TRANSCRIPT

Dr. Johan Auwerx: It is an exciting time to be a longevity scientist because it is a field which has blossomed.  If there would be a life-span research – I’m not interested in living to 100, and I don’t think there’s any point of doing that. But now it became clear that we can work on this healthspan.

Peter Bowes:  Hello and welcome to the Live Long and Master Aging podcast. I’m Peter Bowes. This is where we explore the science and stories behind human longevity. This episode is brought to you in association with Amazentis, a Swiss life science Company that’s pioneering, cutting-edge, clinically validated cellular nutrition under its Timeline brand. Now, longevity research often starts with experiments involving worms, nematode worms, which are considered to be one of the best models for aging research. C. elegans has a short lifespan, making it easy to work with, and many of its genetic and molecular pathways are the same as in human beings. And that’s why these little worms are so valuable in our understanding of the mechanisms involved with the diseases or conditions of old age like diabetes, frailty and obesity. Well, to talk about that and other aspects of his work, I’m delighted to be joined by Dr. Johan Auwerx, a professor at the École Polytechnique Fédérale in Lausanne, Switzerland – the EPFL – where he directs the Laboratory for Integrated and Systems Physiology. Dr. Auwerx is also an adviser to Amazentis. A longevity researcher, he has much experience in working with worms and other organisms to better understand the aging process and perhaps, just perhaps, how we can slow it down as well. Professor, welcome to the Live Long and Master Aging podcast.

Dr. Johan Auwerx: Hello, nice to meet you.

Peter Bowes: Yeah, very good to meet you. You are in Switzerland. I’m on the west coast of the United States. There’s no chance of you and I are seeing each other in person at the moment or indeed in the near future. So we’re doing this remotely. I’m just curious how you are coping during these troubled times?

Dr. Johan Auwerx: Oh, it has been tough because the lab has the first been shut down and then the lab has been opened again. We’re working with reduced number of people. But that’s you know, that’s we’re doing the best that we can. And actually, this COVID-19 crisis is actually relevant, scientifically for us. Because one of the things with the COVID crisis, when people stay home, they don’t move much. And so there is a quite big impact on muscle mass and muscle loss because people don’t have their regular exercise, they don’t have their regular movement. And especially in countries where confinement was very important, such as Italy or France, where you were not allowed out of home. So people actually lose muscle. They exercise about 40 to 50 percent less than normal. And for a certain part of our population, that could be problematic, especially if you get the disease.

Peter Bowes: So I guess that’s, in a way, mimicking perhaps for younger people what older people actually experience during normal times?

Dr. Johan Auwerx: True, true. Totally true. Because you see normal people, older people, they move less, which is a feature. If you look at a young worm or an old worm, you immediately see the difference because the young worm moves much more. And this is the same with people, you know. Once you’re past 70, many of us will be reduced to going from the couch to the television set and eating lunch and dinner. And so this movement is reduced. And now you see this in younger people because they were confined to their homes. And this has an immediate impact on muscle mass and even muscle function. So they don’t recover. You never recover the muscle which you lose. And even in young people, this can lead to major impact on physical activity.

Peter Bowes: That’s interesting, and it’s maybe a side effect, a long-term side effect, of this disease that clearly a lot of people won’t have thought about. And it does raise many issues, doesn’t it, about how we live our lives during normal times and the importance of strong muscles?

Dr. Johan Auwerx: Yeah. And you start realizing that if you ever have a broken leg or have been immobilized in a cast, you see how long it, you know…usually the cast, being in the cast is not the problem. The problem is that afterwards you have six weeks, three months, six months of revalidation. And that’s where you try to recover the muscle. And every time you lose muscle, you won’t recover fully. And that’s the problem with the aging population, obviously, because they are losing muscle mass to the point they become sarcopenia and eventually frail. And this is the main reason is one of the people don’t realize. But losing mobility is one of the main reasons why you why aging is not good for you, because you lose social contact, you lose mobility, you lose independence. And it’s very important that people keep moving and maintain this capacity to move.

Peter Bowes:  And one of the other aspects of this disease, I think that in terms of highlighting issues with our health. And that is, more generally, underlying conditions. Because I think we know now that those people with with serious diseases, whether it is diabetes or heart disease or other conditions, do seem to be more susceptible to this virus. And it does highlight, doesn’t it, the importance of just generally looking after ourselves, to making sure that we are in the best condition possible to be able to confront a virus like this now?

