← Extend Podcast with Darshan Shah, MD
Extend Podcast with Darshan Shah, MD
159: Dr. Anurag Singh: Urolithin A, Mitophagy, and Mitochondrial Health
00:58:31
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- [00:03]
A
Welcome to Xtend 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 are 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. 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 Xtend, 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. 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 xtend, 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. Doctor Anurag Singh, it is such an honor to have you here. Thank you so much for joining the Extend podcast today.
- [02:29]
B
Pleasure is mine, Dr. Shah. It's an absolute pleasure.
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A
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.
- [02:42]
B
Yeah, I was looking forward for a long time as well, so happy to do this today.
- [02:45]
A
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 to 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, and also what are the potential possibilities of even mitochondrial health? And there's so much here to unpack. Yeah, yeah.
- [03:36]
B
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. 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.
- [04:04]
A
Yes, absolutely. So a little bit about you first. You're an MD, PhD, you're a physician, you're a scientist. You live in Switzerland now. And I'm curious about how you came upon this molecule or how 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.
- [04:32]
B
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 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.
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A
Incredible. And so this molecule urolithin A that we're talking about, 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?
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B
Yeah, very relevant question. So in the case of urolithin 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 urolithin A if you're eating the right food. 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. If in its potent form or higher dosing, it has effects on diseases. Like 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.
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A
Right, Exactly. And so, you know, I wanted to ask you that question because I want to emphasize that this URL with an A is a molecule that's naturally made in the gut of many people. Is there a specific microbiome bacterium that makes this?
- [07:28]
B
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, the sort of Middle Mediterranean lifestyle countries in the US and Canada, it's like 10% versus 30, 40% in, in. In European countries and in India, where antibiotic use is rampant, it's almost down to like 5%.
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A
Wow.
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B
So that, you know, that tells you the scope of the issue.
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A
Sure.
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B
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.
- [08:35]
A
Oh, that's so interesting. Okay. So 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, it seems like it's really interesting about how that works together, because are parts of the molecule made by some bacteria parts by another bacteria? I mean, is there a probiotic that you can take that would increase your production of urolithin A or not?
- [09:07]
B
So let's get to how the molecule is made. So the precursors, the dietary precursors. Urolithin A is not found in food. The precursors are polyphenols. These are what we would call label 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.
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A
Got it.
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B
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 in Europe.
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A
You said the Europeans have the highest
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B
percentage of Europe than they do. 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 achromansia, for example, are super enriched in people who are naturally blessed or make urolithin A.
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A
Got it. Very interesting. And so for 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.
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B
Yes, that will be the natural way, but that natural way is a very imprecise way. 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 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.
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A
Got it.
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B
Vitamin C is not juiced from four or 10 oranges. It's made by a sort of a chemistry process.
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A
Yes. So when you're giving someone, let's say, how many milligrams of urolithinase a standard dose?
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B
Yeah. 500 milligram in our study is what works really the, you know, at a healthy level.
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A
Right. And then the physician grade version, the practitioner version is 1,000 milligrams.
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B
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 had 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.
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A
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?
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B
So we did that, actually. I did. I ran a clinical trial and then sort of a crossover trial, and we calculated with the level of exposure we got from. From six. So you to. To get a glass of pomegranate juice, you need to juice about four to six pomegranates. And to get the level of Eklund 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 milligrams.
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A
Yeah, 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 ball game.
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B
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.
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A
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. Got it. So someone can drink five glasses of pomegranate juice and still not make any.
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B
I'm one of them. I've had not six, I've had ten 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, for sure. And then you can do certain things, but some of the initial imprinting occurs very early.
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A
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 the health of your gut and the health of your microbiome. And this is just one discovery that your company is working with, but I'm sure there's going to be thousands of others because.
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B
Absolutely.
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A
Yeah. I always say, like, you know, we have, each and every one of us have a billion dollar pharmaceutical factory inside of us.
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B
I think you nailed it. I say this all the time. The gut microbiome is a polypharmacy.
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A
Yeah.
