Boosting strength, stamina and skin health

As healthy aging science evolves, researchers are able to focus on the lifestyle interventions that have the biggest impact on our lives.  A good, balanced diet and consistent exercise top of the list of daily must-dos, but paying attention to our cellular health is also essential.  It is a pillar of healthy longevity that has emerged as central to our ability to stave off disease and remain physically strong. Dr. Anurag Singh, Chief Medical Officer at the Swiss life science company, Timeline Nutrition, studies the role of the gut metabolite, Urolithin A, which recent research has shown to have wide benefits, including muscle strength, skin health and a potential to protect our immune systems.  

For this interview, LLAMA host Peter Bowes met Dr. Singh at his office in Lausanne, Switzerland, to learn more about his quest to understand how Urolithin A impacts human health.

Timeline make Mitopure, which is a highly pure form of Urolithin A.

This episode is produced in association with Timeline, with which LLAMA has an affiliate relationship. 

DISCOUNT

Mitopure (a highly pure form of Urolithin A) boosts the health of our mitochondria – the battery packs of our cells – and improves muscle strength. Timeline is offering LLAMA listeners a 10% discount on its range of products – Mitopure powders, softgels & skin creams.  Use the code LLAMA at checkout

In this conversation we cover:

• More than a decade of research to bring a biotech approach to nutrition
• Deconstructing the pomegranate, its juices and extracts
• Distinguishing Urolithin A, from Urolithin B, C and D
• Why Urolithin A outshines other molecules
• Reasons to produce pure Urolithin A
• Anurag's training as a physician and his introduction to the field of biotechnology
• Identifying sources of ellagitannins, the precursors to urolithin A
• Why to some people have gut microbiomes that seem to be incompatible with Urolithin A production.
• Enabling the consumer through precision nutrition
• Trial data and real world stories - understanding how anecdotal evidence seeds new ideas in science
• Dosage levels - the current state of research with Urolothin A recommendations
• Explaining autophagy and mitophagy and why their essential for life
• Is it possible to do harm by overdosing with Urolithin A?
• The multiple ways to boost mitochondrial heath - finding the optimum regime
• Pilars of a healthy lifestyle - diet, exercise and boosting cellular health
• Targeting skin as a longevity organ and the impact of topical Mitopure
• Future research; brain health, cognitive ability and possible supplement combinations
• The intricacies and complexities of conducting clinical trials

Watch the interview at YouTube

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Transcript

Anurag Singh: 0:00

The first two pillars of human health are for my own health, I think, is obviously eating good diet. Second is being physically active and you have to do those two things at the start. The third pillar is boosting cellular health, which I think is really the foundation pillar.

Peter Bowes: 0:15

Dr. Anurag Singh is the chief medical officer at the Swiss life science company Amazentis. Hello again, I'm Peter Boese. Welcome to the Live Long and Master Aging podcast, where we dissect the science and explore the stories behind human longevity.

MESSAGE: 0:31

Health optimization is what this podcast is all about. Physical strength and avoiding frailty. And that means taking care of our mitochondria, the energy centers of our cells. Timeline Nutrition make Mitopure - a highly pure form of the gut metabolite urolithin A, which plays an important role in the process. Our discount code is LLAMA. That's LLAMA. You can find out more at LLAMApodcast.com. And in the show notes for this episode, which was produced in association with Timeline.

Peter Bowes: 1:08

This is our latest episode covering the evolving science behind Urolithin A. Something we all produce to a greater or lesser extent, in our bodies. It's a product of our metabolism, the chemical processes that keep us alive. And it's a compound that research has shown is closely linked to healthy aging. Mitopure, which is a synthetic, highly pure form of urolithin A, is the result of more than a decade of research by Amazentis. And over the years that we've been talking about it, it's shown more and more promise as an aid to not only slowing down the aging process, but boosting our energy and helping us feel stronger now. In this conversation, we also discuss the research that suggests Urolithin A could play a key role in the health of our immune system and ability to fight disease. Anurag Singh, welcome back to the Live Long and Master Aging podcast.

Anurag Singh: 2:05

Thanks. Pleasure's mine. Peter. Glad to be back.

Peter Bowes: 2:07

And not only are you back, but I'm with you here in Switzerland at your global headquarters for Amazentis. And it's really good to be here and an opportunity for me to find out more about Urolithin A, Timeline, which is the name that you are now marketing the highly pure form of Urolithin A. Probably useful, though, I think, to go back to the beginning of the story. We've talked about this before, and if you're watching this on YouTube, if you're listening to this, you can just go into our search engine and find our previous episode. But let's talk about how all of this started. There's more than a decade of research has gone into what you're doing with Urolithin. A how did you get involved?

Anurag Singh: 2:53

Yes. So this all, as you mentioned, started about a decade plus back. It started with the concept to bring the biotech approach to nutrition and really bring sort of the deep scientific understanding of how certain plant based and diet based molecules impact human health. And so we started by deconstructing the pomegranate as we last talked. And in pomegranate, there are hundreds and thousands of bioactives that can potentially have human health benefits. And during our investigations, we found that this one particular molecule that we'll talk about, Urolithin A just outshone every other molecule that we were studying at that time. And this is not present in the diets. It's not present in pomegranates per se. When you are taking the pomegranates, they have polyphenolic components such as ellagitannins that then get broken down by a gut microbiome. And that's where the process in the gut microbiome, sort of digestion of these dietary compounds releases urolithin A so it's basically a postbiotic.

