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All About mTOR + Natural mTOR Inhibitors & Activators

Written by Puya Yazdi, MD | Last updated:

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High mTOR levels may shorten your lifespan. Read on to learn what it is, what it does, and how to block it naturally with diet & lifestyle.

What Is mTOR?

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 animals. Our cells increase their working capacity and ATP production. 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 stress such as reduced caloric or nutrient intake, mTOR is inhibited [1].

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 reduce 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.

Functions

mTOR activation allows us to put on more muscle (and fat) [2] and increase various hormones such as IGF-1 [1]. If you are overly muscular, you may have overactive mTOR [3].

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 [4]. NPY (increases hunger) is increased when mTOR is inhibited, which also suggest activating mTOR will inhibit appetite [5]. Confusingly, another more recent study says that ghrelin causes activation of hypothalamic mTOR and inhibiting mTOR inhibited hunger [6]. Maybe low or high mTOR inhibits hunger?

mTOR increases ATP production and creates new mitochondria [2]. It also increases mitochondrial metabolism (by activating PGC1a) [7].

mTOR is involved in various forms of synaptic plasticity and memory consolidation. mTOR blocked the reconsolidation of an established fear memory in a lasting manner in mice, suggesting that its inhibition may be helpful in people with PTSD [8].

However, overactivation of mTOR also seems to cause defects in plasticity and memory [9].

Why It’s Bad

Too much mTOR activation is associated with a large number of human diseases, including cancer, obesity, acne, type 2 diabetes, depression, and neurodegeneration [2, 10].

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, helping tumors grow [7].

Increased mTOR promotes Th1 and Th17 immunity, possibly leading to increased intestinal inflammation [11], among other issues. It increases Th17 cells by increasing another protein called hypoxia-induced factor (HIF)-1α [12].

A reduction in mTOR improved insulin sensitivity in muscle cells, possibly by increasing the process of breaking down sugar (glycolysis) [13, 14].

When T cells (CD4 and CD8) are stimulated, they rapidly reproduce [14].

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) [14].

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 [14].

Diseases Associated With mTOR Activation

The following conditions are commonly associated with mTOR overactivation. It’s important to note that this doesn’t necessarily mean that everyone with overactive mTOR will actually develop them! Many different genetic and environmental factors can influence the risk.

Inhibitors of mTOR

Drugs that inhibit the mTOR pathway are mainly used as immunosuppressants to prevent transplant rejection and in anticancer therapy. The main ones include:

  • Tacrolimus (Prograf, Advagraf)
  • Sirolimus (Rapamune)
  • Temsirolimus (Torisel)
  • Everolimus (Afinitor, Zortress)

The following strategies also inhibited the mTOR pathway, but the studies were mostly done in cells. Consult your doctor before implementing them and never used them to replace approved therapies.

AMPK activation results in the reduction of mTOR. But you can have scenarios where both AMPK and mTOR are 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 [6].

See more about AMPK and how to activate it.

Activators of mTOR

The main activators of mTOR are a variety of amino acids and the hormone insulin. Testosterone is also capable of activating mTOR [57, 58].

Images

Arrow = leads to

The 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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JCI73202.f2

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Takeaway

For health and longevity, we’d want systemic mTOR levels to be low most of the time, with occasional periods of activation.

Research suggests 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 [25].

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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