Optimizing Gut Health For Superhuman Energy Levels with Kiran Krishnan

Ari: Okay. So, that’s a very nice overview of this, how this crosstalk works. Let’s back up to just mitochondria specifically. And I know you have a bunch of slides here in your presentation related to the role of mitochondrial health in disease more broadly. So, can you kind of build out that element for people so they understand, first the picture of mitochondria and health, and then how the gut are influencing and regulating mitochondrial function? 

Kiran: Yeah, absolutely. So, first we’ll talk about mitochondria itself and kind of how they function in a general sense. And then we’ll talk about the most common dysfunctions that we see in mitochondria. The things that are supposed to occur in order to maintain homeostasis and maintain healthy mitochondria. We’ll elaborate then on how those things are not functioning and what happens when those things don’t function properly. What is the health and disease consequence of that? 

And then finally, we’ll get into then what is it that the microbiome produces that is critical to the health and function of the mitochondria? Right. So, we’ll jump into it first. What are the mitochondria? We talked about they are the powerhouse of the cell, as most people would have learned in science in junior high school. They are organelles that sit within the cell that produce all of the energy that our body needs. 

So, the ATP that they end up producing, the adenosine triphosphate, is the energy currency in the human body. Without ATP, we will cease to function as a species, whether you have high levels and good ATP production or low levels and poor ATP production, will determine how you feel each and every day, when you wake up in the morning. Whether your brain is functioning in an alert state, whether your muscles are responding well to the stresses that you put it through, how energetic you are throughout the day, completely dependent on how much ATP your mitochondria can produce in all of the various cells. 

So, ATP production is one of the most important things. Thermogenesis is another important thing. Your mitochondria can burn sugars, it can burn protein, it can burn fat, for it to make that ATP. There’s different mechanisms for each of those. All of those feed at some point into the Krebs cycle. The Krebs cycle then kicks out byproducts that then go through something called the electron transport chain, and the electron transport chain finally kicks out ATP. 

So, those couple of things are important to note. Obviously, unless you’re in graduate school or high-level science classes in college, you won’t need to know exactly what’s happening in the Krebs cycle or the electron transport chain. But I do want you to keep those two things in mind, that the fat metabolites, the sugar metabolites, and the protein metabolites, the way those are converted into this ATP energy currency is they feed first into some stage of the Krebs cycle. . 

And then the Krebs cycle kicks out components that then go through something called the electron transport chain. At the end of the electron transport chain is where ATP ends up ultimately getting generated. That’s important to remember because those are steps in where things can start to go wrong. Calcium signaling is an important part of the mitochondria as well. Calcium is used throughout the body for all types of nerve conduction, for your muscle contraction, for all kinds of things. So, mitochondria plays a role in calcium signaling. 

Heme and steroid synthesis also does occur in the mitochondria. It’s not as relevant to this particular talk, but just important to keep in note that that’s what happens. This next part is really important. Apoptosis, right. So, apoptosis is programed cellular death. That’s really important that the cells have a very strong program signal in there to essentially self-destruct at a certain given time when the cell gets to a certain age. The reason that’s important is because that allows for the regeneration of new cells, and healthier cells, and better functioning mitochondria.  

And when apoptosis fails, that becomes the onset of tumor genesis, right. So, when your programed cell death fails, that’s the onset of tumor genesis or tumor growth. So, apoptosis is extremely important, that is controlled by a healthy mitochondria. A dysfunctional and disrupted mitochondria has dysfunctional apoptotic signals. So, that can become a big problem with the risk for cancer and tumor genesis. 

Cellular homeostasis, of course, maintaining energy balance in the cell. And we’ll get into that a little bit more when we talk about something called redox balance. But insulin control is also a big function of the mitochondria. And lastly, the generation of reactive oxygen species. Most people have heard about ROS, or reactive oxygen species, or you might have heard about it as free radicals, or you might have heard about it as super oxides. These are all byproducts of energy production in the mitochondria, right. Think of it as exhaust that’s being produced when your internal combustion engine produces energy in the car. 

So, it’s an exhaust, if you will, from cellular respiration. Now it’s totally normal, it happens in every cell. And we’ve got things in place to help quench the toxicity of those reactive oxygen species, in particular the glutathione, and catalase, and superoxide dismutase systems in the body. Those are all there to quench that exhaust. But one significant issue happens when you don’t have cellular homeostasis, is you end up getting less energy production and more exhaust being kicked out, and the exhaust is not contained. 

