Mitochondria are not static batteries. They are living systems that need turnover. Mitophagy is the body’s quality-control process: damaged mitochondria are identified, cleared, and replaced so cells can keep producing energy with less friction.
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Is it fair to say most of your mitochondria in your body lives in your muscle? say in your muscle and probably the brain. So, the more you use your muscle, the more of your mitochondria are able to remove that glucose from your bloodstream, protecting your metabolic You nailed it. One of our collaborators did exactly this study where they actually looked at obese people who don't respond to many of the current medications and they found problems in in this glucose [music] transporter chain in the muscle and when they put cultured them with urolithin A, they can suddenly get better glucose uptake. Dr. Anurag Singh, it is such an honor to have you here. Thank you so much for joining the Extend podcast today. Pleasure is mine, Dr. Shah. It's absolute pleasure. We've known each other for a while now. I'm a huge fan of your science and I'm really excited to finally get you on all the way from Switzerland to come and do this for me in New York. Yeah, I was looking forward for a long time as well, so happy to do this today. Yeah, we have a lot to talk about and I mean, not too many molecules have come out over the last 10 years or so that have had quite the impact on the scientific community and also on people's health as [snorts] some of the work that you're doing in mitochondrial health and specifically around the molecule urolithin A. And this is such an interesting molecule. It is absolutely one of the most interesting um discoveries because of its tie-in with gut health. And I think it just opens up a whole new frontier in how we think about our gut and how the gut interacts with the brain, with the the health of every cell and also, what are the potential possibilities of even mitochondrial health and there's so much here to unpack. Yeah, so you know, you nailed it. I think it to me gut is sort of the main organ that connects all to the other organs. So, this gut-brain axis that everybody in the neurodegenerative field is now talking about, you know, how how does it all
start? Parkinson's, as you know, starts in the gut. You know, the first symptom uh people with Parkinson's have is actually problems with their GI system. Yeah. Then there's the gut-muscle axis that we talk about in gut immune. Immune is the biggest reservoir. So, yeah, it's a very timely topic. Yes, absolutely. So, you know, the a little bit about you first. And you're an MD PhD. Um you're a physician, you're a scientist. You uh live in Switzerland now. Yeah. And I'm curious about how you came upon this molecule or how you know, the the company came upon this molecule and how you look at the science of this molecule and kind of what your role is in the scientific piece of this. Sure. Yeah. Well, so I trained for many years as a medical doctor first in India and then the States. And I was always kind of frustrated uh with this notion that I was just treating the symptomatology and not uh the root cause of the where it starts and probably starts much earlier. And so, that got me interested into the whole natural product space. And so, I started working with um actually a fellow colleague of mine who was screening many compounds and that's you know, how my interest in the field grew. And then I was hired to move into Nestle Health Science in in Switzerland and I ran the clinical trials and one day two professors from a very famous Swiss university that nobody knows outside Switzerland though. Uh it's called the MIT of Europe. They came to me and said, "Hey, we have a molecule that is making mice and rodents uh different animal models, you know, seeing these big effects on mitochondria." Um that's where my journey started with the company. But the original history of uh timeline is that the original scientists who were involved with the co-founders, they believe they wanted to bring the biotech approach to nutrition science. A lot of nutrition is blends of vitamins, minerals, probiotics without the deep
biology and science. And so, that's how they handed it over and said, "Well, show us that it can work in humans." And that's what I've done for the last 12 plus years. Incredible. And so, this molecule urolithin A that we're talking about, yeah, maybe you can help us understand you know, you've been involved in the drug discovery pathways and also the nutraceutical pathway. How does a a molecule become a drug versus a nutraceutical? Yeah, very relevant question. So, uh in the case of urolithin A, it's a gut metabolite. It's naturally present. Uh a lot of us have lost the ability to make it naturally because as we started off, the gut microbiome has changed drastically. And so, there's still a substantial population that makes urolithin A if you're eating the right foods. So, if you're drinking a glass of pure pomegranate juice or a bowl of berries and nuts, you will make it. So, the demarcation for me is if it's a naturally occurring compound that has already been shown to have health benefits, sort of in the whole range of health benefits, then it's a nutraceutical. Right. If in its potent form or higher dosing, it has effects on diseases like, you know, if you talk about frailty and sarcopenia, if it can reverse some of the extreme decline, then that's where it gets into the sort of the drug category. Mhm. But fundamentally as a scientist and an entrepreneur, you want to impact as many people as possible and I think you can do that with nutraceutical. Right, exactly. And so, you know, I I wanted to ask you that question because I want to emphasize that this urolithin A is a molecule that's naturally made Yeah. in the gut of many people. Is there a specific microbiome bacterium that makes this? Uh I spent a long time uh researching this across the world. So, I've gone into US populations, uh French, Italians, even uh country from where I come, India. And it's not an easy answer because the gut microbiome across the whole adult population in the world is very
