Longveity: mTOR, Anabolism/Catabolism Balance & the Pursuit of Youth

09/07/2019

If you’ve paid attention to what has been traditionally advocated by media which focuses on looking your best using High Intensity Interval Training, Crossfit and Bodybuilding, you may have read about mTOR.  This is an anabolic/muscle building pathway within the body -- the common advice is that keeping yourself in an anabolic state as much as possible is desirable in meeting your goals within these subcultures.  

mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids. mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain.  It is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.  So, one might think why not encourage as much mTOR as possible if you want to ‘stay young’.

Media including supplement companies are constantly pushing mTOR as the magic pathway to building muscle and talk about keeping mTOR activated, with heavy marketing of Leucine, BCAA, etc. to keep mTOR activated. It's unlikely that keeping an anabolic pathway such as mTOR active is a path to longevity. It's interesting to note, cancer researchers, anti aging researchers, etc are looking for ways to limit/control mTOR. 

It’s not difficult to fathom that pathways responsible for cellular growth, cell division, etc being activated constantly could have long term repercussions. Our bodies need mTOR and too little also is clearly a negative, and with other growth factors such as IGF-1 the risks/benefits will appear as a U shaped graph, where too much or two little increases the risks for various pathologies. Interestingly, drugs that lower mTOR have been found to increase life span of some animals for example.

Bottom line -- pumping leucine into the system (as an example of a supplement, along with BCAAs, etc that are mTOR activators) all the time in an attempt to drive mTOR may be a bad idea long term.  There's evidence that both too much mTOR activity and too little mTOR activity is a problem and it happens in different diseases.  For example, too much mTOR activity is clearly connected to certain types of cancers and neurological diseases, particularly epilepsy and there's some evidence even for autism. Too little mTOR activity is connected to diseases such as atrophy of the muscle in certain situations, even cellular aging.

On the other side of the coin is Autophagy.  The mTOR protein restrains autophagy.  Autophagy is a key catabolic/homeostatic mechanism whose physiological importance is seen in its role as a crucial defender against malignancy, infection and neurodegenerative diseases.  

Thankfully, a brief period of food restriction is an easy way to induce widespread upregulation of autophagy in CNS neurons.  While, disruption of autophagy can cause neurodegenerative disease, and the converse also may hold true: upregulation of autophagy may have a neuroprotective effect.

Autophagy is a self-degradative, catabolic process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing aggregated proteins, clearing damaged organelles, such as mitochondria.  In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular regeneration and protects against genome instability, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections. 

Thus, reduced MTOR activity induces autophagy, ensuring that the cell adapts to its changing environment through reduced growth and increased catabolism/breaking down large into small.  

It has been discussed that fasting causes lifespan extension by decreasing mTOR activity. Some studies have suggested that mTOR signaling may increase during aging, at least in specific tissues like adipose tissue.  And while high mTOR signaling is good during early life, it is maintained at an inappropriately high level in old age. Calorie restriction and methionine restriction may act in part by limiting levels of essential amino acids including leucine and methionine, which are potent activators of mTOR. 

In essence, this is a somewhat roundabout way to say that catabolism gets a bad rap in fitness/wellness circles.  Given that too much of a good thing can turn the other way, it’s important to vary your approach to your health.  Stressors such as calorie restriction and hypoxia that induce autophagy are a good way to balance your efforts to stay at your best as you age.  Finding the right fine line between anabolic and catabolic is an inexact science and more about you knowing your body more and more as you age.  Certainly easier said than done but in the coming weeks we’ll attempt to help by defining strategies to greater interoception/knowing yourself and we’ll outline specific practices that center upon the stressors mentioned that ramp up autophagy - hypoxia and thermogenesis.  

Hope to meet you back here next time.