159: Dr. Anurag Singh: Urolithin A, Mitophagy, and Mitochondrial Health

Mitochondrial decline is one of the most overlooked drivers of aging, impacting energy, muscle function, cognitive performance, and immune resilience long before symptoms become obvious. Many of the changes we associate with aging may actually stem from a loss of cellular efficiency and the body's ability to renew itself. In this episode of Extend, I sit down with Dr. Anurag Singh, Chief Medical Officer at Timeline, to unpack the science behind urolithin A and how mitochondrial health shapes longevity. We break down how the gut microbiome influences cellular function, why mitophagy declines with age, and what clinical research shows about improving muscle strength, recovery, metabolic health, and immune function. We also explore how targeted supplementation and lifestyle strategies can help restore mitochondrial quality and support long-term performance and resilience. Dr. Anurag Singh is a physician-scientist with an M. D. in internal medicine and a Ph. D. in immunology, currently serving as Chief Medical Officer at Timeline, where he leads the development of advanced nutritional and skincare products focused on mitochondrial and cellular health. What We Discuss: (04:58) Drug vs nutraceutical and what urolithin A actually is (06:23) Gut microbiome differences and why most people don't produce it (08:11) How urolithin A is made from diet and polyphenols (10:25) Effective dosing and supplementation strategy (15:32) What mitochondria are and why they matter for aging (21:26) Mitophagy and how mitochondrial quality declines over time (23:43) Main drivers of mitochondrial damage (26:24) How urolithin A supports cellular renewal (28:55) Muscle aging, strength, and performance (33:07) Clinical trial results in older and sedentary adults (35:32) Effects on recovery in elite athletes (37:07) Brain health and neurodegeneration research (43:00) Immune system impact and inflammation (47:29) When to start and how to think about supplementation Thank You to Our Sponsors: Timeline: Visit timeline.com/drshah https://www.timeline.com/partners/darshan-shah for 20% off a subscription on top of the new starting price of $79. Learn more about Dr. Shah: Website: drshah.com https://www.drshah.com/ Clinic: next-health.com https://www.next-health.com/ Instagram: darshanshahmd https://www.instagram.com/darshanshahmd Learn more about Dr. Anurag Singh: Website: https://www.timeline.com/

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:03Dr. Darshan Shah?

  Welcome to Extend with me, Dr. Darshan Shah, a podcast dedicated to cutting-edge science, research, tools, and protocols designed to help you extend your health span. Having become one of the youngest doctors in the country at the age of 21, and trained and board-certified at the Mayo Clinic, I've accumulated three decades of practice as a board-certified surgeon and longevity expert. Over that time, I've discovered that a mere 20% of health knowledge yields 80% of the results when it comes to your health span. We're living in a new era where we are creating a new healthcare system, no longer focused on disease management, but achieving optimal health and vitality. Join me as I interview world-renowned experts, offering you a step-by-step guide to proactively avoid disease, and most importantly, extend your health span.

• 0:49Dr. Darshan Shah?

  Cellular energy, mitochondrial health, ATP, NAD, these all play a central role in how we age, how we recover, and how we perform. Yet, most of us are treating muscle loss, brain fog, and immune decline as separate issues and just a consequence of normal aging. In reality, they're often driven by the same common pathway in our underlying biology. And that's what we're going to focus on today with Dr. Singh. In this episode of Extend, I'm joined by Dr. Anurag Singh. He's a physician, scientist, and expert in mitochondrial health. And we're going to break down the science behind a compound that is absolutely incredible, and I've been super interested in it for a long time. It's called Urolithin A, and it's actually made in your gut.

• 1:35Dr. Darshan Shah?

  It has a massive role in cellular renewal and mitochondrial health. Dr. Singh's work focuses on how mitochondria, the gut microbiome, and aging are all deeply connected at the level of the mitochondria. We're going to unpack what mitochondria actually do, why their function declines with age, and how Urolithin A may help restore the process. We're also going to explore the clinical data and what it means for muscle, brain, and immune health. And I'm talking about the latest data that is just now barely being published. It's quite mind-blowing. So, in this episode of Extend, you're going to learn some incredible physiology of our body, some incredible science that truly makes a difference, and about this one compound, Urolithin A, that I take every single day.

• 2:22Dr. Darshan Shah?

  Dr. Underdog Singh, it is such an honor to have you here. Thank you so much for joining the Extend Podcast today.

• 2:28Speaker 01

  Pleasure is mine, Dr. Shah. It's absolute pleasure.

• 2:31Dr. Darshan Shah?

  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.

• 2:41Speaker 01

  Yeah, I was looking forward for a long time as well, so happy to do this today.

• 2:45Dr. Darshan Shah?

  Yeah, yeah, we have a lot to talk about and, you know, 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 in people's health as 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 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 health of every cell.

• 3:26Dr. Darshan Shah?

  And also, what are the potential possibilities of even mitochondrial health? And there's so much here to unpack.