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B
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 food that we are giving. It is what we call postbiotics, like URL 10a is what is beneficial to us as human host. And there are many of them, I can assure you.
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A
Exactly. And if you look at it as a pharmaceutical factory, it also has the absolute best scientists on the planet because the amount of times, how amount of times it would take a human to create a compound like urolithin A, it would probably even never happen because we've not figured out how to affect the mitochondria in our cell since the beginning of.
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B
Yeah, and it's co evolution. Right. Our ancestors were eating fresh food. They were kind of their gut microbiome very diverse every day. It was not the same food, eating the same sort of diet process, et cetera. And I think we're just losing the capacity to make these healthy gut mitabolites.
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A
Right, right. Even if you look at the story of GLP1s right, this is also GLP1 production is encouraged by akkermancy and other strains of gut bacteria, and that's what keeps us healthy. And because our gut bacteria is decimated from ultra processed food, antibiotics, et cetera, we don't make enough GLP1 anymore. There's a chronic deficiency of GLP1 leading to metabolic dise. Yeah, yeah.
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B
So it's pretty much the same. A lot of the GLP1 is made in the gut, as you said. And it's the same with your lithin 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 all do need to think about supplementation as a way to get that exposure to these beneficial molecules.
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A
Right, right. Okay, let's turn the conversation now 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.
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B
Yeah.
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A
So, you know, I want you to tell the story of mitochondria.
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B
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 as well.
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A
So you have no drugs for them.
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B
That's why 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. 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 that they Are the battery inside our body and how good it recharges or loses charge, makes us 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 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, heart cell will have thousands of mitochondria. But they basically are in every cell other than red blood cells.
- [18:24]
A
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, mitochondria are kind of weird alien cells. 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. And then some of these proteins are activated by light and some of these prote. Like it's a really interesting molecule.
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B
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 shifts happening all around our environment.
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A
Yeah, they can sense the environment separately from our sensory infrastructure. Yeah, yeah, Every cell can do this.
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B
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 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 the mitochondrial health.
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A
So true. And the reason the mitochondrial DNA comes from the mother and it's very important to realize, like the mitochondrial DNA is separate from your 23 chromosomes to 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. The mitochondria are in that egg cell. And that comes from your mom.
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B
Yeah, right, yeah.
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A
So all the mitochondria in every human in this planet has come from a female at some point.
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B
Yeah. And I think what your mom probably ate when you were in neutral probably has a big impact on how your mitochondria during your life would be.
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A
Right, Absolutely. Another interesting thing about mitochondrial DNA, which you said, is these are ancient bacteria. So somehow these ancient bacteria found unicellular organisms and they combined forces synergistically to become multicellular organisms. 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 in every life form on the planet. Pretty much, yeah.
- [21:05]
B
We study mitochondria to 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. 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 closely attached to each other, talking to each other. But in sedentary, frail 70 year olds who are not exercising, 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 want to interact. And so it's fascinating that such a deep cellular network exists at their level with the mitochondria.
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A
And is it true or am I making this up from my recollection in medical school? But sometimes mitochondria can actually combine with each other and form a new mitochondria.
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B
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 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 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.
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A
Yeah. And so that process of cleaning out the old unhealthy mitochondria within a cell is called mitophagy.
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B
Yeah.
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A
And can you go a little bit deeper into how mitophagy happens?
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B
Yeah, sure. So mitophagy is really targeted autophagy at a mitochondrial level. So everybody probably in your audience has heard about autophagy, right, which is where
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A
old cells kill themselves.
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B
Yeah, it's sort of self renewal. And that's the, you know, autophagy, phagy being the cell will destruct and 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 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. So you really need to get the machinery, 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 autophagy.
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A
Got it, got it. And so what are some of the things that can damage mitochondria to where they need to go through mitophagy?
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B
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 the mitochondria kind of get damaged in the hope that, you know, they're needed for the. For a certain purpose, sleep patterns, etc. So there's a lot of things, environmental toxins, we see even. We can talk about it even at the skin level. Even environmental pollutants like microparticles can. Can damage mitochondria.
