 How did you discover urolithin A in the first place? This is a great story. You know, it all started out in the very beginning of the company. We were really looking at natural products and trying to understand what are the compounds inside of natural products that can really create a meaningful impact on people's lives and really target specific biological pathways. And we're looking at a number of different foods. And one of those foods was the pomegranate at the time. And so we're very interested. There was talk about antioxidant abilities of pomegranate. A lot of people were taking pomegranate juice that was very popular time. And so we took this deep dive and we started doing things like juicing the pomegranate, trying to understand what types of compounds are in different strains of pomegranates actually. And this led us to a greater understanding of the various compounds inside the pomegranates and looking particularly at a class of compounds called the elagitanins. And inside of the pomegranate, there's a very rich source of elagitanins. And one of those is the punykalagen, which is a compound that's very predominant in the pomegranate. And I'll tell you about how our discovery went from there into urolithin A. In fact, what's interesting about punykalagen is that while it's in the fruit of the pomegranate, when you consume it, it's transformed into other compounds. And this is something that you don't really think about when you're consuming different types of foods. You think, okay, I'm getting vitamin C from orange juice, et cetera. But here you have punykalagen that's transformed by a gut microflora into urolithin A, which is a post biotic. And so that's sort of how it started in that journey from looking at fruits themselves to getting to urolithin A. How did you guys actually make that connection that there's an intermediary here that we really didn't know about that was you could kind of drink all the pomegranate juice in the world and you might not end up with what you were actually looking for from the benefit of that pomegranate? It was very interesting. When we started, we were looking at specifically at punykalagen and we were testing this in various animal models. And particularly we're looking at animal models of cognition and brain health. And we were feeding punykalagen to mice that had Alzheimer's disease through genetic mutation. And we were seeing an improvement in their swimming as they get older, their swimming and their memory declines. And so we saw this improvement linked to punykalagen. And then we started to go deeper to take a look at how could that actually, as the punykalagen is consumed by the animals, what transforms afterwards. And so this was where we started looking at the postbiotics and we started making different postbiotics that were derived from punykalagen and then taking those into the lab and studying those in the lab. And we did that together with here at the EPFL with Professor Johan O'Rourke who is a specialist in mitochondrial biology. Let me back up for a second. You and I are kicking in the term around postbiotics like everyday conversation, which it is for you and I. But postbiotics, I've written several books about them. But people I think know probiotics was, let's just say, friendly bacteria. And people know prebiotics. They're beginning to understand these are, if you will, the compounds that bacteria want to eat. And postbiotics for our listeners are the compounds that the bacteria make when they eat these certain compounds like pomegranates. Is that a good, simple description? That's perfect. And what we're finding, quite frankly, is that the postbiotics are probably the most important missing link between our gut microbiome and the end effect on our overall health. And that's why I think this discussion, particularly with mitopure, but in postbiotics in general, is so important for all of us to understand. You know, we take for granted that our body is designed to extract all the benefits from the foods we eat. But in fact, it's really depending upon, you know, the composition of the microflora that we have in our gut. And then its ability to actually make this transformation of the compounds in our foods into postbiotics. Once you discovered that, you know, these mice were making urolithin A, then you turned it over to your scientists and said, all right, why is this compound getting these observed effects? And take it from there. We were very curious about, you know, how did that compound transform and translate into these effects? And so we started studying the metabolism of the compound punicallagin, the salagitanin found in the pomegranate. And it was known that it was transformed into compounds like urolithin A and other urolithins in this sort of class of postbiotics. All of your ability to transform into different types of urolithins depending upon the actual gut microflora that each person has. And so we started, we asked ourselves, are these compounds more than just the body's way of clearing the punicallagin from the body? Because most people who had been studying it had been looking at this is what is excreted, you know, when you take this type of a food. And so less at what is the nutritional value. And so we took a deeper dive to see and explore, are there any real health benefits linked to urolithin A? And what did you find? The most exciting thing was when we were working together with Professor O'Rourke, he put it onto cells in the lab and he put it into worms in the lab, and I'll talk a little bit more about that, and he saw an improvement in mitochondria function. And so what's, you know, what was exciting about this was, first of all, Professor O'Rourke is an expert on mitochondria and mitochondrial biology and has tested lots of different compounds, including resveratrol and others. And so he understands sort of the potency of these compounds in his hands and in his various models. But what struck him was how much more potent urolithin A was than all the other