• 3:34Speaker 01

  Yeah. Yeah, so, you know, you nailed it. I think to me, gut is sort of the main organ that connects all to the other organs. So there's this gut-brain axis that everybody in the neurodegenerative field is now talking about, you know, how does it all start? Parkinson, as you know, starts in the gut. You know, the first symptom people with Parkinson have is actually problems with their GI system. Then there's the gut muscle axis that we talk about and gut immune. Immune is the biggest reservoir. So yeah, it's a very timely topic.

• 4:03Dr. Darshan Shah?

  Yes, absolutely. So, you know, a little bit about you first, and you're an MD PhD. You're a physician, you're a scientist, you live in Switzerland now.

• 4:16Dr. Darshan Shah?

  And I'm curious about how you came upon this molecule, or how, you know, 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.

• 4:32Speaker 01

  Sure. 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 with this notion that I was just treating the symptomatology and not 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, 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 Switzerland. And I ran the clinical trials. And one day, two professors from a very famous Swiss university that nobody knows outside Switzerland, though.

• 5:16Speaker 01

  It's called the MIT of Europe. They came to me and said, hey, we have a molecule that is making mice and rodents, different animal models, you know, seeing these big effects on mitochondria. That's where my journey started with the company. But the original history of timeline is that the original scientists who were involved, 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.

• 5:55Dr. Darshan Shah?

  Incredible. And so this molecule, Urolithin A, that we're talking about.

• 5:59Speaker 01

  Yeah.

• 5:59Dr. Darshan Shah?

  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 molecule become a drug versus a nutraceutical?

• 6:12Speaker 01

  Yeah, very relevant question. So in the case of uralithin A, it's a gut metabolite. It's naturally present. 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 uralithin A if you're eating the right food. So if you're drinking a glass of pure palm granite 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. If in its potent form or higher dosing, it has effects on diseases like, you know,

• 6:56Speaker 01

  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. But fundamentally, as a scientist and entrepreneur, you want to impact as many people as possible. And I think you can do that with nutraceutical.

• 7:13Dr. Darshan Shah?

  Right, exactly. And so, you know, I wanted to ask you that question because I want to emphasize that this uralithin A is a molecule that's naturally made in the gut of many people. Is there a specific microbiome bacterium that makes this?

• 7:27Speaker 01

  I spent a long time researching this across the world. So I've gone into US populations, French, Italians, even a 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. 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, a 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%.

• 8:11Dr. Darshan Shah?

  Wow.

• 8:12Speaker 01

  So that, you know, that tells you the scope of the issue.

• 8:16Dr. Darshan Shah?

  Sure.

• 8:16Speaker 01

  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.

• 8:28Dr. Darshan Shah?

  Yeah.

• 8:29Speaker 01

  It's not one species. It's probably a mix of good, healthy bacteria that colonize your gut.

• 8:34Dr. Darshan Shah?

  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 bacteriums interacting with each other in a healthy way.

• 8:48Speaker 01

  Yeah.

• 8:49Dr. Darshan Shah?

  It 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?

• 9:06Speaker 01

  So let's get to how the molecule is made. So the precursors, the dietary precursors, urolithin A is not found in food.

• 9:13Dr. Darshan Shah?

  Right.

• 9:14Speaker 01

  The precursors are polyphenols. These are what we would call lably as antioxidants, et cetera. 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.

• 9:32Dr. Darshan Shah?

  Got it.

• 9:32Speaker 01

  So it's sort of the end product of digestion of these poly dietary precursors. Now, we have looked what are the main bacteria in the gut that these folks have who I call blessed because they're naturally blessed with good, you know, the gut microbiome is a is like a polypharmacy.

• 9:49Dr. Darshan Shah?

  And you're, you said the Europeans have the highest percentage of that.

• 9:52Speaker 01

  Europeans do in our, 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. But what we do see is there is no one probiotic that you can take. We do see things like acromansia, for example, are super enriched in people who are naturally blessed or make urolithin A.

• 10:17Dr. Darshan Shah?

  Got it. Very interesting. And so for your company timeline, the way you encourage urolithin A production by the gut bacteria is feeding it to polyphenol precursors that come mainly from promगrenade juice.

• 10:33Speaker 01

  Yes, that will be the natural way.

• 10:34Dr. Darshan Shah?

  Right.

• 10:35Speaker 01

  But that natural way is a very imprecise way. So if you take hundred 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 the remaining 90%? And so what we do is actually, we actually synthesize 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.

• 11:05Dr. Darshan Shah?

  Got it.

• 11:05Speaker 01

  Vitamin C is not juiced from four or 10 oranges. It's made by a sort of a chemistry process.

• 11:12Dr. Darshan Shah?

  Yes. So when you're giving someone, let's say, how many milligrams of Urolithin A is the standard dose?

• 11:19Speaker 01

  Yeah, 500 milligram in our study is what works really, you know, at a healthy level.

• 11:24Dr. Darshan Shah?

  Right. And then the physician-grade version, the practitioner version is 1,000 milligrams.

• 11:28Speaker 01

  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 and 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.

• 12:01Dr. Darshan Shah?

  Got it, got it. Okay, so for the people that are taking 500 milligrams, for example, of Urolithin A a day, how many glasses of pomegranate juice would they have to drink?