different. Uh The Americans are eating a lot of processed food. The Italians and French are eating the fermented cheeses and drinking, you know, eating fresh food. So, we see a very high prevalence in these countries, the sort of Mediterranean lifestyle countries. In the US and Canada, it's like 10% versus 30-40% in European countries. And in India, where antibiotic use is rampant, it's almost down to like 5%. Wow. So, that you know, that tells you the scope of the issue. Sure. We've taken the gut microbiome of people who are natural producers versus those who don't make I don't make it. I'm assuming because I got a lot of antibiotics. And the answer is you need to have a very rich and diverse gut microbiome. It's not one species. It's probably a mix of good healthy bacteria that colonize your gut. Ah, that's so interesting. Okay, so, you know, when you have this molecule called urolithin A that's made in the gut by a combination of various bacterium Yeah. interacting with each other in a healthy way. Yeah. The It seems like it's really interesting about how how that works together because are parts of the molecule made by some bacteria, parts by another bacteria? Is I mean, is there a probiotic that you can take that would increase your production of urolithin A or not? So, let's get to how the molecule is made. So, the precursors, uh the dietary precursors, urolithin A is not found in food. Right. The precursors are polyphenols. These are what we would call label as antioxidants, etc. These are very complex polyphenols that when you take, for example, you drink a glass of juice or take a bowl of red berries, your gut microbiome will break them into simplified molecules. Got it. So, it's sort of the end product of digestion of these poly dietary precursors. Mhm. Now, we have looked what are the main bacteria in the gut that these
folks have who I call blessed cuz they're naturally blessed with good, you know, the gut microbiome is a is like a polypharmacy. And you're You said the Europeans have the highest percentage of people that Europeans do in our and we'll probably come out with a big publication on this across the world. We have mapped out. Japan is the only place we haven't gone into, but I believe it'll be the highest because people eat so much fermented foods there. Um but what what we do see is there is no one probiotic that you can take. We do see things like Akkermansia, for example, are super enriched in people who are naturally blessed or make urolithin Got it. Very interesting. And so, for um your company timeline, the way you encourage urolithin A production by the gut bacteria is feeding it the polyphenol precursors that come mainly from pomegranate juice. Yes, so that will be the natural way. But, that natural way is a very imprecise way. Mhm. So, if you take 100 people and you give everybody a freshly pressed glass of pomegranate juice, not everybody will make it. 10% people in the US will make it, okay? So, the question is how do you then supplement or provide the missing benefits to that remaining 90%? And so, what we do is actually we actually synthesize the the molecule at its purest form that is identical to the naturally occurring variant. And that's how most vitamins and minerals are made today. Got it. Vitamin C is is not juiced from four or 10 oranges. It's made um by a sort of a chemistry process. Yes. So, um, when you're giving someone, let's say, how many milligrams of urolithin A is a standard dose? Yeah, 500 mg in our studies is what works really, you know, at a healthy level. Right. And then the physician grade version, the practitioner version is 1, 000 mg. Right. And that's the one we are coming out soon for the practitioner focused channel. The difference between the two doses, and we have done a lot of clinical studies on this, is they both
hit the same biology on sort of reversing the poor mitochondrial health into good mitochondrial health, but the gram dose is better in that it starts hitting other organs like the immune system and potentially, you know, other sort of even the brain that we are researching. The 500 is sort of the maintenance dose, gets your mitochondria happy, has muscle benefits. The gram is an augmented dose. Got it. Okay, so for the people that are taking 500 mg, for example, of urolithin A a day, how many glasses of pomegranate juice would they have to drink? So, we did that, actually. I did I ran a clinical trial in an in sort of a crossover trial, and and we calculated with the level of exposure we got from from six So, you have to to get a glass of pomegranate juice, you need to juice about four to six pomegranates, and to get the level equivalent to 500 mg, you need six glasses. So, you need like 25 to 30 pomegranates juiced, and you have to drink five, six glasses of juice to get that one dose of 500 mg. Yeah, so that's why, you know, to your point earlier, the concentration that you can make with synthetically versus trying to do this naturally is a whole different ballgame. Yeah, and and people have I mean, of course, natural ways are the best if you can eat fermented foods and you can, you know, nourish your bacteria in your gut, and maybe that's also a very good way. It's just the exposure levels we see are so variable that some may benefit, some may not with with that variability that you see in the population. And that's why I think a calibrated dose, you know, that we know works and gives the same health benefits across population is the right dose is the way forward. Okay, so then the other question and the other piece of the puzzle, too, is not everyone has the right bacteria to make it in the first place. I'm one of them. I've had not six, I've had 10 glasses of
juice over time, tried to eat probiotics, nothing works. It's sort of and I do believe a lot of the the gut microbiome that is endowed to us is in the first thousand days of our birth. And then you can do certain things, but some of the initial imprinting occurs very early. Yeah, so whether you're born by C-section or natural delivery, whether you're given antibiotics or not, whether you're fed formula or real vegetables and fruits and are they organic, all of that makes a massive difference in in the health of your gut and the health of your microbiome. And this is just one discovery that, you know, that your company is working with, but I'm sure there's going to be thousands of others because Absolutely. Yeah, I always say like, you know, we have each and every one of us have a billion dollar pharmaceutical factory inside of our gut. You nailed it. I say this all the time that the gut microbiome is a polypharmacy. Right? We are all eating these probiotics and prebiotics that are food for the gut the bacteria, but it's what the bacteria does with the the food that we are giving it is what we call postbiotics like urolithin A is what is beneficial to us as human host. And there are many of them, I can assure you. Exactly. And you know, if you look at it as a pharmaceutical factory, it also has the absolute best scientists on the planet because, you know, the amount of times I amount of times it would take a human to create a compound like urolithin A, like it would probably even never happen because it's we've not figured out how to affect the mitochondria in our cell since the beginning of five years ago. co-evolution, right? We are our ancestors were eating fresh food, they were, you know, kind of their gut microbiome was very diverse. Every day it was not the same food. We're eating the same sort of diet, processed, etc. And I think we're just losing the capacity to to make these healthy gut metabolites. Right. Even if you look at the story of GLP-1s, this is also
