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The mTOR Story Part 1 – What Makes This Important Pro-Aging Molecule Active?
Maria Konovalenko   Jun 28, 2015   MariaKonovalenko  

I have mentioned mTOR as one of the main aging genes on multiple occasions. It’s about time I tell you what it is, what it does and why it is so important in aging.

mTOR has a little m in front of TOR, which means I am speaking about mammals. It technically means «mechanistic» TOR, but think of it as the molecule that mice and all of us have, whereas in worms is it just TOR.

mTOR gene produces one mTOR protein that can act in two pretty different ways. mTOR does so, because it forms two complexes with other molecules. These complexes are called mTORC1 and mTORC2. Yeah, I know, it’s a lot of letters, but C1 and C2 stand for «complex 1» and «complex 2», so it kinda makes sense.

So, how are these complexes different? For starters, they have different proteins that are part of the complexes, and these differences define the drastic variance in functions.

mTOR is one of the most studied genes that the scientists have known about for decades, however we still don’t know much about how those complexes react to different signals in the cells, especially mTORC2. We know much more about what the first complex does, but not really a lot about the second complex. This is not good, because both of them play a huge, enormous role in aging and in age-related disease like cancer and metabolic disorders like diabetes.

I obviously won’t be able to tell you everything about mTOR at once, so this time let me focus on what mTOR reacts to. Let’s start with mTORC1, because we understand it’s actions better.

mTORC1 senses nutrients. What does it mean? It means that mTORC1 gets activated by the presence of amino acids ,that are building block of proteins, and after activation sends the signal down inside the cell into the nucleus, and as a result of this signal specific genes get switched on or off. These genes represent several groups responsible for synthesis of proteins, lipids and lysosomes (parts of the cell that degrade garbage), and also for autophagy (cellular garbage disposal mechanism), cell cycle progression, growth, metabolisms, stress response and mitochondria function. I will write about these results separately, otherwise it will be too confusing.

So, nutrients, in particular, amino acids get transported inside the cell and then they activate a group of proteins called RAGs. These guys sit on the membranes of endosomes and lysosomes inside the cells and this is where mTORC1 goes. Then another thing happens. mTOR also senses growth factors. For example, insulin and insulin-like growth factor-1 (IGF-1, a very famous molecule in aging) come to the surface of the cell, then bind to the insulin receptor and then thought a series of interactions of different molecules, this signal goes to a molecule called RHEB and makes it activated. This RHEB guy together with RAG proteins activate mTORC1. I should say that amino acids are absolutely necessary for activation of mTORC1, and hence for its negative impact on aging. Keep this in mind next time you are ordering a steak.

What else activates mTORC1? Energy does! mTORC1 knows how much energy the cell has at the moment. And by energy I mean the number of ATP molecules. This sensing though is indirect, there is another important molecule in aging that reacts to the level of ATP in the cell. It is called AMPK, which stands for AMP-activated protein kinase. Yes, I also wish protein names were easier. By the way, drosophila has some fun gene names like «hairless» and «curly», but mice – not so much, unfortunately. Anyway, in case of low energy AMPK suppresses mTORC1 by acting on the molecule TSC2 that together with TSC1 keep mTORC1 inactive.

Another thing that makes mTORC1 react is stress. No, not «omg, I’m going to miss the deadline» kind of stress, but something like lack of oxygen, which is called hypoxia or DNA damage. This kind of stresses. Hypoxia leads to poorly working mitochondria that produce the majority of cellular energy, ATP. Therefore, AMPK gets active and shuts down mTORC1. DNA damage employs a different pathway, the one that involves a major tumor suppressor gene p53 and also make mTORC1 inactive. This is a way for the cell to take a pause and reduce synthesis that requires a lot of resources and repair itself and survive until the stress goes away.

Surprisingly, we pretty much know nothing about what activates mTORC2. Generally people think it’s growth factors. It’s really interesting that there can be 3 distinct mTORC2 complexes, because one of the proteins that is part of the complex can come in 5 variants, 3 of which can be included in the complex 2. Only 2 of these complex variants get activated by insulin.

OK, so, bottom line – mTOR is super important for aging. It forms 2 complexes that act differently. mTORC1 gets activated, which is bad for aging, by several things including amino acids, growth factors, energy and stress. Growth factors activate mTORC2, which is also not too great for aging.

I will continue this story and tell you why having active mTORC1 and 2 is pretty bad if you want to live longer. Stay tuned.

Maria Konovalenko is a molecular biophysicist and the program coordinator for the Science for Life Extension Foundation. She earned her M.Sc. degree in Molecular Biological Physics at the Moscow Institute of Physics and Technology.

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