• 12:10Speaker 01

  So we did that, actually. I ran a clinical trial and then a sort of a crossover trial. And we calculated with the level of exposure we got from six. So to get a glass of pomegranate juice, you need to juice about four to six pomegranates. And to get the level equivalent to 500 milligram, 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 milligram.

• 12:42Dr. Darshan Shah?

  Yes, 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.

• 12:52Speaker 01

  Yeah, 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 that variability that you see in the 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.

• 13:22Dr. Darshan Shah?

  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. So someone can drink five glasses of pomegranate juice and still not make any.

• 13:32Speaker 01

  I'm one of them. I've had, not six, I've had 10 glasses of juice over time, over time, tried to eat probiotics. Nothing works, sort of. And I do believe a lot of the gut microbiome that is endowed to us is in the first thousand days of our birth.

• 13:50Dr. Darshan Shah?

  For sure.

• 13:50Speaker 01

  And then you can do certain things, but some of the initial imprinting occurs very early.

• 13:55Dr. Darshan Shah?

  Yeah, so whether you're born by C-section or natural delivery, whether you're given antibiotics or not.

• 14:00Speaker 01

  You got it.

• 14:01Dr. Darshan Shah?

  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.

• 14:21Speaker 01

  Absolutely.

• 14:21Dr. Darshan Shah?

  I always say like, you know, we have, each and every one of us have a billion dollar pharmaceutical factory inside of our gut.

• 14:27Speaker 01

  You nailed it. I say this all the time, the gut microbiome is a polypharmacy.

• 14:32Dr. Darshan Shah?

  Yeah.

• 14:32Speaker 01

  Right?

• 14:33Dr. Darshan Shah?

  Yeah.

• 14:33Speaker 01

  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 food that we are giving it that is what we call postbiotics like Yeraltine. Is what is beneficial to us as human host.

• 14:47Dr. Darshan Shah?

  Yeah.

• 14:48Speaker 01

  There are many of them, I can assure you.

• 14:50Dr. Darshan Shah?

  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, how many times it would take a human to create a compound like Urolithin A, like it would probably even never happen because it's, you know, we've not figured out how to affect the mitochondria in our cell since the beginning of.

• 15:11Speaker 01

  Yeah, and it's coevolution, right? We're, we're, our ancestors were eating fresh food. They were, you know, kind of their gut microbiome was very diverse. Every day was not the same food, eating the same sort of diet process, et cetera. And I think we're just losing that capacity to make these healthy gut metabolites.

• 15:31Dr. Darshan Shah?

  Right, right. Even if you look at the story of GLP-1s.

• 15:33Speaker 01

  Yeah, the same.

• 15:34Dr. Darshan Shah?

  This is also, uh, GLP-1 production is encouraged by Akkermansia and other strains of gut bacteria.

• 15:40Speaker 01

  Yeah.

• 15:40Dr. Darshan Shah?

  And that's what keeps us healthy. And because our gut bacteria is decimated from ultra-processed food and antibiotics, et cetera, we don't make enough GLP-1 anymore.

• 15:48Speaker 01

  You got it.

• 15:49Dr. Darshan Shah?

  Chronic deficiency of GLP-1 leading to metabolic disease.

• 15:51Speaker 01

  Yeah, 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, or forefathers probably were making it. Uh, 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.

• 16:16Dr. Darshan Shah?

  Right, right. Okay, let's turn the conversation on to mitochondria because mitochondria, 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.

• 16:30Speaker 01

  Yeah.

• 16:31Dr. Darshan Shah?

  So, you know, I want, I want you to tell the story of mitochondria.

• 16:36Speaker 01

  Yeah, so probably the one thing we all learned in our, uh, school biology or, well, not much in med school, they don't teach much of mitochondria either.

• 16:46Dr. Darshan Shah?

  Because we have no drugs for them. That's why.

• 16:48Speaker 01

  It's the powerhouse of 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? Uh, if it's hundred percent 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 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,

• 17:33Speaker 01

  from our mothers. And it's maternal DNA, sort of what your, 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, 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 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.

• 18:17Speaker 01

  Heart cell will have thousands of mitochondria. But they basically are in every, every cell other than red blood cells.

• 18:23Dr. Darshan Shah?

  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, 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 a 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 that attaches ATP together.

• 19:06Speaker 01

  Yeah.

• 19:06Dr. Darshan Shah?

  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.

• 19:12Speaker 01

  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 organoles to these kind of shifts happening all around our environment.

• 19:25Dr. Darshan Shah?

  Yeah, they can sense the environment separately from our sensory infrastructure.

• 19:30Speaker 01

  Yeah, yeah.

• 19:31Dr. Darshan Shah?

  Every cell can do this.

• 19:32Speaker 01

  I read also 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 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 in labs studying that a lot of these cellular processes can be tied down to mitochondrial.

• 19:58Dr. Darshan Shah?

  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.

• 20:16Speaker 01

  Yeah.

• 20:17Dr. Darshan Shah?

  The mitochondria are in that egg cell, and that comes from your mom.

• 20:21Speaker 01

  Yeah.

• 20:22Dr. Darshan Shah?

  Right?