compounds. And one of the ways that he studies fundamental sort of lifespan and health span is using this worm model. It's a very basic model. It's the C. elegan model that they don't live very long. And so when you feed them different types of bioactives, you can follow life extension. You can also follow the what we call health span, which is like sort of the quality of life as you get older. And you do that by looking at their movements in a dish with time. And what he saw was that when he administered urolithin A to these worms that you got an expansion of lifespan by about 45%. And this compares to caloric restriction, which is sort of the gold standard, getting you the highest expansion and extension of lifespan worms, which is around 50%. And if you compare this to other natural compounds like resveratrol, you're in the 15 to 20% depending upon that experimental setup. It was really quite a dramatic effect on mitochondrial function that he saw it on and in this worm model. These results caused us to really take notice and think that this could be something really special and take it to that next level and start studying it by administering it directly to the various mouse models. I've written about C. elegans in a lot of my books. And I think people should know that it is a really, really useful model that really what happens in C. elegans can pretty much be duplicated in higher animal models, whether it's a mouse, whether it's a Reese's monkey, and as we'll get to a human. So what happens in these worms, luckily, is able to be brought to the clinic. And that's what's exciting about this model. And you're right. Caloric restriction is still probably the gold standard, but quite frankly, nobody particularly wants to do that for obvious reasons, and which looks even better than resveratrol, the famous red wine molecule. So now these Alzheimer's mice are doing better. Take it from there. What we started doing is then feeding it to mice that we're getting older. And one of the first studies we did was what they call a high fat diet model. And this is basically feeding mice sort of the super-sized meat type of diet. And so they get fat as they consume more fat in their diet. And what we did is we fed the mice either urolithin A or we fed with the high fat diet or with the high fat diet alone. And these were mice at the later start of their later part of their years. And what we saw was that as the mice were getting older, we started looking at various parameters. And one of those was their physical activity and physical function and muscle strength. And we saw that the muscle strength was increasing in those mice that were taking urolithin A by about 10%. And there's a grip strength as you measure in these types of models. But the thing that surprised us the most is we looked at the running distance and sort of the spontaneous running distance. You put them in sort of these wheels that they run on and they'd sort of run until they get tired and they stop. And what we saw was that these mice were running more than 40% more than the mice that weren't administered urolithin A. So it was a real shock to us. And then we started looking deeper into the benefits of improving mitochondrial function on muscle function and on skeletal muscle function and the general health. And we went that next step and we said, well, let's take a look in older mice. And this time, in that first study, it was a long term administration. We said, well, let's do it for a shorter period of time and look at older mice. And let's give mice the best diet. So no high fat diet. And so we followed these mice for about eight weeks. And what we saw was something very comparable. And in fact, we saw an improvement between 40 to 50% and running endurance in these mice. And it was very impressive. And taking a closer look, we saw all these biomarkers that were linked to improved mitochondrial function and the skeletal muscle of these mice that were taking urolithin A. And so it was at this point when we started to see in multiple studies conducted by different groups that we were all seeing the same thing in terms of improvement in muscle function that this was something worth going that next step and scaling up into humans and seeing if it actually translated into humans. And I'm already getting something to translate from cells to worms to mice is quite a feat. Translating to humans is another story. And so this is where we took that step of going from a small few grams into manufacturing at a much larger scale and then actually developing products that we could administer to humans supplements and foods. And that's sort of how it started in our exploration in human biology. And I've written about this and you know this as well. You got to have the right set of bacteria to take these precursors to make urolithin A in our gut, correct? Correct. And one of the interesting things is that super old people, people who are thriving at a very ripe old age, remarkably, these people have 50% of them have the right combination of bacteria to produce urolithin A. And yet most of us 14% of us have the right set of bacteria to make urolithin A approximately. It's very interesting. I mean there's been studies that have come out I think it was the year before last on looking at people who are taking a Mediterranean diet and they tend to find more urolithin A in their blood than people who aren't taking a Mediterranean diet. And so that's certainly a combination of eating the right foods because these compounds we were talking about that are in pomegranates are also found in different types of berries, sort of raspberry and strawberry and different nuts like walnuts. But you have to have that right, that microflora. So I have to believe that if you have that right diet that helps steer the bacteria and the composition of the bacteria in the right way because they develop to actually transform the foods that they're eating on a regular basis. The point I'm trying to make is unless you are doing these other