GLP-1 production is encouraged by Akkermansia and other strains of gut bacteria and that's what keeps us healthy and because our gut bacteria is decimated from ultra-processed food and antibiotics, etc., we don't make enough GLP-1 anymore. There's a chronic deficiency of GLP-1 leading to metabolic disease. Yeah, so it's it's pretty much the same. A lot of the GLP-1 is made in the gut as you said. And it's the same with urolithin A in that comparison that a lot of us initially probably did our forefathers probably were making it. Some of us who are still eating farm fresh and as I say are blessed or do have it, but we we all do need to think about supplementation as a way to get that exposure to these beneficial molecules. Right. Okay, let's turn to the conversation on the mitochondria because mitochondria I I [snorts] people hear this buzzword all the time and they're not very clear on what mitochondria are and where they are and what they do. So, you know, I want you to tell the story of mitochondria. [laughter] Yeah, so probably the one thing we all learned in our school biology or well, not much in med school. They don't teach much of mitochondria either. Because we have no drugs for them. That's why. powerhouse the cell, but they don't teach you that it's the fundamental cellular organelle, which is the source, the power plant of energy, right? So, it's like your phone battery, right? If it's 100% means your mitochondria are happy. If it's down to like the red, the 20%, then your mitochondria are not in good shape, and that's essentially what it is, you know, if you make that analogy. They are the battery inside our body. And how good it recharges or or loses charge makes us, you know, move around, get up from a chair, make that run in the morning, or think clearly. So, they are the fundamental let's say currency that allows us to exist. Now, most people don't know that most mitochondria are inherited from the
maternal side, from our mothers, and it's maternal DNA sort of what you're the mitochondria will have, and they have their own special DNA that we call mitochondrial DNA. And this DNA came evolutionary from ancient bacteria. So, back to the tie-in with the gut microbiome and the evolution of [snorts] I call it the microbiome mitochondria connection. It's a very close connection. So, that's the history of mitochondria. And you can actually today aging is probably the biggest stressor on these guys, and there are thousands of them in in cells that are extremely metabolic. So, for example, our brain cells, neurons. Each neuron cell will have thousands and thousands of mitochondria. Muscle cell will have thousands of mitochondria. Heart cell will have thousands of mitochondria, but they basically are in every every cell other than red blood cells. Yes, exactly. And so, to give some further emphasis on mitochondria and why they're so important, every cell in your body needs energy to function. And if you don't have mitochondria, you have zero energy in that cell, and therefore that cell will be dead, like immediately. And so literally without mitochondria you will die. And secondly, um you know, mitochondria are kind of weird alien cells. They have they function in such a strange way in that they can take glucose and oxygen and make ATP, which is energy, but it does this through series of reactions through proteins in the cell membrane that are moving electrons around. And the last one, which is really weird, is like a little motor Yeah. [laughter] that attaches ATP together. And then some of these proteins are activated by light and some of these proteins are like it's it's a really interesting molecule. Absolutely. And that's the science, right? Red light has a big effect. Thermal the temperature shifts have a big impact on mitochondria as well. So they are extremely sensitive organelles to these kind of uh shifts that happen all around our environment. Yeah, they can sense the environment
separately from our sensory infrastructure. Yeah. Every cell can do this. I read also a fascinating paper that even the pressure to at the end of the day to sleep is because your mitochondria are pushing you at a cellular level to to kind of cleanse and do the reset. So there's a lot of new science what we are calling as the bioenergetic theory of life now. There's a lot of top professors and labs studying that a lot of these cellular processes can be tied down to mitochondrial health. So true. And the reason the mitochondrial DNA comes from the mother and is very important to realize like the mitochondrial DNA is separate from your 23 chromosomes that make you up is because when the sperm hits the egg, the sperm is just one Y chromosome joining to the X chromosome. That's it. The rest of it's gone. Yeah. The mitochondria are in that egg cell and that comes from your mom. Yeah. Right? So all the mitochondria in every human on in this planet has come from a female Yeah. at some point. Yeah, and I I what your mom probably ate during you were in neutral probably has a big impact on on how your mitochondria during your life would be. Right, absolutely. Um, another interesting thing about mitochondrial DNA, which you said is, you know, these are ancient bacteria. So, somehow these ancient bacteria found unicellular organisms and they combined forces synergistically to become multicellular organisms. And so, I think that's an important thing to know, too, is that this is a combination of two different organisms that have come together to form humans and every life form on the planet, pretty much. Yeah, we study mitochondria at a very deep cellular level. I take biopsies from older people and and we go deep into doing something called transmission electron microscopy and seeing how they talk to each other. It's really funny. If they're happy and if you're exercising at 70 years old and you look at them, you'll see that they are these elongated forms that are very closely