• 20:22Speaker 01

  Yeah.

• 20:22Dr. Darshan Shah?

  So all the mitochondria in every human on, in this planet, has come from a female

• 20:28Speaker 01

  Yeah.

• 20:29Dr. Darshan Shah?

  at some point.

• 20:30Speaker 01

  Yeah, and I think what your mom probably ate when you were in utero probably has a big impact on how your mitochondria during your life would be.

• 20:39Dr. Darshan Shah?

  Right, absolutely. Another interesting thing about mitochondrial DNA, which you said is, you know, these are ancient bacteria, so somehow these ancient bacteria found unicellular organisms.

• 20:50Speaker 01

  Yeah.

• 20:50Dr. Darshan Shah?

  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 come together to form humans, and every life form on the planet, pretty much.

• 21:04Speaker 01

  Yeah, we study mitochondria at a very deep cellular level. I take biopsies from older people 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 there are these elongated forms that are very close. closely attached to each other, talking to each other. But in sedentary frail seventy year olds who are not exercising, you they're more round, they're more obese mitochondria, looking zombie like mitochondria. And they will be away from each other, almost like grumpy old folks like who don't wanna, you know, interact.

• 21:45Speaker 01

  And so it's fascinating that such a deep cellular network exists at their level and at the cell with the mitochondria.

• 21:53Dr. Darshan Shah?

  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?

• 22:01Speaker 01

  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 the second process, which you said, is sort of this fusion 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.

• 22:46Speaker 01

  So it's almost like instead of fifty fifty balance, it becomes twenty healthy and eighty bad. And so you need to get like a trash crew coming in to clean them out.

• 22:56Dr. Darshan Shah?

  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?

• 23:06Speaker 01

  Yeah, sure. So mitophagy is really targeted autophagy at a mitochondrial level. So everybody probably in your audience has heard about autophagy.

• 23:15Dr. Darshan Shah?

  This is where old cells kill themselves.

• 23:17Speaker 01

  Yeah, it's sort of self renewal. And that's the, you know, autophagy, phagy being the cell will destruct and create, you know, 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 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.

• 24:00Speaker 01

  So you really need to get the machinery to, you know, for the, for your garbage disposal truck to show up and to clean them out. And that's the process of mitophagy. It's very targeted atophagy.

• 24:10Dr. Darshan Shah?

  Got it, got it. And so what are some of the things that can damage mitochondria to where they need to go through mitophagy?

• 24:15Speaker 01

  Gosh, there's so many. The biggest culprit is sugar. Amount of sugar, we process sugar, we take in our, in our diet. Second one would be sort of, you know, stress, 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 is making energy and you're not consuming it, it just sort of gets wasted out and mitochondria kind of get damaged in the hope that, you know, they're, they're, they're needed for the, for a certain purpose. Sleep patterns, et cetera. So there's a lot of things, environmental toxins. Uh, we see even, uh, we can talk about it even at the skin level, even environmental pollutants,

• 25:00Speaker 01

  uh, like microparticles can, can damage mitochondria.

• 25:03Dr. Darshan Shah?

  Wow, 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, and it produces energy to move, to move the mitochondria along. But also it produces waste product, right? And some of that waste products, I think is reactive oxygen species, right?

• 25:31Speaker 01

  Yeah.

• 25:32Dr. Darshan Shah?

  And to your point, like if you're not using this energy, you're just making a bunch of reactive oxygen species.

• 25:36Speaker 01

  You got it.

• 25:37Dr. Darshan Shah?

  That's going to damage the mitochondria, right? 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? Just like the smoke to the fire of energy production.

• 25:49Speaker 01

  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 cells at a simple level are always needing oxygen to survive. And so if they're not processing all that very well, then they will 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 for many years in the field of mitochondrial health, they were targeting therapies that were, let's say, nutrition ways or integrative ways where you could lower the ROS and 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.

• 26:33Dr. Darshan Shah?

  Yeah, you know, there's a molecule called glutathione that can actually be very powerful for cleaning up some of these free radicals.

• 26:40Speaker 01

  Yeah.

• 26:40Dr. Darshan Shah?

  And vitamin C is powerful for this.

• 26:42Speaker 01

  Yeah, so antioxidants are.

• 26:43Dr. Darshan Shah?

  Any antioxidants, right? Yeah, yeah. Okay, so how does urolithin A fit into this whole puzzle?

• 26:50Speaker 01

  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.

• 27:34Speaker 01

  So things like PGC1 alpha, and we can talk about these are markers of when your mitochondria start 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 creatine that hit the efficiency part of the mitochondria. But that's what makes urolithin A very special.

• 28:01Dr. Darshan Shah?

  Yeah, so urolithin A is targeting mitophagy.

• 28:04Speaker 01

  Yeah.

• 28:04Dr. Darshan Shah?

  Basically accelerating the process of removing old damaged mitochondria.

• 28:08Speaker 01

  Yeah.

• 28:08Dr. Darshan Shah?

  Which then become the building blocks to new mitochondria within the cell. And this happens mainly in the muscle tissue.

• 28:14Speaker 01

  It happens everywhere.

• 28:15Dr. Darshan Shah?

