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Feb 08, 2023

Mitochondria, Muscle Strength, and Pomegranates

Chris Rinsch, Ph.D., joins Jeff Krasno to delve into the surprising source of the key longevity benefits long attributed to pomegranates.

Podcast

Commune with Jeff Krasno

00:00

Chris Rinsch, Ph.D., helps us understand the connection between mitochondrial health and endurance and shares how compounds sourced from pomegranates can improve muscle function.

Topics covered

What are the mitochondria
What is mitochondrial dysfunction and how does this impact our health
What is Urolithin A
How can Mitopure support mitochondrial health

Transcript

Jeff Krasno: Welcome to the Commune Podcast. My name is Jeff Krasno. Today on the show, I welcome Chris Rinsch. Chris is a biotech innovator who developed the proprietary technology in Mitopure, a supplement clinically shown to improve mitochondrial health, muscle strength, and endurance in human beings.

Jeff Krasno: Now many of us remember from biology class that the mitochondria are the power plants of the cell. But as we'll soon learn, these little jelly beans-shaped organelles do a lot more than produce ATP. They are essential to so many processes, from apoptosis to gene expression to neurotransmitter production. A Mitopure found its origin in a study where Chris and his team observed a decline of the mitochondrial function in the muscle tissue of individuals experiencing mobility issues.

Jeff Krasno: They asked the question, "How can we reverse the decline of mitochondrial function and boost the recycling of damaged mitochondria?" As it turns out, there is a compound in pomegranates that do just that. But it is not advisable from a blood sugar perspective and from other perspectives to drink the amount of pomegranate juice that you need to get a sufficient volume of those compounds and that is how and why Mitopure was born.

Jeff Krasno: But before we dive figuratively into the mitochondria and the science behind the compound known as Urolithin A, here is a brief reminder about our Commune course platform.

Jeff Krasno: If you're interested in functional medicine and integrative medicine with fantastic doctors like Mark Hyman and Sara Gottfried, Kara Fitzgerald, Jolene Brighten, and Roger Seheult on topics such as gut health, sleep, immunity, hormone balancing, ayurveda, and nutrition, you can sign up for 14 days of free all access to Commune's entire course library, including more than 100 courses on health, personal growth, and social impact. Just go to onecommune.com/trial. Please support this podcast by subscribing and leaving a review on your favorite podcatcher. Without further delay, I present to you Chris Rinsch.

Jeff Krasno: Chris Rinsch, welcome to the Commune Podcast. Great to be with you, man.

Chris Rinsch: Hey, great to be with you, Jeff. Thanks for having me.

Jeff Krasno: Yeah. We had the opportunity to meet in person at a party in Kami in Topanga when our pomegranate trees were in full splendor, I remember, in late October.

Chris Rinsch: It was amazing. It was amazing.

Jeff Krasno: If my memory serves me correctly, I believe we were the last one standing at that party, which probably speaks to our mutual bioenergetic, if you will.

Chris Rinsch: Exactly. Our mitochondria were working at full speed.

Jeff Krasno: Yes, they were. Yes, probably with some extra enhancement. I'm really looking forward to today's conversation. I've been thinking about it. Really, just the state of being alive is contingent on our ability to produce energy. In fact, on some philosophical level, we're just animated information, links in this continuous chain of energy transfer.

Jeff Krasno: But this ability for us to make energy rests strangely on this five micrometer oval organelle known as the mitochondria. It's so cool that the mitochondria has really become more and more part of the zeitgeist if you will. You guys are on the tip of the spear in terms of creating more fluency around this strange little purple bacteria that got engulfed by an archaea some two billion years ago. Maybe we'll talk a little bit about the history of this organelle.

Jeff Krasno: But I'm excited to jump into all the roles of the mitochondria with you, its relationship to aging, and of course, how we can upregulate the functionality of our mitochondria, specifically as it pertains to muscle function, but also as it pertains to brain health and everything that you guys are doing at timeline and with Mitopure. Excited to jump in. Maybe at the very, very, very basic top level, what are mitochondria?

Chris Rinsch: Mitochondria are basically the power plants inside of all of our cells. Essentially what they're doing is producing the energy, the ATP that is needed for all of our cells to function normally for all of the different biochemical reactions to take place inside of the cell. They're essentially this battery that we need to make our cells function and work properly.

Chris Rinsch: Without functioning mitochondria and with a decline in mitochondria number or functionality, basically there's less energy inside of the cells, so less of the cell's functions can take place, so that transmits itself not only through a cellular level, but on a whole tissue level and on an organ level, so you have a decline in functionality at the organ level and also on the whole human body. It's very important for us to function properly. We need that energy.

Jeff Krasno: Just break it down from almost a very basic level, mitochondria exist inside the human cell. Is that correct? Is there a certain prevalence of mitochondria in certain cells versus other cells? How many mitochondria are in a cell?

Chris Rinsch: Sure. Yes, mitochondria are located inside of the cytoplasm of the cell, and certain tissues require more energy than others. There tends to be more mitochondria and a higher density of mitochondria. A particular skeletal muscle, which uses a lot of energy, as well as cardiac muscle and even the brain, there's quite a high density of mitochondria.

Jeff Krasno: Are we talking 200 mitochondria per cell, 2,000 mitochondria per cell, or am I not even in the right ballpark?

Chris Rinsch: I think you're... It really depends on the tissue, but it's not in the tens of mitochondria. It's more in the hundreds and the thousands of mitochondria and that just depends on the size of the cell, too. They're very small, so you can pack a lot in.

Jeff Krasno: Yeah, they tend to cluster, right?

Chris Rinsch: They do.

Jeff Krasno: I remember from biology class, generally, you'd see this mitochondria as kind of this jelly bean-like image inside the cytoplasm of the cell. But in reality, they tend to cluster in groups. Is that right?

Chris Rinsch: You do tend to find them stuck together. We've looked at transmission electron microscopic images in some tissues, and you can see lots of mitochondria sticking together. You can also see the structure of those mitochondria, the cristae inside, and how that cristae formation changes with time and during aging as well.

Jeff Krasno: The mitochondria in some ways are where food and oxygen meet on some level. People are somewhat familiar with metabolism and digestion and how macronutrients get absorbed into the bloodstream and then brought to the cell. Glucose, for example, gets ushered to the cell by insulin and then goes through glycolysis and then eventually into the mitochondria for a couple or the last couple of stages of cellular respiration. You can maybe get into that.