Dr. Johan Auwerx: Yeah, very true, because one thing which you don’t imagine – most people who die, of COVID, you know, respiration is important. Respiration is muscle function. When you respire, it’s your diaphragm and your muscles of your thorax will keep going. If you get a COVID infection in an older person, which has lost a number, a significant number of its muscle mass, you see, then you’re in worse shape. And there’s also these are comorbidities impact on the disease. So, the good, the better you start off, the better you will go with it.

Peter Bowes: So let’s, before we delve into your science and your work, maybe just talk a little bit about your career. If you could give me a little bit of a potted history as to the kind of work that you’ve been doing it and how you started and what inspired you to do this kind of work.

Dr. Johan Auwerx: So I’m medically trained, so I’m a medical doctor. I’m actually a registered endocrinologist. And I started off by being interested in obesity and metabolic diseases. Did a post-doctoral fellowship in the University of Washington, where I worked in the Department of Medical Genetics and also in the Division of Metabolism and Endocrinology. Then I returned to set up my own lab when I came back in France, and spent actually most of my career working in France for the Institute Pasteur and then later on in the IGBMC and Strasbourg. First as a CNRS researcher, a staff researcher, and later a professor of medicine and biochemistry. Until recently, 12 years ago, not so recent anymore, I decided to move to Switzerland because I got the opportunity to take a superb job at EPFL, the Ecole Polytechnique Federale, which satisfied all my criteria because it was a good environment. Switzerland is very supportive of its researchers. It’s got funding. So I decided to move to Lausanne, and that’s where I’m still.

Peter Bowes:  And moving from being a medical doctor and the disciplines that that involves to more of a researcher, I am often curious as to what the mindset is there that makes a scientist want to do that.

Dr. Johan Auwerx: You know, one of the things was I was A, I was a little bit frustrated. You know, I liked being a medical doctor, but on the long term, it’s like monotonous because as a diabetologist, you see diabetics and it’s become a little bit less challenging every day because you know, the field inside out. So I was wanting where do I contribute to contribute most? Do I contribute most in  treating diabetics and giving them a better life, curbing their symptoms? Or, if I start doing applied research and all our research is like really medically oriented. So our lab is very, very translational. So that means I was seeing my my job as contributing to the medical world is instead of treating, trying to develop and identify new ways to treat metabolic disease, and that’s what has been the focus of my lab since the last 20, 30 years.

Peter Bowes:  And just to explain for our audience, when you say metabolic diseases, that can cover a lot, can’t it?

Dr. Johan Auwerx: Yeah, it ecan. And this is also quite interesting. When I was starting my career, metabolic diseases with diabetes and hyperlipidemia – high lipid levels in the blood, high cholesterol. And now you see that this metabolism has become so essential in many aspects of our daily thinking about medicine and about biology, it’s contributing to everything. Now we have neuro-metabolism, immuno-metabolism, cancer metabolism. And the real hard-core metabolism where I started working on, has now become almost, not a peripheral field, but just like one of many fields where metabolism has an impact. And I would say no, many of these fields where that where you see that actually the disease, the underlying causes are really metabolic. Like, for instance, why does a cancer cell grow better? Because it has a better way to exploit the metabolites around it, the nutrients has a better way to harvesting the energy, so it can predominate in the surrounding normal cells. And the same with why do we get Alzheimer’s disease? Probably because our energy supply to our brain cells becomes limiting at a certain time, and that predisposes you to all these in cells in Alzheimer’s, Parkinson’s disease, all have a very big anchorage and in metabolic dysfunction.

Peter Bowes: And much of your work has been based on understanding how our metabolisms are controlled. And that involves a lot. It involves diet and exercise and hormones. It’s a labyrinth, isn’t it? It’s a complex equation.

Dr. Johan Auwerx: Yeah. This is a complex equation, and hence also the name from my lab – Systems physiology, – because I think physiology is controlled by many things. First of all, our genes. You know, physiology is different in everyone because your genetic makeup is different. But, also how we interact with the environment, what you eat, how you exercise, how your lifestyle is. Are you stress person or not? This is very complex mixture. And so to identify or study that in humans is very difficult. That was also one of the reasons why I wanted to go to research, because no human is the same, no human is eating the same, is exercising the same, is having the same stress levels. And different disease models, in animal models, you can much better mimic. You know, I can control my mouse that they eat exactly the same thing every day. They are exposed to the same light, dark cycle, the same stress level. That makes then that you accentuate and it’s easier to find new things. Because they’re not confounded by all these other factors which influence the outcome, the phenotypes.

