GLP-1s, should we all be taking them?

(upbeat music) - Welcome to longevity technology unlocked where we crack open the science that could help you live healthier and longer. And sometimes even make you think twice about what's in your longevity stack. I'm Phil Newman. - And I'm Dr. Nina Patrick. And Phil, speaking of what's in people's longevity stacks. If you told me a few years ago that the busiest thing in aging wasn't just a new supplement or reprogramming cells, but GLP1 agonists, I'd have been kind of surprised. - Yeah, well, of course, you know, we've seen as empathic and wagovy and they're kind totally go mainstream. They're so popular now that pharmacies can't keep up. And we're seeing all of these new businesses emerging that are getting funded so quickly. Frankly, I'm concerned that they themselves are over leveraged. - And they probably are. We're seeing people micro-dosing GLP1s, taking them off label. So that's why we're diving into the question today. GLP1s, should we all be taking them? - Great question. So we're thrilled to have two global authorities joining us today. First doctor Eric Viden, he's the CEO of the Buckhead's Tuts at worldly organization in the biology of aging. - And Dr. Jens Jules Holst, professor of medical physiology and the department of biomedical sciences at the University of Copenhagen. And he first discovered and described the GLP1 hormone. So gentlemen, before we impact the science, can you tell us a little bit about yourselves? Jens, let's start with you. - So I'm a professor at the University of Copenhagen. I'm a doctor. I think this is a little bit important for what I've been doing throughout all these years. I've been interested in diabetes and obesity for a long time, although I started in gastroenterology. I'm still there a little bit all the time. You know, my main interest is gut hormone and pancreatic hormones. So I guess this reflects my original occupation in that direction. So that's what I've been going on. But you know, I'm a university teacher and researcher. That's it. - Great, Jens, thank you. And of course Eric, we see each other on the circuit. I can't remember the last event that we were co-located at, but it'd be great to learn a little bit more about yourself as well. - Well, first of all, thanks for having me. It's an honor to be here with Jens to talk about GLP agonism. A little intimidated by this, but it's great that it's great to be here with you guys. I'm also a doctor and you know, what you might not know is actually I started in diabetes and endocrinology and training in internal medicine. And did my postdoc at Justin Clinics studying insulin signaling with Ron Can. And eventually, you know, my career went into all kinds of directions, but there's always been sort of a first love of metabolism and metabolic disease. And so right now I'm the leader of the Buck Institute for research on aging. I also run a lab which focuses at the interface between epigenetics, metabolism and immunity. - Yeah, and Eric, of course, you know, there's a lot going on at the buck and we're, I'm sure we'll talk about that work as we go along. But I guess there's a little bit of a get to know you. I've got a very important question I'd like to ask you. Listen to that with you Jens. Jens, what's the best party you've ever been to? - I fit to several parts because I must say. - Great. - But one of the most amazing ones was really when we received the breakthrough price in Los Angeles a year ago or something like that. That was really quite overwhelming. It was a very un-European and undanish, but a huge experience and it was a lot of fun, I must say, so it was really overwhelming. - And Eric, what about you? What's the best party you've been to? - Oh boy. (laughs) It's really, I'm not sure you want to hear all of it, but we do come on Eric. - I've been to many parties, but I love live music for me. That's really one of my other passions and besides science and aging research. I just, I never miss a chance to go listen to live music. One of the, and in particular, you know, blues guitar. And so I've been to many concerts. One of the things that I remember as amazing was a Crossroads Festival that Eric Clapton has every three or four years that was in Dallas and took my son there and we spent three days just surrounded by the best jazz blues and rock musicians in the world. - Well, that sounds great. Well, good, so get to know you all a little bit better. I won't tell you about my favorite party. I think we need to take that one offline, but let's talk a little bit about GLP ones. And I guess, you know, we hear a lot about the subjects, but for listeners, Yen's new to this subject or maybe a little opaque about the subject, what are GLP ones I'm gonna send? You know, why do we see that they're starting to make the headlines in the longevity space? - So GLP one is a hormone. It's a hormone produced in the gut. And there it's secreted when you eat. And it functions to reduce appetite because it's located pretty far