mTOR Explained: Understanding the mTOR Signalling Pathway
Every cell in our bodies has a variety of moving parts and components, each of which has specific roles and mechanisms attached to it. If one of those parts is dysregulated or does not work optimally, it can negatively affect the cell.
There has been much research conducted into mTOR signalling pathways. Ongoing research reveals more about these mechanisms and proteins that regulate cell growth, survival, and apoptosis (cellular death).
One team of researchers at Brigham Young University spent five years working to understand the roles and functions of the mechanistic target of rapamycin – or mTOR for short. The aim of this study was to assess how its function may be used to develop cancer therapies, treat diseases, and find ways to optimize cellular function.
In their study published in Nature Communications, the researchers assessed how mTOR complexes are assembled. They found that in a cell, proteins work in complexes with others. In this case, mTOR consists of sub-units called Raptor and mLST8, proteins which assist in stabilizing the mechanistic target of rapamycin. Proteins like these form specific three-dimensional shapes, and how they fold into these shapes can affect their functions.
In many cases, a cellular machine called chaperonin is needed to ensure that proteins fold into their specific shapes for correct function. In the case of mTOR, the chaperonin CCT is needed to fold Raptor and mLST8 and assist them in assembling with mTOR.
This folding is normally a positive factor. However, in the case of diseases like cancer or diabetes, mTOR can operate in an erratic and uncontrollable way. The Brigham Young researchers believe that if CCT can be inhibited from folding mLST8, cancer progression can be slowed or even halted.
On a broader scale, mTOR is an essential cellular process that signals cell growth through the creation of new proteins, which we will explore in more detail below.
Dysregulation of the mTOR Signalling Pathway
AAs mentioned above, mTOR plays a critical role in the activation of genes controlling cell growth. This means that any defects or dysregulation within the mTOR signalling pathway can lead to the development of diseases. These can range in severity from acne to cancer and type II diabetes mellitus. Some genes activated by mTORC1 and mTORC2 can prevent the death of cells and enhance nutrient uptake, causing the uncontrolled growth of cells associated with malignancy.
When the mTOR pathway is activated excessively, it is also thought to be one of the primary causes of cardiac hypertrophy: a key risk factor in cardiovascular disease and cardiac-related mortality. Furthermore, mTOR plays an essential role in the process of ageing. Its roles in immune response and cell senescence enable it to regulate a range of factors pertaining to human health and longevity.
Is mTOR Good or Bad?
mTOR and the mTOR signalling pathway are essential for human development, health, and longevity.
This 2019 study notes that mTOR is a central regulator of human lifespan and ageing. As discussed above, it also promotes optimal cellular metabolism and muscle cell creation when functioning correctly.
However, when mTOR operates dysfunctionally, it can have negative impacts on lifespan and human health outcomes. A study published in Nature Genetics has linked high levels of dysregulated mTOR activity with a range of hamartoma syndromes, including PTEN-related hamartoma syndromes, Peutz-Jeghers syndrome, and tuberous sclerosis complex.
Another recent 2021 study notes that mTOR dysregulation is involved in a spectrum of age-related diseases, including type II diabetes, cancer, and neurodegenerative diseases such as Alzheimer’s disease and dementia.
mTOR Activation – What Triggers mTOR?
mTOR is activated by a range of different amino acids and the hormone insulin. Testosterone can activate mTOR to an extent, according to a study published in Medicine and Science in Sports and Exercise.
Furthermore, mTOR can be activated by proteins, specifically if they are rich in leucine. The consumption of excess calories and excess carbohydrates are activating factors too, as is exercise, which activates mTOR in the muscles, brain, and heart. Other activators include IGF-1, ghrelin the appetite-stimulating hormone, leptin the fat-storage hormone, thyroid hormones, and Interleukin-6.
mTOR and Autophagy
mTOR plays a crucial role in regulating autophagy, and this is backed up by a study published in the Journal of Clinical Investigation. One of its two key signalling complexes, mTORC1, promotes anabolic cellular metabolism, supplying all the necessary components for cell growth.
mTORC1 relies on a range of signalling networks and stimuli to promote the synthesis of lipids and proteins, and to down-regulate catabolic processes like autophagy at transcriptional and post-translational levels.
At a practical level, the regulation of autophagy using mTOR inhibitors is believed to offer promise in therapies for a variety of diseases. This includes diabetes, cancer, and neurodegenerative disease.
mTOR Inhibitors
Inhibitors of the mTOR pathway are primarily given as immunosuppressant drugs to prevent the rejection of organ transplants and may be given in therapies to cancer patients too. These drugs include Rapamune, Prograf, Advagraf, Torisel, Afinitor, and Zortress.
