Beyond Mitochondrial Health: Can Urolithin A Slow Down Aging?

Timeline and Mitopure are the product of more than 10 years of rigorous research and development by the innovative Swiss health science company Amazentis which is comprised of world-class scientists, physicians, and product development professionals.

When it comes to mitochondrial health, few nutrients have burst onto the bioenergetics stage with quite the impressive force as the postbiotic rock star Urolithin A (UA). On this New Frontiers episode Dr. Chris Rinsch, co-founder of Amazentis / Timeline, shares the incredible scientific journey of UA’s discovery and subsequent unfolding of its many benefits, as confirmed by multiple clinical studies. Together, we explore UA’s mechanisms of action, including the role of the microbiome, and exciting preliminary research on UA’s potential to reverse immune aging. Of course, our conversation wouldn’t be complete without discussing the possible role UA may play in slowing down biological aging and extending healthspan – after all mitochondrial decline is one of the hallmarks of aging. Tune in and please leave us a review wherever you listen to New Frontiers. – DrKF

For centuries we’ve known that the pomegranate is an amazing superfood. But why? What happens when we eat foods containing polyphenols? Where do they end up and what is the mechanism behind the health benefits? These questions were the driving factor behind the work of Dr. Chris Rinsch, co-founder of Amazentis / Timeline. And what he discovered is groundbreaking. As the ellagitannins are transformed into bioactive compounds called Urolithins, more specifically Urolithin A, they have the ability to stimulate mitophagy and mitochondrial renewal, leading to improved muscle strength and endurance, immune health, cognitive function, and skin health at the cellular level. Truly remarkable!

Join us as we dive into the studies – past, present, and future – that are showing the incredible potential Urolithin A has for improving both the lifespan and healthspan. If you’re interested in the interplay between polyphenols, the microbiome and longevity, you’re definitely going to want to listen to this one.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald (00:00:02) – Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine, and of course today is no exception. I am very excited to be sitting here with the co-founder of Amazentis. Let me give you his background and we’re going to jump right into some very cool science. Dr. Chris Rinsch is co-founder and president of Amazentis. For more than twenty years, he’s been an innovator in the life sciences arena. Before founding Amazentis in 2007, Rinsch worked in venture capital, investing in pioneering life sciences companies in the nutrition space. He also invested in biotech and worked on developing cell-based therapies at the Swiss biotech company ISOTIS SA, formerly Modex SA. Rinsch has authored original publications in top tier journals, such as Nature Medicine, Nature Metabolism, JAMA Open, and many others, and this is focusing on his research on Urolithin A, mitochondrial health, muscle function, and joint health. He’s also an inventor on several internationally filed and granted patents. He has an MBA from INSEAD in France, a PhD in cell and molecular biology from the University of Lausanne, and a master of science in biomedical engineering from UT Southwestern Medical Center, and a Bachelor of Science and Engineering from Harvey Mudd College.

Dr. Kara Fitzgerald (00:01:26) – Welcome to New Frontiers, Chris.

Dr. Chris Rinsch (00:01:29) – Thanks, Kara. Thanks for having me here today.

Dr. Kara Fitzgerald (00:01:32) – You know, your background is really impressive. And it just begs the question of a little bit of your origin story. How you ended up founding Amazentis and really kind of lighting on Urolithin A. You’ve been up to a lot of interesting stuff in your life.

Dr. Chris Rinsch (00:01:49) – Well, I think the origin of Amazentis and Timeline comes from my immediate previous experience where I was in venture space looking at nutrition and investing in a lot of different nutrition companies and thinking about health and wellness. Looking forward at how we can have products that are really scientifically based and clinically assessed to actually improve your livelihood throughout your life. This versus a lot of the nutritional products that we have today that essentially, it’s kind of taking a “trust me” approach and you’re really not sure. You take them and you hope for the best. That was sort of the origins of taking the tools that scientists are using to discover new drugs and apply that to the foods that we eat and start taking a deeper dive into what compounds are found in the different foods and linking them to biological pathways. Particularly pathways that are associated with cellular health and wellbeing and aging as a whole.

Dr. Kara Fitzgerald (00:03:15) – That’s so interesting. When you founded Amazentis, had you already identified Urolithin A and just rallied your focus around that? Or were you looking at many other molecules at that time?

