The Cellular Stress Connection
Metabolism and stress are intimately and negatively correlated.
In other words, prolonged stress hurts your metabolic rate, while lack of stress allows you to burn all the energy you could ever need.
But not only does stress limit your metabolic rate at the cellular level, the “stress metabolism” is the one and only true cause of reduced energy production and slow metabolism.
- What Actually Is Stress
- Glycolytic vs Oxidative Metabolism
- Energy Production In The High Metabolism State
- Energy Production During A Short Term Stress
- The Big Picture Of Short Term Stress
- Energy Production During Long Term Stress
- The Modern Day Famine
- Key Points
That is because “stress” is not just being mad at your boss, feeling pressure to meet some deadline, or fighting with your significant other.
“Stress”, in its true form, is anything that creates a stress response in the body, which causes the cells to change their behavior to cope with it.
Emotional and mental stress like the examples above can do this, as can physical stress from exercise, lack of sleep, fighting off a disease or infection, and recovering from an injury.
But by far the biggest and most prolonged stress that every person is being subjected to is dietary stress from eating inappropriate foods in inappropriate quantities, while avoiding the very foods that will shut down the stress response.
What is worse is that many of these foods are avoided - not because they are strange foods - but precisely because these people are trying to be healthy and are told to avoid them by mainstream nutrition.
We will get to the more specific examples and recommendations in other articles, but we first need to dive into what the stress response really is.
After all, the better we understand stress, the better we can learn to reduce it and boost our metabolic rates.
“Stress is not a state of mind... It's measurable and dangerous, and humans can't seem to find their off-switch.”
- Robert M. Sapolsky
What Actually Is “Stress”?
While everyone typically knows what stress is intuitively, defining it on the cellular level can be eye-opening.
Specifically, stress occurs when the cell’s need for energy exceeds its ability to produce energy.
That means there are primarily two ways stress gets activated. Either:
- Your cells have an increased need for energy that exceeds normal energy production capabilities
- Your cells have a limited ability to produce energy that cannot match normal needs
Either way, not enough energy is able to be produced with healthy, oxidative metabolism, causing an increase in the stressed, glycolytic metabolism and/or fat burning.
When the stressed, glycolytic metabolism stays on for too long, the oxidative metabolism begins to shut down from biofeedback mechanisms and dysregulation. Continue for long enough and this powerful pathway for energy production is practically non-existent.
This is crucial to understand, because changing the metabolism of your entire body ultimately comes down to changing the metabolism of each individual cell.
One of the best ways to picture this is to think of a forest.
A forest is made up of many trees and each tree is made up of many leaves. If you want to make the entire forest greener, as a whole, you need to make each tree greener individually, which means you need to make each leaf on each tree greener, individually.
In this line of thinking, you also wouldn’t change the leaves on a tree by focusing on one leaf at a time or one tree at a time. No, you would focus on changing the environment of the entire forest, that all the trees live in, so that all the leaves respond and change as a whole.
If you improve the soil of the entire forest, and give it the right amount of rain and sunshine, then all the leaves will change because the entire systemic environment has changed.
The same is true for the body. Change the systemic environment of the body as a whole, and each cell will improve its ability to create energy, resulting in optimal functioning of the entire system.
The question then becomes, what changes to your internal environment are needed so that all your cells can become more metabolically healthy? To answer that, we have to zoom in to the level of the individual cell, study it, and understand what it needs in order to function optimally.
From there, we will zoom out to the body as a whole in order to understand what changes to the entire system you need to make in order to create those cellular changes.
This is exactly how we need to approach metabolism and health within the body.
So in order to figure out what we need to change on the big environmental level of the whole body, we need to start with studying how the cell produces energy in order to understand what it needs for optimal metabolism.
Glycolytic vs Oxidative Metabolism
If stress is ultimately a problem of creating energy in the cell, then the first step is to look at the way the cell produces energy so we can grasp the processes that are going on.
There are 3 primary ways your cells create energy:
1) Oxidative Metabolism - [non-stressed state]
(aka Glycolysis + Oxidative Phosphorylation, Aerobic glucose breakdown, or Glucose Burning with Oxygen)
2) Glycolytic Metabolism - [stressed state]
(aka Glycolysis Only, Anaerobic glucose breakdown, or Glucose Burning without Oxygen)
3) Fat Metabolism - [stressed when elevated or when burning PUFAs]
(aka Fat Burning or Fatty acid beta-oxidation)
The oxidative metabolism is the most metabolic way to produce energy, since it is capable of producing tons of energy rather quickly. In the healthy state, it is highly active and will be the primary pathway your cells use.