Jeff Krasno: Then oxygen is also obviously comes through the lungs and brought through the body through hemoglobin and the blood, and then transferred out also into the cells. It seems like the marriage of glucose and nutrients that were eating for energy production and the oxygen that were respirating meet and have a tryst at some level at the mitochondria. It's pretty fascinating.

Chris Rinsch: Yeah, it is. You're breathing in your oxygen, and it's basically for the mitochondria. Then you're eating all these foods, and the fatty acids are then transformed through the mitochondria into ATP, through the electron transport chain.

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Jeff Krasno: Mitochondria, the catchphrase that most people use is the powerhouse or the power plant of the cell. But mitochondria are also involved in a lot of other functions as well. Do you mind touching on some of the other roles that the mitochondria play?

Chris Rinsch: Sure. Mitochondria are also involved in various signaling pathways inside of the cell. Mitochondria can trigger the cell down a pathway of cell death as well if the mitochondria are significantly damaged. It's an important aspect that we don't think about of all of the different roles of the mitochondria in the cell. Although providing the energy and having proper functioning mitochondria is essentially clear to... Is essentially a key to have all of these processes functioning normally.

Jeff Krasno: We would not be moving our lips, talking to each other right now if we weren't unlocking the chemical energy in food through this incredible process and then being able to transfer that energy into mechanical or kinetic energy or et cetera. You brought up something interesting around cell death or apoptosis or as it specifically pertains to mitochondria. When mitochondria get damaged, there is this process of called mitophagy.

Jeff Krasno: But perhaps we can explore why mitochondria start to become dysfunctional in the first place. I understand it in a part of cellular respiration of essentially the creation of ATP, a byproduct of that is the production of some free radicals or reactive oxygen species that can at some point, damage the cell and the mitochondria. Can you pull on that thread a little bit?

Chris Rinsch: Sure. Throughout the electron transport chain, as you're converting your fatty acids into ATP, essentially, you generate a lot of reactive oxygen species. In the process, these reactive oxygen species, they will act at the level of the cell membrane or the mitochondrial membrane to damage that. As you're causing the damage to the mitochondria during the process of making ATP, essentially inside of the cells, you have a process by which you are taking the mitochondria, and you're repairing the mitochondria.

Chris Rinsch: You alluded to it earlier this idea of mitophagy, it's mitophagy, the cell eating the damaged mitochondria. Essentially, what happens is that the damaged part of the mitochondria is butted off from the healthy part of the mitochondria. Or if it's an entire mitochondria, it will be targeted down this pathway in which there will be... It will be engulfed by and then digested into its component parts.

Chris Rinsch: These component parts can then be essentially recycled inside of the cell and go into creating new mitochondria and growing our existing healthy mitochondria. This is very... It's a cycle that's ongoing, and it's not just happening at one time, but it's a continuous process. The cells need this in order to stay functional from a bioenergetic perspective.

Jeff Krasno: Yeah. It's fascinating. We often hear a lot about autophagy, and that can be associated with fasting and the triggering of certain cellular pathways. Autophagy is a more general term, technically meaning self-eating, but really referring to the breakdown of dysfunctional cells into their amino acid component parts. Then it's what's amazing is that the body can reuse or to recycle those component amino acids for the rebuilding of new proteins, which is just always boggles my mind, the foundational intelligence of the body there. But that's also taking place at the mitochondrial level with mitophagy. Is that right?

Chris Rinsch: Yes, that's right. Mitophagy is really a subset, almost of autophagy. As you are mentioning, autophagy is the term to describe the general recycling of proteins, of aggregated proteins or damaged organelles inside of the cell. It is really quite miraculous that inside of cells, you have this process that is, basically a cleaning process that enables the cells and all the cells machinery to stay functional, so that the cells just don't die over after a certain amount of time.

Chris Rinsch: The particular process that we're talking about, mitophagy, is really essential for the mitochondria, because the mitochondria are getting constantly damaged as they produce ATP. If we can... One of the problems that we'll get to this is that as we get older, this process of mitophagy can decline, basically, and can be disturbed not only due to age, but also due to our general lifestyle choice, our activity, our diets. All of that is very important to maintaining the proper bioenergetic function of ourselves.

Jeff Krasno: I definitely want to excavate all of the detrimental behaviors that we engage in to downgrade our mitochondrial function and our ability to produce energy in general. I do want to poke at a couple other mitochondrial roles because as we touched on, the mitochondria does produce a certain amount of reactive oxygen species, these highly reactive molecules that can cause damage.

Jeff Krasno: But at the same time, at the mitochondrial level, there is the production of certain antioxidants to balance in the best of all worlds, the creation of these reactive oxygen species. Can you talk a little bit about glutathione and even melatonin at the mitochondrial level and how they work to mitigate the production of free radicals?

Chris Rinsch: Well, you have, as you mentioned, glutathione is very important as an antioxidant. It's a very powerful antioxidant in the cell. That's one of many antioxidants that are important to keep the balance of the free radicals in check so that you have your mitochondria, let's say, stay healthy despite all of the stress of creating the ATP along the way. But they're not enough. I think that's the message that you… Just by, let's say, supplementing and providing more antioxidants, you can't really stall the inevitable, which is the damaging of the mitochondria as a normal process in the day-to-day as the cells are functioning.

Jeff Krasno: Just because the history of the mitochondria is so fascinating and interesting, I wonder if you could just spend a couple of minutes touching upon how humans and I suppose, animal life, in general, came to co-evolve with these energy-producing organelles.

Chris Rinsch: I think that's an area where I'd prefer to pass that off to an expert.

Jeff Krasno: Fair enough. We could even just skirt over it. I was reading something fascinating that Lynn Margulis, who was Carl Sagan's wife, and then wrote under the name Lynn Sagan, was the first one to posit the notion that mitochondria actually came from this purple bacteria, I think, sometime in the '60s. She wrote a paper on it, and no one would publish it.

Jeff Krasno: Finally, she got it published somewhere after being rejected seven or eight times. It postulated this notion that, "Hey, the mitochondria looks so much like bacteria under a microscope." If you just go on images, on Google images, actually, anyone can do it. You can just see. There's an incredible resemblance between the two. Then there started to be these other characteristics that they share because the mitochondria actually has some of its own genome. Is that right?

