR-alpha and PPAR-gamma. Someone please connect that to mTOR I know they connect somehow (Reference).

 

[Murph]

So I did a little research into AMPK suppressors and found Palmitoylethanolamide (PEA).
It activates AMPK in fat tissue but decreases it in the hypothalamus (Reference).
It also disrupts the PERK-eIF2α pathway and may disinhibit mTOR this way. (Reference)
Furthermore, it activates PPAR-alpha and PPAR-gamma. Someone please connect that to mTOR I know they connect somehow (Reference).

... Fluge and Mella found elevated transcription of PPAR delta, but did not report differences in PPAR alpha and did not detect ppar gamma.... (in the 2016 PDH paper)

 

[eljefe19]

@Murph Do you think reducing AMPK in the hypothalamus would be helpful?
Would increasing AMPK in adipose tissue be harmful?
What do you think about trying PEA?

Apparently PPAR-alpha can be both activated and suppressed by mTORC1 depending on the cell type, and PPAR-gamma is purely activated by mTORC1. If mTORC1 is underactive in PWME, than perhaps PPAR-gamma is low.
Also, AMPK suppresses both PPAR alpha and gamma (Reference)

@nandixon What do you think about PEA? In summary, it inhibits AMPK in the hypothalamus, activates AMPK in fat tissue, from what I can tell disinhibits mTOR through disrupting the PERK-eIF2α pathway, and activates PPAR alpha and gamma.