How can we "stimulate" mTOR?

[Sushi]

Very weird drug. The patients eyes are open but they feel no pain nor do they remember the event.

As I remember, when used for ME/CFS it is given in a low dose, very slow infusion which apparently prevents the dissociative side-effects. To quote from a letter by Dr. Jay Goldstein (sorry, I don't have a link):

Ketamine can be given in a dose of 25 to 100 mg in 500 ml of normal saline, infused over three to four hours, titrating the rate of the infusion to any adverse reactions which include wooziness, numbness, nausea, and vertigo.

My best friend who is an cardiologist suffered from depression that appeared refractory to the usual SSRI drugs. At the hospital, he received ketamine by an anesthesiologist with remarkable results. From one treatment his depression has been under control for the past several months.

I've read about this. Dr. Jay Goldstein found that it had remarkable effects on ME/CFS patients, but I think that the challenge was getting lasting results. If I do try it, I'll go over all these aspects with the anesthesiologist beforehand. Thanks for sharing your experience with it.

 

[Basilico]

Just doing a quick read it would seem that the most important thing to stimulate mTOR is resistance training and exercise intensity. Could this be why we have this issue as we are unable to exercise, especially intensely?

My husband was a bodybuilder for several years before getting CFS. He continued weightlifting even with CFS until he got to a point where it was causing PEM and also major orthostatic intolerance/vagal nerve activation (He'd do a set of something strenuous like pull-ups with 50 libs attached at his waist and then instead of getting higher BP, his BP would crash really low and he'd get a vagal nerve response to the low BP). I would also like to add that he was taking BCAAs immediately before going to the gym. So I don't think that inability to strength-train is what causes this problem.

My list of mTOR activators

AKG
Carnitine
DHEA
Nicotinamide
Leucine
MCTs
Taurine
Retinol
TMG
SFCAs
Zinc
Folate
Pregnenolone
Cordyceps
Lysine

He has taken many things on this list (though not everything) and none seem to have any effect on his PEM.

@Skippa
In regards to exercise, avoid aerobic as endurance exercise inhibits mTOR specifically mTORC1. Anaerobic exercise is the opposite. I have lifted some light weights three times in the past couple weeks with no noticeable PEM.

It's amazing that there always seem to be drastically different responses to interventions. Weight-lifting helps you while it causes him to get PEM (even when he reduced the weights/reps. He rarely ever did any aerobic exercise because he has a bad knee.

**warning: anecdote follows**

I have always eaten a large amount of protein. lots of meat every day, nuts, tofu, legumes. But when I started taking whey powder I noticed an improvement in my PEM.

We have just discovered that both liposomal glutathione and non-denatured whey are preventing/shortening/improving his PEM. However, taking the precursors for glutathione production do nothing.

***I think that at this point, self-experimentation is really key to find what works for individual people because nothing seems to work for everyone and the controlled experiments are severely lacking. If people don't feel comfortable trying new things, no one is telling them that they must. But I like reading about what others are trying because it gives me new ideas/directions to pursue.

 

[eljefe19]

Guys hands down I think the three strongest agents right now for activating Akt/mTOR are Florinef (activates Akt(just upstream of mTOR)), Cimetidine (reduces mTOR inhibition caused by high Tregs cells by lowering them), and of course aminos, especially Leucine, BCAA's, Glutamine, AKG, Lysine, Glycine, Tyrptophan.

 

[Basilico]

I have a question: @eljefe19 you mentioned that (and I'm paraphrasing here) that the goal is to raise mTor and lower Tregs. I'm a little confused by this, because if the theory of an overactive immune system is either the cause or part of the problem, wouldn't the problem be that Tregs are too low and should be raised?

Tregs are what kill off the immune cells that are no longer needed once the invading pathogen has been killed off. Having too low Tregs would cause the immune system to keep attacking without cause (and thus lead to autoimmunity problems.) I've been to CFS specialists who believed that the inability of the immune system to 'shut off' was at the heart of CFS, though there's obviously no definitive answer about this.

From what I've read so far it sounds like raising Tregs is the goal. I just did a quick search on wikipedia to make sure I was remembering right since it's been awhile since I've read about Tregs and my memory is not the best, and I found: "T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important "self-check" built into the immune system to prevent excessive reactions."

Could you explain why you think it's important to lower Tregs?

 

[Sushi]

My husband was a bodybuilder for several years before getting CFS. He continued weightlifting even with CFS until he got to a point where it was causing PEM ... I would also like to add that he was taking BCAAs immediately before going to the gym.

Guys hands down I think the three strongest agents right now for activating Akt/mTOR are Florinef (activates Akt(just upstream of mTOR)), Cimetidine (reduces mTOR inhibition caused by high Tregs cells by lowering them), and of course aminos, especially Leucine, BCAA's, Glutamine, AKG, Lysine, Glycine, Tyrptophan.

I just looked at my NutraEval levels for L-leucine, L-isoleucine and L-valine (BCAAs)--they are all low. Perhaps this is a factor as to why I am responding well to BCAAs?

My ME/CFS doctor prescribed Lysine and Cimetidine, though it was before this bit of tentative research surfaced. The Cimetidine was because it is an H2 blocker, so there is an added effect there. The Lysine was for its anti-viral effects.

Many have been already getting good effects for OI with Florinef, so it looks like some of the treatments we've been prescribed already might serve double-duty.

 

[eljefe19]

@Basilico more info on Cimetidine here

 

[TigerLilea]

Guys hands down I think the three strongest agents right now for activating Akt/mTOR are Florinef (activates Akt(just upstream of mTOR)), Cimetidine (reduces mTOR inhibition caused by high Tregs cells by lowering them), and of course aminos, especially Leucine, BCAA's, Glutamine, AKG, Lysine, Glycine, Tyrptophan.

