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The mTOR Signaling Pathway: A Key to the Holy Grail Of Medicine

mTOR may just be the key to “unlocking” the Holy Grail [Source: media.salon.com]

Throughout the course of time, humans have encountered an immeasurable number of diverse diseases. It seems that just as we manage to develop a new cure or treatment for a particular disease, another one rises out of nowhere to claim more lives. However, while we seem to be engaged in an endless war as old as the history of mankind, there may be a light at the end of the tunnel for humanity. Recently, scientists have identified a component of human brain cells that could help us prevent or eradicate some of the most devastating diseases affecting millions across the world today: the mTOR signaling pathway.

What is mTOR?

The mammalian target of rapamycin, or mTOR for short, is a protein kinase which helps to control many processes that generate or use large amounts of energy and nutrients. This protein is a central component of the mTOR signaling pathway, which senses and integrates a variety of environmental cues to regulate organismal development and homeostasis. In short, it is essentially a system that allows us to grow and function properly on a day to day basis. This is apparent in the fact that the pathway plays a key role in the functioning of several tissues including liver, muscle, white and brown adipose, and brain tissue.

mTOR is a catalytic subunit of two distinct complexes: mTOR complex I(mTORC1) and mTOR complex II(mTORC2). Both of these complexes localize in different parts of the brain cell, thus affecting their function and activation mechanisms. mTORC1 mainly serves as a nutrient/energy detector and controls protein synthesis. This is the complex that bodybuilders take advantage of in order to gain muscle mass in a short amount of time. For example, steroids are so effective for bodybuilders because testosterone is a powerful activator of mTOR. mTORC2, although less understood than mTORC1, is known to control cell survival and proliferation while also regulating the organization of the actin cytoskeleton.

Overall, the mTOR signaling pathway acts as a master regulator of cell metabolism, growth, proliferation, and survival. This sounds very important and all, but what exactly does being a master regulator mean? Some specific functions of the mTOR pathway not already noted include:

  • Lipid synthesis
  • Stress response
  • mRNA translation
  • Regulation of ATP production
  • Downregulation of apoptotic(cell-death) pathways
  • Control of ion transport
An Overview of the Complex mTOR Signaling Pathway [Source: resources.rndsystems.com]

mTOR has always been at work in your body, but you probably aren’t consciously aware of this fact. Nevertheless, there are noticeable effects of mTOR that you may have experienced in your everyday life. Take, for instance, the act of exercising.

Several studies have proven that exercise enhances learning and memory and produces resistance to stress disorders such as depression. However, the reason why has largely been unknown until recently. That is, the primary suspect behind the countless benefits of exercise is the mTOR signaling pathway.

In a study involving rats, levels of mTOR in the brain increased when the rats went through both voluntary and forced exercises. These increased levels were most readily observed in the prefrontal cortex, striatum, hippocampus, hypothalamus, and amygdala. Interestingly enough, a larger increase in mTOR levels was seen in the rats that exercised voluntarily, whereas rats who were forced to exercise saw a more moderate increase. Nonetheless, these results suggest that mTOR is sensitive to the metabolic signals of exercise and as a result, may generate the “good feeling” that we experience after an intense workout.

mTOR allows us to feel good after we exercise [Source: gettyimges.com]

Significance in Medicine

Clearly, the mTOR signaling pathway is essential to our wellbeing. But there are other pathways in our bodies that have important functions as well. So what makes the mTOR pathway so special? Well, it has implications in some of the most prevalent diseases today including cancer and neurodegeneration. Studies have shown that a dysfunctional mTOR pathway, typically an overactive one, is a common factor in these diseases. This should come as no surprise given that mTOR plays important roles in the functioning of several organs and tissues as mentioned earlier. Let’s take a closer look at how mTOR ties into some of these diseases.

