The mTOR pathway, or mechanistic target of rapamycin, is a protein kinase that plays a vital role in mammalian physiology by regulating energy and immunity, protein synthesis, and metabolism. Activation of this pathway has been found to promote tumor growth and metastasis, whereas an inhibition decreases cell proliferation, which is the reason mTOR inhibitors are used to slow cancer growth.
What Is mTOR?
As a serine/threonine protein kinase, mTOR regulates cell growth, proliferation, and motility, and is critical to cell survival. It also regulates transcription, an initial step in gene expression, and autophagy, a cellular-cleanup and recycling mechanism. Protein kinases modify other proteins via a process called phosphorylation, in which a phosphate group is chemically added.
mTOR is encoded in humans by the mTOR gene, and belongs to the phosphatidylinosital 3-kinase-related (PIKKs) family of protein kinases. It is a key component of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), protein complexes that regulate processes within the cell.
In 1964, A Canadian expedition to Easter Island in the South Pacific, led to the identification of bacterial agents found in soil samples. In one such sample, a remarkable compound with antitumor, antifungal, and immunosuppressive properties was discovered. This compound, called rapamycin, was analyzed and found to inhibit pathways required for cellular growth and proliferation.
Rapamycin was found to inhibit a broad range of cells, including malignant cells, certain species of yeast, and lymphocytes, along with the inhibition of the G1 phase of the cell cycle. In 1994, studies revealed mTOR to be homologous to the yeast genes TOR1/DRR1 and TOR2/DRR2.
Functions Of The mTOR Pathway
The mTOR pathway is a key player in regulating physiology and metabolism, is involved in tissue function, including brain, liver, muscle, and adipose tissue, and is a sensor of oxygen, energy, and nutrient levels within the cell. The pathway has been found to be dysregulated in diseases, such as obesity, depression, diabetes, certain types of cancer, and neurological diseases like epilepsy and autism. Its over-activation is associated with accelerated aging.
The mTOR protein kinase sheds significant insight into how growth is regulated in conjunction with nutrient availability and environmental factors. The two mTOR complexes, mTORC1 and mTORC2, are involved in various aspects of metabolism, growth, and disease. Cell growth and division are dependent on lipid, protein, and nucleotide production, along with the suppression of catabolic pathways, including autophagy.
Because mTORC1 regulates these processes, it controls the balance between catabolism, a breaking down of the body, and the building process of anabolism, and does so in response to conditions in the environment. Oxidative stress has been found to trigger the activation of mTORC1. Click here if you’re curious to the amount of oxidative stress you have.
Disruptions in mTORC1 decrease mitochondrial respiration and the production of ATP, the primary energy currency of the body. The complex has been validated in many model organisms to be a modulator of aging, with mTORC1 inhibitors used to possibly increase health and longevity, while treating neurological diseases and cancer.
As part of mTORC2, mTOR activates insulin receptors and insulin-like growth factor 1 receptors, by functioning as a tyrosine protein kinase. Tyrosine kinases are able to transfer a phosphate group from ATP to cell proteins, while acting as an on/off switch in cellular functioning.
mTORC2 controls survival and the proliferation of cells mainly through the phosphorylation of protein kinases. Most importantly, mTORC2 activates and phosphorylates ATK, a main effector of insulin/P13K signaling that regulates the cell cycle, and has a direct relationship to cellular proliferation, cancer, and longevity through the inhibition and phosphorylation of several substrates, including metabolic regulators and transcription factors.
mTOR, Cancer, and Aging
Because mTOR is involved in cell growth, metabolism, proliferation, division, and survival, along with the integration of both extracellular and intracellular signaling, it’s stands to reason that an over-expression is associated with cancer. mTOR is likely the main pathway that drives growth in animals and humans. The signaling pathways which activate mTOR are altered in certain cancers.
Over-activation of mTOR signaling contributes to tumor development and growth. The deregulation of its activity has been noted in cancers of the lung, bladder, brain, kidney, prostate, and breast, as well as melanoma. An increase in mTOR activity has been found to directly affect cell proliferation through its impact on protein synthesis. Kinases, including mTOR, are often mutated in cancer, which is why mTOR inhibitors, like rapamycin, are used to control cell proliferation.
Studies have confirmed that rapamycin, increases longevity in mice, by inhibiting the mTOR pathway. In fact, calorie-restriction, and time-restricted eating plans like intermittent fasting, increase lifespan by inhibiting the activity of mTOR, which is thought to increase with aging, especially in certain tissues.
The mTOR pathway thrives on amino acids and glucose. When nutrients are plentiful, cells grow and divide, and don’t enter autophagy. Fasting and ketogenic diets inhibit mTOR by limiting protein and carbohydrates, known activators of the pathway. Although, mTOR is mildly stimulated by fasting, due to the breakdown of amino acids, it is still an effective way to prevent the pathway from over-expressing.
Autophagy, AMPK, and Cancer
Autophagy is a cellular-cleanup process in which damaged cells are either recycled or eliminated. This removal of debris is like a cellular reset whereby the body can then regenerate new, healthy cells. Autophagy is associated with adaptation, survival, and enhanced lifespan, and is garnering attention for its role in cancer prevention and treatment.
Like other processes in the body, autophagy declines with age, allowing diseased and defective cells, and possibly even malignant cells, to multiply instead of being recycled and removed. This scenario creates an ideal environment for cancer to grow since all cancers originate from defective cells. Conversely, autophagy promotes the creation of younger, healthier cells, which slows the aging process and is a key process in disease prevention.
AMPK, an activated protein kinase involved in growth regulation and energy metabolism, promotes autophagy and is stimulated by fasting and low-carb diets, whereas mTOR, a potent driver of cellular growth that is stimulated by a steady supply of nutrients, inhibits autophagy.
Higher levels of AMPK are associated with lower levels of abdominal fat, which correlate to longer lifespans. AMPK may suppress tumors, its activation was found to be dependent on LKB1, a tumor suppressor. When AMPK is activated, it restores energy homeostasis by promoting the synthesis of ATP, restricting cellular growth and proliferation, and maintaining cell viability.
The mTOR pathway plays a primary role in metabolism, immunity, pathology, and aging due to its central role in regulating growth and protein synthesis. Under-expression of the pathway fosters maintenance and repair, while a chronic over-expression fuels disease.
The mechanisms in which energy and growth are regulated, in conjunction with nutrient availability and environmental cues, is comparatively new information that is being used to increase lifespan and prevent disease. Implementing a ketogenic diet and intermittent fasting are effective tools that prevent mTOR from being over-expressed.
Have you heard of mTOR? Let me know in the comments:)