Dr. Chris Rinsch (00:03:30) – Actually, it was more of a concept at that time. Let’s try and identify those foods and those bioactives in the foods that we eat that could have the biggest impact on health. And so, we started exploring. We cast the net and looked at a number of different types of food products. One of those was the pomegranate. And so that’s really how it started. There was a lot of talk around the pomegranate and antioxidant effects of the pomegranate at the time. So we wanted to dig a little bit deeper to see if this was more than just a marketing story to sell juice and there was something really behind it. And so, we looked at the pomegranate as well as a number of other foods at that time.

Dr. Kara Fitzgerald (00:04:23) – So impressive. I mean, you guys cast a really wide- Well, first of all, you set a really high bar. Let’s just make people healthier. In fact, fundamentally it sounds like you are asking the question that’s on everyone’s mind now, which is how do we slow aging? How do we reverse it? You were really asking these big lofty questions and let’s apply- I think it’s awesome that you take the power of science and you light it onto nutrition. I think in our field, functional medicine, we really embrace that lens so it’s exciting for us to see what you’ve been doing and how you’ve been thinking.

Dr. Chris Rinsch (00:05:06) – Well thanks. We were very excited at the onset, and now we’re even more excited by what we’ve found and all the work that progressed since the origins of the company.

Dr. Kara Fitzgerald (00:05:19) – I want to jump around. I’ve got a bunch of questions. There’s a lot to talk about here, but I just feel like we might as well go to the origin story, to discovering Urolithin A. Let’s talk about the lab of Johan Auwerx. I think I didn’t say his last name correctly, but let’s just talk about it. Let’s just talk about how you guys got Urolithin A.

Dr. Chris Rinsch (00:05:43) – Well, it really started with us taking a look at the pomegranate and we were really curious to know what was inside of the pomegranate. And so, we went through a whole process of actually even purchasing pomegranates, juicing them, understanding what compounds were inside, and then doing this, what we call in science, a bio-guided fractionation. Which basically means sort of exploding the pomegranate in terms of all the compounds that are found inside of that, and then starting to test those different compounds in the lab on cells to see what type of potential benefits they have.

Dr. Chris Rinsch (00:06:26) – And then we take that to the next step and then take that into mice. In this case, early on in the company, we were looking at behavioral effects on memory. This led us down the pathway of looking at a class of compounds that are called the ellagitannins that are found in the pomegranate. And more specifically, there was one ellagitannin in the pomegranate that’s known as punicalagin. It’s the most abundant one. We started testing that and we were beginning to see some very interesting effects on, actually, the behavior and memory in a mouse model of Alzheimer’s disease at the time. And so, we started from that and started asking ourselves a little bit more questions about this compound. How is it transformed when you consume it? What is that whole pathway?

Dr. Kara Fitzgerald (00:07:24) – Well, let me ask you that. How were you administering it in these animal studies? Were you injecting it or were you administering it orally? And why did you start thinking about that? Why did you think about the gut systemic interaction or the transformation by the microbiome? What prompted you to think about it with these compounds in pomegranate? Or were you already aware of the transformative microbiome activating these. So yeah, curious about that.

Dr. Chris Rinsch (00:07:57) – It’s always been about this concept that we wanted to identify different types of bioactives, polyphenols, that we could put into food. We wanted products that were working and that could integrate into your diet, whether it was a food or a supplement. In terms of the administration, it’s always been through oral administration that we’ve been delivering, in this case, punicalagin. And to your question about Urolithin A, of course, there was knowledge and there were scientists that had been studying the metabolism of various foods that you eat, whether they’re walnuts, certain types of berries, like raspberry and pomegranates, in humans just to see what transpires when you consume these products and the polyphenols, and where do they end up. There was this understanding that some people can actually transform – and we’ll get to that – transform these compounds that are called ellagitannins into other compounds that are called Urolithins through the gut microflora.

Dr. Chris Rinsch (00:09:20) – At that time, no one was really thinking about these metabolites or we call them postbiotics, as actives, but more as just the body’s way of eliminating the polyphenols that are found in the foods. And so that’s sort of- Coming back to your question of how did we land on Urolithin A. It was really taking this very thoughtful approach as to which compounds might emerge if you were to consume these starting compounds, in this case, punicalagin.

Dr. Kara Fitzgerald (00:10:02) – And then you had some- Well, you were probably working with mice, and then you were seeing the transformation into the Urolithins and other compounds, I’m sure.

Dr. Chris Rinsch (00:10:15) – Exactly. What we started doing is we took that sort of- It was a leap of faith at a moment where we said, “Okay, well, I wonder if these compounds are actually bioactive versus just something that the body is eliminating.” And so, we then started taking a closer look at them.