  Everywhere, yeah.

• 28:17Speaker 01

  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

• 28:59Speaker 01

  moved in and done a trial and in 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 the immune cells and their mitochondria.

• 29:10Dr. Darshan Shah?

  Yeah. So you know, I think when you say you started with muscle, that's where you first started studying urolithinase effects.

• 29:16Speaker 01

  You got it. You got it.

• 29:17Dr. Darshan Shah?

  And so 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 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 ages 70.

• 29:36Speaker 01

  Yeah.

• 29:37Dr. Darshan Shah?

  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.

• 29:45Speaker 01

  Yeah.

• 29:46Dr. Darshan Shah?

  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, 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?

• 30:02Speaker 01

  Yeah, absolutely.

• 30:03Dr. Darshan Shah?

  Right? And that can be combat by lifting heavy weights, right?

• 30:07Speaker 01

  Absolutely.

• 30:08Dr. Darshan Shah?

  Like creating that signal to create new muscle. There's studies showing 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.

• 30:23Speaker 01

  Yeah, I see it. Has two pillar strategy to preserving muscle. One is what 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, trying to block myostatin, this sort of signal to block 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 to improve the strength. So that's where I see 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,

• 31:09Speaker 01

  with either creatine supplementation or with exercise, you would get this double.

• 31:14Dr. Darshan Shah?

  Synergistic effect.

• 31:15Speaker 01

  Augmented effect, yeah.

• 31:16Dr. Darshan Shah?

  Yeah, so then you may have improved muscle strength and muscle mass.

• 31:21Speaker 01

  Yeah.

• 31:21Dr. Darshan Shah?

  And some would argue muscle strength is even more important to longevity than even muscle mass is. And you know, 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.

• 31:33Speaker 01

  Oh, for sure.

• 31:34Dr. Darshan Shah?

  Is your muscle. And that glucose sink, which means removing the glucose from your bloodstream, that happens because of mitochondria is being fed that glucose to turn into energies. The more you use the muscle.

• 31:45Speaker 01

  Yeah.

• 31:46Dr. Darshan Shah?

  The more energy you need. Is it fair to say most of your mitochondria in your body lives in your muscle?

• 31:51Speaker 01

  I would say in your muscle and probably the brain, yeah.

• 31:54Dr. Darshan Shah?

  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.

• 32:02Speaker 01

  And that's absolute, you nailed it because we haven't looked at 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 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 so we actually now partner in doing a trial with the National Institute of Aging.

• 32:30Dr. Darshan Shah?

  Oh, great.

• 32:31Speaker 01

  In diabetic people, because diabetic, you know, is. I see diabetes as sort of an accelerated aging.

• 32:37Dr. Darshan Shah?

  Right.

• 32:37Speaker 01

  Kind of condition.

• 32:38Dr. Darshan Shah?

  Absolutely.

• 32:39Speaker 01

  And so they're looking at how frailty sarcopenia can be reversed a little bit. How can metabolic health, of course, as the base of it be improved? And does it have an effect on the brain as well in that study?

• 32:52Dr. Darshan Shah?

  Oh, wow.

• 32:53Speaker 01

  Yeah, it's a fascinating study.

• 32:54Dr. Darshan Shah?

  Yeah, that's gonna be really good information. When is that slated to come out?

• 32:58Speaker 01

  So this is done by the National Institute of Aging in Bethesda. And I think they're about sixty percent done. So I would assume by the end of the year, we'll have some data coming out.

• 33:07Dr. Darshan Shah?

  Oh, that's gonna, you have to give me update on that one for sure.

• 33:13Dr. Darshan Shah?

  We'll get back to the conversation in just a minute. But first, I want to share something that comes up a lot in my practice and honestly, even in my own life. One of the most common things I hear from my patients, these are people who are eating well, training hard, doing everything right for the most part. It's that they still feel off, their energy isn't what it was, and they're not recovering the way they used to. And their workouts feel harder for no obvious reason. And I always tell them the same thing. Fatigue that does not respond to the obvious fixes is almost always a cellular issue. Your mitochondria are the power plants inside of every cell of your body. They fuel the workouts, your focus, your ability to recover and perform. And as we age, they start to break down. Damaged mitochondria can accumulate and drop your energy output.

• 33:57Dr. Darshan Shah?

  And no amount of clean eating or quality sleep fully addresses what's happening at that level. Mitopure by Timeline is a product that I use because it's the only clinically studied form of urolithin A. This is a compound that activates your body's natural processes for clearing out those old damaged mitochondria and rebuilding new, stronger ones. They've done eighteen years of research and multiple gold standard clinical trials, and the data is real. Mitochondrial renewal increases thirty-nine percent after six weeks. Measurable improvements in muscle strength, endurance, and daily energy are seen. And this is not from a stimulant, not from a shortcut, it's from actually fixing the source of the problem at a cellular level. Right now Timeline has actually dropped their prices.

• 34:42Dr. Darshan Shah?