One of my doctors put me on Florinef and I didn't notice any changes or improvements at all.

 

[Tunguska]

Many have been already getting good effects for OI with Florinef, so it looks like some of the treatments we've been prescribed already might serve double-duty.

You hit the nail on the head. It just shows, experimenting this way you're better off starting with the most broad-acting treatments and then specialize to reduce side effects and narrow down. My doctor was an ass (and failed), but he had that strategy down. Now opioids definitely work well for me, it's just a question of finding more sustainable alternatives.

 

[Murph]

here's a nice map of Mtor activation from the paper 'mtor at a glance' (Laplante and Sabatini, 2009)

 

[helen1]

Found another mTOR activator: phospholipids eg lecithin as in egg yolks.

 

[Alvin2]

https://www.ncbi.nlm.nih.gov/m/pubmed/25878205/

L-tryptophan is another amino capable of activating mTOR and also improving TJ epithelial cells (good for leaky gut too?).

Tried it many years ago (prescription only in Canada), did nothing, and the tablets are huge.
5HTP (no prescription required) makes me throw up, can't explain it.

 

[Basilico]

@Basilico more info on Cimetidine here

Thanks for that link. We both tried Tagamet a few months ago (not specifically for PEM, just to see if it helped in general) and unfortunately neither of us noticed anything. Maybe a change in dosage or timing would make a difference.

 

[Tunguska]

here's a nice map of Mtor activation from the paper 'mtor at a glance' (Laplante and Sabatini, 2009)

Unfortunately since it's from 2009, it's missing this part: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031984/
(based on observations from fluge&magella thread, it likely doesn't cause - but contributes - to lowered mTor - at least that's a safe assumption; simultaneously it keeps energy levels from crashing. also, the immune cells have another one someone else posted involving an extracellular signal that looks even stronger, but it doesn't look like anyone can tell if it's a real contributor yet)

 

[eljefe19]

Unfortunately since it's from 2009, it's missing this part: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031984/
(based on observations from fluge&magella thread, it likely doesn't cause - but contributes - to lowered mTor - at least that's a safe assumption; simultaneously it keeps energy levels from crashing. also, the immune cells have another one someone else posted involving an extracellular signal that looks even stronger, but it doesn't look like anyone can tell if it's a real contributor yet)

Has any of your research into FOXO translated into any possible treatments yet?

 

[gregh286]

Guys hands down I think the three strongest agents right now for activating Akt/mTOR are Florinef (activates Akt(just upstream of mTOR)), Cimetidine (reduces mTOR inhibition caused by high Tregs cells by lowering them), and of course aminos, especially Leucine, BCAA's, Glutamine, AKG, Lysine, Glycine, Tyrptophan.

Aminos I definetly 100% agree with.
The only other one i would add is Taruine.
I found this the most potent i have used, way better than standard powders
We seem to need way more than normal, around 200ml of this juice a day does the trick.

http://www.biotechusa.com/products/premium-proteins/protein-fuel/

 

[Tunguska]

Has any of your research into FOXO translated into any possible treatments yet?

No. You could look harder, but there don't seem to be any pure FoxO1 inhibitors available.

It's more a justification for avoiding some herbals (e.g. luteolin), some medications, oxidative stress, and probably other things (it's a broad stress-sensing program).

 

[eljefe19]

No. You could look harder, but there don't seem to be any pure FoxO1 inhibitors available.

It's more a justification for avoiding some herbals (e.g. luteolin), some medications, oxidative stress, and probably other things (it's a broad stress-sensing program).

Check it out I found a paper that relates PD-1, FOXO1 and mTOR.

http://www.cell.com/immunity/abstract/S1074-7613(14)00389-6

I'm too fatigued today, hopefully you can read it over.

 

[Tunguska]

Check it out I found a paper that relates PD-1, FOXO1 and mTOR.

http://www.cell.com/immunity/abstract/S1074-7613(14)00389-6

I'm too fatigued today, hopefully you can read it over.

Link isn't working for me, but it's probably the same as halcyon posted. It's very interesting but I can't draw any practical ideas from it. What I understood was that mechanism is limited to immune cells (if somehow this is wrong, please correct). But on the other hand it's also probably stronger than the one I posted above, so my guess is immune cells are more strongly affected by FoxO1. So in other words a pure systemic FoxO1 inhibitor might modulate the immune system even more than it does skeletal and liver cells (it would have to be done carefully because apparently it could lead to higher virus titers if you have them).

 

[eljefe19]

Link isn't working for me, but it's probably the same as halcyon posted. It's very interesting but I can't draw any practical ideas from it. What I understood was that mechanism is limited to immune cells (if somehow this is wrong, please correct). But on the other hand it's also probably stronger than the one I posted above, so my guess is immune cells are more strongly affected by FoxO1. So in other words a pure systemic FoxO1 inhibitor might modulate the immune system even more than it does skeletal and liver cells (it would have to be done carefully because apparently it could lead to higher virus titers if you have them).

Thanks for the response. I do have some positive viral titers. What are some of those medications that activate FoxO1?

 

[Tunguska]

Thanks for the response. I do have some positive viral titers. What are some of those medications that activate FoxO1?

The titer thing would depend on the viruses you have (from what I understand it's more a question of distribution than just total level... you should ask someone else). But that way it's mostly a cancer and acne treatment target: resveratrol, antibiotics, ATRA/accutane (!). Sort of thing you'd want to take at night (timing's everything)... if you did.