Chris Rinsch: Sure. Mitochondria does have its own genome, although there are proteins that are coming that have genes also from the cell. They co-live together. Over time, as you're mentioning that the mitochondria and our cells, there was that evolution where the mitochondria basically from the bacteria became included inside of ourselves and played that role of generating the ATP and the energy for ourselves and also taking in the oxygen. So this co-evolution.

Jeff Krasno: Yeah, I think it's fascinating. I think about the microbiome, for example, which is such a hot topic. Of course, once we get into our conversations around Urolithin A, we will probably circle back to the microbiome because gut bacteria plays a significant role in the metabolism of certain polyphenols to create endogenous Urolithin A.

Jeff Krasno: But before we get there, I think about what it is to be human. We really co-evolved with all of this bacteria in our gut. We're starting to know about that. We've got 39 trillion cells, mostly in our gut. But now we're learning all over our body, particularly in our nose and in our mouth, even on our skin, known as the microbiome so we co-evolved with these precarious over here.

Jeff Krasno: Then we start to learn about the mitochondria, which seems to be a bacteria that an archaea tried to eat, but the bacteria resisted the digestion of it, and they found some symbiotic relationship. Over time, as the world became more aerobic and there was more oxygen in our atmosphere, it became more viable for these particular single-celled organisms to exist and to create energy. Somehow they became absolutely critical to the expansion of complex life because we just didn't have the ability to make enough energy before the advent of mitochondria.

Jeff Krasno: We were simply the single-cell organisms or, I guess photosynthesis had started to happen. But really, it's this incredible endosymbiosis that then gave birth to all of this amazing life that we see in the world. So it's amazing. We know now that mitochondria play key functions. What is mitochondrial dysfunction? What are some of the components that contribute to that dysfunction?

Chris Rinsch: When we're talking about mitochondrial dysfunction, it's really a question of back to energy and the ATP generation. We've looked at this clinically with a tool called magnetic resonance spectroscopy. What it allows you to do is look at energy production, in fact, the ATP levels. So you put it in a special magnet. You contract your muscle and you can see the decline in the energy. Then when you stop, you can see the return to normal. Depending upon the health of the mitochondria, this is quicker or it's slower.

Chris Rinsch: To summarize, depending upon your condition and it's even your age, you could have a decline in mitochondrial function, and that can have an impact directly on limb function, limb muscle function, for example, mobility or other type of function. In fact, there's a number of diseases that are linked to a decline in mitochondrial function. One of those is linked to this skeletal muscle component. There's others that are even at the level of the brain and brain health as you get older. The decline in mitochondrial function can have a number of negative effects on our lives.

Jeff Krasno: Hey, it's Jeff. I talk a lot about my 16:8 fasting protocol here on the show. A fasting in conjunction with my low glycemic diet, can put me into a state of ketosis. Now this means that I'm converting stored fat into ketones that my body uses for energy instead of glucose. Ketones cross the blood-brain barrier and are the preferred source of fuel for the brain. My brain, like yours, is awfully greedy. It hoards 20% of my body's energy, despite being only 2% of its mass. Ketosis is also associated with the famous ketogenic diet where you maximize the consumption of fats and reduce carbs.

Jeff Krasno: But the keto diet is simply not for everyone and not for everyone all the time. So I've started to take Ketone-IQ. These are exogenous ketones. Endogenous means your body makes it. Exogenous means you got to get it through diet. Ketone-IQ gives my brain an incredible fuel source, especially when I go into bouts of learning, like when I'm researching for the show. Now ketones, like I said, are really the brain's preferred fuel source. I'll go into why that is in a longer episode. Now Ketone-IQ really provides a very steady, calm burst of energy without the jitteriness you can get from caffeine.

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Jeff Krasno: I recently spoke to a doctor named Chris Palmer out of Harvard who wrote a book called Brain Energy, a fascinating book. His unified thesis is really that mental disorders are really metabolic disorders at the mitochondrial level. Essentially… I mean, it makes some sense. If you begin to suffer from some form of neurodegenerative disease, what you're seeing is brain shrinkage and the neuron's inability to properly create energy. His thesis is fascinating. But as far as a lot of your work is concerned, I think you guys have focused largely on muscle function. Can you talk a little bit about sarcopenia and some of the detrimental impacts of loss of muscle function?

Chris Rinsch: Sure. Very early on, we conducted a study looking at a population that are considered prefrail. That's not yet at sarcopenic levels, but it's basically individuals who are starting to have problems, stepping, walking, getting out of chairs, and general mobility problems.

Chris Rinsch: We compared those with a group of age-matched individuals, and this is age of around 70 years old, who were athletic and exercising on a regular basis. We tried to understand fundamentally what is different between the muscles of these two populations. We went and we ran the study that I was referring to earlier with this magnetic resonance spectroscopy, and we saw a decline in the mitochondrial function in the legs of these individuals who were pre-frail.

Chris Rinsch: Then we did biopsies, and we looked at the biopsies, and we saw a decline in the gene expression of mitochondria genes, and showing that there's basically less mitochondria biogenesis, which translate that means production of mitochondria, a regular production of mitochondria. We saw a decline in the various complexes. This is the mitochondrial complexes, which are important in the production of ATP. That was one of our our first observations that the decline in mitochondrial function is really essential for healthy muscle function and mobility.

Chris Rinsch: Now this wasn't a cause and effect study, but it's an observation in this population that were significantly impaired as being prefrail that mitochondria, when looking at the sharing them with healthy, that mitochondria gene set was one of those leading gene sets that jumped out as being impaired. When you think of… Now, we haven't looked at sarcopenia.

Chris Rinsch: Sarcopenia is taking at another step where you're looking at the amount of muscle mass and how that declines with time. Sarcopenia is where there's been more muscle mass loss. So it's not only a loss of function, but also a loss of mass. There's always been historically an approach when you have a decline in muscle mass that you try and increase the muscle mass, which makes a lot of sense.

Chris Rinsch: But then you need to make sure that that increased muscle mass is also very functional. It's not easy to increase muscle mass, certainly as you get older, and that's one of the challenges. Although I have seen some people recently who are in their late 70s and who have lots of muscle and just is super impressive. I don't know how they do that.

