How Urolithin A Stimulates Mitophagy, Renews Mitochondria & Improves Muscle Strength

Bulletproof Radio, a state of high performance. You're listening to Bulletproof Radio with Dave Asprey. Today is going to be a really fun show because we're going to talk about Urolithin A. Okay, maybe you don't think it'll be fun, but trust me, it will because there's a huge amount of new knowledge from two experts who know a lot about plants and how plants interact with our cell biology. The first of the two has a background in cell and molecular biology, biomedical engineering. His name is Chris rynch. He's a PhD, 20 years of experience, has written original publications that have been published in science journals about Urolithin A. This stuff affects muscle function, cells and mitochondria. And you guys know I'm kind of a mitochondriac here. Our second guest is Navindra Seram, a PhD who's a professor and chair of the Biomedical and Pharmaceutical Science Institute or department at the University of Rhode Island. And he runs the Bioactive Botanical Research Laboratory, figuring out what medicinal plants and their natural compounds can do against chronic human disease. Welcome to the show, Navindra and Chris.

Hey, thanks for having us. Thanks, Dave.

I want to start Navendra. It's really interesting that there's a whole university department about this. You know, how do we get compounds from plants and separate them out and do things like that? What got you into plants?

My department, as you said, the Biomedical and Pharmaceutical sciences department, is within the College of Pharmacy at the University of Rhode Island. Now, people are probably wondering, what does nutrition and plants have to do with pharmacy? Interestingly enough, the field that I work in is called pharmacognosy, which is, if you will, you could think of pharmacognosy as being the mother or the father of pharmacy. It's where the discovery of drugs started since ancient times. My background, I'm a third generation East Indian as my name, you could tell Navinder Serum. But I grew up in the British colony of Guyana, which was British Guyana and it's now Guyana since independence. It's in South America. But being a third generation growing up in a very poor third world, a country where there is not access to medicines and physicians like we know over here. I'm in the United States. I've been here for many, many years. So, you know, when we were kids growing up and we had a toothache or a tummy ache, you know, we'll go to mom and grandma, you know, they had an Indian origin and say, you know, what can we take? And you know, they would Say, take a certain plant, make a tea or chew on it, and lo and behold, the plant works or worked. And so from growing up, from my time as a boy growing up, my interest was very piqued in what implants are actually responsible for these effects, powerful effects that we know in humans. And from then I progressed, I did my PhD in the beautiful island of Jamaica, Kingston, Jamaica, the University of the West Indies. And then I migrated to the United States. I did a quick postdoc at Michigan State, spent some time at ucla. Sure, we'll talk about the pomegranate. And we get back to that. And here I am at uri, still trying to understand what are the bioactive constituents in plants and how they can benefit human health. So, a long answer to your short question, but I'm sure we can wrap back around. Dave.

I have a belief system that's crystallized over the last 10 or so years, and I want you to poke holes in it or agree with it, but this is not something I've really talked about publicly, but you're the perfect guy to ask. I think most plants want to kill you. In fact, we know that because if you just pick up a plant in your backyard and eat it, you're not going to like your day. So the process of cooking is largely, or at least in part to or processing. That includes fermentation. All that is to remove a bunch of the toxins in it. I'm seeing extraction methods, whether they're pharmaceutical or alcohol extraction, all that. It's just a way to remove the harmful group of stuff that we can tolerate but isn't good for us and amplify the good stuff. So I'm kind of looking at the pharmaceutical stuff you're doing is just modern cooking in a certain way, which allows us to take plants, we might not want to eat a lot of it, but this one thing in the plant we would benefit from rather than as a pharmaceutical science, really, it's just advanced way of removing the bad so you can leave the good. Is there good thinking there or am I kind of oversimplifying?

There's good thinking there, and we may need a different program. I mean, a lot more time to kind of delve into this. But you were right. You know, sometimes we're extracting, we're doing cooking to maybe again, as you just said, removing or maybe increasing, fortifying, increasing in that bioactive constituents or group that we would want. You know, a good example from the Caribbean, where I grew up, again, is cassava, also known as yucca. This is a very toxic plant and.