Dr. Chris Rinsch (00:10:38) – Just to maybe go backwards a little bit before we jump into Urolithin, what’s interesting is that when you’re consuming, whether it’s animals or humans, when you’re consuming pomegranates or walnuts or raspberries or any of these foods that contain these ellagitannins, they’re transformed by the gut microflora, the bacteria that are inside of our gut, into Urolithins, which are postbiotic, and in particular Urolithin A. But in fact, there’s only about, let’s say, 30 to 40% of the population that’s able to make that transformation. And that was what was very interesting when we were studying that and understanding it’s not really- You aren’t what you eat. You’re a combination of what you eat, plus your whole body’s ability to transform that and to assimilate those nutrients.

Dr. Kara Fitzgerald (00:11:46) – It’s kind of extraordinary. In the animal model, is it similar? Some mice can make these Urolithin A compounds, some mice don’t or varying degrees of efficiency. And then you had to get in there and look at the compounds individually and see who’s doing the heavy lifting in terms of-

Dr. Chris Rinsch (00:12:09) – Actually we didn’t spend too much time assessing the metabolism of mice. But after we started testing some of these, in this case Urolithin A, on cell models and showing its bioactivity, we quickly focused in on that molecule to try and understand what it was doing. I think one of the first things that we were doing, and you had mentioned the lab of Professor Johan Auwerx here at the EPFL, he is a specialist in mitochondrial biology. I provided him a few of these compounds and he tested that in some of the models that he uses. He came back and said, “What exactly did you give me here?” And that was what was really interesting. That he saw this improvement in mitochondrial function in these cell models that he hadn’t really seen before.

Dr. Chris Rinsch (00:13:12) – It was at a different level. One of the areas and one of the ways he studies mitochondrial function and aging is using a model that’s called the C. elegans model, which is a worm that has a very short lifetime and lifespan. By administering bioactive compounds to these worms, you can see their effect on health and longevity by just simply monitoring their lifespan and their prolongation of their lifespan, and also the movement of these worms with time. What he saw was that Urolithin A was having this dramatic impact on the lifespan of worms, and also on just the worm’s ability to move with time as they got older. When you think of these different ways of assessing the lifespan or different types of interventions that you can make that would improve the lifespan and the healthspan, we like to think of things in terms of healthspan and not lifespan. And we can talk a little bit more about the difference.

Dr. Chris Rinsch (00:14:34) – But caloric restriction, for example, has been shown to improve the lifespan of these worms dramatically by around 50%. But when Urolithin A was provided, we were seeing an extension of lifespan by about 45%. And then when you start looking at other compounds that are having an impact on similar pathways, but not identical ones, like resveratrol for example, you see improvement by about 15% and that sort of order of magnitude. So, this is really something at a different level. And it was these findings in the lab that really caused us to think about what this could be used for. What type of health benefits should we be looking at? And quickly, we started looking at skeletal muscle function, because it was so easy to monitor and to measure as animals got older. Animals do follow a similar pattern as us humans in terms of as they get older, their muscle function declines, they’re not as active. So, we started studying that.

Dr. Kara Fitzgerald (00:15:58) – Fascinating story. Thank you for unpacking all of it. How extraordinary and how exciting. So basically, you had this caloric restriction mimetic, at least in the C. elegans model. That’s amazing because caloric restriction is considered to be really one of the strongest or one of the strongest interventions to date. Those early studies must have been just tremendously exciting. And you were extending, obviously, as you pointed out, they were moving, the worms were moving and they were high functioning. So healthspan and lifespan. Just a really neat, neat finding.

Dr. Chris Rinsch (00:16:39) – Yeah. And I think when we saw it moving into a rodent model, which was so powerful to see the translation from different species going from the C. elegans worms to mice, to see that they were able to, in some of the first studies, we were showing improvement in muscle strength by around 10%, improving in running endurance by over 40%, and just duration that the animals would run.

Dr. Chris Rinsch (00:17:13) – It was very impressive. And when we saw the translation of these findings and the translation of the biology to mammals, we decided that this is something exciting and that we should actually take it to that next level and investigate that in humans.

Dr. Kara Fitzgerald (00:17:33) – Yeah, 100%. I just want to say that first of all, you guys spent a lot of time researching. You founded your company in 2007. I just want to point that out to listeners. You’ll see a pretty lengthy bibliography of careful effort in defining this molecule. The other thing that I wanted to point out, or just ask you, I have a couple of questions. I’ll put them out there. There are other Urolithins and Urolithin A is the one that you’ve found to be most potent. And I know sometimes-

Dr. Kara Fitzgerald (00:18:12) – And also, this was the other piece, so I’ll throw this in there. We’re not all making Urolithin A. I’ve tested myself using your lab and I make some. I was really excited to see that I make some. However, I don’t make a therapeutic amount because I measured after I actually used your product, after I took the Timeline product, and obviously I was moving a whole lot more out after that. Many of us don’t make it. And those of us that do make it, I would say that it’s the rare individual that’s actually making sufficient quantities to exert the influence that you were seeing. So (talk about) other Urolithin compounds and thinking a little bit about our ability to make a therapeutic amount.