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A
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 you're. 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?
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B
Yeah.
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A
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. And so can we talk a little bit more about reactive oxygen species? And how does our body kind of mitigate these reactive oxygen species, which are like the smoke to the fire of energy production?
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B
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 a 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 Ross in sort of the free radicals circulating around. But now that we know there are other ways, probably like mitophagy we talked about.
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A
So, 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.
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B
Yeah. So antioxidants are powerful, right?
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A
Yeah. Yeah. Okay, so how does urolithin A fit into this whole puzzle?
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B
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 urolithinate 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 started regenerating. And we'll see that happening in the muscle level. So that's what makes erolithin 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. Of the mitochondria. But that's what makes your lithium a very special.
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A
Yeah. So urlithin A is targeting mitophagy.
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B
Yeah.
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A
Basically accelerating the process of removing old, damaged mitochondria.
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B
Yeah.
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A
Which then become the building blocks to new mitochondria within the cell. And this happens mainly in the muscle tissue.
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B
It happens everywhere. Where?
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A
Everywhere. Yeah.
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B
So we started with muscle because obviously muscle is one of the key longevity organs. And I was trained 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 on healthy people looking at the immune cells and what the mitochondria in their immune cells look like. And the impact of urolithin A on immune cells in their mitochondria.
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A
Yeah. So, you know, I think when you say you started with muscle, that's where you first started studying urolithinase effects with muscle. Right.
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B
You got it.
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A
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. 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. Yeah. 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 now. Right. And that can be combat by lifting heavy weights, right?
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B
Absolutely.
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A
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.
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B
Yeah. I see it as 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 with myostatin, this sort of signal to block 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 to improve the strength. So that's where I see the muscle mass and the muscle quality and the energetics and your lithin 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.
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A
Yeah, yeah. So then you may have improved muscle strength and muscle mass.
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B
Yeah.
- [31:22]
A
And some would argue muscle strength is even more important to longevity than even muscle masses. 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 thing, which means removing the glucose from your bloodstream. That happens because a mitochondria is being fed that glucose to turn into energy. So the more you use the muscle, the more energy you need, is it fair to say most of your mitochondria, your body lives in your muscle?
- [31:51]
B
I would say in your muscle and probably the brain.
- [31:54]
A
Yeah, 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.
- [32:03]
B
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 culture them with urolithin A, they can suddenly get better glucose uptake. And so we actually now partner and doing a trial with the National Institute of Aging in diabetic people, because diabetic. You know, I see diabetes as sort of an accelerated aging kind of condition.
- [32:39]
A
Absolutely.
- [32:39]
B
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? So.
- [32:53]
A
Oh, wow.
- [32:53]
B
Yeah, it's a fascinating study.
- [32:55]
A
Yeah, that's going to be really good information. When is that slated to come out?
- [32:59]
B
So this is done by the National Institute of Aging in Bethesda and I think they're about 60% done. I, I would assume by the end of the year we'll have some data coming out.
- [33:08]
A
Oh, that's, that's gonna, you have to give me update on that for sure. We'll get back to the conversation in just a minute. But first I wanna 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, is 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. 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 18 years of research and multiple gold standard clinical Trials and the data is real. Mitochondrial renewal increases 39% 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. MetaPure starts at $99 for a one time purchase or as low as 79 on subscription. But with my code drshaw, you'll get an additional 20% off your first order. So if you want to start addressing energy at the source the this is where you should go. Go to timeline.com Dr. Shaw that's T I M E L I N E.com Doctorshaw and use my code Dr. Shaw. Okay, so this study that you did on your lithium A and muscle.
- [35:12]
B
Yeah.
- [35:13]
A
Can you describe it to us a little bit and what your findings were?