Chris Rinsch: But yeah, when you're having whatever amount of muscle you have, you want to make sure that it's basically functioning at its peak. I think that's really where the mitochondria comes in. If you can take your muscle cells, even in a sarcopenic individual who has had a decline in their muscle mass and make them function better, then the muscle at itself should function better.

Chris Rinsch: That's one of our underlying approaches to improving muscle function. It's by acting at that level of the mitochondria and basically optimizing the bioenergetics of your cells. No matter How much of an age you are or what the statuses of your tissue are, whether you have large muscles, whether you have small muscles, to try and raise the functionality across everything.

Jeff Krasno: It's interesting. You guys are doing muscle biopsy. Are there simpler, more subjective measures of poor mitochondrial health that one might just discern on their own? For example, is chronic fatigue or brain fog a reflection of mitochondrial dysfunction or, I don't know, like grip strength or your walking gait or whatever.

Chris Rinsch: Yeah. So there's a lot of… Mitochondrial function is really linked to physiological performance. So you can screen people for performance using different types of measurements. We spoke about walking speed. There's the tests that allow you to screen for people who are, let's say, prefrail or more frail by… The six-minute walk is a common one, how far can people walk in six minutes. There's also different measurements, like getting them on a bicycle, for example, and seeing what their performance is on a bicycle.

Chris Rinsch: This is a more non-invasive way, of course, to screen than biopsies. There is the overall energy level, too. We think our general energy level is linked to fundamentally the energy level of ourselves in our body. If our cells aren't and the mitochondria are functioning well, you can expect your energy level to be very high. You were also speaking earlier about brain function.

Chris Rinsch: In addition to memory and these types of cognitive effects, there's been links to stress and the importance of properly functioning mitochondria to help resist stress that you might have. There's a number of different ways that you might feel a change in your mitochondrial function. Even when you're exercising, how easy is it for you to recover after post-exercise.

Jeff Krasno: You mentioned stress as a contributing factor to mitochondrial dysfunction. What are some of the other prevalent contributing factors that cause your mitochondria to dysfunction?

Chris Rinsch: In addition to stress, I would say that aging is one of the primary drivers of mitochondrial dysfunction, just generally speaking. One of the reasons is that as you get older, this process that we were talking about before, I called mitophagy, actually declines. The cleanup of your damaged mitochondria is slower. Consequently, you have more damaged mitochondria accumulating inside of your cells. Generally speaking, on a whole, your cells aren't functioning at their peak.

Chris Rinsch: But then there's also lifestyle choices. It's known that when you exercise that this is stimulating a process of mitophagy as well. You'll see mitochondrial biogenesis if you take biopsies. People who are exercising regularly, you'll see an elevated level of mitochondrial biogenesis and this creation of new functioning mitochondria versus those people who have a more sedentary lifestyle, and you'll see less of that going on.

Chris Rinsch: In general, if you were to look at those having a sedentary lifestyle versus a very active and fit lifestyle, the mitochondria are going to be much more active and much more functioning in those people who are active.

Jeff Krasno: Exercise versus sedentariness plays a big role there. What about sleep?

Chris Rinsch: That's a good question. I'm not really familiar with the impact of sleep on mitochondrial function, but I would say that there's... One thing that we have to think about when we're sleeping that there is this whole aspect of dietary restriction and fasting. Fasting is another element that is stimulating mitophagy and keeping our mitochondria healthy.

Chris Rinsch: When you look at the genetic profiles in terms of on the muscle cells and other cells when they're fast, that you see an upregulation of mitochondrial biogenesis as well and an improvement in mitochondrial function. It would be logical to think that if you're sleeping for a longer period of time and getting more restful sleep, that you're probably favoring a better mitochondrial profile inside of your cells.

Jeff Krasno: I leverage the 16-8 intermittent fasting protocol most of the time. Although we just finished a very busy holiday season. I can't say that I was fundamentally strict over that period.

Jeff Krasno: But if you use your sleep window to chalk up eight hours of fasting, it certainly makes the other eight hours or however many hours you end up fasting a lot easier. There is a component here of fasting stimulating certain cellular pathways, like AMPK is one, for example, that then triggers this cell repair process, autophagy and mitophagy.

Jeff Krasno: It also seems like sleep has some relationship to insulin sensitivity, and poor sleep seems to contribute to insulin resistance. I just want to touch on that for a second as it pertains to diet and lifestyle. Obviously, there's this standard American diet, which is very high in refined sugars and refined grains and starches and ultra-processed foods that is contributing to high blood glucose levels and then down the line, insulin resistance, which has an impact on our mitochondria's ability to create energy. Is that right?

Chris Rinsch: Yes. These diets, as you were referring to, are really not optimal, not only for your body, but for your general metabolism and for your mitochondria function. We would assume it's logical that these types of diets aren't good for you. But there are foods that you can take that are beneficial for your mitochondria.

Chris Rinsch: I think that's where we should be thinking of how can we change our diet or incorporate things into our diet that are going to be helpful to help maintain that an optimal functioning of your mitochondria and eventually stimulate this process of mitophagy.

Jeff Krasno: Exactly. This is the good news. This is the gospel. We've covered a lot of the bad news and all of the different components to dysfunction. But the good news is that our body has adaptive mechanisms that, under the right circumstances, can stimulate processes like mitophagy or what you referred to, mitobiogenesis, the creation of actual new mitochondria in the cell, which is good news.

Jeff Krasno: Just more generally as it pertains to metabolism, you can increase your insulin sensitivity. You could reverse insulin-resistant and become more metabolically flexible. There's all these tons of different things that one can do.

Jeff Krasno: Some of that you already mentioned. There was exercise and fasting. But maybe you want to touch on some of the foods and their constituents that can help trigger some of these healthful processes.

Chris Rinsch: Sure, Jeff. We started looking at the pomegranate quite a number of years ago. One of the types of compounds is actually a class of compounds that's found inside of the pomegranate are the ellagitannins. These are larger compounds, phytochemicals that are found not only in the pomegranate, but they're found in various nuts and berries.

Chris Rinsch: Essentially, what happens is that when you consume them that they're digested in the stomach, and then they're processed in the intestine by gut bacteria. We were talking about the importance of microflora earlier. If you have those right gut bacteria, these compounds, these ellagitannins are processed into a postbiotic that is called Urolithin A.