down in the small intestine. So it signals abundance, you know, there's enough food there. And so stop eating and it also slows down gastro-gumpting and things like that, to put things into balance. So that's the real function of it. And it also inhibits appetite, I said, and this was discovered quite early, but it took a long time before it was possible to use this in a pharmacological tool. And that was because it also has side effects. So it took it a long development, and also it has broken down extremely rapidly in the body. So you had to solve those problems, you know, how to avoid the side effects and how to prepare the hormone in a way that it could be given in, you know, in a reasonable dosing first one-s a day and then once a week. And so all of these steps had to be kind of overcome. But it's using the body's own mechanism. That is a regulation of food intake and insulin secretion, by the way. But it's actually secondary to assumptions. And I guess there's another question that I'd like to ask you just on the back of that. You know, we've seen the most recently approved drugs hidden in the market, but these drugs have been in humans for quite a long time now, right? Yeah, I mean, it was 2005 was the first, was the year of the first approved drug for this. And this was for diabetes use, yeah. So 20 or 20 years, this year. And Eric, how do these GLP1 agonists fit into the broader picture of lifespan, health, span and aging? It's that's a key question because as your audience will appreciate, they are, you know, I'll just, maybe just highlight some differences in the aging field in terms of what is a longevity drug because that there's some disagreement at that level there. I take the stands that anything that increases human longevity even if you start from a, from a obesity, for example, is going to be a prolonged, longevity drug. So anything that will increase lifespan and health span in the population at a global level will be beneficial and will increase people's lifespan. And so in this respect, simply having a new drug that will tackle the enormous obesity epidemic is going to be really important. We know obesity right now is driving a decrease in life expectancy in the US. And I predict this will happen in Europe as the obesity crisis is not really a uniquely American process. We see it across the world. So in this respect, just suppressing obesity is going to be a really key, key tool to increase human longevity. There's a second group of people in the longevity field who take a more pure way of longevity by which, you know, a molecule has to be increasing longevity in a somewhat normal individual. And this is where, this is the role of GLP1 resupti-agronis is a little less clear. There's growing evidence that there seems to be, at least in some model systems, a fact of these molecules that go beyond, that are independent of weight loss. And I think this is really where it becomes very interesting. I would argue that most of us are somewhat overweight, even though we might not be considered overweight. And so, you know, I've experimented myself with GLP1 eigenes just to feel, OK, what is it like? And I lost five pounds, five to seven pounds. So, and I was not overweight to start with. So it's, and I suspect, you know, even that small difference in weight already made a difference in some of my metabolism. So I think it's kind of a blurry line in terms of, what is the longevity medicine? I think these molecules are going to be remarkable and reach and allowing us to tackling the obesity epidemic in seconds. I think there might be a silver lining that goes beyond this that even individuals are not obese and not type to diabetics are going to benefit from those. Yeah, yes. Yeah, so I'd actually add that, you know, with this first drug that was approved by the exenetide, there was psychology studies done by the Amidin pharmaceutical company. And so they gave rats and mice exenetide for their lifetime in very high doses. And it turned out that the higher doses they gave them, the longer class they live it. So this was really, I mean, they were healthy animals, but that's what happened. It turns out that there's a good explanation for this because what happens is that those rodents, just like people. they eat a little bit too much in reality if they are on ad lip food. So if you can prevent that weight gain, then you can also increase that lifespan. So that's what happened actually. But it's very interesting. The other thing that I'd like to emphasize here is that if we compare this therapy with bariatric surgery, which I think is really relevant and important, we know now that bariatric surgery given to people that had diabetes when the surgery was before, they can expect to live nine years longer from very, very large studies. So you can say it is, it seems to be a long ability, but I completely agree that this is because it prevents a number of the problems that may arise as we grow older. Yeah, and I guess leaning into that, it ends a little bit. We've