Mammalian Target Of Rapamycin (mTOR) is a longevity pathway that primarily controls Autophagy, it was discovered thanks to an expedition to Easter Island in the 1960s.

mTOR stands for mammalian target of rapamycin and every expert in the longevity field has touched on this topic. However, this longevity pathway doesn’t seem to be well understood by many people. For example, many experts say mTOR inhibition is crucial for longevity, but others argue activation of mTOR is critical for health and muscle growth. Is mTOR an on/off switch or are there intensity levels of how much of it is activated or inhibited? This article will dive into a deep overview of the mTOR pathway and answer the most common questions people have about it.

WHAT IS MTOR? 

mTOR is a very large protein kinase and it anchors a pathway that is one of the central regulators of growth and metabolism in organisms. In this context, growth is the process of accumulation of mass by cells in organisms by using nutrients from their environment and thus increasing in size. It is thought that this pathway senses two different types of states at the organismal level:

  1. The fasting state – when the organism is starved of nutrients.
  2. The fed state – when there is an abundance of nutrients.

It regulates many processes at the cellular and organismal level that are either pro-anabolism – the use of nutrients to create mass; or pro-catabolism – the breakdown of mass delivery nutrients. The system regulates size at multiple levels. It regulates at the level of cell size, as well at the level of organ size, and increasingly at the level of the body size, where we don’t have too much information.

There are two mTOR containing protein complexes called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). In response to growth factors and nutrients, mTOR has a fundamental role in coordinating anabolic and catabolic processes. Scientists know a lot more about the mTOR complex 1 pathway, opposed to mTOR complex 2. When mTORC1 is activated, it triggers cell growth and proliferation by promoting protein synthesis, lipid biogenesis, which leads to lipid metabolism (breaking down fat cells for energy and synthesizing structural and functional lipids), metabolism, and reduces autophagy. The deregulation of mTORC1 is shown to be linked to aging and development of diseases including cancer, obesity, type 2 diabetes and neurological disorders, in humans.

DOWNSTREAM OUTPUTS

In the mTOR pathway, there are many downstream outputs that could be grouped in either:

UPSTREAM INPUTS

mTOR seems to sense anything that happens to a cell: all kinds of nutrients such as amino acids, glucose, all kinds of growth factors, such as energy sources, oxygen levels, DNA damage, osmotic stress. It seems as if mTOR has an antenna and anything that goes into the cell, it detects it. This suggests that there must be many sensors for all these upstream signals and somehow those outputs have to be integrated to give a coherent signal to mTOR, which then regulates growth and regulates cell size.

WHAT MESSAGE IS THE MTOR PATHWAY TRYING TO TELL THE BODY?

It’s trying to tell us that the mTOR growth pathway cares about two classes of upstream signals:

  1. Local nutrient levels: A cell shouldn’t try to grow or increase in mass if it doesn’t have nutrients. 
  2. Hormonal signals: In a multicellular organism, the second level of controls come from hormonal signals. For example, the most well known signal is insulin. These specialized signals are sent from one tissue to the rest of the body to tell the body something specific is happening that matters. Referring to the case of insulin, the signal is telling the body that there’s glucose. Therefore, the mTOR growth pathway has to integrate nutrient levels and growth signals. What a regulatory pathway like the mTOR pathway does is regulate the use of those nutrients if they’re available or regulate the production of those nutrients if nutrients are not available. 

The mTOR pathway has been attributed to regulating lifespan in part because of its function to act as a nutrient sensor. Insulin and insulin-like growth factor 1 (IGF-1) signaling (IIS) network are nutrient-sensing pathways and are thought to act as determinants of longevity. One of the supporting mechanisms of the beneficiary effects of dietary restrictions is thought to be the suppression of the IIS/mTOR axis. It not only increases lifespan across different organisms, but improves healthspan as well by delaying the onset of age-related diseases. Dietary restriction includes restricting calorie by 20-40% and restricting specific nutrients for intermittent time periods.

A really effective intervention to improve aging in humans is dietary restriction. More specifically, the reduction of protein and amino acid intake extends both lifespan and healthspan in mice. In addition, it is linked to reductions in cancer, diabetes, and overall mortality in humans. Reducing specific amino acids such as methionine and tryptophan can cause these effects. Moreover, restricting the amino acid leucine and other BCAAs improved metabolic health markers such as glucose tolerance and reduced fat mass gain in mice.