- [35:15]
B
Yeah, so we've done many. We started out obviously with older adults. 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 we said, okay. We took 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 took chunks of their muscle tissue. This is a procedure we call muscle biopsy. And we asked in an unbiased way, 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, 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 a. 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, 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 the 40, 50 year old said, well, this is a product for older people, why should we take it? So we went and we said, okay, let's address that hypothesis. I'm a very evidence based person. So we took healthy but inactive sedentary people and who are in their early to mid, early 50s 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 10 to 15% more leg strength by doing nothing
- [37:29]
A
extra except taking your lithium A. Yeah,
- [37:31]
B
regularly over a period of four months. So that was the early data.
- [37:35]
A
Sure.
- [37:36]
B
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 65. You know, that's probably the pinnacle of human performance. And what surprised me was we actually managed to improve their VO2 from 65 to 70.
- [38:02]
A
That's incredible.
- [38:03]
B
And it was not so much if they won a race at the Olympic and suddenly people on Eurelith and they were showing up with gold medals, it was their recovery how fast. 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.
- [38:22]
A
Super interesting. You know, I think about also this dosage issue of 500 to 1,000. Was there an additional benefit to taking 1,000 over 500 for any one of these groups?
- [38:35]
B
Yeah. So the 500 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 20 to 30% renoval, you'll see 40% upwards renoval. 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. Better VO2 max, the better recovery, lowered inflammation in these populations. So you get this almost sort of a additive effect happening over time.
- [39:07]
A
Got it, got it. Let's talk about the brain.
- [39:10]
B
Yeah.
- [39:10]
A
And some of the studies you've done around your lithium A and mitochondrial 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. 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. 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? Yeah. So talk to a little about some of the studies you've done with brain health.
- [39:56]
B
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. 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. The Buck Institute got actually a multimillion dollar grant, the Buck Institute of Aging in California. 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 for
- [40:37]
A
reversal of Alzheimer's symptoms or prevention.
- [40:40]
B
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. The National Institute of Aging, there are two researchers, Professor Willem Bohr and Professor Evander Fang. They published a big Nature paper immediately after. So almost two to three labs competing to publish, which is a very common story.
- [41:09]
A
That's great for your company, which was
- [41:11]
B
great because 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 likely to have an effect 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 urlitin A was doing the best job at hitting these sort of neuroinflammation and these amyloid aggregates that happen in the brain.
- [41:45]
A
So interesting.
- [41:45]
B
So they came to us and they said, well, you gotta 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 disease 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 give you the data.
- [42:27]
A
Yeah, can't wait.
- [42:27]
B
But a lot of efforts around the world on erolithin a brain happening.
- [42:32]
A
Yeah. A little tangent here real quick. What are some of the markers you're using for mitochondrial health?
- [42:37]
B
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 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 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 just a little blood tap? And so that's 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 going to hit all your key organs.
- [43:42]
A
Got it, got it. And could you talk a little bit about what PGC1 Alpha is?
- [43:45]
B
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 coming back in peak state. And so there's a lot of new healthy mitochondria. So it's used as sort of. Yeah. Marker that your mitochondria are regenerating.
- [44:09]
A
Is this a genetic marker or is it actual.
- [44:11]
B
Yeah, it's a gene. 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
- [44:19]
A
of genes Makes sense. And is this a gene that is a mitochondrial gene, or is it not
- [44:26]
B
a mitochondrial gene, but it is reflective of hitting the mitochondrial pathways.
- [44:30]
A
Oh, so interesting. Okay.
- [44:32]
B
Yeah.
- [44:33]
A
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. Yeah. Because obviously all of our immune cells use mitochondria to create their energy.
- [44:46]
B
Yeah.
- [44:46]
A
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 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 is not just that. It is much more than that.
- [45:20]
B
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 your mitochondrial health could have big implications for your immune health, they say, well, we have vitamin C. How's this molecule different?
- [45:41]
A
What about zinc and vitamin C?
- [45:42]
B
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 or pneumococcal vaccination and would 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 on muscle health, I always picked up, when we look at the plasma metabolomics or plasma biomarkers, we would always, always see in these populations HSCRP 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 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 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. So we said, okay, 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 these fatigue T cells back to their peak youthfulness.
- [47:22]
A
Wow.