Chris Rinsch: We've spent a lot of time now studying Urolithin A, and together with a number of collaborators at scientific institute here, the EPFL, as well as other institutes. What we've shown is that this postbiotic Urolithin A, it can stimulate this process called mitophagy.

Chris Rinsch: This is pretty exciting because this is something that's coming from the foods we eat, and it has this potential to interact at the cellular level and basically help reduce, in reverse, the decline of mitochondrial function that happens naturally and boost by boosting this level of recycling the damaged mitochondria.

Chris Rinsch: We've spent a lot of time studying this. This is something I think that it'd be very pertinent for people to take. It's the first, and to my knowledge, the only nutrient that is actually stimulating this process of mitophagy when consumed orally.

Jeff Krasno: It's fascinating. I'm so curious to know how you landed on pomegranates. I just want to make sure that I understand the mechanism of action here. If you consume exogenously pomegranates, and we can talk maybe about the particular that the part of the pomegranate that has the ellagitannin and compounds, but also maybe raspberry. I think walnuts and pecans maybe have ellagitannins as well.

Jeff Krasno: They go through the normal process of digestion, but some of that goes into essentially your colon, your large intestine, and gets metabolized by certain strains of bacteria and postbiotics or metabolites are produced by that bacteria to produce this compound called Urolithin A that seems to have a really, really positive effect on mitochondria and as you say, mitophagy. Is that a general understanding of what's happening?

Chris Rinsch: Yes, as you say, it's quite a pathway. It's quite a process from the foods that you take to actually getting this compound.

Jeff Krasno: That says nothing of actually getting into your car and driving to the farmer's market to get the walnuts in the first place to get the pomegranates or to grow them. Is there a particular bacterial strain or species in the gut that synthesizes Urolithin A? Or do we even know what that might be?

Chris Rinsch: Yeah. It's very interesting. We've looked at this over the years, and it's very complicated to basically isolate the right strains that can perform this conversion. There's been a couple of groups out there that have postulated that some strains that could be acting on it. But it's been yet to single out an individual strain that will perform this activity.

Chris Rinsch: It's probably due to a combination of bacterial strains that are playing different roles in terms of the chemical modifications. Because it's creating something, but you have a starting compound that's coming, in and it's being chemically modified, and you're having different modifications. This makes it a little bit more tricky.

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Jeff Krasno: I've got to retrain my reductionist, Newtonian brain. I always want to know like, "What is the specific bacterial species that metabolizes ellagitannins into Urolithin A?" You're absolutely right. It rarely works that way. It's just these bacteria are working within a mosaic and a matrix, and it's probably very difficult to put your thumb exactly on the process.

Jeff Krasno: I assume, though, in general, people have to have a very healthy gut microflora to be able to create this postbiotic? Probably not everybody has the ability to synthesize your Urolithin A at the gut level.

Chris Rinsch: You're right, Jeff. We actually conducted a clinical study a couple of years ago in Chicago where we had people take pomegranate juice and consume a glass of pomegranate juice, and we monitored their ability to basically produce Urolithin A. We took blood samples, and we measured Urolithin A in those samples.

Chris Rinsch: Essentially, what we saw was that only about 30-40% of the population was able to produce measurable amounts of Urolithin A. They were measurable, but based on other work we've done, they were not at the level that you would need to actually have the benefits that we see with Urolithin A when it's administered in a more direct form, direct manner.

Jeff Krasno: That's interesting.

Chris Rinsch: Sorry to interrupt, but I think one of the challenges also with taking pomegranate juice is just the high amount of sugar. During that study, we compared the amount of Urolithin A that you get into the body with a glass of pomegranate juice versus directly administering 500 milligrams of Urolithin A.

Chris Rinsch: What we saw was that you needed basically six times more pomegranate juice. You basically need to have about six glasses of juice to get the same levels as directly administering. It's not an effective way to get what you need to give you those benefits.

Jeff Krasno: It sounds like it might make you prediabetic in the meantime, too. I wear a CGM, and I can only imagine what six glasses of pomegranate juice would do to my levels app. I think that's fascinating. Really, only 30% or 40% of the people can even synthesize Urolithin A from ellagitannin.

Jeff Krasno: Even in the best-case scenario, potentially that points to people's compromised gut flora, but it's also maybe just bioindividualities. Some people just don't have the ability to generate certain compounds.

Jeff Krasno: Also, I suppose when you're drinking the pomegranate juice, through the process of processing a pomegranate, you're losing a lot of the white, pulpy part of the pomegranate. Is that where you find most of the ellagitannin?

Chris Rinsch: That's back to your point of where are the origins located inside of the pomegranate. You have your arrows that are bright red, and then you have this yellow-whiteish membrane that surround and all of those. It's really this yellow-whiteish membrane that's very bitter when you taste it that contains all of these ellagitannins. I don't encourage you to bite in and chew some of that because it's not enjoyable at all.

Chris Rinsch: But in the process of basically making pomegranate juice and compressing the pomegranate, you squeeze out these ellagitannins from this yellow membrane, and that goes into the juice, and so then you are able to consume it. We've actually measured levels of ellagitannins and juices and some commercial juices, and they do seem to be pretty consistent.

Chris Rinsch: There is a very consistent processing of the juice, although it doesn't give you enough, and you still have that whole process that we discussed of converting the ellagitannins into Urolithin A, and then having that actually get absorbed into the body.

Jeff Krasno: You've been able to synthesize a pure Urolithin A compound. I'm curious, how do you actually do that? I don't assume that you have a bunch of petri dishes with bacteria in them and feeding them ellagitannins. Is there a process in the lab by which you create pure Urolithin A?

Chris Rinsch: Yeah, it's a very clean process. It's industrially similar to a way vitamin C would be manufactured. This is using synthetic chemistry where we make a product that is ultra-pure, so likely much pure than you would be able to purify out if you were to try and extract Urolithin A from some type of a fluid, for example, a body fluid after you would produce that normally. The nice thing is that you have that, that you can then titer out into very specific doses, and then you can analyze the impact of specific doses on mitochondria orally. That's what we've been doing.

Jeff Krasno: What is the proper dosage that you would recommend for the Mitopure product?