Peter Bowes: And you say we are all different, and that’s increasingly obvious to us. I’m curious in terms of your work, what do you better understand now that perhaps can help us, help people understand how we react in different ways to, and as probably the most common one, is how we react in different ways to diets and how some diets fail, how some are successful. We respond positively to some food combinations and not to others.

Dr. Johan Auwerx: Yeah, this is in a large extent, so the diet is an environmental factor and your diet will be different than my diet. So then we have the second very important factor is our gut microbiome, which digests and helps us digest, which is widely different between people or different nations or where you live, whether you eat a lot of seafood, etc. Now we have our own obviously our own genetic makeup, which which is also very important, how you react to a thing. And it’s not only your genetic makeup, it’s also our time in, I would say, or time in development. And I’m giving you a very easy example. If you are young and you become very quickly fat, like, for instance, a young boy who gets weight on, that’s extremely bad. If you’re at the end stage of your life, let’s say you’re 88 and you’re fat, you’re going to be more protected. So the same thing, gaining weight while being young is a risk factor, whereas a positive factor towards the end stages of your life. And so this makes it very complicated because there’s another dimension that a longitudinal dimension, which is often neglected in many studies. And this you also only can almost mimic in animal models. And in humans it’s very difficult to do these long term longitudinal studies.

Peter Bowes:  And just talking about fat there, that that is because fat has many, many functions. And clearly those functions, as you say, according to our age, might vary in their importance according to the stage of life that we’re in. And those side effects of being fat can clearly be very negative. And I think that’s the one that most people understand and get, that generally being overweight and especially tummy fat, stomach fat, is not good for us.

Dr. Johan Auwerx: Yeah, no. And like I say. So that’s why dietary advice can almost not be universal. Because, you see, when I’m counseling this young kid who becomes obese and you say curb your calories. When I go and tell this older person, who’s barely having enough energy to keep his muscle and his system functioning, I should say, take more protein, take more fat, take more glucose. And this is what often is neglected. So you have no universal dietary advice. And so the whole field of the microbiome complicates things even more for, because we ignore largely our microbiome. I don’t know, there’s only no studies coming out. Like, for instance, there is this interesting food stuff we’re working on, which is called Nori Nori is staple in Japanese food. It’s the seaweed, it’s the green thing around your sushi. You know, this is very healthy, but only if you’re Japanese because you have eaten so much of the seafood that you have adapted the bacteria which can digest it. Whereas if I or you would eat it, we wouldn’t have the same health benefits.

Peter Bowes: It’s interesting, a friend of mine, a scientists in this country, in the United States, has said to me in the past that, look, he you said you come from Europe. I was born in northeast England. That kind of diet that people eat in England is what my body is used to. Therefore, changing to and adapting to a new diet won’t necessarily be good for me and good for my body.

Dr. Johan Auwerx: Yeah. When I was still a medical resident, at the University of Washington, I spent time in Seattle. There was this big study where they were looking at Japanese living in Japan, Japanese living in Hawaii and Japanese living in the continental U.S. And you saw a clear gradient that because they were more and more exposed to the Western diet, high fat content, and it’s not sure that every Japanese will react the same way. There are some probably who deal well with it and some not.

Peter Bowes: And the fact that and as you’ve explained, there is no one diet that we can say is going to be good for everyone. And we’ve got a growing understanding of that. And of course, it does explain why there’s a tremendous amount of confusion and frustration amongst people that they just don’t understand what is going to be the best course of action for themselves. And it poses a challenge, I assume, for people like you and for me to explain the science and where we are and not to advise people, but just to to share those ideas in a way that they make sense to people, that people can then try to evaluate for themselves how to conduct their lives.

Dr. Johan Auwerx: Yeah, no, no. And a good example was even the medical profession is sometimes not well informed. Advice where, you know, we I grew up in a time when eating fat was bad. And you need to go on a carb diet. If you grow up now, you would hear the opposite. That’s because science evolves. And, you know, what we knew at that time was linked and focused on one disease type. And so things change over course as we learn more.

