Target mTOR: A Cellular Switch for Growth and Energy Production

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. 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 responds.

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.

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 cellular debris.

Autophagy is the process that degrades this cellular debris.  But it is usually only active when mTOR is decreased.

Autophagy is equivalent to a ‘detox’ from a scientific perspective.  We need a balance between growth/disposal of cellular debris, and rest/clean up.

mTOR: Its Contribution to Disease 

Too much mTOR activation contributes to a large number of human diseases, including cancer, obesity, type 2 diabetes, depression and neurodegeneration (R).  

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 Th17cells to proliferate. This works through HIF1α.  Blocking glycolysis inhibited Th17 development while promoting Treg cellgeneration. (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 Benefits

mTOR activation allows us to put on more muscle (and fat) (R) and we increase various hormones such as IGF-1 (R).

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.

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).

In Summary:

For health and longevity, we want systemic mTOR levels to be low 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

    • Aging (R) –It is hypothesized that caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity

    • Cancer (R)– Breast (R)

    • Autoimmune disease – increases Th1 and Th17

    • Depression (R)

    • Diabetes (R),

    • Obesity (R), -cause or effect? 

    • Alzheimer’s (R),

    • Macular degeneration (R),

    • Kidney disease (R),

    • Epilepsy (R),

    • Autism (R) – mTOR prevents the ‘pruning’ or ‘autophagy’ of excitatory synapses in autism spectrum disorders.  (R)

    • Chronic pain (R),

    • SLE (R)

Activators of mTOR:

ncb2763-f1

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

  • Protein, especially leucine

  • Excess calories

  • Excess carbs

  • Exercise (R, R2) – activated in brain, muscle and heart while inhibited in the liver and fat cells.

  • Orexin (R)

  • IGF-1 (R)

  • Insulin

  • Testosterone (R)

  • Ghrelin (R) – in hypothalamus

  • Leptin (R) – in the hypothalamus

  • Thyroid hormone (R) – in the hypothalamus…and other cells (R)

  • Oxygen

  • Ketamine (R).  (In the brain – produces antidepressant effect.)

  • IL-6 (R) – in muscle and fat

Natural Inhibitors of mTOR

Protein restriction, resveratrol, curcumin, EGCG and metformin inhibit mTOR in different ways.

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)

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

nature11861-f1.2

 

 

 

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