seen the clinical studies that have been going on. There's been some very interesting retrospective biobank studies that we've looked at for this. And of course, we're seeing the cardiovascular benefits that these drugs obviously are really changing the way that we're starting to think about on target and off target effect. So do you see perhaps in your conversations in Pharma that there is this concept of moving away from treating a disease and moving into this preventative sphere? So, yes, both yes and no. Because one of the problems we have is of course with obesity, of course, is a number of complications. And if you can reduce that set of complications that are associated with obesity, it follows more or less that you can also, you can prolong life and avoid immortality. But actually, there's an interesting study that was done with the TLP1, Akinus, that is the harmony studies that were done, cardiovascular outcomes trials that were done with alpeglu type. And it had a very nice effect on cardiovascular risk, the mace as we call it. It was reduced by 20%. But there was no change in body weight. Absolutely no change in body weight in that study. And that of course makes you think what is going on here. So the conclusion right now is I think that there are additional mechanisms, it's not only the weight loss, there are certainly also other mechanisms. And people are talking very much now about what you can call the cardiovascular, renal, hepatic, metabolic syndrome and suggesting that these are interconnected with a more or less common hasophysiology. And so it becomes more and more interesting to try to see if this is what happens, that GLP1 interferes with exactly that common pathology. And that is why it is so helpful in all conditions. And if I can jump into this, this all ties in many ways to insulin resistance. And we've known not only in metabolism and indoctrination, but also in the aging field, insulin metabolism has been known for the longest time to be one of the central pathways that tries the aging process. And remember the work of Cynthia Kenyon, identifying the death pathway, the work, and just off without the same thing. The insulin pathway really seems to be central in terms of aging. And think about metformin, think about SGLT2 inhibitors now, which also are emerging as drugs that target it. So it just makes a lot of sense to have a drug that targets insulin sensitivity and obesity actually have a potential longevity effect. And I just, since Jens was talking about exandatite, there's a study that just was published. And I think it's cell metabolism by a Hong Kong group that actually looked in mice with all its limitations, but it was a pretty well-executed study. They gave mice that were the equivalent of a 60-year-old, and they did not induce any weight loss. And in these mice, they were able to do all of the omics and identified a whole series of pathways that actually seems to be critically involved in the response. And they showed a reversal of aging processes, epigenetic clops, functional strength, but also molecularly a signature that actually looked like MAPA mice in, which was quite interesting. And what was even more interesting for me is the fact that a lot of these effects seem to be mediated by the hypothalamus. And in particular, a set of neurons in the archewod nucleus, which are involved in satiety control and so on. And that data has been shown in humans as well. So there are so many lines of evidence that are making a lot of sense, biologically, it's hard not to look at it and to be hopeful. And this is why I think you're seeing so much enthusiasm from the longevity community about these drugs. Exactly. I'm glad you brought up insulin resistance being the core problem and also bringing up a bit about the brain because there has been a lot of hope around GLP ones for brain health. And I think you both probably read the Nova Nordisk Alzheimer's trial, clinical results that just came out last week. Looking at their older diabetes drug, Rebelsis, what do you think this failure means in terms of neuroprotective hopes? I'm still a bit more hopeful because they were looking directly at mild and moderate Alzheimer's. But what are your views on GLP ones still being neuroprotective? Did I start? Yes, let's go through the ends. Okay. So first of all, you have to note that this was with the oral GLP one. And it was with the old dosing, if you will, with the 14 milligram dose as the maximum dose, right? And so that is considered, I mean, I consider that as suboptimal GLP one therapy. So that is, it's not the, so the they're right now working on getting higher doses approved and they're working very hard on getting the 25 milligram dose approved. And they're also looking at the 15, that has been published already with quite impressive results and certainly also greater weight loss results. So what I'm trying to say is that there's a difference between the different GLP one, Echinist. There's a power difference, you know, a potency