Peter Bowes: 3:54

Let me ask you this right at the beginning. Urolithin A we've talked about it a lot. Urolithin B, C, and D also exist. Can you - this is a family. Can you explain the difference? And our B, C and D are they as important to us as urolithin A?

Anurag Singh: 4:10

They probably have some importance for human health. So what we saw is that all of these urolithins have some, let's say, impact on longevity pathways and hallmarks of aging. The urolithin A just stood out because it had so much better effects compared to urolithin B, C, and D, and it's sort of the whole gut transformation process where from the ellagitannins you release first urolithin C and then you can either produce urolithin A or B in sort of the, you know, in the chain of the generation of Urolithin A we see that urolithin A is the most predominant molecule produced in human sort of the gut ecosystem. About 30, 40% humans make this molecule and about 10% make Urolithin B. So these would be the two. Our researchers looked at all urolithins, but just urolithin A has been so much more potent compared to all the others.

Peter Bowes: 5:01

And a big part of why this started was that pomegranates anecdotally have a reputation for being healthy fruits, a healthy part of our diet. Now, clearly it depends on where you live in the world, whether traditionally pomegranates have been something that you consume. But I guess the first challenge was to try to delve into the yes, the anecdotal evidence, but see whether that was backed up by modern day science.

Anurag Singh: 5:28

Sure. So we started by studying the pomegranate and really studying how different juices and extracts of pomegranate were having an impact. And there was a lot of research done previous to that on pomegranate juice or extracts, you know, in different models of biology and disease and even in a lot of human trials, they had been studied with sort of inconsistent effects. There would be trials where they would see a benefit in a few percentage of people but not see an effect. And the more we studied it, we realized that sort of heterogeneity of the response that they were seeing in these trials basically boiled down to whether, naturally, people are making urolithin A or not. And so we decided to sort of circumvent and short circuit the natural process by making pure urolithin A and delivering it in calibrated doses directly. And then everybody could benefit and you could basically remove that heterogeneity in all the studies we do.

Peter Bowes: 6:24

And did the potential of urolithin A or indeed the supplementation of urolithin A, did that come as a surprise to you as a long term scientist and also as a doctor and as originally a practicing doctor? You originally come from India, you've lived around the world, you've studied in the United States as well. But when you looked in detail at the potential of Urolithin A, did it give you cause to pause and to step back and think, hmm, this is this is fascinating.

Anurag Singh: 6:56

Yeah. So I was trained as an internal medicine physician and believe it or not, in medical schools, they don't teach the importance of nutrition and how big a role good nutrition and good, you know, how it can delay the whole sort of hallmarks of aging. People can be less disease or less symptomatic as we age. Now so my interest really started because one of my mentors in the US was at that time studying a lot of natural compounds from pineapples or apples. And we were sort of, you know, that's how I got into the field 20 years back. And that led to a whole sort of understanding that these natural bioactives had potential, as you know, to boost human health. The surprise came when I studied. Then I moved to studying probiotics for a long time in my career. The surprise came that actually it was these probiotics. You know, the gut microbiome had such a big impact on human health that it could harness some of these things we are eating on a regular basis, like pomegranates or nuts, which have all these really, you know, these polyphenols which I initially thought were the main compounds for, for the benefit that it was this postbiotic that was the key to all the effects we were seeing. So that was a surprise moment.

Peter Bowes: 8:05

And to be clear, polyphenols, which are found originally from the pomegranate, not exclusive, of course, to pomegranates. There are other sources of what's needed to generate urolithin A. So there are. You can you explain to me there are other fruits. There are there are nuts. There are other aspects of our diet.

Anurag Singh: 8:23

Yes. So there are walnuts, which are very rich sources of ellagitannins. Pecans as well. Then there are other berries such as raspberries, very rich in ellagitannins. So there are a lot of these, you know, traditionally, if you look or even evolutionary, a lot of we find now we have gone in and looked very - you can actually find urolithin A in nature even if it exists. So a lot of in Spain the Iberian pigs, they eat acorns. Acorns are one of the richest sources of ellagitannins. And so you can basically take Iberian ham and you can detect urolithin A because, you know, these kind of farm fed animals which are taking acorns on a daily basis. So, you know, it has been a long journey to try to understand how urolithin A impacts human health. But it's been fascinating journey, just studying the different microbiome of different people who can make it or not make it is a fascinating journey itself.

Peter Bowes: 9:17

Well, that aspect is particularly fascinating that and as you explained to us last time, we all can generate urolithin A, we can all use the ellagitannins in our diet that we get from these particular foods to different extents. And most, vast majority of people, of course, don't know the answer to that question.

Anurag Singh: 9:36

Sure.