attached to each other, talking to each other. But, in sedentary frail 70-year - olds were not exercising, you they're more round, they're more obese little mitochondria, looking zombie-like mitochondria, and they will be away from each other, almost like grumpy old folks like who don't want to, you know, interact. And so, it's fascinating that such a deep cellular network exists at their level and at the cell with the mitochondria. And is it true or am I making this up from my recollection of medical school, but sometimes mitochondria can actually combine with each other and form a new mitochondria? Yeah, so there's three ways you can regrow healthy mitochondria. One is a process we call mitochondrial biogenesis, which means you kind of are growing new real estate inside, so more new mitochondria that will now give you more energy. Then, that second process, which you said, is sort of this fission-fusion process where they kind of merge with each other and kind of tie up and, you know, if one is kind of fatiguing out, they join forces and kind of become a super potent. The third is what we can talk about a bit more is this mitophagy process. And aging actually puts such a big energetic pressure that you get you end up with the balance shifting inside the mitochondria into more damaged mitochondria accumulating. So it's almost like instead of 50 / 50 balance, it becomes 20 healthy and 80 bad. And so you need to get like a trash crew coming in to clean them out. Yeah. And so that process of cleaning out the old unhealthy mitochondria within a cell is called mitophagy. And can you go a little bit deeper into how mitophagy happens? Yeah, sure. So mitophagy is really targeted autophagy at a mitochondrial level. So everybody probably in your audience has heard about autophagy. This is where old cells kill themselves basically. Yeah, it's sort of self-renewal. And that's the you know, autophagy fagy being the cell will destruct and create kind of be reborn as a healthy
functional cell. Most damaged mitochondria will put out a signal that I'm damaged and they will sort of we call them the eat me signal. What happens is the process of recognizing this sort of eat me signal declines with aging or is accelerated for example in conditions like Parkinson's disease or Alzheimer's disease. And so you basically end up with the a cell full of damaged goods, right? Damaged mitochondria that are clogging the real estate. So there's even no way you can create biogenesis or fission fusion for example. So you really need to get the machinery to you know, for the for your garbage disposal truck to show up and and to clean them out. And that's the process of mitophagy. It's very targeted autophagy. Got it. And so what are just some of the things that can damage mitochondria to where where need to go through mitophagy? Gosh, there's so many. The biggest culprit is sugar. The amount of sugar we process sugar we take in our diet. Second one would be sort of you know, stress is a big just you know, if you're living a very stressful life, poor levels of physical activity. If you're not exercising, your mitochondria it's called the energy sort of waste. You know, if your body's making energy and you're not consuming it, it just sort of gets out and the mitochondria kind of get damaged in the hope that you know, that they're needed for the for a certain purpose. Um sleep patterns, etc. So, there's a lot of things environmental toxins. We see even uh uh we can talk about it even at the skin level. Even environmental pollutants like microparticles can can damage mitochondria. Wow. Yeah, so your mitochondria basically reacts like your body does to all of these insults. And I think, you know, one of the ways I like to think about mitochondria is like it's a little engine, right? And this engine uses glucose as coal and it
goes into a furnace and whatever you're and it produces energy to move the mitochondria along, but also it produces waste product, right? And some of that waste product is I think is reactive oxygen species, right? And to your point, like if you're not using this energy, you're just making a bunch of reactive oxygen species. That's going to damage the mitochondria, right? Yeah. And so, can we talk a little bit more about reactive oxygen species and how do we how does our body kind of mitigate these reactive oxygen species which are like the smoke to the fire of energy production? Yeah, it's what we call the free radical theory also. That you know, you have these sort of signals inside where you know, the the cells at a simple level are always needing oxygen to survive. And so, if they're not processing all that very well, then they'll generate more and more free radicals. And that's what is like the danger signal to the to these mitochondria or to the cell at a bigger level. And so, in for many years in the field of mitochondrial health, they were targeting therapies that were let's say nutrition ways or integrated ways where you could lower the ROS in in sort of the free radicals circulating around. But now that we know there are other ways probably like mitophagy we talked about as well. Yeah, you know, there's a molecule called glutathione that can actually be very powerful for cleaning up some of these free radicals. Vitamin C is powerful for this. Yeah, so antioxidants are probably antioxidants and yeah. Okay, so how does urolithin A fit into this whole puzzle? So, I think urolithin A is a very special molecule. What makes it special is that it is probably one of the few molecules out there that has this unique mechanism of action, right? Which is mitophagy activation. We talked about how this cleanup process slows down with aging. What urolithin A does is it basically starts the machinery again of cleaning these damaged mitochondria. Now, these
damaged mitochondria ultimately become the building blocks of newer healthy mitochondria. So, what we see when we do trials in older adults who are very sedentary, in about a week or two weeks, you will see mitophagy signals. In about a month, you will start seeing biogenesis happening. So, things like PGC1-alpha and we can talk about these are markers of when your mitochondria are starting to regenerating, and we'll see that happening in the muscle level. So, that's what makes urolithin A very special compared to other molecules. There's NAD, which is very targeted to biogenesis. There is things like CoQ10 and and creatine that hit the efficiency part of the mitochondria, but that's what makes Urolithin A very special. Yeah, so Urolithin A is targeting mitophagy. Basically, accelerating the process of removing old damaged mitochondria, which [snorts] then become the building blocks to new mitochondria within the cell. And this happens mainly in the muscle tissue. It happens everywhere where you you know. So, we started with muscle because obviously muscle is one of the key longevity organs. And I was trained with to sort of work with older adults who had all these poly issues, right? What happened with aging, they were having cognitive issues, they had mobility issues, their immune system was kind of not responding to any flu vaccination that you would give them. And so, after 20-plus years of studying older adults, I have come to the realization that the fundamental at the basis of all their problems is poor mitochondrial health, whether it's immune health, muscle health, or brain health. So, yes, we started with muscle, and that's where we have the biggest body of evidence. But now we have moved in and done a trial in on healthy people looking at the immune cells and what the mitochondria in their immune cells look like and the impact on of Urolithin A on on immune cells and their mitochondria. Yeah. So, you know, I I think when you say you started with