Dr. Chris Rinsch (00:19:03) – Yeah sure. There are a number of different variants of Urolithins. As a class they’re called the Urolithins and basically, it’s just slight modifications of the molecule and it’s due to variations in our gut microbiome. There are scientists out there that have just focused on trying to understand what percentage of the population can make different variants and just identifying and describing all those variants. The process that we followed was first of all, we focused on Urolithin A because it was one of the most commonly seen variants found in those people who are actually able to convert the ellagitannins or ellagic acid into Urolithins. And we’ve studied basically four of the Urolithins: this Urolithin A, B, C and D. What we saw was that Urolithin A, in a laboratory setting on cells, was the most potent. The fact that this was the most predominantly observed in the population, we felt that this was the most appropriate one to look at and take a deeper dive.

Dr. Kara Fitzgerald (00:20:37) – Okay, good. Yeah. People have asked me about that. And I know that there is some biological benefit in the other Urolithins, they’ve been studied. But my understanding was that they are less impactful based on your research. So, from the get-go you knew that it seemed like Urolithin A was working its magic in mitochondria specifically. Is that true or was that a kind of a journey? And is that why you started to focus on muscle? And then let’s move over into talking about some of the human research.

Dr. Chris Rinsch (00:21:15) – Yeah, it was a journey, I have to say. When we started, we saw this effect, as I was mentioning, on memory. Then we went to try and understand and dig down a little bit deeper to understand how it was working. We saw this effect on improved mitochondrial function. We then had to take that next leap in terms of effort to understand actually what it was doing to improve mitochondrial function.

Dr. Chris Rinsch (00:21:44) – And this was quite a journey to tease out those mechanisms of action. And this was done in the laboratory of Johan Auwerx, as we were speaking about before. I think what was exciting was the discovery that was made there together. We basically identified that it was stimulating a process called mitophagy. Mitophagy is part of this process, it’s a sort of a subset of a bigger process inside of the cell that’s called autophagy. And what this is, is the cleaning up of cellular waste or garbage and the recycling of it. When we think of mitophagy, we think of the cleaning up of damaged mitochondria and allowing those damaged mitochondria to be broken down, recycled and then healthier mitochondria to be created to maintain this high-functioning mitochondrial level inside of your cells.

Dr. Chris Rinsch (00:22:58) – We’ve been talking here about mitochondria without going into details of what they’re doing and how they’re helping people. And for those who don’t know, mitochondria are basically the power plant inside of our cells. They’re like the little batteries that provide the energy and that energy is used for all of these cellular processes inside the cell and keeping the cell functioning. When your mitochondrial function declines, it’s not really good for your cells, to start with. But then the tissues that are made up of these cells stop functioning as well as they do normally.

Dr. Chris Rinsch (00:23:44) – But going back to mitophagy and that journey, we performed a lot of studies to try and understand this process. It was exciting to see that Urolithin A stimulates this process of mitophagy and this basically allows the mitochondria- When they’re producing energy, they get damaged and it allows the damaged mitochondria to be basically sequestered, recycled, and then you have a lot of healthier mitochondria inside. The results of these studies were published in Nature Medicine, and the reason for that, this was the first compound, a natural one too, very safe, that was shown to actually induce mitophagy in animals, when fed to the animals. That was a pretty exciting finding.

Dr. Kara Fitzgerald (00:24:51) – Really exciting. And going back to the C. elegans studies, it explains healthspan and lifespan because of healthy mitophagy, the ability to recycle- And it’s not just getting rid of the old mitochondria because then we’d run out of mitochondria eventually. But it’s the renewal. It’s the renewal journey. I think it’s incredibly important to underline that and highlight it and exclamation point it. This renewal journey is stimulated by the Urolithin A molecule. That’s why they lived longer and healthier and moved better, and the mice had better memory, and all of these things. This extraordinary, far-reaching effect. The breakdown in mitophagy is a key hallmark of aging. This drives the aging journey forward. Scientists can go in and mess up mitophagy and basically make whatever they’re studying old. So, it’s just this fundamental process that we need to get right.