The glycolytic metabolism and fat metabolism are used when the oxidative metabolism cannot keep up with the cell’s energy needs. If glycolysis and fat burning are turned on for too long at elevated levels, the oxidative metabolism starts to downregulate and shut down, lowering the cell’s energy production capabilities. This happens in order to spare fuel in the body, as high amounts of these energy pathways signify to your body that food is scarce.
This is the basis of this entire program, as you will soon see.
In regards to the breakdown of glucose (the oxidative and glycolytic metabolisms), glycolysis happens no matter what.
If there is oxygen in the cell and the mitochondria are healthy, then glycolysis will create a molecule called pyruvate, which will continue on through the oxidative metabolism.
But if the oxidative metabolism part of that equation is shut down from too much of the stress metabolism and/or lack of oxygen in the cell, then the first part, glycolysis, will form lactic acid instead.
This will be important when we talk about energy production in the stress states.
But first, let’s start with how your cells’ internal physiology look when you are in the healthy, high metabolism state.
Energy Production In The High Metabolism State
In the healthy, high metabolic state, most of your cells create the majority of their energy through the oxidative pathway, which produces far more energy than the glycolytic pathway, and is faster than fat burning.
But more importantly, it produces the most carbon dioxide (CO2) of all three pathways, which helps to increase oxygen uptake into the cell, reduce inflammation, and maintain a strong ion gradient between the inside and outside of the cell.
Since CO2 is an important promoter of the high metabolism state, it has naturally been associated with lower risk of disease and lower mortality rates (your cells do not get sick when they are producing enough energy for work optimally).
Basically, this means that CO2 production increases metabolism and energy production, while maintaining strong cellular boundaries (ie. preventing cell leakage and edema).
When your body is primarily creating energy through this oxidative metabolism pathway, all of your cells will be churning out lots and lots of ATP - the energy unit in cells. It is the most efficient metabolism for producing energy.
The strength and ability of your mitochondria to produce energy via the oxidative metabolism determines your metabolic rate and overall health.
In the truly healthy state characterized by high metabolism, the mitochondria are running on full force, so that many molecules of glucose are getting combined with oxygen simultaneously, producing a very high output of energy that can easily meet the cell’s needs.
In fact, in the highest levels of health and stress resistance, this energy production exceeds the cell’s need for energy so that it begins “wasting” energy as heat through proteins called “uncoupling proteins” in the mitochondria.
These proteins essentially cause the final steps in the oxidative metabolism to get “skipped”, so that ATP is not created and only heat is liberated, but the glucose has still been burned and the CO2 has still been created.
Because there is so much oxidative metabolism happening in this state, there is tons of CO2 being created, which is helping shuttle more and more oxygen into the cell and continuing to encourage even more burning of glucose via the oxidative metabolism (assuming that there is enough glucose supplied to the cell).
In other words, CO2 is creating a positive feedback loop of high energy production, stimulating more and more oxidative metabolism.
So we end up in a situation where high amounts of oxidative metabolism are promoting even higher amounts of oxidative metabolism and even more energy production, which is the only limiting factor is the amount of glucose you eat.
I have referred to the high metabolism state as “resistance to stress”, and this is precisely why. Your cells are creating more energy than they need and wasting a lot of it as heat.
If your energy demands increase, rather than activating a stress response, you can easily cope because energy is so abundant.
That is the true meaning of the high metabolic state that makes you more resistant and adaptive to stress.
However, one caveat here is the skeletal muscle cells, which have been designed by evolution to behave oppositely as the rest of your cells at rest.
During rest, in the high metabolism state, your muscles will burn primarily fatty acids for all the very easy tasks that they have to perform when there is no stress and low amounts of activity.
Essentially, the muscles do not need high energy, so they do not use the glucose. The rest of your body, however, which is fulfilling all the longer-term health functions, is using more energy, so it gets the glucose.
In other words, wherever glucose goes is where your body is directing its greatest energy production.
This is crucial to understanding how the short-term stress response works and why.
Energy Production During A Short-Term Stress
When we talk about short-term stress, we are talking about the way we would have encountered stress out in nature.
Typically we would realize we were in danger and then act to escape that danger. After the stress ended, we would relax and recover from that stress.
Let’s use an example from nature: You see a lion out on the savanna that wants to eat you.
In response to the danger, your brain sends a signal to your body to activate the stress response and shift your body into a completely different physiological state.
Priorities shift. Now, regeneration, hormone production, digestion, and immunity are not nearly as important as getting away from the life-threatening danger.
And in order to get away from this danger, you need your muscles to have lots of energy for physical movement and your brain to have lots of energy for thinking on your feet.
Lo and behold, that is exactly where your body redirects blood flow - to the muscles and brain, and away from the organs and digestive tract.