Cancer

Because mTOR is involved in cell growth and division, it is evident how a malfunctioning mTOR pathway can lead to tumor growth and development. The deregulation of mTOR signaling has been noted in cancers of the lung, bladder, brain, kidney, prostate, and breast, and even the skin. There are several mechanisms that explain as to why this happens. First, tumor suppressor genes such as the PTEN gene usually become mutated and are unable to function properly. Next, increasing mTOR activity has been shown to drive cell cycle progression and increase cell proliferation mainly thanks to its effect on protein synthesis. Moreover, active mTOR also indirectly supports tumor growth by inhibiting autophagy, which is a cellular-cleanup process in which damaged cells are either recycled or eliminated. With these regulation systems disabled, cancer cells are free to divide rapidly and metastasize throughout the body, leading to the problems typically associated with cancer.

Neurodegeneration/Alzheimer’s

In regards to neurodegeneration, mTOR signaling intersects with Alzheimer’s disease (AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression. In general, results from studies have demonstrated the presence of mTOR signaling hyperactivity in AD brains. This abnormal mTOR signaling appears to be closely related to the presence of both amyloid beta and tau proteins, which aggregate and form two hallmarks of the disease: amyloid-beta plaques and neurofibrillary tangles, respectively. Other signs of neurodegeneration as a result of overactive mTOR include astrocyte atrophy and abnormal development of glia and neurons in the central nervous system(CNS).

Aging

Although it is not really considered a “disease”, aging is another phenomenon closely tied to the mTOR signaling pathway. mTOR is normal and essential in childhood, where it acts as an engine of growth. However, in adulthood, mTOR becomes an engine of aging and your body begins to break down. The pathway requires nutrients to thrive, particularly amino acids and glucose. When there are plenty of nutrients, cells are able to grow and divide, and thus, do not enter autophagy. Autophagy, as mentioned earlier, promotes the creation of younger, healthier cells, which not only acts as a key process in disease prevention, but also slows down the aging process as well. When autophagy is inhibited, the rate of aging accelerates.

Slowing Down mTOR

At this point, you may be thinking “Yes, mTOR can be extraordinary useful in researching human illnesses, but are we doomed to suffer from our own control systems?”. Well, not necessarily. There are, in fact, some things that you can do to inhibit an overactive mTOR system. There is evidence that implementing a ketogenic diet and practicing intermittent fasting can actually be effective tools that prevent the mTOR signaling pathway from being overexpressed. This is because both of those methods limit protein and carbohydrate levels, which are known activators of the pathway. But perhaps the most important inhibitor of mTOR is rapamycin(remember what mTOR stands for). Researchers are beginning to explore ways to more effectively deliver rapamycin to those that need it in order to help restore the mTOR pathway to its normal state.

Application in Society

After learning about the importance of the mTOR signaling pathway and how it is currently a central focus in medical research, you may be wondering about the promising results. Why haven’t we discovered a viable cure for cancer? Or diabetes? Or Alzheimer’s? So far, there has been limited success in medical applications of the mTOR signaling pathway and its derivatives simply due to the inherent complexity in the regulation and function of mTOR. “There’s just so much that we don’t yet understand about the mTOR signaling pathway” states researcher Mathieu Laplante from the Howard Hughes Medical Institute. Perhaps one day, with sufficient data and understanding of mTOR, humanity will finally be able to turn the tide in the war against disease.

Humanity’s Fight Against Disease [Source: istock.com]

References:

  1. Davis, J. (2020, March 09). What is the mTOR Signaling Pathway? Retrieved June 11, 2020, from https://www.news-medical.net/life-sciences/What-is-the-mTOR-Signaling-Pathway.aspx
  2. Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274–293. https://doi.org/10.1016/j.cell.2012.03.017
  3. Lloyd, B., Hake, H., Ishiwata, T., Farmer, C., Loetz, E., Fleshner, M., . . . Greenwood, B. (2017, January 24). Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior. Retrieved June 12, 2020, from https://www.sciencedirect.com/science/article/pii/S0166432816310439
  4. MTOR Signaling Pathway. (n.d.). Retrieved June 12, 2020, from https://www.raybiotech.com/mtor-signaling-pathway
  5. Watanabe, R., & Wei, L. (2011, April 01). Ryosuke Watanabe. Retrieved June 11, 2020, from http://jnm.snmjournals.org/content/52/4/497.full

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