muscle, that's where you first started studying Urolithin A's effects on muscle, right? And so, um one of the things I always think about with muscle and specifically aging is obviously, you know, right around the age of 40, we start losing muscle. And it happens um at a kind of a slower rate at first, and then it kind of drops off a cliff if you look at the graphs of muscle loss over time in around the age of 70. And that 70-year - old drop-off, if you don't have a good reserve of muscle, it can drop so far down very quickly that you lose your mobility. A lot of people lose their bone strength, which is very much tied to your muscular health. And then, this is where you become a little old man or a little old lady, become very frail, maybe you're confined to a wheelchair, maybe you fall and break a bone. All of that is due to not enough storage of muscle mass, right? Now, Absolutely. right? And that can be combatted by lifting heavy weights, right? Like Absolutely. Like creating that signal to create new muscle. Um the studies show that creatine can help maintain muscle mass. Vitamin D can help maintain muscle mass. But now, we have this additional compound, urolithin A, that can also be useful in the maintenance of muscle mass. Yeah. I I see it as two pillar strategy to preserving muscle. One is what you're you're saying with creatine, high protein supplementation, that you need to pay attention to the mass, that you have enough of this reserve, right? And pharmaceuticals have gone in that path, uh trying to block the myostatin this sort of signal to to block uh the the muscle damage. But the second is muscle quality, which is the energetics of the muscle. Even if you have leftover muscle that can give you good force that allows you to lift weights and and to improve the the strength. So, that's where I see it the the muscle mass and the muscle quality and the energetics. And urolithin A specifically hitting the muscle quality and the energetics. And so, if you combine it potentially, as you're saying, with either creatine
supplementation or with exercise, you would get this double synergistic effect. augmented effect, yeah, so then you may have um improved muscle strength and muscle mass. And some would argue [snorts] muscle strength is even more important to longevity than even muscle mass is. Um and you know, when you when I look at muscle as well, something I always say is your metabolism lives in the muscle, right? Kind of like the biggest glucose sink you have in your body is your muscle. And that glucose sink, which means removing the the from your bloodstream, That happens because our mitochondria is being fed that glucose to turn into energy. So, the more you use the muscle, Yeah. the more energy you need. Is it fair to say most of your mitochondria in your body lives in your muscle? I would say in your muscle and probably the brain, yeah, muscle and brain. So, the more you use your muscle, the more your mitochondria are able to remove that glucose from your bloodstream, protecting your metabolic health. That's absolute Yeah, you nailed it because we haven't looked at it. One of our collaborators did exactly this study where where they actually looked at obese people who don't respond to many of the current medications and they found problems in in sort of this glucose transporter chain in the muscle and when they put cultured them with urolithin A, they can suddenly get better glucose uptake and and so we're actually now partnered in doing a trial with the National Institute of Aging Oh, great. in diabetic people cuz diabet you know, is is I see diabetes as sort of an accelerated aging Right. uh kind of condition. Absolutely. And so they're looking at how frailty sarcopenia can be reversed a little bit, how can metabolic health of course at the as the base of it be improved and does it have an effect on the brain as well in that study, so Yeah, it's a fascinating study. Yeah, that's going to be really good information. When is that slated to come out? is done by the National Institute of Aging in in Bethesda and I think they're about 60% done, so I Mhm. I would assume
by the end of the year Mhm. we'll have some data [snorts] coming out. Oh, that's that's going to You have to keep me updated on that one for sure. Okay, so this study that you did on urolithin A and muscle, can you describe it to us a little bit and what your findings were? Yeah, so we've done many. We started out obviously with older adults. Okay. Uh older adults uh when we started out, the big question was how do you also measure mitochondrial health in the clinic? This is always has been a big question. Yes. And so, I we said, "Okay, we took uh a bunch of folks, as I mentioned, who were in their 70s exercising, and a bunch of folks who were very sedentary, frail almost. And we looked we took chunks of their muscle tissue. This is a procedure we call muscle biopsy. And we asked in an unbiased way, you can ask uh the 30, 000 genes in the muscle, human muscle, which are up and which are down. The top 30 genes were all linked to poor mitochondrial health in the people who were frail and sedentary. So, we took that population, the sedentary older folks, we gave them a month-long supplementation with either placebo, a 500 mg urolithin A, or a gram of urolithin A. And in about a month, we started seeing their bad, unhappy mitochondria become happy. So, it takes a while. It's not And this is well known in exercise studies. If you took 70 75 80-year - olds, as you said, just get them moving or lifting weights, you can kind of So, urolithin A is kind of hitting the same biology at the mitochondrial level that regular exercise would would do as well. And then we went in and we did longer trials in the same folks um for about 2 and 4 months, and we started seeing the older adults they just had more energy. So, if you put them in a gym and make them do a leg press test, they would have 20% more energy to keep going 20% longer. So, these were the first trials, and then obviously, uh the the 40 50-year - olds said, "Well, this is a product for for older people.