So, imagine you turn on your car and you’ve got it in a closed garage, right. So, you’re producing energy, but you’re not utilizing the energy because you’re not moving, but you’re kicking out a lot of exhaust and it’s stuck in a confined place, and that creates significant toxicity. If there was any living species in that garage, they would succumb to that toxicity over a period of time. Same thing happens to the cells. 

If there’s no energy homeostasis, you have something called a redox imbalance. That redox imbalance will eventually drive inflammation, damage to the cells, and damage to the mitochondria, because the exhaust is too high. It’s not getting quenched. So, that’s a really important thing. Now, some of the control mechanisms to maintaining this energy balance, besides the quenching of this exhaust, is something called mitophagy. 

So, mitophagy is the removal of dysfunctional mitochondria, because as these mitochondria go through their work of producing energy every minute of every single day, and they continue to produce that exhaust, that exhaust will damage the mitochondria eventually, and that damaged mitochondria has to be recognized as being damaged and then removed from the system. You don’t want cells full of damaged mitochondria. That signifies aging, which I’ll talk about down the road. 

Ari: Just to interrupt briefly, just to give a little teaser. I know that there is a link specifically with certain metabolites from the gut microbiome processing of certain phytochemicals, and the production of compounds that directly relate and amplify mitophagy. 

Kiran: Exactly, yeah. In fact, that’s the most powerful signal of mitophagy comes from the microbiome. And that’s why this is so important to note that mitophagy’s such a key component to a healthy mitochondria within the microbiome, because inevitably, like any car engine when it runs for a period of time, the engine’s going to get worn out. It’s going to get toxic. It’s going to get gunked up. You can change the oil as much as you want, but you’re not going to run the engine out for half a million miles, or six hundred thousand miles. You’re going to have to replace it. 

The same way the engine’s in your cell will run out, especially because they are susceptible to those reactive oxygen species exhaust that comes out. So, the key to maintaining healthy functional cells, is to have a really good, healthy process of identifying dysfunctional mitochondria and then getting rid of it through the process of mitophagy, and then stimulating the regeneration of new mitochondria called biogenesis. So, that balance is really critical. We want to emphasize that. 

Ari: Yeah. And just to connect the dots with energy, the concept of energy, superhuman energy and chronic fatigue. There’s a bunch of research that has linked mitochondrial dysfunction, and Dr. Robert Naviaux’s work around the cell danger response, which is sort of the shutdown of mitochondria and them shifting into this mode where they’re spewing out, in your terms, lots of exhaust, and very little energy, and lots of these damaging free radicals. And their cells, their mitochondria have been kind of locked in this state of not producing a lot of energy, but producing lots of damaging exhaust, damaging free radicals. 

Kiran: Exactly, yeah. And of course, if they’re not producing energy, what does that mean? Well, it means that they have no way of effectively breaking down things like proteins, fats and sugars in order to utilize it in their energy mechanisms, right. So, you get a net of inability to metabolize these compounds that you’re continuing to take in. So, a lot of those things end up getting stored. And that has, of course, all kinds of other effects within your system. 

So, the inability of these engines to break down the nutrients that are being fed to it and then the inability of the body to identify the damaged engines, the mitochondria, remove them and regenerate new mitochondria, causes a whole host of conditions. And, of course, at the base level drives energy dysfunction within a person. Now, again, this is all happening in every single organ in your body, including your brain, and your heart, and every single muscle in your body. 

So, when these muscle tissues are suffering from an energy imbalance, a redox imbalance, too much exhaust, not enough energy production. Mitochondria are not being cleared out and they’re not regenerating new mitochondria, your net result is that organ system starts to fail. And whether it’s your skeletal muscles, where you don’t have enough energy to move, or it’s your brain, where you’re going into brain fog and having memory recall issues and becoming slower. Whether it’s your heart and your cardiac output starts to go down, which means your heart is not pumping out as much blood with every beat. So, then the rest of your body doesn’t get enough blood or nutrients. Your whole system starts to degenerate down, right. 

So, it all starts with this mitochondria dysfunction. So, those are very important things to keep in mind. Redox imbalances within the mitochondria, that’s the imbalance between not producing enough energy and kicking out too much exhaust, is a big driver in what they call free radical diseases. The most well studied free radical diseases are all the various forms of cancer, right. 