  Mitopure starts at ninety-nine dollars for one time purchase. Or as low as 79 on subscription. But with my code, Dr. Shaw, you'll get an additional 20% off your first order. So if you want to start addressing energy at the source, this is where you should go. Go to timeline.com slash Dr. Shaw. That's T I M E L I N E dot com slash Dr. Shaw and use my code, Dr. Shaw.

• 35:08Dr. Darshan Shah?

  Okay, so this study that you did on Urolithin A and muscle.

• 35:12Speaker 01

  Yeah.

• 35:12Dr. Darshan Shah?

  Can you describe it to us a little bit and what your findings were?

• 35:14Speaker 01

  Yeah, so we've done many. We started out, obviously, with older adults.

• 35:19Dr. Darshan Shah?

  Okay.

• 35:20Speaker 01

  Older adults. When we started out, the big question was, how do you also measure mitochondrial health in the clinic? This always has been a big question. And so I, we said, okay, we took a bunch of folks, as I mentioned, who were in their seventies 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, you can ask 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.

• 36:02Speaker 01

  We gave them a month-long supplementation with either placebo, a 500 milligram 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 do as well. And then we went in and we did longer trials in the same folks for about two and four months. And we started seeing in the older adults, they just had more energy. So if you put them in a gym and make them do a leg press test,

• 36:47Speaker 01

  they would have 20% more energy to keep going 20% longer. So these were the first trials and then. Obviously, the forty, fifty year old said, well, this is a product for for older people. Why should we take it? So we went 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 who are in their early to mid early fifties. And we gave them four months of supplementation. Now, these folks did not change their diet or their physical activity. And after four months, when you got them to the clinic and tested their leg strength, they had about ten to fifteen percent more leg strength.

• 37:27Dr. Darshan Shah?

  By doing nothing extra, except taking your Lithin A.

• 37:30Speaker 01

  Over, yeah, regularly over a period of four months. So that was the early data.

• 37:34Dr. Darshan Shah?

  Sure.

• 37:35Speaker 01

  And then 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 seventy, sixty five.

• 37:52Dr. Darshan Shah?

  Yeah.

• 37:52Speaker 01

  You know, that that's probably the pinnacle of human performance. And what surprised me was we actually managed to improve their VO2 from sixty five to seventy.

• 38:01Dr. Darshan Shah?

  That's incredible.

• 38:03Speaker 01

  And it was not so much if they won a race at the Olympics, suddenly people on your Lithin, they 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 and muscle.

• 38:21Dr. Darshan Shah?

  Super interesting. You know, I think about also this dosage issue of five hundred to a thousand.

• 38:28Speaker 01

  Yeah.

• 38:29Dr. Darshan Shah?

  Was there an additional benefit to taking a thousand over five hundred for any one of these groups?

• 38:34Speaker 01

  Yeah, so the five hundred milligram dose, 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, twenty to thirty percent renewable, you'll see forty percent upwards renewable with the gram dose. Strength, it was same, it was almost comparative. But then the gram dose is where you start seeing the endurance benefits, better VO2 max, the better recovery, lowered inflammation in these populations. So you get this almost sort of an additive effect happening over time.

• 39:07Dr. Darshan Shah?

  Got it, got it. Let's talk about the brain.

• 39:09Speaker 01

  Yeah.

• 39:10Dr. Darshan Shah?

  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.

• 39:23Speaker 01

  Yeah.

• 39:23Dr. Darshan Shah?

  It uses the most glucose out of any other organ in the body. And also probably produces the most energy out of any other organ in our body. And so keeping the mitochondria healthy are extremely important.

• 39:36Speaker 01

  Hmm.

• 39:36Dr. Darshan Shah?

  And I think there's also a direct symptomatology of having poor or weak mitochondria that you can feel immediately as brain fog, slowed mentation. You could probably measure this very easily also with cognitive testing as well, right?

• 39:51Speaker 01

  Uh huh.

• 39:52Dr. Darshan Shah?

  Yeah. So talk to us about some of the studies you've done with brain health.

• 39:56Speaker 01

  Yeah, when you're small and very focused company, you can only start first with one organ and one. So that's where we were focused with muscle. And 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.

• 40:18Dr. Darshan Shah?

  Sure.

• 40:19Speaker 01

  The Buck Institute got actually a multimillion dollar grant, the Buck Institute of Aging in California.

• 40:24Dr. Darshan Shah?

  Yep.

• 40:25Speaker 01

  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 topmost compounds in their.

• 40:36Dr. Darshan Shah?

  For reversal of Alzheimer's symptoms or prevention?

• 40:40Speaker 01

  You know, Alzheimer's is not one pathway. It's neuroinflammation. It's these protein aggregates that happen. So what they were seeing was a sort of a molecule that hit multiple hallmarks of aging in these kind of models.

• 40:55Dr. Darshan Shah?

  Wow.

• 40:55Speaker 01

  The National Institute of Aging, there are two researchers, Professor Willem Bore and Professor Evandra Fang. They published a big nature paper immediately after. So almost two to three labs competing to publish, which is a very common story.

• 41:09Dr. Darshan Shah?

  That's great for your company.

• 41:10Speaker 01

  Which was great because we didn't have to do anything.

• 41:12Dr. Darshan Shah?

  Yeah.