Why should we take it?" So, we went in and we said, "Okay, let's let's address that hypothesis." I'm a very evidence-based person. So, we took healthy but inactive sedentary people in who were in their early to mid early 50s, and we gave them 4 months of supplementation. Now, these folks did not change their their or their physical activity. And after 4 months when you got them to the clinic and tested their leg strength, they had about 10 to 15% more leg strength. By doing nothing extra except taking your urolithin A. Or, yeah, regularly over a period of 4 months. Mhm. So, that was the early data. Sure. And then an a very famous researcher who only works with Olympians came to me and said, "Well, what do you think? Would it work for Olympians if it's having such good effects?" And I said, "I don't think so, but you can try." And so, she ran this study and these Olympians have a VO2 max of about 65. Yeah. You know, that that's probably the pinnacle of human performance. And what surprised me was we actually managed to improve their VO2 from 65 to 70. That's incredible. And it was not so much if they won a race Yeah. at the Olympics, suddenly people on urolithin A were showing up with gold medals. It was their recovery. How fast the these top-tier athletes said their recovery was faster and they felt less sore. So, we have that kind of a data for different populations on muscle. Super interesting. Um you know, I think about also uh this dosage issue of 500 to 1, 000. Yeah. Was there any additional benefit to taking 1, 000 over 500 for any one of these groups? Yeah, so the 500 mg dose uh when you looked at just at the biopsy level and the mitochondrial signature and you see this dose-dependent response. You see let's say 20 to 30% renewal, you'll see 40% of upwards renewal with the gram dose. Strength, it was same. It was almost comparative, but then the gram dose is
where we start seeing the endurance benefits. The better VO2 max, the better recovery, uh lowered inflammation uh in in these populations. So, you get this almost sort of a additive effect happening over time. Got it. Let's talk about the brain. Yeah. And some of the studies you've done around Urolithin A and mitochondria activity in the brain. So obviously, you know, the brain very similar to muscle has a lot of mitochondria that are very active. It's one of the hungriest organs in our body. Yeah. It uses the most glucose out of any other organ in the body. And also uh probably produces um the the most energy out of any other organ in our body. And so keeping the mitochondria healthy are extremely important. Mhm. And I think there's also a direct symp - symptomatology of having poor or weak mitochondria that you can feel immediately as brain fog, slowed mentation. You can probably measure this very easily also with cognitive testing as well, right? Mhm. Yeah. So talk to us about some of the studies you've done with brain health. Yeah, when you're small and very focused company, you can only start first with one organ in one. So that's where we were focused with muscle. But the more we publish in top journals, the more top professors and laboratories around the world got interested in this molecule. So in total honesty, the brain angle came to us from other labs that got interested in the molecule. Sure. Um the Buck Institute got to actually a multi-million dollar grant, the Buck Institute of Aging in California. Yeah. And they were looking at a whole library of compounds that could reverse Alzheimer's and early dementia. And they found Urolithin A was one of the top most uh compounds in there. Uh in of Alzheimer symptoms? Uh for You know, Alzheimer's is not one pathway. It's neuroinflammation. It's these protein aggregates that happen. Uh so what they were seeing was a sort of a molecule that hit multiple hallmarks of
of aging in in these kind of models. Wow. Um the National Institute of Aging, there're two researchers, uh Professor Willem Bohr and and uh Professor Evandro Fabbro, they published a big nature paper immediately after. So, almost two three labs competing to publish, uh which is a very common story. That was great for your company, too. Which was great for because [laughter] we we didn't have to do anything. They actually ran a whole library of about 4, 000 repurposed drugs that were already out there, natural products. And they found that the one that was the safest and the most uh likely to have an effect. And before that, they actually found that Alzheimer's in the brain of people, mitophagy was the biggest problem. And so, they were looking for compounds that would hit mitophagy, and they found urolithin A was doing the best uh job at hitting these sort of neuroinflammation and these um amyloid aggregates that happen in the brain. So interesting. So, they came to us and they said, "Well, you got to do something in this area. If you don't do, we'll do it." And so, we started partnering. So, these trials are just starting to kick off. One is focused on mild cognitive impairment uh with with the same group I was telling you about. And there's a second trial uh happening with Parkinson's disease. Yeah. Uh on our side, the questions we are tackling with urolithin A is very simplistic. In some sort of healthy populations, does it get into the brain first? What biomarkers does it affect? Does it hit on inflammation markers that we can pick up? Does it hit on mitochondrial markers that we can pick up? So, these are the trials, and hopefully you'll have to invite me back to get into the data. to have you back. So, but a lot of efforts around the world on uh urolithin A and brain happening. Yeah. Just little tangent here real quick. What are some of the markers you're using for mitochondrial health? It's a question I get a lot. Um we have looked across the board. There is no one gold standard biomarker. You really have to look at a constellation of of markers. We use something called
ceramides a lot now. Yeah. Uh these have been associated higher levels of ceramides with mostly cardiovascular problems and we see that ceramides if you throw on cells induces abnormal mitophagy and so you need to reverse. So we see lowering of plasma ceramides, we see a lot of fatty acid oxidation metabolites like acyl carnitines get inhibited. We see everywhere PGC1 alpha go up. So that for me is actually a very good biomarker to tell if it's working. Problem is well, do you have to do a biopsy or can you do it with a just a little blood tap and so that's the where we are and it's very easy to do it with just a routine blood draw and look at your immune cells and see if it's hitting the mitochondria in your immune cells is a de facto way that it's going to hit all your key organs. Got it. And could you talk a little bit about what PGC1 alpha is? Yeah, so it's it's a it's sort of a [sighs] a very well-known gene that regulates mitochondrial biogenesis. So it's almost seen as a de facto marker of that your mitochondria coming back in in peak state. And so there's a lot of new healthy mitochondria. So it's used as sort of a yeah, marker that your mitochondria are regenerating. Is this a genetic marker or is it actual um Yeah, it's it's a gene. So you need to do like a qPCR or you need to look at or RNA sequencing to look at that panel of genes. Makes sense. And is this a gene that is a mitochondrial gene? It is not a mitochondrial gene but it is reflective of of hitting the mitochondrial pathways. Ah, so interesting. Okay. Yeah. Um, all right. So you know, we've talked about brain health, we've talked about muscle health and I know that now there's a new body of evidence coming out around immune health because obviously all of our immune cells use mitochondria to create their energy.