In the muscles, which normally burn lots of fat at rest, glucose burning gets ramped up to supply faster energy.
When the oxidative metabolism in the muscle cannot keep up with the high energy needed to overcome the stress, some of the glucose will start going through glycolysis without going through oxidative phosphorylation.
More accurately, what’s happening is that your muscle cells are burning lots of glucose, but your body simply cannot get oxygen into the muscle cells fast enough.
The extra glucose that does not have the oxygen to go through the oxidative metabolism is getting burnt through the glycolytic metabolism and turning into lactic acid.
You may have heard of lactic acid before. It is what causes the burning sensation in your muscles when you do a high rep weight lifting set.
This example actually illustrates what is happening perfectly:
During a high rep weightlifting set, your muscle’s energy needs are elevated beyond what it can produce with oxidative metabolism, because it cannot get enough oxygen into the cell fast enough.
So the oxidative metabolism is going at full force, and whatever energy is needed beyond that comes from the glycolytic metabolism, which produces lactic acid and makes your muscles burn.
Overall, this means that the energy output by the muscle cell is increased, enough so that it can do what it needs in order to get you away from the danger.
Now, your muscles are using glucose for fuel primarily by breaking down your internal stores of glycogen. But the body is actually pretty limited in the amount of glycogen it can store. The liver can hold about 100 grams (400 Calories worth), and the muscles can hold about 300 grams (1200 Calories worth), on average.
The glycogen that is stored in the muscle is “trapped”, meaning that only that muscle can break it down for fuel, whereas the glycogen in the liver and other organs can be used to supply the blood with glucose and to be transported throughout the body.
This means that preserving glucose is a high priority during stress, since it is needed for maximal energy production, which makes sense when we look at the hormone response your body releases during a stress response, particularly with glucagon, cortisol, and adrenaline.
Glucagon and cortisol both help to put more glucose into the blood for the muscle cells to use. Glucagon does this by breaking down stored glycogen, while cortisol does this by breaking down amino acids from your muscles into glucose via a process called “gluconeogenesis”.
One of adrenaline’s main functions, however, is to increase lipolysis, or the release of free fatty acids into the blood.
This happens to limit the amount of glucose being used by cells and tissues that are non-essential to overcoming the stress, saving more glucose for the blood in order to keep all the important mechanisms for survival working and to supply the working muscles with fuel (in addition to their own glycogen breakdown).
By releasing fatty acids into the blood, all of the cells in your body will take up less glucose and start using fatty acids instead.
This is a universal concept that applies to all cells via a process called The Randle Cycle, which states that fatty acids in the blood will compete with glucose to be taken into the cell, effectively lowering insulin sensitivity.
Basically, fatty acids are the back-up fuel, used to prevent your body from running out of the glucose it needs to survive.
However, you might be wondering how the working muscles can use that glucose if the fatty acids are lowering the glucose uptake to all cells. The answer lies with the GLUT-4 receptor.
This is a special “insulin independent” receptor on muscle cells that gets activated when they contract, especially during higher intensity movements. When it is active, your muscles will still take in glucose, even if they cannot respond to insulin because of the increased free fatty acids.
That means the muscles that you are using to overcome whatever danger you are in are still absorbing glucose out of the blood to be used for fuel.
Note: This is part of the science behind the “post-workout window”, where carbs get preferentially stored in the muscle - the GLUT-4 receptor is active, meaning carbs you eat can get stored in muscle without insulin.
However, in the organs and other tissues that are not actively needed - that do not have active GLUT-4 receptors - this increase in fatty acids means reduced uptake of glucose. These cells all downregulate glucose burning and switch to primarily burning fat, which means slower and lower energy production.
The Big Picture Of Short-Term Stress
There is a lot to take in and understand here. If the science is hard to grasp, that is okay. What is important is to stay focused on the big picture and the two big takeaways:
- The cells that need more energy to help escape the danger are producing energy at full force, using both the oxidative metabolism and the glycolytic metabolism. They are creating energy as fast as possible.
- The cells that are not needed to overcome the stress flip into the stress metabolism to preserve energy for the active cells, creating energy through the much slower fat metabolism and some glycolytic metabolism.
If you recall, this is flipped from what we talked about in the healthy metabolism. Now the organs are burning fat while the muscles are burning glucose, because fueling the muscles is more important for escaping the stress.
Remember: Glucose goes where the priority for energy is.
Now, once the danger is escaped and the stress is over, your body will gradually return back to the healthy state with lots of oxidative phosphorylation and a high metabolic rate.
But this is just for short-term stresses.
What happens if the stress is not some immediate danger to escape from, but instead a long-term danger like a famine?