things unless you are what you eat but you are what the things you're eating ate, you're kind of screwed if you think you're going to make a lot of urolithin A and probably we should be making a lot of urolithin A. All right, so what happens when we give it to humans? Our first study was trying to explore what was the dose you need to give to humans to actually see that effect. And so we did what normally pharma companies do when they take a first drug into humans. We applied the same sort of methodologies for nutrition and we started giving different doses and we used that to sort of identify what would be an active dose. And what we saw was that after giving people 500 milligrams of urolithin A for a period of 30 days we saw an impact on the mitochondria function in the skeletal muscle, particularly in the leg skeletal muscle. And we saw that with both 500 milligrams a day as well as one gram a day. And we assessed this in a couple of different ways but the key way was the direct assessment by taking a muscle biopsy. So we went and took a biopsy before and after and we looked at the gene expression pattern. And what you really saw was this and this is a very unbiased approach and meaning that we didn't you know we saw all the genes that were expressed and then we looked at the ones that were changed after taking urolithin A for a month. And what we saw was that there was an increase in the expression of genes linked to mitochondrial function which is very interesting because when you have this enrichment of the genes of mitochondria function it's a clear sign that there's increased mitochondria biogenesis. And this is something that you want to see and you see this in athletes after they're exercising. And we've also seen it in another study where we were looking at people who are sedentary versus active and we were seeing a decline in the expression of these genes and those people who are sedentary and what they call free frail so they're starting to have mobility problems versus those people who are active and maintaining active when they're old. So mitochondria function is really a key indicator of overall muscle health and that's what I thought was very exciting about that first study. So you didn't interfere with an active exercise program you didn't say okay you know you're going to take mitochondria but you're also going to go on a treadmill 30 minutes a day. This was sedentary these people were older people who were average age of 70 but sort of 65 and maybe 80 something like that and they were sedentary individuals and so they weren't exercising so there was nothing that was sort of turning on the mitochondria no change in diets etc. So very exciting to see that in the very beginning and of course we then started repeating that in more robust studies but I let you. Mitogenesis you and I know what that means for our listeners mitogenesis means make more mitochondria and quite frankly the more mitochondria you have packed in your cells the better. We also toss around the term mitophagy and some people have heard of autophagy as probably a really good way to extend lifespan improve health span just basic science here mitochondria have their own DNA apart from the cellular DNA and mitochondria can reproduce without the cell dividing and make more of themselves and mitogenesis but they can repair themselves from damage which is part of mitophagy or god forbid they can explode and have apoptosis which is a bad thing that I've written about and you and I know about so you're finding not only mitogenesis with urolithin A but also mitophagy repair of mitochondria yes yes well that was I think that was that kind of goes back to the lab experiments that were done and trying to understand how was urolithin A impacting the mitochondria and we were talking about um mitochondrial biogenesis and what's fascinating is that you know inside of your cells you have all of these mitochondrists not just you have one mitochondria in your cell you have hundreds and thousands depending upon you know what cell type and these mitochondria are working non-stop to creating energy for all the different biological reactions that are taking place inside of your cell and in the consequence of doing that these mitochondria get damaged because of these reactive oxygen species that are produced and the cell that is in the body in the cell it has come up with a very clever way of dealing with that they have sort of a its own recycling mechanism and that recycling mechanism is called mitophagy and so basically those damaged parts of the mitochondria are separated from the healthy parts and sequestered and brought into a basically a little cellular garbage bag and they're digested by cellular enzymes that allows the the damaged part of the mitochondria to be broken down and then recycled by the cell into and to make healthier mitochondria and and this is a normal process that's always going on inside of our cells that we need to maintain now um the problem happens when that mitophagy slows down and there's a lot of things that can link to that one is simply you know poor diet that can link to a lot of metabolic disturbances the other one is simply um being not very active we're talking before about older people who are active versus sedentary being active actually stimulates this process you were talking about mitophagy but also mitophagy so that this activity is stimulating that and then it's maybe not be evident but as you get older this rate of mitophagy declines and this has been shown to be recently one of those one of those hallmarks of aging that people talk so much about is the decline in mitochondria function as you get older and this decline is largely due to a decrease in the level of mitophagy this is what's very interesting about you know how do you maintain proper cellular health from an energetic standpoint as you get older and just at every stage of your life and the way to do this is to maintain your mitochondria health and we were talking about mitochondria biogenesis