Some studies on isolated cells have also discovered other compounds that inhibit the mTOR pathway. Protein and calorie restriction practices such as intermittent fasting are capable of inhibiting mTOR, and exercise can inhibit mTOR in the liver and fat cells. Drugs like Metformin, commonly given to patients with type II diabetes, have been used in trials to suppress cancer cell proliferation due to their ability to down-regulate mTOR signalling, according to a study published in the journal Biochemistry.
Supplements for mTOR Regulation
There are many supplements capable of regulating mTOR signalling and activation in the case of dysregulation. Some of the most well-researched and effective options include:
There are many supplements capable of regulating mTOR signalling and activation in the case of dysregulation. Some of the most well-researched and effective options include:
NAC
A randomized, double-blind, placebo-controlled trial conducted in 2012 found that N-acetylcysteine, or NAC, can reduce disease activity by blocking mTOR in T-cells in patients with systemic lupus erythematosus, an autoimmune condition.
Resveratrol
Another study published in the Journal of Biological Chemistry found that resveratrol, a compound found in grapes and red wine, can inhibit mTOR signalling by promoting interactions between mTOR and DEPTOR. Additionally, resveratrol offers potent anti-inflammatory, antioxidant, and neuroprotective properties.
Curcumin
Curcumin, a primary compound in the spice turmeric, has been proven to inhibit mTOR signalling pathways in cancer cells. Studies suggest that the supplement executes its anti-cancer activities by blocking these pathways in tumor cells, thereby inhibiting their growth and proliferation.
Fisetin
Fisetin can regulate obesity – a condition associated with many negative health outcomes, including cardiovascular disease, cancer, and type II diabetes. It regulates obesity by targeting mTORC1 signalling, according to a study published in the Journal of Nutritional Biochemistry.
In addition to its anti-oxidative and anti-inflammatory properties, fisetin was shown to inhibit adipogenesis – the creation of new fat tissue – and the accumulation of intracellular fat deposits. It does this by regulating mTORC1 pathway signalling and suppressing the phosphorylation of Akt, S6K1 and mTORC1 in adipose tissue.
Quercetin
A 2013 study noted that quercetin, an abundant bioflavonoid found in a range of plant foods and supplements, can inhibit the mTOR signalling pathway, which is often over-activated in cancer cases. Quercetin’s actions have been suggested as a tool for the treatment of cancers and other diseases associated with the dysregulation of mTOR.
Milk Thistle and Silymarin
Even milk thistle and its primary compound silymarin have been shown in studies to inhibit cell cycle progression and mTOR activity in activated human T-cells. One study in the journal Basic and Clinical Pharmacology and Toxicology suggests that silymarin’s actions could have great potential in treating autoimmune conditions and increasing the success rates of transplantation procedures.
Omega-3 Fatty Acids
In a 2014 study published in the journal Oncogene, researchers found that omega-3 polyunsaturated fatty acids prevented mammary tumor development and progression by targeting the mTORC1 and mTORC2 pathways.
The study noted that in breast cancer cell lines, n-3 PUFAs (omega-3 fatty acids) ‘rapidly and efficiently’ suppressed both mTOR complexes and their signalling. Thereby inhibiting cancer cell proliferation and angiogenesis while encourageing natural cell apoptosis at the same time.
Green Tea and EGCG
Several studies have found green tea and one of its primary constituents, Epigallocatechin gallate (EGCG), to be effective mTOR pathway inhibitors. A study published in Biochemical and Biophysical Research Communications found that EGCG inhibits both phosphoinositide-3-kinase and mTOR pathways, helping to explain its potent anticancer properties.
Another research paper published in Anticancer Agents Med Chem highlighted EGCG’s ability to inhibit mTOR, along with other natural products like caffeine, curcumin, and resveratrol.
mTOR in a Nutshell
When operating optimally, the mTOR signalling pathway is an essential process for promoting muscle growth and development and normal cellular function, apoptosis, and autophagy. However, dysfunction within this pathway can give rise to a range of diseases, including various cancers, neurodegenerative conditions, and autoimmune diseases.
Along with common immunosuppressant drugs, supplements such as N-acetylcysteine, resveratrol, curcumin, fisetin, quercetin, silymarin, omega-3s, and EGCG, have proven to aid in regulating mTOR activity and modulating the risk of developing preventable mTOR-related diseases and conditions.
If you’re looking for ways to maintain optimal health, Vitality Pro can help. We offer high-quality, science-backed supplements that can aid in restoring your cellular health and promoting optimal mTOR signalling and function.