Yeah. So, [snorts] let's talk about what are some of the studies you're doing in immune health and why you think those are important and you know, for me the more I look at aging in general um and longevity, I would say that the immune system has risen to the top of the most important system regulating most aging pathways, you know, and so Yeah. it's really it's it's so tied to every organ system Mhm. and every cell in our body in many different ways that you know, we just think we have this misconception that the immune system is just there to fight infections and this it's not is not just that. It is much more than that. I'm so glad you said that Darshan because you know, I'm a trained immunologist and whenever I try to tell the folks who are non-scientists around the world that this or hitting your improving your mitochondrial health could have big implications for your immune health, they say, "Well, we have vitamin C." [laughter] How's this molecule different? What is What about zinc and vitamin C? Yeah. [laughter] No, but back to your question. So, you know, first I always saw that immune health is a big problem in the aging trajectory because that's where my training was and most older adults were not responding to flu vaccination and or pneumococcal vaccination and would you know, fall sick very routinely and that sets them off in sort of this frailty syndrome actually. And then as we got into mitochondrial health and started looking at all these trials that that we were talking about in muscle health, I always picked up when we look at the plasma metabolomics or plasma biomarkers, we would always always see in these populations hs-CRP go down, cytokines. These are soluble factors that immune cells make whenever they feel threatened and these are called pro-inflammatory cytokines. They would be blunted. So, we got interested in in immune health that way. And I started doing this trial in the same time another professor came to me and said that urolithin A is actually having a big impact in models of colorectal
cancer. And he published this big paper in immunity showing that actually your immune cells get fatigued. Uh-huh. We all have cancer cells. They're fighting these these T cells as we call them. They are super energetic and they kill these cancer cells off. But when they get fatigued is when the cancer cells Right. proliferate. And so he said, "Well, your compound is actually rejuvenating these T cells and they're killing the cancer off. Wow. So you need to do a trial. So we said, "Okay, let's we won't go to cancer first." So the trial we've just published shows that taking a month of a gram dose actually brought the these fatigue T cells back to their peak youthfulness. Wow. They had 20% more mitochondria. If you threw bacteria at them, they would just kill it 20 30% more. And the immune system of these 50-year - old almost looks like the immune system of 40-year - old. That's crazy. Yeah, and I personally think back to what you said, immune health is sort of the first stepping block in this longevity march. If you fix it, you can delay the rest. Yeah. Well, you can certainly delay cancer because if with a healthy immune system, you can fight off cancers as you mentioned with colon cancer which is becoming a much bigger problem at younger ages Yeah. right now. But also I think, you know, the immune system is incredibly valuable in protecting your cardiovascular health, your brain health by when you have a strong immune system you actually lower chronic inflammation, right? Yeah. It's the overactive immune system that's not making any headway with all of the toxins and whatever it's fighting that creates this chronic inflammatory state. But if the immune system wins, the inflammation gets dampened. Absolutely. And that's I mean, kind of look at long COVID. People still don't know. Right? It's an immune problem that started with now is having brain fog effects. It's having these very bad effects on muscle and mobility. So, I do think immune is if you fix the problem early, you can have big effects on muscle and even
cognitive health. So, the trial we are doing actually the follow-up trial is taking people in checkpoint inhibitors, so immunotherapy and augmenting that with urolithin A added to it. Because to me, that's the signs where people would say, "Wow, a dietary supplement can be added to a standard of care cancer therapy." That is where the signs we need to bring for supplements. Yeah, that's that's incredible. So, at what age should someone think about starting to take urolithin A? So, the youngest people we have worked with are these Olympians who are in their early 20s. And the oldest clinical trial participant I had was an 89-year - old lady who swore her gardening improved. So, [laughter] and she did not know because it was a blinded placebo-controlled trial and she told me after the trial, "Oh, doc, you need to tell me what I was on because I'm kind of losing the benefits I saw." And she was on on the active product. But, I would say if you follow the signs in longevity today, the earliest changes are happening in your early 40s with you know, at a plasma proteome metabolome levels. And so, you need to to prevent what's going to happen to you in your 60s and 70s, already start improving your cellular health in your early 40s, I would say. That's the fundamental for me to hit cellular health. Yeah, you got to start it around 40. Um I I fully agree with you, but I also think there are benefits of starting younger. You know, obviously when you're young, you don't have a lot of financial resources, so you're trying to protect your pocketbook. So, I get it if you don't start, but by the time you're 40, you just got to start taking care of yourself. we have top NBA teams taking it. We have a lot of Tour de France cycling teams taking it. Um we know a lot of uh other sports of you know, athletes are taking it because they they know they need to step on the court every other day and they need to be at the top of the game.