It has cyanides in it.

But you know, somehow the people figured out in ethnobotany and ethnomedicine that by cooking cassava and throwing away the water, you can get rid of the cyanogenic glycosides and then you'll consume the food for its starch. So you know, humans and plants have co evolved for centuries. And you're right, plants, plants don't care about us. They're obviously protecting themselves and they produce these natural products or these secondary metabolites for their competitive advantage. Well, we could argue that maybe as plants and humans co evolved, the plant became very colorful or it has its beautiful berries because humans can see color. So eat me, cultivate me so you can disperse of my seeds and you can make me procreate and keep on going. Maybe that's one thought. Certainly you have toxic plants, but certainly we have these edible plants which humans have been cultivating and consuming for centuries. And to get back again to the question, you know, by consuming these natural products, these are hardcore chemical compounds. These are not vitamins and minerals and fats and carbohydrates and proteins. These are, you look at their chemical structure, you know, these are really true drug like type molecules. And when you think of our body of recomming these molecules over time, you know, our liver getting to do its thing in terms of detoxifying and our kidneys and excreting and our, again, you know, our gut microflora, I'm sure Chris is going to tell you more about that. Converting some of these natural polyphenols that are found naturally in the plant into further bioactive constituents, which I think it's really where the rubber meets the road.

When we talk about plant based compounds, like you said, there's so many of them and caffeine and nicotine are amazing. By the way, smoking's bad for you. In case anyone's misconstruing what I'm saying there, I just like the anti Alzheimer's effects and the cognitive enhancement effects. But polyphenols as a class are something I wrote extensively about in my anti aging book because there's just so much evidence there. But a lot of the plants that contain polyphenols have stupid amounts of sugar or other toxins that I don't really want to get in large doses in order to get the polyphenols. And that's where the line between medicinal plants and herbs and food plants starts to get really blurry to me because I'd love to have half a gram of this compound, but I don't want to eat 40 pounds of food to get it because that would be hard.

Right.

Are we at the point now where you feel like we know enough about these colored compounds in foods that it's safe to say you don't have to eat the rainbow and get all the lectins and all the other bad stuff. You could just take a pill that contains all the good stuff from the rainbow and throws out all the bad stuff with no sugar. Are we there?

I think we're close to there. You know, the, the cutting edge instrumentation that we have, you know, throughout the world and with the scientists, the ability to, again, as you just said, to enrich in certain bioactive constituents and remove some of the unwanted constituents within the plant foods. For example, I'm just going to throw it out as an example. Cranberry juice. People may not like the taste. Or if you're having cranberry juice with the added sugar, you may not want that added sugar. But is there a cranberry extract that could deliver the bioactive constituents to. In cranberries which are potentially going to protect urinary tract from being infected and that.

Why do you say potential there is that? Because you're academic and you just have to say everything is potential.

You got to.

We know D Mannose stops bacteria from sticking to the lining of your urinary tract. Right.

Well, the FDA this last July just allowed a qualified health claim for cranberry. You could check it out.

Okay, there. There we go. So now, now we can say it's real because the FDA said, sorry, I.

Got you Navendra with some coffee at Steve. Thank you. But again, you know, yes. Delivering the bioactive constituents in a calibrated form with standardized. And you know what it is without the unwanted constituents. I think we're there.

You think we're there. I'm feeling that way too. You can get almost any polyphenol separated out you want. A lot of times you can't get them in a supplement that you want. And also knowing which ones and in what ratio, it feels like there's a little bit going on. But hey, if you eat a salad, you don't know which polyphenols at what levels you got in your salad either. So it's no worse than the current situation of just eating some random stuff. Because a health Expert in the 70s said, Eat a lot of colors.

Exactly. And plants are fundamentally. They're going to be. They're going to variable. They're variable. A green tea from India is going to be different from green tea, maybe of the same species or sub variety or whatever it is from California. So how are you gonna ensure that you're getting that perfect quantity or that number of polyphenols, whatever you're aiming for, consistently in a standardized form, you know, from foods? That's one of the pluses of supplements. However, you have to be cautious in that the supplement that you're getting is a good supplement. How do you know that, too? So that's another question to ask.