Dr. Kara Fitzgerald (00:25:55) – It makes sense that you would jump over to looking at muscle, because of course muscle is dense with mitochondria and you said that it was easy to research that organ. But mitochondria are everywhere. It makes sense. The brain is a pretty energy dense organ and it makes sense that you would see benefit there. And I bet some of those early studies when you were exploring, you were seeing some pretty neat stuff mechanistically. Any comments there? Or we can just sort of move into-

Dr. Chris Rinsch (00:26:26) – I think that was really what caused us to transition and start investigating this in humans and that’s been a pretty exciting journey in itself. Going from a mouse to a human is a big step. And as we know, not everything that shows some type of positive effect in mice will translate into humans.

Dr. Kara Fitzgerald (00:26:58) – Probably most fail. Right? But you guys started with something that was consumed, what was considered a healthy food in humans and then work backwards. Yeah.

Dr. Chris Rinsch (00:27:09) – I think the nice thing is we’re talking about something, as you said, healthy. This is coming from the pomegranate and different types of nuts and berries. The world’s population has been consuming this since the dawn of time. In terms of the safety profile, you can’t really ask for a better safety profile than this. And that gives you this comfort, at least, when you go into humans and you test something in humans. And so, we did these first tests and the first tests were really designed to see the translatability, but also to understand potential dosing levels.

Dr. Kara Fitzgerald (00:27:52) – That was my question. Yeah.

Dr. Chris Rinsch (00:27:54) – So yeah. We went through this whole process of testing at different doses, escalating the dose, taking the same approach that even a pharma company would take with a new drug where you would go in and you would carefully titrate that dose to try and identify the one that’s having the right effects and the right benefits.

Dr. Chris Rinsch (00:28:23) – And this is all part of our approach of raising that bar in terms of the level of science to be used on nutritional products. In that first study, it was very interesting because it was a one month-long study and we were looking at doses, escalating the doses, and we found that 500mg taken daily for one month was having an impact on mitochondrial function in the skeletal muscle. We took biopsies before administering the Urolithin A to volunteers, and then again after a month. Then we looked at the gene expression patterns and what we saw was that there was an upregulation of mitochondrial genes. This is clearly linked to an improvement in what they call mitochondrial biogenesis, which is the creation of more mitochondria, a hallmark of healthy mitochondria. We saw other effects in terms of biomarkers that were circulating. It was at this point in identifying those doses that we said, “Okay, now we can start looking at the physiological impact on muscle at these doses and giving that over a longer period of time.”

Dr. Chris Rinsch (00:29:59) – That’s when we started to do some studies that were longer in duration, running studies that were two and four months long, and looking at the impact of Urolithin A after these time periods. One of the first studies that we did was in middle-aged, healthy individuals, but who were sedentary and overweight. We looked after four months of administering Urolithin A at 500mg and also one gram on a daily basis. And this is where we saw something that was very exciting. We saw that we had an improvement in muscle strength by about 10% following this daily administration. And mostly when you think of improving muscle strength, really you need to think about actually doing some type of physical exercise to do that and doing that on a repeated basis. But in this case, we’re looking at individuals who were sedentary and overweight and we saw this improvement.

Dr. Chris Rinsch (00:31:20) That was really a big breakthrough and that caused us to also start to explore that in older populations that we saw after two months. In an older population that was 65 and older, looking at people who had a decrease in mitochondrial function at the onset, we saw an improvement in muscle endurance and the hand muscle, they call this first interosseous muscle, and also in the leg muscle, after a period of two months. That was also a very exciting finding. And essentially, we started to see after a number of different clinical studies, we started seeing one study after another confirming the similar types of benefits from different angles, which was pretty exciting to see. Yeah.

Dr. Kara Fitzgerald (00:32:25) – It seems like you guys just had sort of a ride, just more and more excitement. There must have been some sort of failures or something along the way. We don’t have enough time in this podcast, but it just seems like step after step after step was just sort of expanding how extraordinary this molecule is.

Dr. Chris Rinsch (00:32:46) – Well, we’ve been fortunate that actually the science is really solid. When you look in the literature, since we started publishing, there’s been a number of other labs out there that have published and have explored the benefits of Urolithin A in different animal models, all linked to mitochondrial function.