Peter Bowes: Well, I want to talk in some more detail now about worms, nematode worms. I mentioned your research with worms in the introduction as so many longevity scientists do because they are such a good model, as I explained briefly. But maybe you can explain it in better terms, in more detailed terms, why you work with these tiny organisms first

Dr. Johan Auwerx: First reason is, A, they’re genomically very similar. So they have the same genes, mainly the same genes, as we do as the first reason. B, they’re very easy to modify genetically. So if you want to knock out or introduce an overexpression of a gene, it takes days or not even hours or certain circumstances. If you use our RNAi, which at the most, takes like months. Third reason is that they are an excellent model for longevity because researchers are impatient as anyone. So if you would do a study, a longevity study in the mouse, it takes three years. If you do it in humans, you can not do it. You need four generations. If you do in a worm, you can do it in a month. So I think the worm is an excellent model, you need to know its capacity, but also its limitations. So certain things are very well mimicked in the worm longevity. Mitochondria mobility is very well mimicked. But I would say if I were, if I’m, I’m an endocrinologist. I would be interested in and research in communications between organs, where you require hormones in circulation, then the worm would be a poor model. Like, for instance, we’re working on some genes in the heart. The worm doesn’t have a heart, so you cannot mimic. So you need to know the benefits and the limitations. And most of our work is related to aging and muscle function, and they’re excellent models.

Peter Bowes: And, is it easy in terms of management in the laboratory to work with these creatures? I would assume it must be, since they’re so they are very tiny.

Dr. Johan Auwerx: You need the scope for it. It’s actually very easy, believe it or not. Before I came to Lausanne, I never saw a C. elegan, so I hired a postdoc with the expertise. That’s about 12 years ago. And we set it up and now my entire lab is working it. So it’s very low cost. So it’s, compared to a mouse, the experiment is very fast. It’s low cost. Another advantage, and that’s where we benefited, we got a few grants for ….because they’re invertebrates. So you’re not confronted on all the animal authorizations. So, so it makes life in one way easier because you don’t have the ethical concerns which are coming with bigger animals.

Peter Bowes: That is very interesting. And to the point that you made just a few moments ago about longevity research more generally. That by its very nature, longevity, it is a long time. And ultimately all of your research, you will want it to apply to and be relevant in human beings. So I guess at some point those studies have to progress towards the human trials, and that’s where things are going to start to slow down.

Dr. Johan Auwerx: Yeah, yeah, no, no. They will, that’s very good, so we usually use worms. And then we if we make an observation in the worm, then we translate into mammalian cells because there is this phenomenon of senescent cells become older also. And obviously we quite often translate into the mouse. We have a lot of genetically modified mice, models, mouse models. But what we now do often is jump from the worms straight to the human, because with the genetics so powerful now we have all these large cohort studies. One famous one is the UK Biobank, where people collected more than 500,000 British people and its whole genome sequencing. They’re now in the process of doing whole genome sequencing. They sort of genotype them and they collect that phenotypes. So if I know a gene in the worm, which is variant, which causes a phenotype, I can almost bio-informatically, by using these large databases, these cohorts, confirm what I find in a worm. I wouldn’t say, and we have just recently finished a study where we were looking at a new gene involved in ceramide synthesis ceramides is type of lipid, kind of weird lipid, which is the basis of wax. And so we found a gene by worm studies. But when we looked in the UK Biobank, we saw that mutations in this gene were associated with loss of motility, the same as in a worm, or our worm didn’t move. The humans have like less grip strength like this exercise capacity. So that was a perfect example where you skip all the mouse and monkey and non-human primates research and go straight into humans.

Peter Bowes: And if you if we just step back and think about what you’ve just said, the correlation between what is happening to a nematode worm, this tiny organism, and what can happen potentially in a human being, it’s quite staggering, isn’t it?

Dr. Johan Auwerx: It’s fascinating. It’s that, you know, but the same you know, the same basic principles of biology are maintained there. What what do what why are we humans here? We’re here to reproduce, we are here to feed ourselves. We you know, all these basic functions are conserved. If you go into more elaborate functions, you would even be astonished how much is conserved like brain function. A worm has about a little bit over nine hundred cells – 300 of them are neurons. So, in proportion, a worm has even more brains than humans or brain cells than humans.

Peter Bowes: Interesting. Some of your especially fascinating research involves extending the lifespan of C. Elegans, the nematode worm. Can you just talk me through that?

Dr. Johan Auwerx: So what we generally do is we look at worms and see how their lifespan is affected. And then we have several ways of trying to improve or increase lifespan, and that could be by genetically mutating a number of genes in the worm. But it could also be by giving them compounds. We give them certain food substances or we can give them certain drugs and then we can see whether they prolong the lifespan of the worm. And then due to the easy genetics, we can also very easily identify the genes which you hit with a compound. Because we can take you know, you have all this possibility to RNAi gene knockdown, lots of function studies, which gives you actually the mechanism very, very fast. And so we’re now like we are we’re starting to gear up even do drug screening in the worm, which is quite different than what usually you do when a drug screening. A drug screen, you throw a compound on an enzyme, a protein, and then you see whether it activates or inhibits it. And then the second step is you throw it on a cell and you see where it does the same thing in a cell. And the third thing is you go to an animal model. If you do it in a worm, you can skip step one and two, because you if you know the target, you do it immediately in a worm. And what gives what more information you get out of this is that you also know where the compound is toxic because if will worm doesn’t like the drug, it will crawl off the parade. You will see that they die or you see that they suffer. So in one way, a model for drug discovery and at the same time a model of toxicology in vivo.