before and the production of of healthy mitochondria but getting rid of the damage mitochondria is equally important because you don't want to have a bunch of damaged mitochondria inside of your cells and not a lot of energy and then the cells sort of being starved for that energy and so this is what makes mitophagy so interesting and then going back to what we were talking about urolithin A the discovery that was made by but in yoan oryx's lab around urolithin A and and the mitochondria function it also went to that next stage and showed that the mechanism of action was by stimulating mitophagy and what was so exciting is that this is the first compound that was a non-toxic compound that was a safe natural compound that was shown to stimulate mitophagy not only in worms and in cells but also in mice and then we see this these very nice effects on mitochondria function in humans and you subsequently publish papers about improvement in humans in muscle function in in a fairly short period of time can you elaborate on that we ran a number of studies now looking at muscle function I think one of the more interesting ones is is a study that we did in people that were middle age of overweight sedentary and what they saw was that after four months of taking urolithin A at 500 milligrams a day they showed an improvement in leg muscle strength by about 10 so this was something that was a notably physiological impact on the health and that you don't see you know just sitting around taking a supplement right this was a big conversion from just taking a biopsy to actually seeing a functional benefit we've we've since done other studies looking at people who are older and having a lower mitochondrial function and what we saw was that after two months we improved muscle endurance both in the first interosseous muscle which is the basically your your hand muscle and it's the kind that you use to sort of grip your arms that you open and and also your leg muscle so that was really exciting to see that transformation there so we started to see we've now started to see the impact of urolithin A and a number of different human studies all linked to mitochondria function now I know you guys are are very interested in nutrition 2.0 if we're listening okay if I'm 70 years old my mitochondria aren't doing very well and it would be really smart for me to take urolithin A but my 35 year old listener is now saying well I'm not 70 years old I'm at my prime when should I start you know considering something like urolithin A like might appear it's an interesting point that a lot of people have asked us you know what well I'm not old enough for it yet and quite the contrary it's never too you're never too young we have a lot of athletes that are taking our product and really enjoy it in fact we've we've recently run a study in an elite and sub elite athletes for a period of a month and they experienced better muscle recovery after and less received exertion after a month of taking our product and these are athletes at the highest level who are training we're at a training camp and you'll see the impact differently depending upon what your lifestyle is like you know if you're an athlete you're looking you're probably thinking about muscle recovery as you get older you're looking to maintain that muscle strength maintain that endurance and so it's a trade-off and of course there's there's things that you don't feel but it's you're having an impact on the mitochondria function you may not feel it in terms of muscle but you may feel it in a different way like general energy for example and just to be clear this is perfectly legal for athletes to take the Olympic committee will not ban this substance no no for sure I mean we've been you know the nice thing about urolithin A is you know we've been consuming urolithin A for thousands and thousands of years this is what you get when you consume pomegranate juice when you consume walnuts raspberries there's there's nothing at all harmful with urolithin A it's the the safety has stood the test of time of you know of thousands of millions of people consuming it so you've talked about muscle recovery muscle strength I think getting back to one of your original points about these mice who weren't very smart um and memory and everything we we tend to forget that our brain is a rather a big consumer of ATP and our brain our neurons are packed with mitochondria we want to flex our brain muscle well into late adulthood what you find in you know in muscular mitochondria is that now happening in mitochondria and neurons as well well there have been a number of preclinical studies in mice basically administering urolithin A to them and not by us by other scientists and and they have seen an improvement in memory in in various animal models and it's logical that that you would see that simply because that there's a demonstration that in a lot of disease models and a lot of progressive degenerative diseases of cognition there's a strong link to mitochondrial function and not only for just memory but also a mood disorders too it's a whole sort of spectrum of cognitive deficits have a mitochondrial link and I know you and I have talked you know offline that our immune system is also a very important part of us in fighting disease and in fighting cancer and you've recently done some studies looking at mitopure's ability to improve the the immune system surveillance as well for sure I mean there's been now a couple of studies that have been published on mitopure and the effect on immune cells and the benefits are quite remarkable you basically are seeing that it's helping the immune cells retain their stemness which basically means it's preventing this immune aging and that's something that's that's really exciting we have a clinical study underway now over in Germany where we're doing a full spectrum analysis on all the different immune cells and individuals taking urolithin A and so this is something that you know we hope to have some more knowledge