Chris Rinsch: The product that we're selling is Mitopure, which is our proprietary Urolithin A. The dose is 500 milligrams, and that's the starting dose. We've done a couple of studies now. Actually, we've done three double-blind, placebo-control studies with Mitopure. What we've shown is that at 500 milligrams, we can see that benefit on the mitochondria function, and that we also see benefit on muscle functionality.

Chris Rinsch: Our very first study, we looked at 500 milligrams and a gram after a month, and what we saw was an improvement. This is through biomarkers. We were speaking about muscle biopsies. We looked at muscle biopsies before and after taking our product for a month, and what we saw was an increase in gene expression of mitochondrial genes and a gene set that's enriched process, so what they call a mitochondria gene set.

Chris Rinsch: It's a number of genes that's involved in the normal mitochondrial. Yeah, health and functioning. You see all these genes upregulated, and together they have the combined effect of improving and increasing the mitochondria geneset and enriching that inside of the cell. That was one of our very first studies.

Chris Rinsch: Then the second study we conducted was in individuals who were 40-65 years old and who were sedentary and had a little bit more overweight. We looked after four months. This is the first time that we actually investigated the effect of Urolithin A on a physiological endpoint. We looked at the muscle function after four months, and we saw an improvement in leg muscle strength by over 10% in those people were taking 500 milligrams and 1,000 milligrams. At the higher dose, we were beginning to see some effects on VO₂ peak and even on six-minute walk.

Chris Rinsch: Also, we continue to run these other studies where we... These other biomarkers, as I mentioned, the biopsies, and also looking at basically blood biomarkers that you'd find in the plasma. What we've consistently seen is that when we look at biopsies, we see an improvement in mitochondria function through this gene set enrichment of mitochondria genes.

Chris Rinsch: In terms of biomarkers, we also see an impact on biomarkers, particularly acylcarnitine. Acylcarnitine basically is downregulated. That's what we see when we compare the before and after snapshots in individuals who've been taking Urolithin A.

Chris Rinsch: This has been shown in the past that people who have more of an impaired mitochondria function that they have elevated acylcarnitine levels because this is part of the whole metabolism process of the cell in terms of consuming those acylcarnitines.

Jeff Krasno: Fascinating. At this juncture, do you understand the mechanism of action of Urolithin A at the mitochondrial level? Certainly, you guys have been unbelievable in terms of your commitment to clinical research and to creating a product that's been validated by science. But I wonder if you actually understand what the mechanism of action is at the mitochondrial level. What is this Urolithin A compound actually doing? Do we know?

Chris Rinsch: Well, it's a good question, Jeff, that we are hard at work on. I think your question alludes to what are the molecular interactions of Urolithin A inside of the cell? What are the cascade of events that occur that leads to mitophagy? What we can say is, one of the ways we look at mitophagy and determine that there's mitophagy happening inside of the cells, one of many. But it's looking at ubiquitination of your mitochondria.

Chris Rinsch: Basically what happens is that your mitochondria get... When they're damaged and they're targeted for this process of mitophagy, they become decorated with ubiquitin, and this targets the mitochondria to that pathway.

Chris Rinsch: With regards to all of the other processes that are involved from the Urolithin A arriving to the cell to that, we are still working hard at that. In fact, this whole process of mitophagy, this is relatively new over the last 10 years that people have been working on mitophagy. It's a pretty new field with a lot of really smart academic groups working on it and trying to understand what are the different ways of mitophagy.

Chris Rinsch: I think one of the reasons that we think that we've been rather successful in our stimulation of mitophagy is that it's a gentle stimulation because there are other pathways that are stronger.

Chris Rinsch: The fact that we're dealing with Urolithin A, which is basically this nutrient that's been in our... That we've been exposed to since the dawn of time, this is very, very safe. There's no risks associated with it, which make it so that it is having this gentle but yet potent effect on ourselves. We will see more in the future as we continue our research along that way.

Jeff Krasno: I mean you mentioned that the risk profile is very low, no side effects, but you guys have also been stringent in terms of going through all the processes and the GRS process and all of that, so you guys are...

Jeff Krasno: Also, I'll just mention, I think you guys have been around as a company since 2007 doing clinical research. This is hardly a product that's just gotten thrown on to the shelves on a whim. This is a product of 15 years of research, which is admirable.

Chris Rinsch: Well, thank you. I think, and as you say, it's something that we've worked on on a preclinical and a clinical manner for over these last 15 years. I think, what we've taken is more of a traditional biotech mentality of let's raise the bar in terms of the level of validation that you need and the science, because it's really...

Chris Rinsch: Fundamentally, it's the science that should be driving the effects of any type of nutritional supplements that you take, and we want everybody to be comfortable that the science is rock solid. We've really made that effort to create great clinical studies. As I mentioned before, our clinical studies are all double-blind, placebo-controlled studies, and we've published them in all leading academic journals that are out there. I think this is important for anybody working in this space to stay at this level of rigor.

Jeff Krasno: Hey, it's Jeff. Now, I always heard vitamin supplements are a waste of money as they just pass through your system. Expensive pee, right? Well, now I understand why, and the reasons it's so hard to absorb large doses of certain nutrients through the pills, powders and gummies at the store.

Jeff Krasno: Now when you take these supplements or even consume foods, your digestive system must extract vitamins and minerals, and depending on the nutrient, convert them to a form your body can use. Now some nutrients depend on proteins to transport them into the bloodstream and to the cells for absorption. Now often, these supplements contain such large quantities that your body doesn't have enough resources like transporter proteins to absorb the nutrients.

Jeff Krasno: Since your body can't store water-soluble vitamins like C and the B family, as well as minerals like magnesium, zinc and selenium, they wind up excreted and never reaching the cells where they are needed to support your immune system, metabolism, nervous system, and so much more.

Jeff Krasno: Now, I didn't know all of this when I started taking LivOn Labs Lypo-Spheric Vitamin C. I just know that if Skyler was giving them to me, they must be good. Well, it turns out that LivOn Labs understands the difficulty of high-dose nutrient absorption, and they became the first dietary supplement company to use liposomal encapsulation technology to enhance nutrient absorption.

Jeff Krasno: Liposomes are double-layered spheres that LivOn Labs uses to surround, protect and transport water-soluble vitamins and minerals into the bloodstream and to the cells for absorption. Liposomes are made of essential phospholipids, the same material that makes up your cells, so they easily pass into the cells and deliver the nutrients staying behind to fortify the cell membrane.

