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
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.
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)
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)
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.
mTOR: The Good
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 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.
Diseases Associated With mTOR Activation
This is not a complete list.
- 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
- Protein, especially leucine
- Excess calories
- Excess carbs
- Exercise (R, R2) – activated in brain, muscle and heart….Inhibited in the liver and fat cells. All good…
- Orexin (R)
- IGF-1 (R)
- Testosterone (R)
- Ghrelin (R) – in hypothalamus
- Leptin (R) – in the hypothalamus
- Thyroid hormone (R) – in the hypothalamus…and other cells (R)
- Ketamine (R). (In the brain – produces antidepressant effect.)
- IL-6 (R) – in muscle and fat
Natural Inhibitors of mTOR
- Protein restriction (R, R2): Leucine restriction (R), Glutamine restriction? (R), Methionine restriction? (R), Lysine restriction? (R), Arginine restriction? (R), Threonine restriction (R), Isoleucine restriction (R),
- Glutamine? (R),
- Calorie restriction (R),
- Ketogenic Diets (R)
- Intermittent Calorie Restriction (R),
- Exercise (R, R2) – Inhibited in liver and fat cells. Activated in brain, muscle and heart….All good…
- Cortisol/Glucocorticoids (R)
- Metformin (R), (by enhancing PRAS40’s association with RAPTOR)
- NAC (R) (Clinical Trial: “profoundly reduced mTOR activity” in T cells)
- Resveratrol (R)(C1/C2), unique– increased the association between mTOR and its inhibitor, DEPTOR. (R)
- Aspirin (R) – colorectal cancer cells,
- Cod liver/ Omega-3 (R) (C1/C2),
- Extra Virgin Olive Oil (R)
- EGCG/Tea (R, R2) (C1/?) – ATP-competitive inhibitor of both PI3K and mTOR (R)
- Curcumin (R, R2) (C1/C2) ….unique mechanism – separates raptor from mTOR (R)
- R-Lipoic Acid (R) – also decreased p70S6 kinase (R)
- Caffeine (R, R2, R3)(C1/?),
- Fisetin (R) – fat cells,
- Apigenin (R) (AMPK+, Akt-)
- Quercetin (R), ( PI3K/Akt-, AMPK+, Hamartin+)
- Genistein (R),
- DIM (R),
- Ursolic acid (R),
- Alcohol (R) (C1/C2),
- Emodin (found in Fo-Ti, Resveratrol, Rhubarb, Aloe,) (R) (C2),
- Andrographis/Andrographolide (R), (PI3K/Akt-)
- Pomegranate/Ellagic acid (R),
- Reishi (R)
- Milk thistle/Silymarin (R),
- Oleanolic acid (R)(C1),
- Anthocyanins/Grape Seed Extract (R),
- Astragalus (R), (colon cancer)
- Rhodiola (R)
- Carnosine (R)
- Plumbagin(black walnut hull) (R), Glucagon (R), AICAR (R)
- Pathways: IGF(-)…PI3K(-)…Akt(-)… AMPK(+)…
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)
Arrow =leads to……Flat bar at the end of line=blocks.
You can see mTOR C1 and C2 are two different ‘complexes’ of proteins.