So this is something that can help their recovery very fast. Is there anyone who should not take your urolithin A? Uh so far I would say we've done 25 clinical trials, almost 3, 000 participants. We haven't seen a contraindication. Uh but I am evidence-based, so I would say wait for all these cancer studies to come out and the uh but and there is also the studies where people say, "Well, I'm on a blood thinner or I'm a on a statin, should I be taking it? Or I'm on GLP-1, should I be taking it?" And I think there's a use case in all of them because statins do have an impact on mitochondrial health. Uh GLP-1 will have huge impacts on metabolic health. I just think use by use they can doctors can tell their patients to take it, but as an evidence-based person, I would say wait for that data. Mhm. Yeah. And is there any side effects you've seen? Not at all. That's the magic of working with a natural compound that almost all of us at one point had and and uh but yes, you you What we have done is we have gone above a gram to see if higher doses would give a benefit. And for example, it's not always that you'd keep doubling that you'll get the double benefit. So the 2 g, you kind of saturate the absorption of the molecule. Uh what we haven't done is we haven't done a gram in the morning and then a gram in the uh or 500 in the morning and 500 in the evening like twice a day kind of regimen. So these are the directions we are headed. Got it. Taking this supplement at night time, would it cause you to sleep better or sleep worse? Uh Or no effect? All our trials are done in a fasted state in the morning with intake because your fasting is inducing autophagy. So the idea is that this will augment it even more. Uh I've had many folks tell me they've been taking it in the middle of the day or
with a meal and it and this is such a robust molecule. You can take it with a gummy, you can take it with a pill, you can put it in your smoothie. So I I don't think but night actually I don't know many people who take it in the night. I guess you'll get it peaks in the blood around 4 to 8 hours. So you may suddenly get an energy rush with its peak that you may not want to wake up in the night. But I think based on the trials we've done, first thing in the morning is the right recommendation. it. Okay, fantastic. This has been an excellent excellent kind of overview of Urolithin A and also what mitochondria are, all of that. And so I'm really happy that you joined me to talk about this particular topic. But I'm also curious, you know, you're a physician, you're a scientist. You look at a lot of molecules, right? And you probably take some. So I'm curious from your perspective, how do you look at the supplements that you're taking and and what are you taking and what's and why? So I would look at all the level of clinical evidence on the table. Second, we have a great group of mitochondrial scientists who are who have an amazing lab back in Geneva where we are based. And so we are always, even if you were to make a a new product with Urolithin A, we'll just would not blindly do what the whole supplement industry does is to mix A and B and suddenly 1 + 1 would be better than two. Sometimes it's zero, right? So we'll we'll do a careful scientific analysis and experimentation. So, what and that will kind of guide me into what I need to take. We have seen in the lab that urolithin A really boosts the effects of creatine, for example. The whole what we were saying on muscle mass and the energetics part. So, I'm a big fan of creatine and the level of clinical insights that exist. I do take 5 g of creatine. There's debate whether higher should be better for cognition or not. I do take magnesium. It's It's something we have
seen works very well with uh urolithin A. Vitamin D. There's a lot of studies that actually urolithin A augments vitamin D receptor expression on a lot of cells. Okay. Um so, that those three are pretty much the standard. Of course, urolithin A. And then if I can prescribe for a good mitochondria, I would say sleep is an important one, but it's not a supplement you can take yet. Sure. Yeah. What about um CoQ10 you mentioned earlier? This is very directly related to mitochondria. You can combine it with CoQ10 um and probably you'll get an additive effect. Um I just don't take it because I think I'm a bit biased there on urolithin A's effect on mitochondria that I do think I already have sort of a base for mitochondria health. Um yeah, that's pretty much my stack of those four. Great. Do you have any thoughts around you know, we talked a little bit earlier about NAD molecules and the different forms that are available out there? Yeah, it can be confusing because there's so many different pro forms and different So, there's these, you know, for the listeners, vitamin B3 is is the sort of the [snorts] established what we call nicotinamide or niacinamide. This is the standard form. Now, what they have done, different companies have made different NAD prodrugs, as they call it, or pro forms. One is called nicotinamide riboside, NR, and one is called NMN, which is nicotinamide mononucleotide. Uh the data on muscle hasn't convinced me, but the data on on sort of cellular health is there, right? With aging, we all know NAD declines, and it's NAD is critical for different aspects of of mitochondrial electron transport chain, so augmenting and supplementing with it makes sense. Yeah. I agree. How much? I don't know. Right. Yeah, I think um and I think there's also a lot of controversy around NMN because I know the FDA took it off the nutraceutical market. I don't know if it's come back yet or not.
it's back. It is back now. Okay. back. But you can combine it. I think there are folks uh who who have have tried strategies or published at least a few publications that UA and NAD molecules hit different biologies of mitochondria, and combining them can be augmentative. Uh we we've looked in the lab, not in a trial, in a lab, and it seems to be augmented effects on mitochondria health. Right. So so they both are different parts of the entire pathway anyway. One is not, you know, uh and NAD precursors are feeding this NAD metabolism to to create ATP, whereas urolithin A is inducing mitophagy, so it's two completely different things. Yeah, and if you clean the waste and then you nourish the renewal process or the biogenesis, you could get a double uh sort of benefit. type of effect. Yeah, that's fantastic. Well, this was amazing. Thank you so much, Dr. Singh, for coming on the podcast and giving us this master course in urolithin A and mitochondrial health. How can people learn more about urolithin A and you and get more information and keep up with the research that's going on? Yeah, first thanks for having me, Darshan. It was an absolute pleasure. People can learn about uh the science we do. They can go to mitopure. com to learn about the science, and they're interested in products containing urolithin A or mitopure, they can go to timeline. com. Okay. Thank you so much. Pleasure. Thanks.
Transcript auto-generated by YouTube. Verbatim — duplicates intentionally preserved.
Much of the conversation returns to muscle because muscle is metabolically active and dense with mitochondria. When mitochondrial quality declines, strength, endurance, and recovery protocols often feel less reliable. Supporting mitochondrial renewal is one way to protect the capacity that makes daily life feel easier.
Urolithin A is produced when certain gut microbes transform compounds found in foods such as pomegranates, berries, and nuts. Not everyone converts those precursors efficiently. That is why the discussion sits at the intersection of nutrition, microbiome diversity, and targeted supplementation.
The promise is not stimulation. It is restoration at the cellular level. When energy systems become cleaner and more resilient, the body has more room for training, recovery, focus, and the quiet confidence of feeling capable.
Mitochondrial health is not only about making energy. It is about keeping the system clean enough to adapt.
Build the basics first: strength work, protein, sleep, and consistent movement remain the foundation for mitochondrial health.
Use food diversity to support the microbiome that helps produce compounds like urolithin A.
Treat supplements as precision tools, not replacements for the practices that create resilience.