- [47:23]
B
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.
- [47:36]
A
That's crazy.
- [47:36]
B
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 now.
- [47:46]
A
Well, you can certainly delay cancer because 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, 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?
- [48:11]
B
Yeah.
- [48:11]
A
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.
- [48:23]
B
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 happening, 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 on checkpoint inhibitors. So immunotherapy and augmenting that with your lithin a added to it because to me that's the signs where people would say, wow, a dietary supplement can be added to a cancer standard of care. Cancer therapy. That is where the signs we need to bring for something else.
- [49:08]
A
Yeah, that's incredible. So at what age should someone think about starting to take urolithin a?
- [49:15]
B
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 saw her gardening improved. So and she did not know, because it was a blinded placebo controlled trial. And she told me after the trial, well, 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 science and 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 prevent what's gonna 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.
- [50:06]
A
Yeah, you gotta start around 40. 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 40, you just got to start taking a lot of athletes.
- [50:23]
B
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.
- [50:43]
A
Is there anyone who should not take urolithin A?
- [50:46]
B
So far I would say we've done 25 clinical trials, almost 3,000 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 there is also the studies where people say, oh, I'm on a blood thinner or I'm on a statin, should I be taking it? Or I'm on GLP1, 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. GLP1 will have huge impacts on metabolic health. I just think use by use, doctors can tell their patients to take. But as an evidence based person, I would say wait for that data.
- [51:29]
A
Yeah. And is there any side effects you've seen?
- [51:33]
B
Not at all. That's the magic of working with a natural compound that almost all of us at one point had. And but yes, 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 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 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.
- [52:07]
A
Got it. Taking this supplement at nighttime, would it cause you to sleep better or sleep worse or no effect.
- [52:15]
B
All our trials are done in a fasted 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 the meal. And it's. 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. Yeah, 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.
- [52:57]
A
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 why?
- [53:27]
B
So I would look at all the level of clinical evidence on the table. Second, we have a great group of mitochondrial scientists 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 just would not blindly do. What the whole supplement industry does is, 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 Ural 108 really boosts the effects of creatine. For example, the whole. What you're 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 higher should be better for cognition or not. I do take magnesium. It's something we have seen works very well with urolithin A, vitamin D. There's a lot of studies that actually urlithin A augments vitamin D receptor expression on a lot of cells.
- [54:40]
A
Okay.
- [54:41]
B
So 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.
- [54:54]
A
Yeah. What about Coq 10? You mentioned earlier this very directly related to mitochondria.
- [54:58]
B
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 are neurolutinase effects on mitochondria that I do think. I already have sort of a base for mitochondrial health. Yeah, that's pretty much my stack of those four.
- [55:13]
A
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.
- [55:21]
B
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 the sort of the establish. And what we call nicotinamide or niacinamide. This is the standard form. Now, what they have done, different companies that made different NAD PRO drugs, as they call it, or PRO forms. 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 sort of cellular health is there. Right. With aging, we all know NAD declines and it's. NAD is critical for different aspects of mitochondrial electron transport chain. So augmenting and supplementing with it makes sense.
- [56:07]
A
Yeah, yeah.
- [56:09]
B
How much? I don't know.
- [56:10]
A
Right, right. Yeah. 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.
- [56:19]
B
I think it's back.
- [56:20]
A
It is back now.
- [56:21]
B
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 and combining them can be augmented. We've looked in the lab, not in a trial, in a lab. And it seems to be augmented effects on mitochondrial health.
- [56:42]
A
Right, right. So they both are different parts of the entire pathway anyway. One is not, you know, NAD precursors are feeding this NAD metabolism to create ATP, whereas your lithium A is inducing mitophagy. So it's two completely different things.
- [56:59]
B
And if you clean the waste and then you nourish the renewal process with the biogenesis, you could get a double
- [57:06]
A
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?
- [57:23]
B
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.
- [57:36]
A
okay. Thank you so much.
- [57:38]
B
Pleasure. Thanks.
- [57:41]
A
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.