In fact, if you look at all of the areas in which free radical diseases are prevalent because of this redox imbalance, it affects the heart with things like cardiac fibrosis, hypertension, tachycardia. It affects the skin, kidneys, joints, lungs, brains, immune system, blood vessels, multi organs, eyes, your vision, everything. These are all characteristics of degenerative conditions because your mitochondria within your cells are becoming more and more dysfunctional. This is all very well established. 

And in fact, in the case of cancer, they’re actually trying to change the definition of cancer as more of a mitochondrial metabolic disease, rather than the initial idea that cancer has a lot to do with genes that turn on tumor genesis and or not. It becomes more, and more of a metabolic problem, of an energy balance problem, that redox imbalance, then this genetic dysfunction within tumor genesis. So, that’s an important thing to note. 

And in fact, healthy mitochondria and animal studies can actually reverse the progression of cancer. They’ve been able to show in this example that I’m showing here, that introduction of noncancerous mitochondria into a highly malignant breast cancer cells could reverse the malignancy. They’ve been able to show that that you can mitigate the unregulated cell growth. You can decrease the viability and hypoxia. 

Well, what does that mean? Well, one of the problems with cancer cells is they become more and more viable in hypoxia, in conditions of low oxygen. And hypoxia is one of those ways in which the body controls cell death, right. And it tries to get the cells to shut down so they can get rid of those damaged cells. The cancer cells tend to have a high resistance to hypoxia. But when you add non-cancerous mitochondria into these cells, then you start to find more and more sensitivity to hypoxia starts to occur. 

And it, of course, turns off the unregulated cell death. All kinds of changes at the cellular level occur where you actually start reversing the process of cancer. Now, again, all of this hangs on the balance of this low biogenesis, or low regeneration of new healthy mitochondria, low mitophagy, meaning you’re not cleaning out the damaged mitochondria. And then this redox imbalance, too much exhaust, not enough energy. This is the metabolic crux of cancer. 

This also is a metabolic crux of things like Parkinson’s, and Alzheimer’s, and neurodegenerative diseases, right. So, aging and significant neurodegenerative diseases are driven by this same mechanism, the same dysfunction of mitochondria. Same thing, and this is a study looking at dysfunction in lung disease. Same emphasis on mitophagy. How important this process of cleaning out damaged mitochondria is. 

This is the same thing in oxidative stress and cardiolipin to mitochondrial dysfunction, in nonalcoholic fatty liver disease, which is becoming an epidemic in the Western world. Nonalcoholic fatty liver disease didn’t really exist in any prevalent rate 40 years ago, 50 years ago, 60 years ago. Any time you had liver disease, it was typically due to alcoholism or cirrhosis due to viral infection, hepatitis, right. Now, we’re seeing more and more that nonalcoholic, non hepatitis liver disease is at a much higher prevalence rate than the alcoholic and hepatitis version. 

So, it’s called nonalcoholic fatty liver disease. It moves into something called NASH, nonalcoholic steatohepatitis. And people start to go into liver failure. Once your liver fails, the rest of the system is quick to follow. This is driven by low biogenesis, low mitophagy, and redox imbalance as well. There’s another hepatic, study on hepatic disorders. Same thing. Low biogenesis, low mitophagy and redox imbalance. And then aging. There’s something called the Free Radical Theory of Aging. The Mitochondrial Free Radical Theory of Aging. Abbreviated MFRTA. 

Basically, what they’ve shown is that the biggest driver of degenerative conditions like aging, including diseases that can be named, is that the free radical generation within mitochondria causes disruptive mitochondrial function, lowers mitophagy, and lowers mitogenesis. If we can maintain those two things, we would age at a much slower rate. 

The one really, really landmark study that published, showed where they took tissue samples from a five-year-old and they compared it to tissue samples of a 90-year-old. They gave them to a pathologist, blinded. So, the pathologist did not know which tissue came from which subject. And then the pathologist were to assess the difference between the tissue samples. The only thing they could find as a difference between the two tissue samples, is that the 90-yearold had as much as 95 percent damaged dysfunctional mitochondria. And the five-year-old had a hundred percent functioning mitochondria. 

Ari: Wow. 