Energy Production During Long-Term Stress
In both the relaxed and short-term stress states, the oxidative metabolism is still working the entire time. The amount of activity is dependent on the amount of glucose and oxygen in the cell, but that is the only thing limiting it.
However, when the stress becomes long-term, like in a famine, the by-products of the stress metabolism send signals to shut down the oxidative metabolism altogether, lowering the potential for each cell to create energy, along with the total amount of energy burn.
Essentially, this is your body’s defense mechanism against starving to death.
To further explain this, let’s hop back into the short-term stress physiology we just discussed.
Your muscles are burning lots of glucose in order to produce lots of energy. Oxidative metabolism is maxed out, so extra energy is being created with the glycolytic metabolism, creating lots of lactic acid.
Meanwhile, your organs and other cells have switched to fat burning and decreased their energy output.
Now, in the famine situation, you are not burning increased amounts of glucose in the muscle like you are in the short-term stress. However, eventually, you do run out of glucose. You are still making some from the breakdown of protein from the muscle, but on the whole, your glucose is much lower.
In this internal state, all the cells are burning fatty acids primarily, producing far less CO2 than the oxidative metabolism would provide.
Remember what we talked about with CO2 - it is helping to bring oxygen into the cell and maintaining a strong ion gradient between the inside and outside of cells.
With less CO2 being produced from the fat metabolism, less oxygen can get into the cell (via the Bohr and Haldane effects) and the minerals inside and outside of the cell that your nervous system uses for communication become dysregulated.
Remember that oxygen is needed for the oxidative metabolism. When oxygen is not around, glucose will get burned through the glycolytic metabolism, producing the inflammatory lactic acid.
On top of that, less oxygen in the cell makes it hard even for fat metabolism to happen, meaning this process gets slowed and even less CO2 is created, meaning even less fatty acid burning, meaning even less...
It is one big negative spiral.
To put this more simply, burning fat as your primary source of fuel will spark the negative spiral of energy production to lower the ability of your cells to produce energy.
In prolonged stress and famine, glucose from carbohydrates is scarce and we shift into this fat-burning, stress metabolism that tanks our metabolic rate.
The end result of maintaining this long-term stress response is your body shifting into scarcity mode, trying to hold onto as much energy as possible by shutting down the very pathways that are capable of producing the most energy.
Your body is getting the signal that food is scarce, and it is responding by conserving energy.
The Modern Day “Famine”
But now you might be asking, what does starvation have to do with me, when there is plenty of food around in today’s culture?
The answer lies in the signals you send your body.
These signals have been misconstrued in mainstream nutrition, and people end up eating totally inappropriate diets that send the signal to their bodies’ that food is scarce.
Despite eating lots of total calories, your body thinks that you are starving and that it needs to store energy and shut down long-term health systems.
Even if you eat carbs in this state, that glucose has a hard time getting to your cells because the fatty acids flooding your system are lowering your insulin sensitivity (remember, The Randle Cycle).
Even if that glucose does get into your cells, there is not enough oxygen in the cell to take it through the oxidative metabolism because very little CO2 is being produced, and it breaks down through the glycolytic metabolism. This creates higher levels of lactic acid, which can have lots of negative, pro-inflammatory effects throughout the body and continues to promote the glycolytic metabolism.
In other words, eating carbs in this stress metabolism will lead to elevated glucose levels, fat gain (as your body does anything it can to normalize blood glucose), inflammation, and many other negative consequences.
But the most important thing to understand is that it is NOT the glucose that is the problem. The problem is how your body is responding to the glucose, based on where you are on the Metabolism Spectrum.
If you would like a step by step guide on how to increase your metabolic rate through nutrition and lifestyle factors then make sure to check out The Thermo Diet only inside of UMZUfit.
- Healthy metabolism is characterized by high levels of the oxidative metabolism and high CO2 production, which reinforces higher and higher levels of energy production, limited only by the amount of glucose and oxygen that can get into the cell and the strength of the mitochondria
- At rest, muscle cells are completely opposite from most other cells in your body and prefer to burn fat to perform all the low intensity movements that you perform throughout the day, saving glucose for the more important functions of the organs and other cells
- Short-term stress is characterized by a shift to burning glucose in the muscles in order to produce energy faster, accompanied by a shift to burning fatty acids and lower energy production in the other cells to limit the use of glucose and save it for the working muscles
- Long-term stress is characterized by high levels of fat burning and decreased CO2 production as glucose gets depleted from the body, which reinforces lower and lower levels of energy production and actively shuts down the ability for your cells to perform oxidative metabolism of glucose
- Despite eating plenty of calories in the modern world, stress, aging, disease, and fat gain all occur because we are constantly activating the “stress” or “famine” metabolism in our bodies’, sending signals to conserve energy and shut down long-term health systems
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