Peter Bowes: 9:36

Where do I stand on the scale? And I know there is a test. And in fact, you have a test. And I did the test personally. And as it happens, I'm actually quite good on that scale. But to what extent? When you look across populations, do people vary in their ability to generate urolithin A?

Anurag Singh: 9:55

Sure. Great question. So we have studied different - we have gone in different parts of the world. We've studied the French. We've studied the Canadians, we've studied the American population. I can tell you the French have the best. Maybe it's the diet they're eating, a lot of fermented cheese, etcetera. And so what we see is about 30/40% in the healthy French population, for example, you would see naturally produce urolithin A levels; in the Canadian and in the American sort of metropolitan areas. If you go, you see the percentage drops down. So almost only about ten, 15% people are naturally making it. And that can be two things. They're not eating well. Right. So they're not eating fruits and nuts in their daily diet on a daily basis. And second is even if they are eating it. So for example, my own case, I think I'm eating right, but my body just does not have the right gut microbiome. And you could boil it down to my early years in India with a lot of antibiotic use that just knocked my microbiome off. So a lot of us think we are eating right, but we just don't have the right gut microbiome. And that's the second key pillar that we think is absolutely key to urolithin A production. So percentage wise it's variable depends on where people in the world are eating right. Perhaps more fermented food versus more exposure to fruits and nuts, but in general see about 30% in healthy human population. But the levels are variable. So you would really need direct supplementation to get unless you are one of those lucky 25% that just can naturally produce. So it was actually in the alleys of our building that we device or with Chris Rinsch, our CEO. I thought about, hey, let's make a test so that people can already see if they're actually naturally making this molecule and if they are at what levels, and then they can decide how to supplement with this molecule.

Peter Bowes: 11:43

Is it an aspiration to get doctors around the world and medical institutions to incorporate that test, perhaps at some point in the future, along with the regular blood tests that we're all used to?

Anurag Singh: 11:55

I mean, that's the vision that precision nutrition would basically guide you to how you should target your advanced supplementation needs. Today, we are all taking multivitamins, especially during Covid. Everybody is taking a lot of zinc and a gram of vitamin C, just because it's known that these have immune benefits, but very little of it gets absorbed. We don't even know what diet exposure of vitamin C we are having. If you're drinking a glass of orange juice. So that's basically what we want to change is enable the consumer to know where they stand in terms of the levels they're producing, and then they can calibrate the level of supplementation they need.

Peter Bowes: 12:35

And just going back to the conversation about the variable degrees to which we can produce urolithin A and that perhaps to some extent, being dependent on where we were born and where we grew up and the kind of diets that we were used to. I think that's really fascinating because of course that applies to other aspects of of nutrition. And perhaps it's a myth that there is one kind of diet that would benefit mankind. And I think the science suggests that that's absolutely not the case, that some of us are just not made to utilize certain foods that our stomach microbiome isn't used to. And of course, we have widely different diets across the world.

Anurag Singh: 13:16

Yeah, that has been the biggest, let's say, in 20 years of doing nutrition research, the biggest learning for me, that optimal, well food first approach, for sure, because if you can already get the benefits from food, that's great, but a lot of us can harness the nutrients. I gave my example in terms of urolithin A. So a lot of us think that we are eating right, but and we are taking optimal diet, but it's really down to the gut microbiome. And that was the ya-hoo moment for us. Now you could figure out what's that gut microbiome species or strain that is involved in probably thing that you could also instead of taking the pure supplement, take juice and a potential probiotic. I've spent five years trying to find that probiotic or that gut microbiome strain. It's not easy because the gut microbiome is such a complex ecosystem. So yeah, I think that's where we are at in terms of research.

Peter Bowes: 14:11

Well, let's talk about where we are now with Urolithin A and what Timeline, which is the name under which Mitopure is sold around the world. Now, when we first spoke 2 to 3 years ago, you were just about to launch. You'd done the more than decade of research to, to get to the point where you were beginning to market Mitopure. So I'm curious what you've learned since then and especially the global reaction, much of which will be anecdotal evidence that you've gathered from individuals that have been using this.