Kiran: That’s the only difference in eighty-five years of aging. That’s where they see the difference. 

Ari: Amazing. I want to add a little layer to this, because I’m pretty familiar with the research around this as well. And there’s research showing between the ages of 40 to 70, most people lose about half of their mitochondrial capacity. And there’s numerous studies, they’ve quantified it in different ways, about eight to 10 percent loss of mitochondrial capacity per decade of life. 

There’s also research that suggests between 20 to 40, you lose half. So, if you think about it from 20 to 70, most people are losing 75 percent of their mitochondrial capacity. But there’s also some really interesting research, I’m going off on a bit of a tangent here, but I just can’t help myself from interjecting because it’s related to this, showing that in people who are exercisers into old age, who have adequate hormetic stimuli into their mitochondria and are really challenging and stimulating their mitochondria on a regular basis through physical activity, they don’t lose half of their mitochondrial capacity between 40 to 70. 

So, this process, I mean, here we’re talking about the role of the gut health and microbiome health in regulating mitochondrial health. But it’s also intertwined with so many other factors and in particular hormetic stimuli that are driving this process of biogenesis and allowing you to not lose so many mitochondria as you age. 

Kiran: Yeah. But here’s the amazing connection there is that the hormetic stimuli also has an impact on the microbiome, right. So, those that exercise, especially if they’re doing, kind of a medium intensity exercise several times a week, they actually maintain diversity in their microbiome for longer. And it actually reduces leaky gut. 

So, one of the, we did University of North Texas, where we did our first leaky gut study. They’d also previously published a study showing 30 minutes of low intensity exercise prior to a meal reduced the endotoxemia, or the leaky gut that would arise from that meal. So, the exercise has a very deep connection to the effects of the mitochondria, sorry, the microbiome. And then here’s the other thing, as you mentioned, after the age of 40, losing mitochondrial function. Another hallmark of after the age of 40 to 70 is a significant loss in diversity in the microbiome. 

Ari: So, it just goes to show, nothing exists in isolation. Everything in the body is intertwined. 

Kiran: Everything is in intertwined. All of these behaviors support the systems that we require. So, yeah. And then at the end of the day, looking at the microbiome, there’s so many things you can do to support its health, intermittent fasting being one of those things, right. So, you can take a lot of things which will help. And we’ll talk about some of those. And then some aspect of it is just not taking anything. Giving your microbiome a chance to rest. 

And then a recent study just published this week showed that intermittent fasting has a significant impact on ameliorating or preventing the cognitive decline that’s seen in type two diabetes. And of course, it even increases and improves metabolic function in type two diabetics. But it’s completely dependent on the presence of the microbiome. 

So, in animal models, when they remove the microbiome, those benefits went away, right. So, it all, every one of our behaviors has an impact somehow on the microbiome. And that impact on the microbiome will then translate to metabolic impact on our body. So, it’s really, really fascinating. Now, when we look at the defective mitochondria, I call it the defective mitochondria triad. What we’ve been beating into your brain for the last 15, 20 minutes is low biogenesis, low mitophagy, and redox imbalance. The consequence of each of these is pretty clear. 

With low biogenesis, of course, we get lower ATP production because we’re not regenerating new mitochondria to keep up with the energy needs. And that in itself starts to lower the ATP production, which then drives imbalance, redox imbalance. But that also leads to the most noticeable things are fatigue and tissue degeneration, right. And fatigue is a characteristic of virtually every chronic illness. It affects neurons, muscles, your mucosa, immune cells, tendons, and so on. It just makes it hard to get out of bed at the least, and at the worst it creates all kinds of chronic illnesses. 

Low mitophagy, of course, gets there from higher reactive oxygen species, low ATP, loss of apoptosis control. It also causes things like fatigue, tissue degeneration, overgrowth in the case of cancer cells, and again affects every single biological system in the body. Redox imbalance is the imbalance between the two. Also leads to fatigue, degeneration, impacts every single system in the body. 

So, what is then the connection between the mitochondria and the microbiome as it relates to these three really important dysfunctions that seem to occur inevitably in everybody as we get older, and if we don’t curb our behaviors? So, what I talked about earlier about the connection, the intimate evolutionary connection between your microbiome and your mitochondria still exists today. Mitochondria are ancient pleiotropic bacteria. They respond to signals from other bacteria. And most of the bacteria in our system lives in our gut.