mTOR Introduction

mTOR forms two functional complexes, C1 and C2.  The C1 complex is more significant in health and disease.  mTOR responds to signals from nutrients, growth factors, and cellular energy status and controls cell growth and proliferation based on this (by regulating protein synthesis).

In more simple English, whenever we have lots of nutrition (mainly protein) and calories we essentially tell the body that plentiful times are here.   We are ready to kick some ass and hunt some animal. Our cells increase their working capacity and ATP production is increased.  Cells increase division and  we are primed for growth and repair.  mTOR is the protein that senses this and puts ‘the pedal to the metal’.

However, in times of any stress such as reduced caloric or nutrient intake, mTOR is inhibited (R).

It’s important to realize that mTOR can increase performance and we shouldn’t view it as either good or bad.  It more like depends.

mTOR is one of those things that’s good to have cycled.  Sometimes we want to increase it to grow muscle and improve certain aspects of cognition, while the rest of the time want to have low levels to increase longevity, decrease cancer risk and decrease inflammation.

You see, mTOR increases energy production, but also creates more junk products.

Autophagy is the process that degrades these junk products.  But it is only usually active when mTOR is decreased. In other words, the body doesn’t start cleaning up until the party is over.

Autophagy is equivalent to a ‘detox’ from a scientific perspective.  We need a balance between growth/junk products and rest/clean up.

mTOR: The Bad

Too much mTOR activation contributes to a large number of human diseases, including cancer, obesity, type 2 diabetes, depression and neurodegeneration (R).  It can be responsible for acne as well (R).

To give a real world example, I recently had a client who was lectin sensitive and went on a paleo-type diet of meat and veggies.  He was still having issues with inflammation.  His testosterone and hormones were through the roof.  After putting some picture together, I asked him if he put on muscle really easily.  He said he did and how all of his friends were jealous that he barely worked out and had good musculature.  It turns out that he also has severe problems with acne.  Based on this picture, mTOR overactivation is a good hypothesis.  He has a very high protein intake and experiences inflammation, acne, depression, easy muscle growth and elevated hormones.

mTOR is associated with cancer and indeed it increases angiogenesis (via HIF-1a), a process through which new blood vessels form from pre-existing vessels. (R)  This helps cancer grow.

Increased mTOR promotes Th1 and Th17 immunity, leading to increased intestinal inflammation (R), among other issues. It increases Th17 cells by increasing another protein called hypoxia-induced factor (HIF)-1α. (R)

A reduction in mTOR Improves insulin sensitivity in muscle cells. (R)

Technical: mTOR increases glycolysis, which is what allows Th17 cells to proliferate. This works through HIF1α. Blocking glycolysis inhibited Th17 development while promoting Treg cell generation. (R)

When T cells (CD4 and CD8) are stimulated – by lectins or other means- they rapidly reproduce.   (R)

The rapid production of T Cells requires energy.   Activation of mTOR allows the T Cells to rapidly expand by shifting how they get energy.  Instead of getting energy from the mitochondria (via oxidative phosphorylation), they get it primarily from breaking glucose down (glycolysis). (R)

When you prevent this process of glucose breakdown, T cells realize that they don’t have what it takes to rapidly expand and fight pathogens.  So instead they turn into Treg Cells, which dials the immune system down. (R)

This is a good picture that shows you the conditions needed for these four T Cells.

Screenshot-2014-11-19-11.21.231-1024x781 copy

mTOR: The Good

mTOR activation allows us to put on more muscle (and fat) (R) and we increase various hormones such as IGF-1 (R). If you are overly muscular (R), I would suspect overactive mTOR.

This makes evolutionary sense.  When we had food it was a good idea to increase muscle and fat and when we didn’t it made sense to turn our systems down in order to conserve energy.

In rats, mTOR activation in the hypothalamus has been shown to decrease food intake and body weight. Leptin causes satiety by this mechanism (R).  NPY (increases hunger) is increased when mTOR is inhibited, which also suggest activating mTOR will inhibit appetite (R).  Confusingly, another more recent study says that Ghrelin causes activation of hypothalamic mTOR and inhibiting mTOR inhibited hunger. (R)  Maybe low or high mTOR inhibits hunger?

mTOR increases ATP production and creates new mitochondria . (R) It also increases mitochondrial metabolism (by activating PGC1a). (R)

mTOR is involved in various forms of synaptic plasticity and memory consolidation.  mTOR inhibition may be helpful in people with PTSD because it blocks reconsolidation of an established fear memory in a lasting manner (R).

However, overactivation of mTOR also causes defects in plasticity and memory (R).

The Take Away

For health and longevity, we’d want systemic mTOR levels to below most of the time, with bouts of activation.

It’s preferable to have mTOR more active in your brain and muscles rather than in your fat cells and liver.  Exercise is ideal because it does exactly this. (R)

Diseases Associated With mTOR Activation

This is not a complete list.

Activators of mTOR

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The main activator of mTOR is a variety of amino acids and the hormone insulin.  Testosterone also is capable of activating mTOR (R, R2).