Anurag Singh: 14:43

Sure. So I think when we last spoke, we had just started getting our first RCT - randomized clinical trial - data from different populations, for example, and we were preparing for our first launch. And this was right in the, if I recall, in the peak of Covid. And so that was quite a challenge. And and what we have seen since then is we have launched a product. I had the honor to actually speak to even the first 20 people, the early adopters. And a lot of these folks were, you know, different profiles. For example, an older elite athlete who was probably declining after a surgery of a sort of a knee surgery declining and is trying to get back on his bike and not able to recover properly. And so tried the product came back to us telling me that, oh wow, my recovery after I'm 60 plus my recovery was so bad, sort of. After my surgery I had given hope. Now I've been on this molecule for about three four months and my recovery is so much better. I'm beating the time I was, you know, beating, doing when I was in my 40s. So this sort of feedback and of course these are anecdotal. Then there were folks with muscle disorders, people who have autoimmune muscle diseases, for example, who were having trying everything out there from stem cell injections to pharmacological interventions, not seeing many benefits. And they were coming back to me and saying, hey, we are using this in our now on your product and we can actually climb a flight of stairs. So this started seeding other ideas. And in the two years since then that we spoke of, we've managed to publish some of that data and really top journals. We have entered into collaborations with really the top schools out there in universities like Harvard and Northwestern, where we are now really trying to get into different populations. But what led from these initial first conversations was we need to target athletes. So that was one sort of stream, because athletes, in terms of muscle and mitochondrial performance are considered the optimal population. And there was a professor from Australia who came to us and said, well, you think they do have optimal health, but actually overtraining has a compromise effect on their mitochondria. So for two years, we actually were ambitious enough to launch a trial during Covid and study really Olympian level athletes who were middle distance runners. And now we're just starting to get some of the data, which suggests that actually urolithin A improves cellular health, which helps in the recovery of these folks. Then there was the hospital setting, again, big news in hospital during Covid times. The moment you walk into an intensive care in seven days, you lose about 10% of your muscle mass and strength, which is about a decade in the health health span. And so this started coming back to us with a lot of investigators saying, well, what it works great in healthy settings for older adults and middle aged adults, would it work for somebody who's hospitalized? Will it get them out of the hospital faster? So these are kind of research we are doing in terms of extending our knowledge on the muscle and physical performance. But there are a lot of other streams like immune health. And we can talk about skin longevity as well.

Peter Bowes: 17:58

Exactly. I want to talk about both of those. But just going back to the anecdotal evidence, and you did elaborate just now, obviously on the scientific evidence and the studies that you're doing. I'm curious, as a scientist, are you instinctively skeptical about some of the anecdotal evidence? Because of course, there is no control. We are an n equals one. When you have an individual saying, yeah, I actually feel better having taken this product, it could potentially be all in the mind that you're taking the product. Therefore you think you feel better and that you need to be, I guess, careful in terms of the importance that you lay on that anecdotal evidence.

Anurag Singh: 18:38

Yeah. So you can overplay it. But but I think over the years what I've learned is that actually it seeds new ideas in directions for research where you could potentially go. So like the first 20 people, five were athletes and they were telling us about recovery and heart rate variability being, you know, impacted with Urolithin a and I thought, wow, if that's the case, let's actually design the next RCT. So to prove that what we're hearing is real. So I think if you have the trial data, then the real world data that you hear from consumers really can supplement the message. That's how I see it today. And n of one you mentioned about that. Yes, you need to listen to people because when you start, we are now giving questionnaires, for example, to consumers who want to sort of give feedback. And we have a very calibrated scale even where people can tell us about, you know, is it strength, is it endurance, is it fatigue? And and we're trying to capture this information now instead of n of one. We just taking a lot of those n of one. And we're trying to do a lot of data mining and data visualization to see where is the signal in the real world where people are not everybody is eating different, everybody is doing different physical activity. And it points to improvement in strength and endurance, which is where our clinical trial data shows. So I actually think it's a very complementary approach.

Peter Bowes: 20:05

I want to ask you about dosage, the little sachets, the berry flavored powders, which are the ones that I've been using. I tried the capsules as well, but I actually like the taste of the powder. It's 500mg. I think that has been the standard dosing level. But I know you've also done research at different levels of dosing and much, much higher than that as well. Where do you stand on that in terms of what you're recommending and what potentially higher doses, the kind of results that you can get from that?

Anurag Singh: 20:37

Yes, so 500 gives you a very good boost on mitochondrial and cellular health. This is when we, you know, our first trials we did we took a little blood or plasma, as you say, to look at really molecular signatures of 500. And then we looked at even longer trials on things like muscle strength effects. And 500 is the dose that actually wakes your mitochondria back. What happens with aging is that our processes like mitophagy, which is the cleaning of the bad mitochondria, slow down. So 500mg is sufficient to activate mitophagy. Clear the waste and make mitochondria healthy and happy, as they say. And then have impact on muscle health and muscle function. And in the broad picture. Now add a gram which is the sort of the top dose if you've looked at the levels of absorption. A gram is where you top it out basically in terms of absorption. So if you go beyond a gram to two grams, you start seeing similar levels. So you can keep just doubling every time. At a gram, we start seeing even better effects and even quicker effects on things like endurance, for example. VO2 max improves about 5 to 10% in different populations, but the gram starts having impacts beyond muscle. And that's why personally, even I take a gram because it starts having impacts on inflammation. So a lot of older adults, a lot of even elite athletes, their bodies are inflamed. And that's where we see very consistent signature at higher doses to to have a very potent anti-inflammatory effect.

Peter Bowes: 22:05

You mentioned mitophagy 500mg being the the level that triggers mitophagy. Again, we've talked about this many times, our previous conversation and others, but I always think it's worth just emphasizing what mitophagy, autophagy is in terms of of cells and mitochondria in particular and why it's so important.