Dr. Chris Rinsch (00:33:11) – We were talking about it and you were mentioning it earlier, mitochondria are found in basically all of our cells with the exception of the red blood cells. So, if you improve mitochondrial function, you’re going to improve not only your muscle cells, as we were speaking about, we’re also talking about the brain, your cardiac muscle is another muscle. It just-

Dr. Kara Fitzgerald (00:33:37) – Lung function, gastrointestinal function. The enterocytes turn over so rapidly. All of these energy demanding-

Dr. Chris Rinsch (00:33:49) – Yeah, it’s very exciting. We’ve started with muscle, but now we’re expanding into new areas and one of those new areas that we’re looking at is immune health. This is going to be our first study in immune health where we’re looking at individuals who are taking our product for a month and doing a very in-depth characterization of the impact of Urolithin A on immune cells because there’s been some very interesting effects on reversing immune aging in animals. We want to explore that in humans and see how that might be beneficial.

Dr. Kara Fitzgerald (00:34:37) – Can you speak to any specifics, like what kind of cells you’re seeing change?

Dr. Chris Rinsch (00:34:42) – Yeah. I think that in the human studies, we’re in the process of conducting the clinical study so we’ll have data next year to talk about what’s being impacted at the human level. This is work that’s done with collaborators. We see an effect on T memory cells, an improvement there. And then generally an impact on the immune cells themselves and this whole immune aging and reversing this immune aging. But I should caveat all this, it’s all in mice right now. And that’s the reason why we’re currently doing this test in a clinical study in humans. And all of our clinical studies are double-blind, placebo-controlled, randomized studies with the intention of trying to really understand how these work.

Dr. Kara Fitzgerald (00:35:47) – I talked to Anurag (Singh) and you’re partnering with a lot of universities. Your research is being conducted on this molecule all over the world in some really interesting applications. Cardiovascular disease, to your point, I think some neurodegenerative conditions are being investigated, if I’m not mistaken, and these are in humans. Can you speak to some of those partnerships that you’re doing?

Dr. Chris Rinsch (00:36:17) – Sure. I was just mentioning a study that we are doing over in Germany right now on the immune system. And this is something that we’re actually doing with the same professors who have published a study last year on mice in the journal Immunity, where they were showing mechanistically how it was improving immune cells. So, we decided to advance that into humans. And you were speaking about the brain.

Dr. Chris Rinsch (00:36:49) – Brain, of course, is something very interesting to us. Anything that we do in humans is all in healthy people. We’re not looking at neurodegeneration. We’re looking at the impact on healthy people and how it can improve brain function, cognition, etcetera. And this is something that we plan to do in the future. We’re currently not conducting any studies on the brain yet, but it’s part of the long list of different types of benefits that you want to improve and prevent from deteriorating as you get older. That’s what’s really exciting there. I think one of the other areas that we’ve been working on that’s very fascinating is focusing on administering Urolithin A in another way, and that’s also topically. We’ve been all about nutrition and we tend to think about everything that you eat should be improving your health and that way of having an intervention.

Dr. Chris Rinsch (00:38:17) – But topical application is very important for improving your skin health.

Dr. Kara Fitzgerald (00:38:22) – Can you just give me the backstory on that? I’m a huge fan. I use the topical Urolithin A, the Timeline product, every day. I’m a huge fan of it. Did it just make sense to you that a topical application could work? What’s the backstory on that?

Dr. Chris Rinsch (00:38:41) – Several years ago we were thinking about all of the different potential applications. And as we were speaking, mitochondria are in all the different cell types, and I thought it would be interesting if we could put this topically. So, we started exploring that, looking at that on skin cells in vitro to see if we were going to have an impact on skin cells too.

Dr. Chris Rinsch (00:39:14) – And of course we were starting to see that as well. So, we said, “well, let’s take a look and see what type of impact we can have when we apply that on skin”. So, we developed some formulations. You were mentioning that in one of your earlier podcasts that you had our Chief medical officer, Dr. Anurag Singh, and he basically worked on coming up with different types of clinical studies to evaluate the skin cream and show its different benefits, taking into account the types of benefits that we were seeing in cells and humans when administered orally. One of those benefits being an impact on mitochondria health, and the other that we continue to see is this impact on inflammation. So, we started taking a look at both of those.

Dr. Chris Rinsch (00:40:20) – What’s fascinating is that most people, when they think of skin creams, they think of cosmetics. We like to think of our product more as skin health because it’s not just about the cosmetic appearance. Of course, that’s very important, but it’s also about the fundamental skin health and it all starts at the cellular level. As we were just speaking earlier about organ and tissue and that starting at the cellular level, it’s the same thing in the skin. When you can apply it right to your skin, you know right where it’s going. And there’s no mystery there. This way we’ve been able to study things quite effectively and look at the effect on inflammation or post-UV exposure and we see an impact on the reduction of inflammation post UV exposure. We’ve also been able to look at, just generally, the effect on mitochondrial function and skin cells, and then also the impact that has on other pathways inside of the cells, including collagen production, etcetera. Then, of course, the question is do I see anything different when I look in the mirror? And yes, I think that’s one of the exciting things too, is that you do see an impact on your skin.