Yeah, there's quality and quality issues all over, especially from smaller companies. You either get really good stuff from smaller companies or really bad stuff imported from God knows where with no quality control. And it's hard to tell unless you're an experienced buyer. So I'm 100% with you there. All right, I want to dig in then on Urolithin A, because I've been a fan of pomegranate for a long time. When I lived in California, I had a pomegranate tree in the backyard. They're stupidly full of sugar, but I always thought they were good because they have something called the palm one enzyme, which is good for detoxing certain pesticides. I had a family member who was crop dusted once and got really sick afterwards, and he actually used palm one as part of his detox pathways. But I didn't know much about Urolithin A. So can you walk me through what it is and what you've discovered about it?

Maybe I'll start and then push it over to Chris for. Very quickly, as I said earlier, if your readers are now joining or anything like that. But I had moved to the usa. I had done my postdoc at Michigan, and then I went to UCLA, where this is more than 15 years ago. At that time, at the UCLA center for Human Nutrition, I was working with a very famous scientist. His name is David Heber. He's written, you know, several books. One of them is what Color Is yous Diet? As you just referred to Dave, eating a colorful diet. And at that time, you know, we were trying to understand what in the pomegranate fruit and juice are, are bioactive and are going to be important for certain potential health effects that people had observed for pomegranates in animal studies and, you know, limited number of human clinical studies at that time, that if you look at a pomegranate fruit, it has a very thick, leathery rind or a husk or this peel that, you know, the pomegranate is really regarded as a king of fruits. It has a crown on its head, on the top, and it's in all of the holy books. It's an interesting fruit where, you know, the rind is not edible. You gotta really have to love bitter stuff. It's very bitter. Although in Indian, a traditional system of medicine known as Ayurveda, they would take the rind and they would make a spice of it. And in certain cultures, like in Iran and Persia, they will take the pomegranate and really soften it up before they stick a straw and drink the juice. So where I'm getting, where I'm going with this is the seeds which are the, you know, covered with these beautiful red, fleshy, called the aril, the A R I L. Those are the edible parts and the red ruby color, those are because of certain polyphenols known as anthocyanins, which are responsible for giving several berries and certain other vegetables and grains beautiful color. But it turns out that in the peel of the fruit there's this large class of polyphenols which, Dave, you know about polyphenols very well. Polyphenols are probably the most abundant and ubiquitous phytonutrients. I'm going to use that word, phytonutrients in our diet in terms of edible fruits and vegetables and grains. And in the pomegranate, the class of polyphenols which are most abundant are known as ellagitannins. And in particular, there's an ellagitannin known, known as punica lagine, named after the botanical name or the Latin name of pomegranate, which is punica granatum. So puniculagin, as well as other elagitannins are known as hydrolyzable tannins. It means that without getting into too much chemistry, when you consume these polyphenols and it gets into the body, they hydrolyze in the stomach because of its acidic ph, as I mentioned earlier, its acidity, and they release ellagic acid into circulation. So the enigma that we had at that time when we were studying the consumption of pomegranate food products, including its juice, is how can we account for the potential health benefits of pomegranate when we cannot see physiological or detect physiological levels of the natural compounds, uni, collagen, it doesn't survive in its stomach nor ellagic acid in very, very tiny quantities in blood. So what the heck is going on? And it took us some time, and our group at that time, as well as other groups for example, in Spain got to the understanding that the ellagitannins and ellagic acid as they get into the gut in the lower colon, in the colon, that they were subjected to biotransformation by gut microflora to convert them from their ellagic acid form into these class of phenolics called urolithins, of which urolithin A is one of the most abundant. So it turns out, and I'm sure Chris is going to jump in here in a little bit, that the conversion of ellagic acid to urolithin and urolithin A and urolithins, which would then enter the urolithins, enter back into, enter hepatic circulation and then those molecules would achieve physiological levels. So if I were to jump, make a leap of faith that to get the potential health benefits of pomegranate, you would need to produce urolithins in the body, because it's not a natural compound. However, this is where the catch is. Your gut microflora, Dave and Chris's and mine are quite different. We have this natural inter individual variability that happens between, I don't know, ethnicity, maybe the foods we're used to eating. And therefore I may be a converter or a responder or a, or someone who is able to produce, because of my microflora, urolithins from ellagic acid. But you're not.