Anurag Singh: 22:25

Sure. Yeah. So autophagy is basically at a cellular level. It's a sort of recycling of all the waste inside a cell. Mitophagy is a very targeted form of autophagy that is specific to the mitochondria. And there depending on what cell type it is or muscle cell has thousands of mitochondria in a cell, a neuron even has thousands. A blood cell doesn't have so many. It has a few from 20 to about a few hundred. So a white blood cell, red blood cells don't have mitochondria. So what? It really depends. If you look at a mitochondrial life cycle, a healthy mitochondria, you can promote near healthy mitochondria. And there are strategies out there like NAD modulation to grow the number of healthy mitochondria. But if you see in terms of a dynamic, the healthy and the unhealthy are always in a state of flux. The mitochondria in a cell now, as we age, the unhealthy sort of kind of become too much. And that's where the whole mitochondrial dysfunction theory sets in, that you have more faulty mitochondria than healthy mitochondria. And then people try to use things like CoQ10, for example, or L-carnitine to take whatever's the good mitochondria to make them produce more energy. Where your Urolithin A is very special is that it activates this third pathway in mitochondrial life cycle, which is mitophagy, which is basically you're taking all the bad mitochondria which have put out an eat me signal, and you're putting them in a trash bin kind of system and you're recycling them. So now they become the building blocks of newer, healthy mitochondria. And that's what makes urolithin A or Mitopure so different and so unique.

Peter Bowes: 23:56

Yeah, exactly. So you mentioned you've been taking one gram. Double the dose that I'm using and that there could be some impact and positive impact on inflammation. Now I think we're all aware that inflammation is is a huge problem bodily function that initially is designed to protect us. But things can go significantly wrong if we are too inflamed, as it were. Can you delve into that a little bit in terms of what is actually happening and why there could be a beneficial effect?

Anurag Singh: 24:28

Sure. Back to two reasons why I take one gram again is because a my body doesn't make I've tested myself a number of times, and I cannot get even a single ounce of urolithin A from diet. So that's why if you're already making it, probably you don't need to take that high level, 500mg may be sufficient.

Peter Bowes: 24:46

Yeah. Valid point.

Anurag Singh: 24:47

And second, there's a history in my family history of having a lot of inflammatory bowel disease and gut disorders and inflammation. So you know, and having studied the molecule and seeing its effects on the immune health and inflammation, I take it for that reason. Now, how does it work on inflammation? Is, immune cells particularly the special kind of immune cell called T cell. They have about of they need mitochondria to function better. And so if they're not functioning better they are also going a bit crazy in our bodies - these immune T cells. And so with aging you get all these diseases like even cancer starts happening because the immune system cannot control all these processes. And so what we think now is that taking Mitopure is making these immune cells, mitochondria more efficient. And that allows the immune cells to function better. And so instead of they can make these sort of soluble factors that we call cytokines. They can they can dampen these things. And so in clinic as a clinician it's very easy to measure. The readout is things like C-reactive protein. So a common blood test that clinicians use very normally. So instead of always looking for this holy grail of what's that one mitochondrial biomarker. Do we need biopsies. Do. You need to, you know, you can just look at immune health or CRP, and that makes it so much easier to track the effect in clinic.

Peter Bowes: 26:13

Is it possible to overdose? We're talking about 500mg or 1g. Is it possible to overdose and do harm? Doctors talk about doing no harm. That's the first principle. What's the research telling you?

Anurag Singh: 26:28

So the research is telling us that this is a molecule that has evolutionarily been present. So a lot of us innately were eating fresh food and gathering fruits and nuts and eating them. And so a lot of us have evolved to make this molecule. And during the process, a lot of us have lost the ability to to make it. We have done a whole safety and toxicology assessment that we also vetted with the Food and Drug Administration, the FDA, where we presented all the findings. There basically is no adverse effect limit of this molecule. So you can give it almost a 5% in the diet, which would be equivalent to ten gram even in human dosing. And you won't see a side effect for this. Now, what we have looked at in, in human trials is as you as I was mentioning, as you go from 500 to a gram, you increase the absorption. And that's why you get other higher, better effects. But as you go from a gram to a two gram or even more than that, you won't up the levels of exposure of the molecule. It sort of hits a plateau. So you won't get this overdosing effect with this molecule. And it has a very nice half what we in clinicians call it as a half life. So when does it go up in the system and when does it clear out from the system. And it's about a day. So it works very nicely from a dosing regimen that you take it in the morning after overnight fasting when already you're autophagy sort of is is there because fasting is known to do autophagy. And that's how we test it in our trials.

Peter Bowes: 27:59

You mentioned fasting. So I think it is known amongst some people that if you want to boost your mitochondrial health, your muscle health, that there are some beneficial effects of fasting. Now, there are lots of different fasting regimes - there's time restricted eating. So what applies to one doesn't necessarily apply to everything. Nevertheless, I think it's generally accepted that if you want to have good mitochondrial health, that it is an element of your lifestyle that could be useful. And there are other ways to boost your mitochondrial health as well. So I'm curious in terms of people might be watching or listening to this thinking, well, I do a lot of exercise, which is another aspect of boosting mitochondrial health. I dabble in a little bit of fasting occasionally. Is that enough, or is there a virtue in combining a bit of supplementation, a little bit of exercise and fasting as well?