Peter Bowes:  And my conversation with Professor Auwerx continues in a moment. You’re listening to the Live Long and Master Aging podcast. This episode is brought to you in association with Amazentis, a Swiss life science company that’s pioneering, cutting-edge, clinically-validated cellular nutrition under its Timeline brand. And we’re going to talk about Timeline’s product Mitopure, which is highly pure form of urolithin A, a compound some of us are able to produce in our guts from ellagitannins compounds that we get from fruits like pomegranates, select berries and nuts. It’s a complex sequence of events and we’re about to hear why it matters to all of us as we grow older.

Dr. Johan Auwerx: It started off by working on pomegranate extracts, actually, which wasn’t yet purified Urolithin A. And so we saw that these pomegranate extracts were beneficial in worms. We also saw that they had beneficial effects on cells. And I can go in details about what the beneficial effects were. And so by then looking at the ingredients in pomegranate extract, we came to this Urolithin A, and then we could work with a single compound. We were working to make sure we  could reproduce the same beneficial effects of the pomegranate. And then we knew that we had an active compound, and that compound is actually increasing the lifespan of the worm. But more important for me than increasing the lifespan is increasing the health span. And let me explain to you what health-span means. I’m not very interested in living until 90 years and spending the last 20 years of my life and going from the television to the fridge and eating, etc. So I’m interested in staying vigorous, active, outgoing, socially active for the latter part of my life. And that’s what healthspan is. So we need to keep the people active. That’s beneficial just until you really are at the edge that you cannot live further. And this we evaluate in the worm and this was striking, because the thing is that worms fed on Urolithin look youthfully. They move like young worm. You know, an old wor, iff you look at a worm plate, you need to poke it with a little stick and then it moves its head. And that’s what all it does. It moves its head and feeds on the bacteria there. If you have a vigorous young worm, it will move like it, crawl on the plate, it explores the things. And so this is what you really want. You don’t want them to make longer and just move their head. You want them to be agile, to be healthy. And that’s what we saw with this Urolithin that we really kept there. And they are very, very good shape.

Peter Bowes: And I’m glad you brought up healthspan before I did, because I normally drop that into the conversation very quickly because it is something – and you describe it beautifully – it is something that I feel very passionately about. So passionately, that I called my company Healthspan Media, which is producing this podcast, because it is a concept that is so important, I think, to all of us for exactly those reasons that we want to live long and be healthy and perhaps have that period of time that ends in death to be very short. Compressed morbidity, as people often talk about. And I think the challenge, again, for scientists and media people as well, is to explain that concept, because once you get it, is easy to appreciate, isn’t it?

Dr. Johan Auwerx: And I’m often asked this question, do you think it’s ethical to work on lifespan? Because people you see with all the increasing health cost, people are concerned. You know, why would we keep people longer in life if we have already a huge burden on them? And then the right answer is we don’t want to keep people, uh, longer in life. We want them to be healthy and exit when they are, you know, when the system has reached its limits. And that’s what healthspan is, you know, you just just push the borders and you make people active and moving well for a long time.

Peter Bowes: And in terms of of healthspan, one issue that fascinates me is the fact that we actually understand a lot of the science already and we know about those issues and those chronic diseases of old age. And, generally, and I’m talking in general terms, how to either prevent those diseases or significantly slow down their progress by adopting different lifestyles that involve a better diet. And certainly, as far as I’m concerned, that is a diet that has more fruits and vegetables and less red meat. Others disagree with that, and a lifestyle that includes a lot of exercise. They’re very simple, and kind of old fashioned, but they work.

Dr. Johan Auwerx: Yeah, and they are very important for the simple reason that a drug will not affect healthspan. You know, we have already too much medical expenses. So we need to change the quality of life by simple measures which everyone can afford, which society can afford. So let’s suppose I find a drug which costs like ten dollars a day, which would extend lifespan that would economically be unsustainable. If you will find a food or a lifestyle change which does the same, that would make a major impact. And that, I think, is also an important realization for for people interested in this area. The most changes have to come from very inexpensive things which are accessible to all, because otherwise we’re not going to reduce the burden of long life on the society.