Dr. Chris Rinsch (00:41:53) – I think one of the notable things is you do see an impact on wrinkles in your skin. Not that I would call this a wrinkle cream, and that’s because it’s acting fundamentally at the cellular level and having that impact on the structure and the cells. Yeah. Yeah.

Dr. Kara Fitzgerald (00:42:20) – And when do you see this? When do you actually see these changes? What kind of turnaround? What kind of time does one need to invest?

Dr. Chris Rinsch (00:42:27) – With the products that we’ve developed we start to see benefits as early as two weeks, which is quite quick with respect to the oral nutrition products, that this is changing your cells and getting them to function differently, and the tissues to function differently. It’s not something that’s overnight. It does take time and regular application.

Dr. Kara Fitzgerald (00:43:01) – It’s exciting. I’ve been pretty happy with the products myself. I was aware of your company for quite a while and just really paying attention to some of the science you were doing. So, it’s really an honor to be connected with you now and just continuing to participate in learning and sharing the science that you’re doing. I have a couple of other fundamental questions. How did you light on the dose? Actually, I have a few questions. I’ll throw them out there. Why are you limiting to healthy populations? Will you move away from that model? Curious about that. Dosing – I think a gram tends to be the most efficacious, correct me if I’m wrong. And then, were there any side effects with any of the amounts of dosing that you experimented with? Because my experience is that it’s incredibly well tolerated.

Dr. Kara Fitzgerald (00:44:05) – I’m a clinician in practice and I prescribe this to my patients. It’s just a non-issue for everyone, even some of the most sensitive of individuals that I have.

Dr. Chris Rinsch (00:44:15) – Yeah. Well, maybe I’ll start with your last question and go backwards. We were talking about the safety level before. Historically people have been taking different types of foods for centuries that administer the precursors, these ellagitannins, that yield Urolithins. This is also a very positive thing in that we see that this is very safe in general. There’s a long history of exposure and there’s a lot of safety. There’s even been publications, not by our company but by other academic scientists, where they’ve looked at women who are consuming pomegranate juice and they found Urolithin A in breast milk. This is something that’s been exposed naturally to the population for as long as we can think.

Dr. Chris Rinsch (00:45:22) – But back to the question of the dosing. We did look at dosing and we’ve looked at different dosing levels. 500mg is a dose that we saw after one month was having a measurable impact on mitochondrial function. 500mg is also improving muscle function after four months. It’s my understanding, and through all the science that we’ve done, that 500mg is really a dose that you can rely on to see a functional impact and to experience that functional impact. It’s true, we have run a few studies at a higher dose, and sometimes we do run studies at higher doses in certain populations. For example, we ran a study looking at elite and sub-elite athletes and we studied that over a period of one month instead of a period of several months. We wanted to understand what impact we would have on this population. This is research that has been presented earlier this year.

Dr. Chris Rinsch (00:46:51) – What we saw was that there was an impact on muscle recovery following these different types of trainings. In this case, runs that were done over a period of three months and the perceived effort, and then different biomarkers that were linked to muscle recovery. There may be situations where a higher dose may offer benefits if taken in a shorter period of time, but we like to recommend the 500mg dose because we’ve studied that now and we’ve seen some very reliable results.

Dr. Kara Fitzgerald (00:47:38) – Good. That’s great to hear. Yeah. And, side effects.

Dr. Chris Rinsch (00:47:43) – Yeah. We haven’t seen any side effects. We’ve had tens of thousands of people who have been taking it as customers. And then we’ve had hundreds of people who have been taking it in the context of very carefully studied clinical trials that have been, as I said, double-blind, placebo-controlled studies where we take a look at all types of panels of biomarkers and in the blood, etcetera, and we have never seen a side effect.

Dr. Kara Fitzgerald (00:48:20) – Yeah. Again, this is a molecule we’ve evolved with. It seems like we evolved with that kind of information to sort of direct molecular traffic.

Dr. Chris Rinsch (00:48:35) – Well, you’re right. It’s an interesting observation that somehow, our intestinal flora has evolved to extract the benefits of these compounds found in the pomegranate and walnuts and other berries and transform them from these large, complex molecules into these simpler structures that have this impact on mitochondria, and that improve mitochondria, and that are absorbed into the body. It’s fascinating to see this evolution that we have and that the microflora has had to be able to extract those benefits. Yeah.