Jeff Krasno: The LivOn Labs liposome-encapsulated supplement line includes vitamin C, a B-vitamin complex that contains pre-methylated folate, a magnesium specifically formulated for the brain, and the master antioxidant, glutathione. Guess what? Only the ingredients necessary for maximum absorption. That means no sugar and no fillers, no colors, no artificial flavors. If you don't want to know what that tastes like, and trust me, you probably don't, make sure to follow the instructions on the package.

Jeff Krasno: Right now, LivOn Labs is offering Commune listeners free sample two-packs of all their liposome-encapsulated supplements with any purchase. This is a great way to try all six of their powerful supplements and get accustomed to their weird, unique, goo-like consistency. Just get yours at livonlabs.com/commune. This offer is only available through my link. You must go to livonlabs.com/commune. LivOn Labs has a 100% satisfaction guarantee or your money back, so you have nothing to lose. Go to livOnlabs.com/commune.

Jeff Krasno: Let's talk maybe a little bit about delivery. I do actually have... First of all, I might also say that the packaging is exquisite. You guys did an absolutely beautiful job.

Chris Rinsch: Thank you.

Jeff Krasno: I have here, for those who are watching this on YouTube and not just listening to the audio, I have one of the packages here that I was lucky enough to receive. This one is 500 milligrams of a powder that just gets...

Jeff Krasno: Well, for me, I just put it in a glass of water, and it tastes good, but it's relatively innocuous. It's not a strong flavor, per se. But I also know that there's a capsule version, I believe. Then I did actually try the shake version, which I actually quite enjoyed. It's a protein concoction there with whey protein, I believe. But it was very good. I actually did it yesterday before my resistance training, and it was great.

Chris Rinsch: As you mentioned, Jeff, our thought was it's important to take this in the morning, and most people have a ritual around their breakfast time. We wanted when we started, and we launched with the product that you just showed, which is this berry-flavored powder, and we wanted people to have a food experience, basically, that they could control, and depending upon their preferences. You can mix it into a yogurt. You can also mix this into your favorite smoothie. But the idea was, let's give people an opportunity to take a nutrition product as something other than a pill. That's why we introduced this product.

Chris Rinsch: We've also introduced soft gels as well. We have this protein shake, which has 20 grams of whey protein that you were mentioning, which yeah, I take that. I took that just the other day too. It's great. Tastes great.

Chris Rinsch: In addition to that, we've recently taken a look at other delivery ways for Urolithin A, and this not ingestible, but more topical. We've come up with, and this was a thought we had a few years ago of what would be the impact when applying this directly on the skin because our skin is the largest organ of our body, as we all know, and it has cells, and it's influenced by our natural aging, our intrinsic aging of ourselves, as well as these extrinsic effects or sunlight that we're exposed to that cause photoaging. We embarked on exploring how can Urolithin A potentially counter intrinsic and intrinsic extrinsic aging.

Chris Rinsch: This last year, we ran some studies on that as well. What we saw is that we have an impact on both forms of aging when applied topically. We see that following UV radiation and application of Mitopure and our Timeline formula that we see a reduction in inflammation. We've also seen basically a reduction in wrinkles as well when combined in our formula. We decided to introduce that just recently. That was launched just at the end of this last year, and we just started shipping that in the US.

Jeff Krasno: Oh, wow. I wasn't aware of that. Is that in the form of a balm or a lotion? Or how does one apply Urolithin A topically?

Chris Rinsch: It's a cream. We have a cream that is... We have a day cream, we have a night cream, and we have a serum. That's applied in the morning, it's applied at night, allowing your cells to get the same benefits and energize your cells, even from the outside.

Jeff Krasno: Amazing. It still has the same bioavailability or enough bioavailability to be impactful.

Chris Rinsch: Yes. We focused on measuring basically endpoints that are visible, like wrinkles, which is what people are looking at when they look in the mirror, and also looking at inflammation following exposure to UV light. We were glad to see that these benefits continuing when applied topically.

Jeff Krasno: Just back to the ingestible product for a second. Let's say, I get on my routine and I'm taking 500 milligrams per day. How long does it take in terms of duration to actually see an effect?

Chris Rinsch: In our latest clinical study, where we were looking in individuals over 65, what we saw was that after two months, we saw an improvement in muscle endurance in both the hand muscle, this first interosseous muscle, which is the muscle you use when you're opening jars and those types of things, and then also in the leg muscle. We looked at a very targeted endurance of those muscles, leg muscle and the hand muscle.

Chris Rinsch: After two months of taking the product, we see significant improvement there. Then in terms of, I think I was mentioning before, the other study that were in population of 40-65, these individuals saw improvement. We only measured after four months, and this we saw an improvement of greater than 10% muscle strength improvement after that time.

Jeff Krasno: This is not something that you're just going to take one day and expect to see an immediate change in subjective?

Chris Rinsch: No, it's not a stimulant. I think that's important. It's not like taking… When we think of energy, you think of caffeine, which is that instant stimulus. We like to think of this more like energy 2.0, that you're fundamentally changing your cells and what's happening inside the cells and those mitochondria are being optimized, and that takes time.

Chris Rinsch: Biology takes time. The cells need to improve, and then the cells interact with one another, and then all of that together takes time. I think an easy way to think about how long does it take to see an effect. When you go into the gym and you exercise, how many gym sessions do you need before you start to see an improvement in terms of your muscle strength and your muscle performance? It's not just go to the gym one time. You have to do it on a consistent basis.

Jeff Krasno: Right. We live in a culture that wants immediate results. I think any of us who have committed to a health journey or any journey, a learning journey, for example, you don't just build new neural networks overnight. It's a process of continuing to stay committed to whether that's learning how to play the piano or upgrading your mitochondrial function, or hypertrophizing your biceps.

Jeff Krasno: You guys have just done just such an exemplary job on all fronts. You've really taken your time. You've done the research. You've packaged up just, as I said, a beautifully presented product. Now you're really helping upgrade a lot of people's lives. Because as we touched on earlier in the conversation, what are we if we are not energy? Really at the core of what it's like to be alive is to create and burn energy. You've gone right to the origin of the whole thing here.