Peter Bowes: But at the same time, do you accept and this is where my understanding and my beliefs have evolved over time, that some supplementation is good. And I often say it’s an insurance policy because we don’t live perfect lives in terms of exercise and diet, and therefore some supplementation. And we’re coming back to Urolithin A , a pure form might appeal, which is the pure form of Urolithin A, which we’ve talked a lot about. And I know your research is very relevant to this, that that is a form of supplementation that could be beneficial to us?

Dr. Johan Auwerx: Yes, yes. And this is still, I would consider in the category which is not expensive because this is like buying a yogurt, eating some additional food or fruit. So it’s in this price category. So there, I think, you know, you’re hitting the right spot. And we know start knowing that all through the last twenty years, who worked on a lot of natural products with your so-called grass, which mean they’re non-toxic, identified active components in them, like Urolithin. And another one is a component where we were going to get nicotinamide riboside. And we see that they have enormous benefits. They have benefits as strong as drugs. They’re cheap, they’re easily accessible, so this goes into that category where you can help and improve public health.

Peter Bowes: I’m interested with your Urolithin A, in terms of the beneficial effects, in terms of endurance. And I know you’ve done experimentation with mice in this respect.

Dr. Johan Auwerx: Yeah, we have done first experimentation in the worms. Because we can actually test endurance in the worm. You can have the worm move in liquid. It’s like a worm in a swimming pool and you have the worm like one-minute swim against the current. If you do that three, four times, then you can see whether the worm trains well. If you do that experiment with a worm on Urolithin, it becomes a super swimmer. And in mice, you can actually put them on endurance running mice are natural runners. Regular mice runs kilometers a night. So they’re active at night. So they run. If you give them a running wheel, they run. Some mice run five kilometres a night. If you do that with Urolithin, you see that they really are improving performance. And you can also see that endurance, which they have if you if you really run them until exhaustion because on the running wheel, that’s not until exhaustion, because they they like to run. That’s a spontaneous training. If you make them run until exhaustion, you see that they significantly, by 30, 40 percent, extend the capacity that they can run.

Peter Bowes: And is the evidence that this extends to human beings?

Dr. Johan Auwerx: There is evidence because this is not you know, I’m involved Amazentis as we said before. So they have been starting doing studies in humans. And all the indicators go that that really also have beneficial effects on exercise capacity in humans. This has not been tested in athletes. This has been tested on older people. And you see that there are significant defects. I’m not sure whether any supplement. You know, this is an interesting question. And it’s interesting, domain. Whether, let’s say you have a top athlete, whether by providing a supplement, you could make them better. I’m not sure about Urolithin there. But I’m sure about a couch potato. You can make him much better, with Urolithin.

Peter Bowes:  If our endurance is significantly improved, apart from the fact that we all want to be able to do more and physically do more. Runners, joggers want to be able to run faster. And if you are lifting weights, you want to be able to increase your performance. But then just applying it to ordinary people. You want to be able to walk that extra mile to work if you need to, walk to school or to come home from the supermarket carrying your shopping and not be out of breath when you get there. Very basic advantages. But in addition to all of that, the very fact that it is encouraging us if you like to exercise more because it is easier, the knock-on effect of greater physical activity is going to help us in other ways as well.

Dr. Johan Auwerx: Yeah. And, you know, if you are more active you’re better active, your metabolism becomes better, you’re going to burn more calories. You’re probably going to lose weight and keep your weight easier. So you’re going to feel better. We know that Alzheimer’s, the best prevention for Alzheimer’s is daily exercise. We don’t understand why it is yet. But you see, it will have an impact. Frailty is, like I say, a crucial aspect of aging. It’s like you can not move. You know, aging is you need to be able to think. You need to be able to have your sensory systems to work. You need to have your motor system to work. The motor system is often the thing which degrades the fastest. And if Urolithin could help your motor system active, all the rest will follow. You see, you got to have a better cognitive function, because exercise is preventing neurodegenerative diseases is preventing, like loss in cognition. So you will have a massive impact, not only on the muscle.

Peter Bowes:  And just to use the word frailty there, I think I used it a little bit earlier. Just to dive a little deeper into what frailty means. I think the common understanding is a frail old person who is perhaps a little stooped and perhaps prone to to falling over. But it’s more than that, isn’t it, in terms of how our body is functioning?