Anurag Singh: 28:55

This is the mantra I follow for myself the first two pillars of human health, or for my own health, I think is obviously eating good diet. Right? That's the first pillar. Second is being physically active. So getting enough exercise in and you have to do those two things at the start. The third pillar is boosting cellular health, which I think is really the foundation pillar and how you think about supplementation. Even a lot of people do stacking and trying different supplements. I think it's the third pillar, because there are a lot of times when I, I don't I'm not able to exercise. And, you know, the working lifestyle, I think I'm more a weekend warrior. And so that's where I think it fills the gap, the sort of the maintenance is by doing and taking things like Mitopure and other nutritional advanced supplementation. That's my approach. I think you need to take all the three pillars.

Peter Bowes: 29:48

So let's talk about immunity. And you've touched on this a little bit, but I know there is some fascinating research happening now. There are studies planned for the future to determine whether supplementation of this kind could have much broader effects on our body and boost our immune system, which in itself could have many positive consequences.

Anurag Singh: 30:13

Sure. Well. And there you have to think from two perspectives, and that's the two perspectives we are chasing. How can you already take a good functioning immune system and make it function better in healthy folks? And second, where the immune function is weakened or nonexistent? How can you then bring Mitopure into play? And so we are now we have collaborations in two fronts, and we are actually running two randomized trials, one in healthy middle aged folks like you and me. And the goal is there, can we boost immunity and the mitochondrial health of immune cells in this sort of setting beyond what we think is healthy? So can we take a normal functioning immune system and keep it at optimal function so it can fight infections better? You know, it can. We all know the challenges of new infections, having seen the last three years of Covid and how it shapes. And then the second aspect, which think is very interesting from a from a cancer perspective. With aging, we see increasing incidence of cancer happening around the world. And with cancer you get two things. You get cachexia, which is basically muscle wasting. And second thing you get is a lot of these cancer patients who even beat cancer, they're taking what we call as neoadjuvant, which is basically chemo and radiotherapy. And that knocks off even their healthy immune system. And so we are very in fact, there will be we published last year at the back end of last year, a great collaboration with a German group, Florian Greten and Dominic Denk, which showed that basically even your Urolithin A can be used to fight colorectal cancer because it's a gut derived molecule. And then by adding even on top of, let's say, standard of care, medical care, you can actually improve that standard of care. And so now these are kind of the sort of cancer trials not to treat or cure cancer, but how can you position it in a way that people who have fought cancer and sort of come out of it, how can they then lead better activities of daily life with their muscle helping optimal and their immune health also coming back at the peak?

Peter Bowes: 32:19

In fact, I spoke to Dominic Denk, Dr. Denk very recently, and so that episode is on both our YouTube site and our audio platforms as well. And I agree with you. It is really fascinating research. And for those two reasons that there is potentially a preventative element as well to it, but also in terms of helping people who are at different stages of cancer. And again, just to emphasize, there are more human studies, many more human studies still needed to to fully understand that process. But I think it is fair to say that it's promising so far.

Anurag Singh: 32:55

Yeah. I mean, you have to start with small steps, and that's what we think we are taking in this in this journey and really working with the top oncologists and immunologists like Dominic. And in Switzerland, we are working with Professor George Coukos is probably one of the top oncologists and just was recognized as one of the top cancer researchers in the world. So yeah, very proud to take these steps. And I think the field of immune metabolism, you'll hear a lot more.

Peter Bowes: 33:23

So I think what's coming through to me from this conversation that we're having is compared with a couple of years ago, the breadth of potential for what you're doing, supplementation with urolithin A is becoming more apparent. We're talking about the immune system here. We're not just talking about mitochondria and physical strength. And you're also moving into and in fact, you've launched a product, a topical product, which of course involves a relationship with the skin. So a very different way of, of use and and of application. How did that arise? And again can you explain what the science is behind it.

Anurag Singh: 34:00

Well it started it's actually three pronged. A lot of our initial early adopters of our oral products actually started coming back anecdotally and telling us back to our conversation. And how do you take feedback from consumers? Some of them are saying, oh, our skin is looking better. And we started thinking, ah, that's interesting. And so the first sort of experiments you do or investigations you do is, well, let's take skin cells from older folks and just put my pure on top and see if we can see what we used to see with the muscle cells. Would it do would it improve. Would skin cells of a 70 year old have declining mitophagy. And that was the case. We looked at skin samples from 70 year old women to 30 year old women, for example, at the start. And there was a mitochondrial dysfunction in 70 year old skin samples and then a decline in mitophagy. So we started playing around and we saw that Urolithin A was doing basically what we knew it in muscle and immune cells to do. So it was a it was improving mitochondrial energetics. So now the skin cells had more energy. And second, over time, skin is also a very big immune organ. A lot of our immune cells reside in the skin with exposure to things like UV rays. The skin gets inflamed. And so by putting Mitopure on skin cells, we started seeing that there was an anti inflammatory profile, much what we had already known about mitochondria. And the third was well with aging, people always ask me oh my mitochondrial function is declining I know it but how do I measure it. And it was very difficult to find saying, oh, you have to go to do an exercise test and jump and test your VO2 max, which is probably the closest we have today to measuring good mitochondrial aerobic capacity, sort of. And so visually aging, everybody feels it. Everybody sees on a daily basis that your skin is losing hydration. Their wrinkles are coming in. And so we were very clear that we didn't want to go and target beauty, for example, as most cosmetics companies would do. We are a longevity company, and we wanted to target skin as a longevity organ and see if we could reverse some of the signs by improving mitochondrial health. And that turns out that's the case, that mitochondria have a very key role in skin health. And as we age, the mitochondria provide fuel to things like collagen production. And so we see that in our trials that we're about to publish, actually, we are seeing that topically applying Miropure for about eight weeks, reduces wrinkles, it improves collagen production, and most importantly, it's anti-inflammatory. So you can target both intrinsic and extrinsic aging.