• 41:13Speaker 01

  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 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 job at hitting these sort of neuroinflammation and these amyloid aggregates that happen in the brain.

• 41:44Dr. Darshan Shah?

  So interesting.

• 41:45Speaker 01

  So they came to us and they said, well, you got to do something in this area. If you, 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 with the same group I was telling you about. And there's a second trial happening with Parkinson's disease.

• 42:03Dr. Darshan Shah?

  Yeah.

• 42:03Speaker 01

  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 you the data.

• 42:26Dr. Darshan Shah?

  Yeah, I can't wait.

• 42:27Speaker 01

  So but a lot of efforts around the world on urolithin A and brain happening.

• 42:31Dr. Darshan Shah?

  Yeah, just a little tangent here real quick. What are some of the markers you're using for mitochondrial health?

• 42:36Speaker 01

  It's a question I get a lot. 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. These have been associated, higher levels of ceramides with mostly cardiovascular problems. And we see that ceramides, if you throw on cells, it induces abnormal mitophagy. And so you need to reverse. So we see lowering of plasma ceramides. We see a lot of fatty acid oxidation metabolized like acylcarotenes get inhibited. We see everywhere PGC one alpha go up.

• 43:19Speaker 01

  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 just a little blood tap? And so that 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 and your immune cells is a de facto way that it's gonna hit all your key organs.

• 43:41Dr. Darshan Shah?

  Got it, got it. And could you talk a little bit about what PGC1 alpha is?

• 43:45Speaker 01

  Yeah, so it's it's a it's sort of a very well-known gene that regulates mitochondrial biogenesis. So it's almost seen as a de facto marker of that your mitochondria are 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.

• 44:08Dr. Darshan Shah?

  Is this a genetic marker or is it actual?

• 44:11Speaker 01

  Yeah, it's a gene. It's a gene. So you need to do like a QPCR or you need to look at RNA sequencing to look at that panel of.

• 44:19Dr. Darshan Shah?

  Makes sense. And is this a gene that is a mitochondrial gene?

• 44:24Speaker 01

  It is not a mitochondrial gene, but it is reflective of of hitting the mitochondrial pathways.

• 44:30Dr. Darshan Shah?

  So interesting. Okay.

• 44:32Speaker 01

  Yeah.

• 44:32Dr. Darshan Shah?

  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.

• 44:41Speaker 01

  Yeah.

• 44:41Dr. Darshan Shah?

  Because obviously, all of our immune cells use mitochondria to create their energy.

• 44:45Speaker 01

  Yeah.

• 44:45Dr. Darshan Shah?

  So 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 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 it's really, it's it's so tied to every organ system 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.

• 45:20Speaker 01

  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 improving a mitochondrial health could have big implications for your immune health. They say, well, we have vitamin C.

• 45:39Speaker 01

  How's this molecule different?

• 45:40Dr. Darshan Shah?

  What about zinc and vitamin C?

• 45:42Speaker 01

  Yeah. 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 we were talking about and muscle health, I always picked up when we look at the plasma metabolomics or plasma biomarkers, we would always, always see in these populations H S C R P go down, cytokines, these are soluble factors that immune cells make whenever they

• 46:26Speaker 01

  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. 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 proliferate. And so he said, well, your compound is actually rejuvenating these T cells and they're killing the cancer off. So you need to do a trial. We said, okay, let's, we won't go to cancer first.

• 47:11Speaker 01

  So the trial we've just published shows that taking a month of a gram dose actually brought these fatigue T cells back to their peak usefulness. 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.

• 47:35Dr. Darshan Shah?

  That's crazy.

• 47:36Speaker 01

  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.

• 47:45Dr. Darshan Shah?

  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 right now. But also I think, you know, So 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?

• 48:11Speaker 01

  Yeah.

• 48:11Dr. Darshan Shah?

  It's an 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.

• 48:22Speaker 01

  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're 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 science where people would say, wow, a dietary supplement can be added to a a standard of care, cancer therapy. That is where the science we need to bring for supplements.

• 49:07Dr. Darshan Shah?

  Yeah, that's, that's incredible. So at what age should someone think about starting to take urolithin A?

• 49:14Speaker 01

  So the youngest people we have worked with are these Olympians who are in their early twenties. And the oldest clinical trial participant I had was an eighty-nine-year-old lady who swore her gardening improved. So, 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.

• 49:40Dr. Darshan Shah?

  Okay.

• 49:41Speaker 01

  But I would say if you follow the science and longevity today, the earliest changes are happening in your early forties 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 sixties and seventies, already start improving your cellular health in your early forties, I would say. That's the fundamental for me to hit cellular health.

• 50:06Dr. Darshan Shah?

  Yeah, you gotta start. Around forty, 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 pocketbooks. I get it if you don't start, but by the time you're forty, you've just got to start taking care of yourself.

• 50:21Speaker 01

  A lot of athletes, we have top NBA teams taking it. We have a lot of Tour de France cycling teams taking it. We know a lot of other sports, 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.

• 50:42Dr. Darshan Shah?

  Is there anyone who should not take your Lethine?