You are one of the most highly cited scientists in agricultural science for five years running. And you partnered with Chris to launch, to launch Mitopure. You're supporting Chris with Mitopure. And Chris, you've got a degree in cell and molecular biology and you spent 20 years, as we talked about before figuring out, okay, how do we take these compounds and how do we bring them to market so people can take advantage? And you guys partnered around this idea of urolithin A, which you can't get in pomegranate, but you might get if you ate a lot of pomegranate, if you had the right gut bacteria and isolated this compound. Tell me more about urolithin A and what you have discovered about what it does in the body.

Sure, Dave, thanks. Thanks for asking. So when we started Amazentis at the very beginning here in Switzerland, the company was reaching out to try and understand what, much like Navindra was saying and sharing earlier, what actually are in some of these foods that we're eating and that are bringing these health benefits to everybody. And so we were looking at pomegranates and I knew that Navindra was looking at pomegranates. So Navindra got involved as a scientific advisor early on, and we started looking at what type of compounds might be emerging from the pomegranate. And urolithin A is one of those. And so we started going into the more of the biology of, of these compounds, the biology of urolithin A. So we actually produce urolithin A. As you know, it's not in the actual pomegranate itself. It's only generated if you have the right gut microflora. So we produced urolithin A very, in a very pure manner and started testing that in the laboratory. We started testing that on cells to see, well, how is this really acting? Is it, Is there some type of beneficial action of urolithin A? And in fact, what we saw was that it was acting on, at the level of the mitochondria in cells that we were testing on, and more particularly on muscle cells. And we found this very interesting. It was very potent in terms of stimulating the mitochondria. We started testing this on these small worms they call C. Elegans, very small worms. And scientists are using those to assess the lifespan because they have very short life. And if you increase their lifespan, you can see that in a very short period of time because they don't live very long. What we saw was that when we started incubating and feeding these worms with urolithin A, they were increasing their lifespan by about 50%.

I didn't get that one. In my Superhuman book, I list a whole bunch of different compounds that are going from about 15% up to 95%. That's one. I didn't know about that study. So, okay, guys, you think you're not going to live to 100 and something if that works on you to the same percentage? Well, there's at least it's possible. So. All right, keep going.

Well, so this is worms, of course, this is not animal humans. But what's exciting there is that we could see that it was having an effect not only in mitochondria, but it was also having an effect on quality of life at this very simple organism level. We moved on from worms into mice, and we started feeding urolithin A to mice in their normal diet. And what we saw was that they started when we testing their just their ability to run, we saw that they started running about 40% further and longer than mice that weren't taking diets with urolithin A. So it was a big surprise to Us when we saw this and instantly recognized that there was some type of an effect on the muscle function and muscle endurance from that. And we also were looking at muscle strength, and we saw about a 10% increase in muscle strength in these mice.

Over what time this was.