Dr. Kara Fitzgerald (00:49:23) – Yeah. It’s this incredible Gaia hypothesis. This symbiotic interaction of where we came evolutionarily. Yeah. It’s pretty neat.

Dr. Kara Fitzgerald (00:49:37) – So, we knew these were superfoods, these pomegranates, walnuts etcetera. We’ve known these are superfoods. And as you said, we’ve been consuming them across cultures for millennia. And so now, to apply the scientific lens to it, to actually be able to see at this level what’s happening, right down to the microbiome transforming it and what it’s doing systemically, it’s just really – it’s an exciting place to be in. And it certainly is really validating the importance of nutrition. And, you know-
Dr. Chris Rinsch (00:50:10) – It comes back to earlier parts of our discussion. What is that next level of nutrition, this nutrition 2.0? And it’s more than just eating healthy. Eating healthy and eating a Mediterranean diet is very important, but what might be the future of nutrition? We all want to maintain ourselves at our peak throughout our life, and if we can eat foods with the right type of bioactives that have been studied and at the right dose to have a specific benefit, that sort of map to what our health needs are, this is great because it empowers us and we don’t have to wait until we get sick. Because most of the conditions of aging are slow degenerative conditions. That’s why we call them degenerative diseases, whether it’s sarcopenia or other types of diseases that are degenerative in nature with old age. If you can take things earlier and throughout your life that are preventative in nature and help keep your cells functioning at their peak, there’s probably a pretty good chance that you can slow down that process and that you can live a healthier and more fulfilling life as you get older. This goes back to that whole healthspan versus lifespan. You really want to be able to maintain your healthspan at its peak so you can have a great quality life.

Dr. Kara Fitzgerald (00:52:01) – Yeah. Amen to that. Well, Chris, it’s just been a great conversation. This was a lot of fun. I will say, one of my passion areas has been epigenetics and specifically looking at the nutrition influence on the epigenome. And of course, Urolithin A has to be an epinutrient rockstar, in my opinion. We know the precursor molecules have influence on the epigenome, and that is one of the hallmarks of aging. But it’s where a lot of my attention has gone. And I look forward to you guys researching that. I’ll just throw that out there since you’re the co-founder and-

Dr. Chris Rinsch (00:52:44) – Kara, we’re very interested in this topic too. This is something that we do want to take a closer look at in the future and try to understand what the impact in terms of epigenetics is if you’re taking Urolithin A on a regular basis. As you said, there probably will be an impact and we’re interested to understand that.

Dr. Kara Fitzgerald (00:53:09) – Well look forward to hearing what you guys found. I have no doubt it will be exciting and interesting. We’re already seeing research on higher polyphenol diets having broad influence on gene expression via certain epigenetic marks. So, yeah, it’ll be an area I’ll keep bugging you on whenever I have an ear from one of you guys. Thank you so much for joining me, Chris. It was just a pleasure to meet you and to get to pick your brain today and I look forward to meeting you in person one of these days.

Dr. Chris Rinsch (00:53:42) – Sure. Well, thanks so much, Kara, for having me. It’s been a fun discussion and looking forward to seeing you in person one of these days.

Dr. Kara Fitzgerald (00:53:51) – Yes. To be continued. Ciao.

Dr. Chris Rinsch (00:53:54) – Goodbye.

Chris Rinsch is co-founder and President of Amazentis. For more than two decades, he has been an innovator in the life sciences arena. Before founding Amazentis in 2007, Rinsch worked in venture capital investing in pioneering life sciences companies in the nutrition space and in biotechnology developing cell-based therapies at the Swiss biotech company ISOTIS SA, formerly Modex SA. Rinsch has authored original publications in leading scientific journals, including Nature Medicine, Nature Metabolism, Jama Open, Cell Reports Medicine and others, for his research on Urolithin A, mitochondrial health, muscle function, and joint health. He is also an inventor on several internationally filed and granted patents.

Rinsch holds an MBA from INSEAD, France, a PhD in Cell and Molecular Biology from the University of Lausanne, a Master of Science in Biomedical Engineering from U.T. Southwestern Medical Center, and a Bachelor of Science in Engineering from Harvey Mudd College.

Timeline Nutrition

Timeline’s Research Page

Article: Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents

Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults

Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults A Randomized Clinical Trial

The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans

Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population

Topical application of Urolithin A slows intrinsic skin aging and protects from UVB-mediated photodamage: Findings from Randomized Clinical Trials

Johan Auwerx

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