• 50:45Speaker 01

  Uh, so far, I would say we've done twenty five clinical trials, almost three thousand participants. We haven't seen a contraindication, but I am evidence based. So I would say wait for all these cancer studies to come out and uh, but. And there is also the studies where people say, well, I'm on a blood thinner or I'm on a statin. Should I be taking it or I'm on GLP one? 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. GLP one will have huge impacts on metabolic health. I just think use by use, the doctors can tell their patients to take it. But as an evidence based person, I would say wait for that data.

• 51:29Dr. Darshan Shah?

  Mm hmm. Yeah. And is there any side effects you've seen?

• 51:32Speaker 01

  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 will get the double benefit. So the two gram, you kind of saturate the absorption of the molecule. What we haven't done is we haven't done a gram in the morning and then a gram in the or five hundred in the morning and five hundred in the evening, like twice a day kind of regimen. So these are the directions we are headed.

• 52:07Dr. Darshan Shah?

  Got it. Taking this supplement at nighttime, would it cause you to sleep better or sleep worse?

• 52:13Speaker 01

  All our trials are done in the fastest state in the morning with intake, because fasting is inducing autophagy. So the idea is that this will augment it even more. 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 don't think, but night, actually, I don't know many people who take it at night. I guess you will get, it peaks in the blood around four to eight 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.

• 52:57Dr. Darshan Shah?

  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 join 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 what are you taking and what's and why?

• 53:27Speaker 01

  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 we were to make a new product with Urolithin A, we'll just would not blindly do what the whole supplement industry does. It's oh, mix A and B and suddenly one plus one would be better than two. Sometimes it's zero, right? So we'll do a careful scientific analysis and experimentation. So one, 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.

• 54:09Speaker 01

  For example, the whole, what were you saying on muscle mass and the energetics part? So I'm a big fan of creatine and the level of clinical and science that exists. So I do take five grams of creatine. There's debate whether Should be better for cognition or not. I do take magnesium. It's it's something we have seen works very well with Urolithin A, vitamin D. There's a lot of studies that actually Urolithin A augments vitamin D receptor expression on a lot of cells.

• 54:40Dr. Darshan Shah?

  Okay.

• 54:40Speaker 01

  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 it's not a supplement you can take yet.

• 54:52Dr. Darshan Shah?

  Sure, sure. Yeah. What about CoQ10 you mentioned earlier? This is very directly related to mitochondria.

• 54:58Speaker 01

  You can combine it with CoQ10 and probably you'll get an additive effect. I just don't take it because I think I'm a bit biased there on Urolithin A's effects on mitochondria that I do think I already have sort of a base for mitochondria health. Yeah, that's pretty much my stack, those four.

• 55:12Dr. Darshan Shah?

  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?

• 55:20Speaker 01

  Yeah, it it can be confusing because there's so many different proforms and different. So there's these, you know, for the listeners, vitamin B3 is is the sort of the established and what we call nicotinamide or nicinamide. This is the standard form. Now, what they have done, different companies that made different NAD prodrugs, as they call it, or proforms. One is called nicotinamide riboside NR and one is called NMN, which is nicotinamide mononucleotide. 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 mitochondria and electron transport chain. So

• 56:04Speaker 01

  augmenting and supplementing with it makes sense.

• 56:07Dr. Darshan Shah?

  Yeah.

• 56:07Speaker 01

  Yeah. How much? I don't know.

• 56:09Dr. Darshan Shah?

  Right, right. Yeah, I think I'm, 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.

• 56:19Speaker 01

  It's back.

• 56:19Dr. Darshan Shah?

  It is back now.

• 56:20Speaker 01

  It is back. But you can combine it. I think there are folks who have tried strategies or published at least a few publications that UA and NAD molecules hit different biologies of mitochondria. Mitochondria and combining them can be augmentative. We've looked in the lab, not in a trial, in a lab. And it seems to be augmented effects on mitochondrial health.

• 56:42Dr. Darshan Shah?

  Right, right. So they both are different parts of the entire pathway anyway. One is not, you know, and NAD precursors are feeding this NAD metabolism to create ATP, whereas Urolithin A is inducing mitophagy. So it's two completely different things.

• 56:59Speaker 01

  And if you clean the waste and then you nourish the renewal process of the biogenesis, you could get a double sort of benefit.

• 57:06Dr. Darshan Shah?

  Synergistic 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?

• 57:22Speaker 01

  Yeah, first, thanks for having me, Darshan. It was an absolute pleasure. People can learn about 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.

• 57:36Dr. Darshan Shah?

  Okay, thank you so much.

• 57:37Speaker 01

  Pleasure. Thanks.

• 57:40Dr. Darshan Shah?

  Thank you so much for listening to the podcast today. Please remember to subscribe if you like this episode and give us a good review and share a link with your friends. It really helps to support all of our efforts. I also want to remind you that the information shared on this podcast is for educational purposes only and is not intended to replace professional medical advice, diagnosis, or treatment. Please consult with your healthcare provider or physician before making any decisions or taking any action based on what you hear today, especially if you have any underlying health conditions or on any medications. Your doctor knows your personal health situation the best, and it's always important to seek their guidance.