Now, at this point, we were looking at mice that were metabolically challenged too. They were taking a high fat diet over several months. And so we thought, well, okay, this is something that takes place over several months. You may need to feed and consume over several months. But then we said, well, let's accelerate this. Let's actually trial over a much shorter period. We went into older mice that normally have a decrease in muscle function, if you will, just like humans, as you get older, your muscle function starts to decrease. After we had looked at mice that were taking urolithin A for several months and seeing that it was improving their benefits in terms of their muscle function and muscle ability to run, we looked at older animals. And what we did see there was that at a shorter period of time of consuming, we were able to induce an increase in endurance of about 40% as well. We thought this was very exciting, of course, and this encouraged us to take this to the next level and to bring it into humans. And so that involved a whole other step of basically taking urolithin A and making this at a purity and at a quality level that was fit for human consumption. The first study that we did in humans was a single ascending dose and a multiple ascending dose study with urolithin A. And we did that, the multiple ascending dose. We studied the effects over a month, and what we saw was an impact directly on the mitochondrial function in the skeletal muscle tissue. So essentially, people were taking softgels that contained urolithin A on a daily basis for a period of a month. And we looked at two types of biomarkers. One biomarker, by taking a muscle biopsy at the very beginning before starting to take the product, and at the end, after a month, we looked at the gene expression profile, and what we saw was an increase in mitochondrial gene expression. So very exciting to see that the effects that we were seeing in cells at a cellular level, in the lab and in the worms and then in mice, we're actually translating into humans. And we were seeing this type of beneficial effect on the muscle cells.

And as I understand it from looking at the literature before the interview, it's primarily because of mitophagy. Is that the only or the main effect, or are there other things going on? And can you tell people what mitophagy is.

Yeah, it's an excellent point, Dave. So urolithin A is acting on the mitochondria and improving the mitochondrial function by stimulating a pathway that's called mitophagy. So what happens is, as you're getting older and you're leading perhaps a more sedentary lifestyle, the mitochondria that are inside of your cell, they start to get damaged and they get old as well. And so each of our cells that are containing mitochondria, they have an innate process of cleaning up the damaged mitochondria and recycling them. And this process is called mitophagy. As you get older, mitophagy declines. And so the number of healthy mitochondria inside of your cell declines, and so your cells are less, let's say, bioenergetically optimal, if you will, with that decline. Consequently, the cells aren't functioning well. The mitochondria are a little bit like batteries inside of our cells, so they get run down. And so what we've seen with urolithin A, and this was a subject of a paper that we published several years back in the journal Nature Medicine, was that urolithin A was stimulating, or is stimulating mitophagy and inducing this recycling process of the damaged mitochondria to keep your cells and your mitochondria very fit and very bioenergetically, let's say, optimal, if you will.

There's plenty of evidence around urolithin A for me to have started taking it. I think it's too early for me to say. You know, I felt a huge difference. I do a lot of mitochondrial stimulation and mitophagy stimulation. But this is something that I'm permanently adding, based on the evidence, to my personal stack. And you guys put it in timeline.

Yes, timeline. We've put it into this product here. It's a little sachet that you can basically pour into your smoothies in the morning, into your yogurts, and into your cereal.

Is it heat stable?

Well, we have seen. Yes, that is heat stable.

I haven't tried this yet because I don't want to ruin it, but if I put it in bulletproof coffee and I blend the crap out of it, am I going to break it up like you would with peptides, or is it going to be stable?

No, I would say you should be pretty comfortable blending it in your coffee.

All right, I'm going to give this a shot. I think it'll add a little fruity note, and I don't think it'll be bad. And I have put grape seed extract in coffee, which gives it kind of like a dry tannin note, like a dry wine, depending on which brand of grapeseed extract. So this isn't a tannin anymore, but all right, I'm going to give that a try. I should have done it before the show. I just didn't want to waste a perfect good sachet of know, urolithin A if I was gonna deactivate it or something. Okay, why can't I just take a urolith in a capsule? Why do I need a powder?

Well, you know, we started out with this powder because we thought it would be a great consumer experience. So many people are used to taking pills all the time. But, you know, what we see is this, is this nutrition of the future is going to be nutrition that, you know, that is studied scientifically and clinically proven to have a benefit that's targeted for you. And so we wanted to introduce our product in a powder form that you could include into your food. Now, some people like to eat things in food, some people like to take pills.

I'm rooting for the pills because I already take a handful of pills. It'd be easy to toss one in. But in the meantime, I'm really intrigued at the idea of stacking things that add autophagy or mitophagy. And so the idea of what if I did spermidine and I did timeline together during a fast and then exercising at the end of the fast and things like that. Of course, there aren't studies about this stuff yet. A lot of people are saying, how do I get more out of an activity that I'm already doing? And so I'm already in my mind going, all right, what's my timing going to look like for this? And it seems like either during or at the end of a fast is when I'm going to start using timeline, because that'll probably be more convenient anyway.