In a study where mice were exposed to an isocaloric, but high BCAA diet, it led to hyperphagia and obesity and reduced lifespan in the mice. However, total BCAA intake or high mTORC1 were not related to the mechanism, but amino acid imbalance was. Amino acid imbalance in this context means a change in the relative amount of dietary BCAAs to other amino acidos like tryptophan and threonine. It is possible that the beneficial effects of protein restriction on lifespan and healthspan are mediated through the mTOR pathway.

MTORC1 AND AGING

There is a lot of interest on how mTORC1 impacts the aging process. It has been associated in a number of processes involving aging. Some include cellular senescence, immune responses, stem cell regulation, autophagy, mitochondrial function, and proteostasis. 

An active mTORC1 pathway suppresses autophagy, but with the inhibition of mTORC1 with calorie restriction or rapamycin, autophagy happens. When autophagy is induced, cells start to break down, the damaged, unhealthy cells die off, and when this happens, the body has to make new versions of them, which is a rejuvenating cellular process. 

Adult tissues are filled with adult stem cells called somatic stem cells. These somatic stem cells allow regeneration under normal physiological conditions and under response to injury. Although they’re able to rejuvenate and differentiate into a variety of cell types, they can accumulate mutations or undergo epigenetic changes. When this happens, it may compromise cell function and may undergo stem cell exhaustion, in which the cell loses its ability to divide. Somatic cells avoid this by maintaining a quiescent state until activated. A suppression of mTORC1 is correlated with reductions in metabolic, transcriptional, and translational activity – all characteristics of quiescent stem cells. Stem cells either accumulate with age or reduce in number, depending on the tissue type. In aging tissues, stem cells represent impaired stem cell functions because of cell-intrinsic factors, such as accumulation of DNA damage and epigenetic alterations, to name a couple and extrinsic factors, such as chronic inflammation, which inevitably leads to impaired tissue regeneration.

Suppressing mTORC1 shows to be beneficial for heart health, specifically aging in cardiac tissue. A study where rapamycin was given to 24 month old mice showed improved cardiovascular function and reversal of age-related heart inflammation and cardiac fibrosis. The study benefits on mice were thought to be linked to changes in inflammatory, metabolic, and anti-hypertrophic profiles. In addition, calorie restriction and rapamycin profoundly reversed age-associated proteomics change observed in aged-hearts, which were characterized by a reduction of proteins involved in mitochondrial functions, electron transport chain, the citric acid cycle, and fatty acid metabolism.

The mTORC1 pathway has so many impacts on aging, while many other pathways don’t. There are no other pathways that have such universal impacts on lifespan. A defining feature of mTORC1 is that it is a regulator of many processes, it doesn’t have a restricted amount of things it regulates. By preventing the age of a cell or rejuvenating cells, there are many things that are impacted and mTORC1 coordinates all these processes. With one intervention, many things are impacted. This is what makes mTORC1 unique – it regulates many different pathways.

ACTIVATING MTORC1

There are at least 7 proteins that are involved as actual sensors for mTORC1. If you try to stimulate the pathway by any single amino acid, it doesn’t do anything –  pathway is not activated. If you take the combination of any 2 amino acids, the same thing happens – it doesn’t activate the pathway. If you take combinations of 3 amino acids, in particular leucine (LEU), arginine (ARG), and lysine (LRK), mTORC1 is greatly activated and the marker of pathway activity is the phosphorylation of S6 kinase (S6K1). In the absence of amino acids, there’s no phosphorylation. When you add 20 amino acids, there is a nice activation. Combinations of 2, don’t do much – 20% of activity. The three LEU, ARG, LRK, give us about 90% of activity. 

CONCLUSION

Because mTOR is a central regulator for a variety of age-related processes, it is portrayed as an attractive target to control or delay age-related diseases and conditions. We now know from genetic studies, as well as other studies using diets that there’s an optimal level of mTORC1 activity for organs and organismal health. The optimal activity amount is represented by diets that are a little bit restricted relative to a normal western diet. Supplementing this theory are tons of data supporting how calorie restriction has shown to improve healthspan and lifespan. mTOR has also been shown to be inhibited by rapamycin or rapalogs (rapamycin analogs). However, the safety of long term use of rapamycin isn’t deemed to be fully safe. A safer way to manage mTOR activity optimally is through dietary restriction, including calorie restriction and protein restriction. By maintaining an optimal level of mTOR activity, you can influence a variety of age-related processes. 

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