and and share with the public next year when the study is completed and all the analysis has been made this observation that administering urolithin A to mice was able to boost immune systems and I think you're referring to this paper where it was a boosting immune systems in mice and helping the mice immune system fight cancer better which I thought was very interesting and of course you can't you know that type of thing you can't talk about for for humans but uh because we're talking about supplement but I think that the fact that you see the impact on the immune system is is just so exciting I mean because the immune system has immune cells have mitochondria too right and so you're having this broad spectrum effect on the body by improving the mitochondria function and this is where I think that you know the power of of urolithin A and mitopure have for general health this is not just something that's targeting muscle we were talking about brain before we have a we're have plans to run a study um looking at the effects in brain you know there's this broad impact on mitochondria function in cells and those cells are basically everywhere in your body so that's the exciting uh future as a former transplant surgeon heart transplant surgeon nothing made us happier than having a getting to do a heart transplant in a 75 year old person uh why because their immune systems were so lousy that we didn't have to give them a lot of immunosuppressant drugs uh to allow them to accept that heart as opposed to doing it in a in a 10 year old child we really have to you know whack the immune system because it's so vigorous and your point is well taken that anything that we can do to improve our immune systems function surveillance ability as we get older is is well worth it um in so many ways I started taking uh mitopure actually I think when it first came out I'm in my mid 70s now and my wife and I are avid hikers um and hike a lot over in Europe and Italy and France and we we happen to notice through the years that a great number of people from Germany and Switzerland were hiking trekking with trekking poles and uh we'd say oh we we can spot the Germans and the Swiss because they're all all got their trekking poles and as as time went on particularly on challenging uh particularly downhill slopes I found that I'm going you know I can see why these guys are using trekking poles because my you know ability to head down these rather treacherous slopes is not as good as it used to be and I'm I was talking to my wife I'm going you know maybe it's time for me to consider these poles for a balance ability and I was really kicking it around and then I started taking mitopure and quite frankly within a couple of months my balance and my ability was back to you know what it was 15 years ago and my wife and I laughed about she said well I guess you won't be needing the trekking bowls like all the Swiss and Germans we see I said well not yet so it and that was all I changed I you know I didn't change my exercise routine I didn't change you know my diet that's the only thing I I I added and I tell my patients look you know I I can tell you this this was the effect at least in me so good for you I don't want trekking bowls yet sorry well that's a that's a great story you know I mean it's we've had so many people write in and tell you know their own stories about how it's improved their energy or or their muscle function people who have had you know leg cramps you don't have leg cramps on a personal level you know energy I found a lot of energy it's been now more than two and a half years that I stopped drinking coffee you know I just don't feel the need for it and it's very fascinating just just to see that level of energy you get on a daily basis you know there a lot of this at least for me is my neuro feedback from my legs to my brain was definitely improved and you know I could feel it and I could see it in my balance so good for you what's the future hold for timeline and where you going from here well we were talking about the all the difference of health benefits that you might be able to to achieve by acting on mitochondria and you've been talking about the nutritional aspects you know we think now that there's this potential to have this very holistic approach to aging with mitochondria going across all the different health benefits including topical and you were mentioning earlier the topical creams to me and this is something that we're very excited about because you have something you have a molecule here that's you know this is working on your skin and we've recently published an article on this and you can actually see the benefits so it's not when you're it's not like taking a pill and you feel it you you look in the mirror and you see it it's not just sort of your physical look but it's the biology of your cells that is important the skin is the largest organ of your body if you put product on that can activate your mitochondria this is something that we think is very potent by taking something and applying it locally to your skin we've we've run studies we've seen the impact on inflammation sort of post UV exposure we see the anti-inflammatory properties that we've seen taking orally that it goes it also applies topically we've also seen benefits on on gene pathways and proteins around collagen expression and this is something very exciting because we know that as you get older the collagen the lack of collagen in your skin is what starts to cause that sort of change in that structure of your skin and then that changing physical appearance so you can swallow it and you can put it on your skin yeah i think that i think that's what is ideal right and that's what people want that's a holistic solution thanks for watching but don't go anywhere the next episode of the Dr. Gundry podcast is waiting for you now now this one's a no-brainer anyone who actually thinks that cereal is good for you and is a health food please think again but let's make sure let's read the label