Chris Rinsch: Thank you, Jeff. We're really excited that obviously when we started the company, it was hard to anticipate how things would evolve, but with Urolithin A, we see this impact with all of… We get so much feedback from our customers and impacts on different aspects of their life. It tends to be more energy and muscle-focused, but it's different for each person in that some people are mountain climbers and they swear by it when they climb Mount Everest. We had somebody who climbed Mount Everest and sent us a picture of him on top of Mount Everest with our package. We said, "Is this real?"

Chris Rinsch: The guy is wonderful and he's been very careful in monitoring all of the improvements that he experienced when taking the product. Then we have people who are cyclists and people who are runners and other, whether it's professional or just amateur athletes or just normal non-athletic people, we've seen a lot of and heard about a lot of benefits. I think that's what's rewarding to us is to being able to create something that people are feeling a benefit about. I know everybody here at Timeline is really dedicated to that as a mission.

Jeff Krasno: Where can one avail oneself of the might appear timeline product, because as I understand it, is it only a direct-to-consumer offering or are you guys with that?

Chris Rinsch: We sell online on timeline.com. If you go on to our website, you can have access to all of our nutrition products, as well as the topical products, where we're also providing nutrition to your skin as well.

Jeff Krasno: Love it. All right. Chris, it's been a delight to get schooled in the mitochondria and the different things that we can do to upregulate our mitochondrial function, and specifically the Mitopure product and Urolithin A. It's just fascinating. We're on the cusp of this new frontier where we can have a lot of agency over our own health.

Jeff Krasno: I talked to my dad, and he'll be 81 next week. His relationship with health was for most of his life was just going to see his primary care physician once a year. He would take a battery of tests and be like, "Okay, you're fine. Move along." That's it. Things have really, really changed. There's so many tools, there's so much data available now for people to really become the CEO of their own healthcare, and you're playing a huge part in that. Thanks for all the work that you're doing.

Chris Rinsch: Thank you, Jeff, for having me. It's great to be able to contribute in this way, and we hope that people can benefit from Urolithin A, and that it will help them all reach their own health objectives as they work on them and try and optimize their own nutrition.

Jeff Krasno: Nice. Well, to be continued, I'll see you in Topanga, I hope, sometime in the near future.

Chris Rinsch: I hope so. Thanks so much, Jeff. Appreciate it.

Jeff Krasno: Thanks, Chris.

Jeff Krasno: Thank you for listening to my conversation with Chris Rinsch, developer of Mitopure, a supplement that improves mitochondrial health, muscle strength, and endurance in humans. If you enjoy this show, please subscribe on Apple Podcasts and leave us a review.

Jeff Krasno: If you're a regular listener, you know how much effort we put into this show's creation, and we really do our best to keep ads to a minimum. If you're looking for a way to support our efforts, the best way is to subscribe to Commune. You'll get access to more than 100 courses featuring the world's top authors and thought leaders. You can check it out for 14 days for free. No strings attached at onecommune.com/trial. Of course, feel free to reach out to me directly with questions, suggestions, criticism of the constructive variety at jeffk@onecommune.com.

Jeff Krasno: Lastly, and not leastly, I'd like to thank the folks that make this show possible week over week over week, including Jacob Laub, Megan Stone, Violet Augustine, Silvana Alcala, Wellington Gonzalez, and Ryan Tillotson. That's all from the Commune for today. My name is Jeff Krasno, and I am here for you.

Jeff Krasno: Hey, it's Jeff. I always heard vitamin supplements are a waste of money as they just pass through your system. Expensive pee, right? Now I understand why and the reasons it's so hard to absorb large doses of certain nutrients through the pills, powders, and gummies at the store.

Jeff Krasno: When you take these supplements or even consume foods, your digestive system must extract vitamins and minerals. Depending on the nutrient, convert them to a form your body can use. Now, some nutrients depend on proteins to transport them into the bloodstream and to the cells for absorption.

Jeff Krasno: Often these supplements contain such large quantities that your body doesn't have enough resources like transport or proteins to absorb the nutrients since your body can't store water-soluble vitamins like C and the B family, as well as minerals like magnesium, zinc and selenium. They wind up excreted and never reaching the cells where they are needed to support your immune system, metabolism, nervous system, and so much more. I didn't know all of this when I started taking LivOn Labs Lypo-Spheric Vitamin C. I just know that if Skyler was giving them to me, they must be good.

Jeff Krasno: It turns out that LivOn Labs understands the difficulty of high dose nutrient absorption, and they became the first dietary supplement company to use liposomal encapsulation technology to enhance nutrient absorption. Liposomes are double-layered spheres that LivOn Labs uses to surround, protect, and transport water-soluble vitamins and minerals into the bloodstream and to the cells for absorption.

Jeff Krasno: Liposomes are made of essential phospholipids, the same material that makes up your cells. They easily pass into the cells and deliver the nutrients staying behind to fortify the cell membrane.

Jeff Krasno: The LivOn Labs liposome encapsulated supplement line includes vitamin C, a B-vitamin complex that contains pre-methylated folate, a magnesium specifically formulated for the brain, and the master antioxidant, glutathione.

Jeff Krasno: Guess what? Only the ingredients necessary for maximum absorption. That means no sugar and no fillers, no colors, no artificial flavors. If you don't want to know what that tastes like, and trust me, you probably don't, make sure to follow the instructions on the package.

Jeff Krasno: Right now, LivOn Labs is offering commune listeners free sample two packs of all their liposome encapsulated supplements with any purchase. This is a great way to try all six of their powerful supplements and get accustomed to their weird, unique, goo-like consistency.

Jeff Krasno: Just get yours at liveonlabs.com/commune. This offer is only available through my link. You must go to liveonlabs.com/commune. Liveonlabs has a 100% satisfaction guarantee or your money back, so you have nothing to lose. Go to liveonlabs.com/commune.

Mitochondria, Muscle Strength, and Pomegranates

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VO2 max and longevity – Optimizing your healthspan

Boosting skin health: plant-based foods that keep you young

Mitochondria, Muscle Strength, and Pomegranates

Table of contents

Topics covered

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VO2 max and longevity – Optimizing your healthspan

Boosting skin health: plant-based foods that keep you young

Meet Mitopure’s New Veggie-Cap Softgels