Peter Bowes: 36:41

Again, coming back to the dosing question, if you're using a topical version of this product as well as the the capsules or the the powder, the berry flavored powder, you're getting more of the product. What is the implication of that?

Anurag Singh: 36:56

So we haven't yet done that trial yet, where we have sort of added one plus one and showed that it's better or equal to or better than two. A lot of consumers are asking for that, and we see that there is an opportunity. There are a lot of nutrition companies are not doing topical products, and vice versa. Topical companies are not even thinking oral products. And we think by applying sort of improving cellular health systemically through the oral product, and then going specifically to skin with the topical product is will deliver an added benefit. We just haven't tested in a randomized trial, but we think it will be additive.

Peter Bowes: 37:33

But to use the phrase 'generally considered to be safe' you're confident of the safety factor there?

Anurag Singh: 37:40

Yes. So on the skin, well, we started by doing a skin tolerance test. And it's basically what you do is you take a topical product and you keep applying it every day for for six weeks. And if it's it's sensitizing the skin or it has some allergenic potential or it's not safe, you will pick that signal up. So we actually did that with 120 participants at the start of our skin program, 20 to 75 plus age, different gender, different skin types even. And we found that it was very safe when applied in different doses. And then we found the dose that was giving the best efficacious dose. So all our products do they have 1% Mitopure in the product.

Peter Bowes: 38:21

So we're talking about skin. We're talking about the stomach with the original product. What next is scope that you haven't made public yet that you're looking at? And it's kind of whirring around in your mind that it could be the next horizon?

Anurag Singh: 39:06

Yeah. So you could think what's next in terms of what's the next benefit. So we've already kind of moved the needle from muscle to immune and skin. And now we are collaborating what I call the hybrid research and development approach, where we are now partnering with really top professors and investigators. So three independent labs have come, including the Buck Institute of Aging has come back to us saying this molecule has great effects on brain health. So typically, again, with aging neurons, cells have a lot of mitochondria. You get a lot of cellular dysfunction, mitochondrial dysfunction happening in the brain. And we are seeing this molecule out of thousands of molecules is the most promising because we know it's safe and it's showing the effects that it's. So we are empowering those investigators. We are collaborating with giving a product, and we're planning to do a number of trials that will be led by these universities, but we will just support them, for example, with the product. So that's the sort of expanding the health benefit. And then the second is.

Peter Bowes: 40:06

Just on that point, maybe it's early days yet, but when you say brain health, are you talking about cognition? Are you talking about memory? What aspect of brain health?

Anurag Singh: 40:15

Yeah, it's really cognitive health overall. So the first signs we are seeing is really in models of neurodegeneration. So these are models that kind of mimic MCI what I call as mild cognitive impairment. Early on that starts happening post 60/65 years of age and let's say a 10% of the population. So you're targeting these early signs of cognitive decline and per se especially a benefit like memory or attention, which will be the, let's say, the follow up trial, where you go and try to tease out what's the specific benefit. But can we improve? Cognitive health in general is the first sort of benefit we are targeting.

Peter Bowes: 40:55

Excellent. So I interrupted you. You were going to continue.

Anurag Singh: 40:58

Yes. So so in terms of what's next in terms of is there other urolithin A-like molecules or have we you know, so we are looking in terms of what can we combine it with. So there are other well proven actors that we know have a high level of science behind them. And so we're trying to take a look from a either a proprietary intellectual property where we can combine it with. So our skin creams are actually a great example. We looked into the literature and we found that niacinamide, which is an NAD booster, for example, has already been shown high level of efficacy. And it's it's available. A lot of people can. Use it. But then we kind of combine niacinamide with pure in these products at different doses, of course, of niacinamide. In addition, we looked at other active. So we're trying to see where we can even improve the effects of what we are seeing, for example, with Mitopures with other nutrients that can be sort of synergistic. So that's one approach we are taking. And then of course we're looking at other postbiotics as well.

Peter Bowes: 42:01

And just more generally, in terms of the breadth of your research, and clearly a big part of what you do is dependent on these collaborations with independent scientists around the world. That I guess is is hugely challenging to operate as a company like this, a relatively small company. Just give me an idea of the logistics involved. We've talked many times about new human trials. That is a huge venture to launch into in terms of people involved and and the expenses involved.