Dr. Johan Auwerx: It’s much more than that. So Sarcopenia is lots of muscle mass frailty. It’s really, you lose independence. It’s like you say. You’re prone to all these diseases you’re prone to, you’re not moving anymore. Like you say, one of the main reasons why people break their femurs and actually become bedridden is because they’re frail, they’re not stable. When they move, they cannot move as they want. Major reason for falls and stability. So it’s like really a very bad. You know, frailty is like I can’t call it a syndrome, but it is a very, very bad sign if you become frail when you’re old. If you’re an older person, I was saying to you that you actually really want to keep the weight. Frailty is also associated with muscle loss and usually weight loss. So that’s why also in these older people, we need to give good dietary advice that we keep their energy resources up.

Peter Bowes: Crucially important for all of us, especially as we’re living in a world now where there are more people over the age of 65 than there are under 5 for the first time. And we’re all, clearly, moving in that direction, which just highlights the importance of taking those, as far as those proactive measures as we are younger and younger can be 20 or 30 or it can be 50 or 60. That there’s no age at which we can’t do anything to improve ourselves as we get older.

Dr. Johan Auwerx: True. Yes. You can start with these things. You know, you just you need to adapt to a healthy lifespan as soon as possible. And if you do it at 20, you will have more benefit. And if you do it at 40 or if you do it at 60. And these small measures like dietary supplements, like exercising, lifestyle changes, will do miracles in the long run.

Peter Bowes: So, in a similar vein, then, as you look forward in your life, and this is one of my favorite questions with people that I interview, I’m curious, based on your research and the knowledge that you’ve gleaned over the years, how do you apply it to your own life with your longevity in mind?

Dr. Johan Auwerx: So if would apply it to my life. First thing is, I exercise every day, so not vigorous exercise. I’m not an exercise freak, but I walk and I swim as much as possible. Second, I try to reduce stress because I think that’s a hidden factor or society has become too stressful, like all our devices. You want to answer computers all the time, your emails. You need to be able to disconnect – sleep well. This is part of this lifestyle changes. I would say that the second thing and the third thing is you need to eat healthy. And there I try to do you know, I adapt my diet to the situation. I’m now eating differently than when I was 20. I’m probably eating no more than when I was 20, because I know again in this crucial age range where I need probably the more energy supply and I try to supplement my diet with healthy things. You know, like, for instance, taking nicotinamide riboside, Urolithin supplements at certain times. I do that. And I do that, I adapt that to my needs. I feel when I need to be boosted – when, you see it’s like natural, you’re not overdoing it. There’s people who take like 10 supplements. I would never do that.

Peter Bowes: I was interested in what you raised a question in my mind. You mentioned NAD and you were talking about, Urolithin A. You see no issue – and clearly, both are focused on mitochondria, mitochondrial health, ultimately on muscle strength. You see no issues in taking at least those two types of supplementation?

Dr. Johan Auwerx: No, no. I think because they have very different mechanism of action in one way, like. Urolithin has a very particular mechanism which is geared towards aging. And, you know, your mitochondria, when you age, they suffer. They accumulate damage, reactive oxygen species which are damaging. And so what Urolithin does, it clears up your damaged mitochondria and basically then afterwards regenerates your new mitochondria, which are not damaged. So it’s purging the old ones and letting the new and healthy ones survive.

Peter Bowes: This is mitophagy.

Dr. Johan Auwerx: Yeah. Yeah, mitophagy. Correct.

Dr. Johan Auwerx: Nicotinamide riboside or Nicotinamide mononucleotide any booster’s, they just boost number of mitochondria. They they don’t have this major effect on clearing the damaged mitochondria. So they do it ignorant, what’s the starting point? So actually, you could envision a team where you would say, I first take a cycle of Urolithin. I clear up my bat once and then I supplement within NR and then I go off the NR and then you’re fine. So we don’t know yet. And humans also the exact dose, the exact way of administration. Do you need to take it continuously? Do you need to take pulses, clear out, wait a little bit? So these are all things which we’re going to have to find out by research, and I don’t have to answer for that. But it’s fascinating that all these possibilities exist. This is what we call mitochondrial medicine. This was a field which wasn’t existing like ten years ago. That we know of all these tools to fine tune our mitochondria.

Peter Bowes: And as you say, there are still questions outstanding. It is ongoing science. I’m interested to know where you stand on giving something a go and trying it without fully understanding it? So, without fully understanding the long-term implications of a certain supplementation or indeed without fully understanding the absolute correct dose? There is a point at which you say this is safe and I’m going to try it.