Yeah, I was going to say in terms of how you use it and the actual effects. We were speaking about one of our earlier clinical studies, but more recently we've done a clinical study that was four months long where people were taking timeline on a, on a daily basis over a spirit of four months at 500 milligrams. And what we saw was an improvement in leg muscle strength after that four month period. We also did similar types of tests that we did in our, our initial study where we looked at biomarkers not only in the muscle, but also in, in the plasma. And we saw an impact there, particularly on acyl carnitines. A decrease in acyl carnitines over time, showing an impact on mitochondrial function. Basically, as acyl carnitine levels are higher, that's indicative of mitochondria that are less healthy. And so as they go down lower, that's a sign that your mitochondria function is improving. And, and the fact that you see that in your plasma is an indication that there's something happening not only at the level of muscle that we saw when we did these biopsies in the leg, but also more systemically in the body. Of course, all of our cells, except for our red blood cells, contain mitochondria. But so far the focus of our research has been on the skeletal muscle and on your muscle function and strength. And so I see in the future a possibility to examine other potential beneficial effects of timeline in other areas of health.

So that study that you referenced was on people age 40 to 65 years, which is kind of cool because the research that was backing a lot of what I did with Superhuman and even a lot of what I'm doing with Fastest Way, it says everyone over age 40 has early onset mitochondrial dysfunction. That's Frank Shallenberg's research, which is based on measuring oxygen consumption efficiency. So it's very clean. We don't know exactly what's going on, but we know what goes in and what comes out so we can tell they're not working the way they used to. So you targeted the group where everyone has an issue, which is pretty neat. And then you found that they got stronger leg muscles after four months of taking it on a daily basis. 500 milligrams. What's the dose that's in timeline? Is that the same dose?

Yes. We've included 500 milligrams in our daily dose in each of these little caches. And so, yeah, so this gives you a very convenient way of getting the product. Now if you, if you say, well, okay, I'd prefer to get it through. And you were referring to natural ways. And so was Navindra through a pomegranate. Well, you'd have to have a lot more pomegranate juice a day. In fact, what we've recently this year completed a clinical study where we did a head to head comparison with one glass of, of pomegranate juice and one sachet of thyme mixed into a yogurt. And we looked at the bioavailability of urolithin A in the blood during the first 24 hours after taking Several time points and blood draws. And what we saw was that there was about a sixfold higher level of urolithin A. Looking at this sort of area under the curve for that first 24 hours when you take one sachet of thymeline versus 18 ounce glass of pomegranate juice. So, and this is also, and the other thing that we found was that those people taking pomegranate juice, we only saw about 40% of people who were actually converting. And this was sort of, you know, you had low converters and mid converters and high converters where all the rest, you know, weren't able to do that conversion. So, which really highlights the value of one, you don't want to be taking, you know, six glasses of pomegranate juice every day. And you know, if you can take one little sachet that contains 500 milligrams of urolithin A, you're getting a really precise dose that's been scientifically and clinically evaluated in humans to give you a physiological benefit. And so we're really excited to be able to do that and offer this to people in such a convenient manner.

One of the problems with pomegranate juice is like any fruit juice, if you take one 8 ounce glass of that stuff and you're doing continuous glucose monitoring, say I use the levels health device to do that, you're going to have this postprandial blood sugar spike that is aging and that it causes advanced glycation end products in the body. So I couldn't in good conscience tell people listening, hey, drink a big glass of sugar water with some ellagic acid in it on a daily basis. Because the long term effects of any kind of fruit juice are not that good on the human body. What is the likelihood of any change in blood sugar from timeline? Have you guys looked at that at all?

Yes. Well, you know, in terms of our.

Product.

We haven't really seen any type of negative or side effect of our product. And we've now studied it. And many people in that one juice study that I Referred to, over 100 people took the product.

So they didn't see big blood sugar swings, very low level.