Natural Inhibitors of mTOR

Given that protein restriction, resveratrol, curcumin, EGCG and metformin inhibit mTOR in different ways, I bet taking them together would create serious mTOR inhibition.

AMPK Activators Inhibit mTOR

AMPK activation results in the reduction of mTOR.  

But you can have scenarios where both AMPK is activated and mTOR is also activated because AMPK doesn’t inhibit it directly; it inhibits another protein that directly increases mTOR.  For example, Ghrelin, the hunger hormone, activates AMPK and mTOR in the hypothalamus. (R)

See more about AMPK and how to activate it.

Images

Arrow =leads to……Flat bar at the end of line=blocks.

You can see mTOR C1 and C2 are two different ‘complexes’ of proteins.

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35 COMMENTS

  • Oliver K.

    Do you have any idea whether Tianeptine activates MTOR and if Tianeptine is actually a negative for autism-related disorders? I don’t understand the relation here.

  • Jimmi Andersen

    “Exercise (R, R2) – Inhibited in liver and fat cells. Activated in brain, muscle and heart….All good…”

    Wouldn’t it be bad to have it activated in the brain for someone with autism? I have read that autistic people have too many connections in the brain and that in a mouse model the autistic symptoms dissappear after giving them rapamycin.

  • Rob Maskell

    Might be worth mentioning the recent (this year) research into the causes of granuloma formulation in sarcoidosis, it seem that MTOR is implicated
    https://www.meduniwien.ac.at/web/en/about-us/news/detailseite/2017/news-im-jaenner-2017/metabolic-sensor-causes-granulomas-to-form/
    Great site, has really helped.

  • Abu

    Great Info Joe. I must say incredible website too. Ur ability to glean info from various sources and put in cogent form is remarkable!
    What I am missing from your website? A Forum
    MARLON.B, I can corroborate what you are saying about fasting. I have done lots of n=1 trying to fix my extreme Insomnia. I would say it requires extra ordinary will to make a dent in Insomnia by fasting. It requires straight 16-17 hrs of fasting continuously for 4 weeks at least to be able to resynchronize circadian cycles.
    You have to be ravenously hungry at fast-break time and
    you must eat some sweets to spike insulin.
    But I must admit it is extremely hard to maintain and relapse to insomnia is very common once you abandon fasting.

    1. Nattha Wannissorn, PhD

      Hi Abu, we have a free insomnia resource list. Just click here, enter your name and email, and it will be on its way.

  • jhon

    I have a question about mtor I don’t understand. lets say I were to take a break from the gym for two weeks without any exercise and my mtor levels would recover, I understand that. What would happen if I were to take a break and at the same time take mtor inhibitors like drink coffee or take metformin for those two weeks, would the mtor pathway activate stronger like a spring effect or would I be defeating the purpose by diminishing mtor levels even further? Or should I try to activate it even more in that break period by having a caloric surplus? Thanks

  • Jenny

    Hello, enjoyed this article and would love to hear your thoughts on something. I take rapamycin daily for a rare but serious lung condition. I have a moderately high protein diet but upon hearing about protein & mTOR activation, I would like to change that. My first impulse is to quit meat/dairy/eggs except for very rarely. Assuming I do not replace them with veggie protein sources, which I presume would have the same mTOR effect, I am wondering what to eat. Above it says that carbs stimulate mTOR as well, so I’m at a loss where to begin. Any guidance you have would be greatly appreciated.

    1. Tom Comstock

      Ketogenic diet that is high in quality fats and low in protein and simple carbohydrates would be a way to go.

      1. Jenny

        Thank you, Tom. I’m researching that now. I’m finding that a low-protein diet is more difficult than I’d assumed.

  • Jeff

    Still working out the timing on this. On workout days I am taking mtor blockers, ampk simulators upon waking and weight workout starts 2 hours later and lasts 1-1.5 hrs including warm-up and cool down. Taking mtor activators , bcaas during and post workout. On non workout days the same on waking but waiting as long as I can before eating, sometimes 6 hrs after waking. So 18hrs fasting with mtor blocking enhanced in the am for 6 hours.

    At least one mtor blocker, salicylic acid, has a 2-3 hour half life for low doses. So does taking leucine 2 hours later defeat the purpose? Or does salicylic acid completely block mtor like rapamycin does, making bcaas pointless for many hours after taking it.

    I’m ok with slow gym process but I don’t want to go backwards. So far progress is slow but inflammation is way way down and mood is elevated. Energy is great but the first two weeks was down. Cardio feels fine anytime, but is limited to running around with my 2 year old mostly.

    I think most people of sufficient age will go through a detox period on this as many of the mtor blockers act as senolytics as well (quercetin, butyrates, berberine, tocotrionols)

  • Karoline

    How would you suggest the man suspected for high torc1 activation, could make changes in his diet, for lowering it?