Dr. Johan Auwerx: Yeah, so so the main reason why I think it’s safe is because it’s a food. It’s a product which we have been exposed to all over our life. If you go to Turkey or the Middle East, people drink pomegranate juice all the time. So it is a compound which has been taken by humans safely for a long time. What we don’t know is like I you know, what we don’t know is whether it in all conditions is safe, whether it’s an all disease situation is safe. And that’s what our clinical trials are for. Because that’s what clinical trials are designed for. You know, you test it now in a particular configuration like Sarcopenia, and then you will see, yes, it’s safe in sarcopenia. That doesn’t mean that we can then conclude yet we can give it for any other disease that will require another trial. But I feel okay about these supplements, which we we’re mentioning about because they have been, people have been exposed to them so long. And, you know, there’s definitely health benefits of people eating a Mediterranean diet who drink their pomegranate juice every day. And, you know, this makes it easier. You don’t have to pressure pomegranate, you can take just a supplement.

Peter Bowes: Would you say, you know, I detect it in your tone and your voice. It’s an exciting time to be a longevity scientist?

Dr. Johan Auwerx: It is an exciting time to be a longevity scientist because it is a field which has blossomed. It’s, you know, 20 years ago, people were actually not so, you know. The longevity science was seen with like a kind of marginal view in science because people were saying this is all a little bit so and so. And I think, now we know much more mechanism and we know the field has also changed from lifespan to healthspan, which is a big difference. You see, if there would be a lifespan research, I’m not interested in living to 100 and I don’t think there’s any point of doing that. But now it became clear that we can work on this healthspan. And that’s where I’m excited about.

Dr. Johan Auwerx: And as you look forward to whatever your great age is, whether it is 80 or 90 or 95 or maybe even 100, who knows? What is your, what’s the main driving force for living long and being healthy? In other words, pursuing a good healthspan. A lot of people ask, leaving aside lifespan, but even just healthspan, what is your main motivation as a man living in this world, sometimes struggling as we always do, just getting through the day. But what is your main motivation to live as long and healthy as you can?

Dr. Johan Auwerx: Because I think the main motivation is social interactions, interacting with your family. You enjoy things, what you’re doing. If that stops, then probably it’s not so healthy. So I think that’s the main motivation. You need to feel useful for the society. And I think if you’re healthy, you’re useful for the society. If you live like, societies where people live long are usually societies where people are very strongly clustered, like in Okinawa, in Japan or in certain islands in the Mediterranean. You see that it’s where the grandparents care for the children and grandchildren. So, where the grandparents transmit their dietary uses and habits to the younger generation. It’s where the grandparents, you know, which is also striking most of the societies where people live long are mountainous because they are exercising more. You know, if you need to walk like 15 flights because you need to climb the hill every day, you’re exercising. So this is like I think that’s why I think you want to live longer. Because you want to maintain that. If that’s not part of your life. You my question, do I want to live longer? And this is also I had one discussion with a person from a health insurance company. If you see all the people going into retirement homes or senior communities, they do much worse than people who stay anchored in their local family. In their small cities where they see their grandchildren. You saw this with COVID crisis. One of the big problems was the grandchildren couldn’t see the grandparents. You know, I think it brings us back to COVID. You see this is what keeps the cycle alive. Why you want to live longer.

Peter Bowes: You’re absolutely right. COVID does highlight so many of these crucial issues in our lives. And the exciting, horrible though it is, I think one of the exciting aspects of this is that it has raised these issues in our minds. And I think longer term, we can benefit from some of the things that we’ve learned.

Dr. Johan Auwerx: Certainly. Certainly. And like I say, also the fact that we move now less, that there’s less like dependence on airplanes, etc. There’s also a thing where we drastically work on from with COVID. We saw what we learned there. And I think this is one thing which you learned that was a big thing that the grandchildren and the grandparents couldn’t get together. So why do you want to live healthier and longer? Because you want that family ties to be happy and that will make you better.

Peter Bowes: Ok, Auwerx, this has been a fascinating conversation. I really enjoyed it. Thank you very much, indeed.

Dr. Johan Auwerx: Thank you

Peter Bowes: And if you’d like to find out more about Johan’s work, I’ll put some links into the show notes for this episode. You’ll find them at the Live Long and Master aging website. The LLAMA podcast dot com – LLAMApodcast.com. The LLAMA podcast is a Healthspan media production. This episode was brought to you in association with Amazentis, a Swiss life science company which is pioneering, cutting-edge, clinically-validated cellular nutrition under its Timeline brand. And if you enjoy what we do, you can rate and review us at Apple podcast. It’s always good to know what you think about what we’re doing and perhaps what you’d like us to cover in the future. You can follow us in social media at LLAMA Podcast and direct message me at Peter Bowes. Many thanks for listening.

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