Anurag Singh: 42:36

Yeah, it is quite an adventure. And I'll give you the example of a trial. Well, we published in JAMA recently as one example. And then I'll talk about a new study that we are starting with. So this was a study that we wanted to do in 70 to 90 year olds. It was led and actually conducted at University of Washington in Seattle. And the investigators, one of the most recognized professors to study mitochondrial dysfunction in humans, where you put people in an MRI like magnet and you measure their mitochondrial health as they exercise an MRI-like machine. And so not many people around the world had that infrastructure. So we started collaborating. It was around the time Covid also hit. It was not easy to recruit 70 plus because it was hitting a lot of older adults. So there were challenges. Now, a trial like this costs about a million plus, and that's the kind of investment we have to commit to early on in our in our journey to providing that level of science to back our products. And then it takes we had to bring in organizations that actually go measure. If every older participant in a trial is actually taking the product on a daily basis, you have to call them up to keep reminding them, are you did you take your product today? And you have to count actually the number of pills at the end of the trial? Well, we gave them 120. Did they come back with only eight because they should have taken so many. And so it's a huge endeavor. And then once you have all the data, you have to securely put the data in a secure server. Then you have to have a statistician look at the data from different angles. So it's each clinical trial has been a 2 to 3 year. I can write a book about it.

Peter Bowes: 44:17

Well, it's interesting you should say that because I, only one, but I was a subject in a clinical trial, actually two, there have been two over the last few years clinical trials that I was I was the subject and I mean, I did it deliberately because I was curious about the process, but it really brought it home to me how the scientists are dependent on the the diligence of those individuals and their commitment to be to be fair and open and honest, and the potential that if those people are not compliant, how it could really skew the results of the trial.

Anurag Singh: 44:49

Absolutely. It's a major, let's say, obstacle in readouts of clinical trials is the compliance. And and we say, okay, participant took 80% of the time the product we you include them in the analysis at the end of the trial. And a lot of times it's about the right communication to the participant. Did they understand what the study they were participating in? I will never forget in my life, the oldest participant in this trial I was telling you was an 89 year old lady. She finished the trial, which was a four month trial. We didn't know. She didn't know if she was on the placebo or the active product. She came back saying after, well, when am I going to get to know which product I was was because I still garden a lot and I felt the product was improving, that I wasn't so sore after that. And she's like, you have to tell me so I can actually buy a product and be on it. Versus.. It took us another six months to finish that trial because you have to get enough participants. And when we unblinded, I message her saying, well, you were she was on the the active Mitopure product and she knew it. So sometimes you have to and then we sent her a four month subscription for free because she believed in the product so much. So this, you know, we won't increase our knowledge of science if it was not for people like, you know, you mentioned you participated. And I think that's absolutely brilliant. People need to volunteer and take part in more studies.

Peter Bowes: 46:19

Just in closing, I detect your continued enthusiasm for this over the years that you've been involved. And as you look to the future, what continues to get you out of bed in the morning to do this kind of work?

Anurag Singh: 46:32

Sure. Well, I've been at it for almost ten years now here on the research. Well, two things. One is the great team we have here. We have an absolutely we have a small team, but that everybody puts multiple hats. And so that's just, you know seeing it go. When I started I think I was employee number three. And now we've of course grown ten times more, 12 times more. But seeing the product go from a discovery at the bench in a lab level, that's when I started taking it to humans to now the breakfast table, as I say of people, is the satisfaction is so immense, right? And the second is just when I talk to people who are on the product who tell me these great things and, and that's one of the reasons why I moved from clinical practice, because as a physician, you're seeing a few patients a day and you're seeing the same kind of patients in the day. Now, I see actually my work impacting hundreds and even thousands of people on a daily basis. So that's what gets me up in the day. And then seeing the immense potential and also the validation that what we spent 10, 15 years doing, trying to change how nutrition research should be done and laying the template, because a lot of times when I started, people were blending probiotics, vitamins all in one thing and selling it. You know, you wouldn't really do a lot of research. You would just put your marketing dollars on it. And we've spent the research dollars and then said, okay, we believe in the product, now we're going to sell. So yeah, that's what's exciting.

Peter Bowes: 48:00

Anurag Singh it's always a huge pleasure to talk to you. Thank you very much.

Anurag Singh: 48:04

Sure. Well, pleasure is always mine to talk to you, Peter. Thanks.

Peter Bowes: 48:09

In our next episode, a conversation with Dr. Nicola Vannini, who's a researcher at the Department of Oncology at the University of Lausanne in Switzerland. In experiments with mice, he and his team have been looking at how exposure to urolithin A affects the ability of a special type of stem cell to maintain healthy blood and a well-functioning immune system.

Nicola Vannini: 48:32

They one from old mice that were treated with urolithin. Afterwards, they were transplanted in recipient mice and the results were quite astonishing.

Peter Bowes: 48:42

It's a really interesting study. More from Dr. Vannini in our next episode of the LLAMA podcast. This has been a Healthspan Media production. There's a full transcript of my conversation with Dr. Singh in the show notes for this episode, which you'll find at our website LLAMApodcast.com. Thank you for listening.