  • Amme

    HI, thank you for the interesting info. This made me really confused. I’m a lean person with a high metabolism that in nearly underweight but with muscles form the gym. I eat double protein in grams my weight and also fat – lower on carbs like 50 g / day. I saw a lecture with Ron Rosdale https://www.youtube.com/watch?v=Yv-M-5-s9B0&list=PLWhDhUuVNt2IFYtr3FbABJjtIs1Ce-Zv4 and figured that it is nearly impossible for me to eat 0.65% of a gram per kilo weight when i workout at the gym 3 times a week. That would get my body to dissapear. I relly don’t get how I can built more muscles on that small protein amount or even maintain the muslemass that I have! Is this a choice we are foreced to make here? Either we restric the protein to 0.65% of a gram per kilo weight and DON’T build or maintain our strength or build muscles or simply stop maintaining or building our muscles just to avoid cancer and inflammations? I would appreciate anyones feedback on this. This is beyond my comprehension…
    /Amme

  • Cristy W

    By this logic, wouldn’t people with tuberous sclerosis complex all be overly muscular? Surprising that didn’t make the (top of the) list of mTOR overactivation. I haven’t observed one particular body type with TSC, and while their angiofibromas are often mistaken for acne, it’s quite a different type of lesion. The ketogenic diet is sometimes effective in suppressing epilepsy associated with TSC.

  • Vasiliki Didaskalou

    Would you consider consulting a Type 1 diabetic who lives in Melbourne Australia (me)? I am desperate for help from someone who “gets” the whole picture. I have no idea what my mTOR is as I just discovered this today but my hormones / issues are out of whack and need help to get myself balanced again no thanks to poor diabetes control of course.

    1. Joseph M. Cohen

      I would, but not with the intent to cure Type 1 diabetes

  • Jason Klinger

    Any updates on NAC? if it down regulates mTor but increases TH1 what do you do if you are Th1 dominant?

  • kieron

    does Zoloft inhibit mtor

  • Nono

    the best natural mTOR is luteolin

  • andrea

    what does it mean ” we’d want systemic mTOR levels to be low most of the time, with bouts of activation.”
    can you give me some examples

    by from italy

    1. Ben Donahower

      2nd this question. it would be great to get more guidance as to how long we should inhibit mTOR and then how long we should be in a period of activation. what is the cycle?

      1. Toni

        Great article Joe!
        And I’m so happy to find your blog.
        If you decide to elaborate this topic some more, please include your knowledge or opinion about this particular thing too (inhibiting mTOR for two weeks and than elevating it for one week OR inhibit all the time except days of workout OR something third …?).
        Greeting from Slovenia

  • Janni

    Nice website. Thanks!!

  • Ole

    What does calorie restriction entail? Is it below 2000 cals or does it mean to not eat above 2200 ish?

    1. Nicole

      Typically “calorie restriction” means reducing calorie intake by approximately 10-20%, so that would be going from 2000 calories a day to 1800-1600 a day.

  • abraham weiss

    Thanks! Here’s one more mTor inhibitor.
    http://www.ncbi.nlm.nih.gov/pubmed/24799956

  • Adrian

    Great detailed right up Joe! A recent MTOR activator I have literally this week started using is Phosphatidic acid for the purpose of increasing lean muscle mass.

  • Daniel

    This is probably why my dandruff and skin lesions disappear when I do protein fasting for few days. Fascinating…. I finally seem to understand….

    1. Joseph M. Cohen

      Thx!

  • Joanna

    Thanks for this!

    1. Joseph M. Cohen

      🙂

  • catiepops88

    Brilliant. You are totally the new Jack Kruse – only, intelligible. Bravo!

    1. Joseph M. Cohen

      Thanks! Every time I get a compliment on an article I read it over again and think, damn this isn’t up to par…and fix it up more.

      1. Marlon.B

        Great article, n well written for people to understand, I was with weider research for the better part of 40 yrs, I personally fast on water for 21 hrs a day n then eat, this not only reduces any inflammation, n for me is the key to anti aging, but mentally lookin forward to a great meal that u find absolutely yummy (scientific term) has a positive effect on ur brain allowin u to increase al ur feel good hormones, it also allows the sleep cycle to begin, not inhibit it as some suggest, we all kno Wat tryptophan induced sleepiness after turkey dinner does, so I mimic a smaller version of that at night at around 6-7 Breakin that 21-23 hr fast! This satisfaction of eating and socialization lowers cortisol, induces deeper n better REM sleep, and then the following day as a full time bodybuilder , fast , drain some of those fat cells, and repeat, I also only train a very limited amount of days per week to minimize free radical production!

        1. Stanley Organ

          Marlon, I thought that when you fast the body compensates for this by increasing cortisol and thus can interrupt a good nights sleep.

          1. Marlon .b

            You r correct , but I break my fast at 7 or so at night and will eat my caloric requirement for the day in on sitting after a23 hour fast, so by the time I sleep it’s the opposite, I am basically drunk on food and can barely keep my eyes open, Wat u r refferin to is wen u go to bed hungry as most dieters do!

            reply icon
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