or power difference. Right now, I think we can assume that GPs probably is the most efficacious of them. So I mean, I'd like to see the same result with GPs. That's what I'm trying to go. I'm trying to go. So, but there are other comments here that should be made. That is, was it a good idea in the first place? So the GLP one, Echinist, the ones that we're talking about, they don't enter the brain. So if you think that Alzheimer's is a pathology that is occurring specifically within the brain, then there is no real reason to believe that it should work. There are a number of experimental studies that have been done over the years where people have been looking at brain sections and cultures and what have you, where you can add GLP one directly to the neuro root issue. And there are a lot of receptors at the brain. I can come back to that. And there we have seen these positive results. But in fact, in the living human being, a GLP one does not enter the brain. It reaches the brain by connections in what we call the the circumventricular organs, where there are neurons that expose the GLP one receptor, so that you can excite those neurons and they then in turn can influence cerebral processes. So I mean, I hadn't expected that there would be any effects on Alzheimer's, except that we have all these observational studies that were positive of course. But why is that then? So that's where we come back to what we're talking about already. So the weight independent effects and here I'm particularly thinking about inflammation and I'm talking about the vascular system. Because the vascular system is common also for the brain of course. And inflammation will also affect the brain if you have a low grade systemic inflammation. So that's a much more likely mechanism of action. And there we have again what I said, the most efficacious drug is the most likely one to to be successful. So there is a number of important considerations here. Yeah, and I guess Eric, if I make a couple of points, yeah, I think it's important to remember also that Alzheimer's has been called in some circles type three diabetes because many of the abnormalities that we see in terms of type two diabetes actually are present in the brain. There's there are profound metabolic defect in terms of glucose utilization and Alzheimer's. So there's a logical thinking from a mechanistic point of view, but also as Jen mentioned, the epidemiology was there that some patients seems to be doing better or they seem to be a decrease. One thing that really bothers me about the study is the fact that this was done in people who were diagnostic diagnosed already. And we know that when you get to the stage when you have a functional cognitive defect, there's already a very significant neuronal loss. And clearly, I mean, no one was expecting these drugs to be inducing neurogenesis or repair the brain. So I would I remain hopeful that would better administration earlier, and perhaps in a population at risk, you can imagine a clinical trials where we will target the people who are at the highest risk, April, E4, you know, the carriers and really follow them earlier before there are any symptoms. I would predict we're going to be seeing some beneficial effect. Maybe not the cure all, you know, we just conducted a study with Dean Ornish, even in people who were registering the earliest cognitive defect and just lifestyle changes, which are associated with increased insulin sensitivity and so on. Just those over six months period, we were able to register at different. So I'm not sure what happened in this study. I certainly would not turn the page on the potential of these drugs in terms of neurodegeneration in the future. So I guess we've answered the question that I was going to ask you because really what you scoped out there is that the failures of maybe the drug candidate selection and the cohorts. But yeah, I guess, you know, what does the next generation GLP1 brain study look like if we're going to do it properly? What does that look like? How did those in started early? Yeah, so I guess we already have a very large number of our survey schools that all support that you can improve cognitive impairment in the patients. And again, I'll come back to the effect on, so the metabolic effects, of course, because you can reduce whatever we call glucose toxicity and dipotoxicity to the extent that this is relevant for cerebral problems as well. And I think there are. And you can you can you can combat atherosclerosis somehow, which is of course of great importance and inflammation again. So all of these factors that you that you can demonstrably affect with the GLP1 agonist will also be affected if you have a cerebral problem. So so there are a number of good reasons to I completely agree with Eric. There are a number of good reasons to believe that this will be effective. But for other reasons, then a direct effect on the pathological process in that specific disease. So I guess, you know, we need to think about what the, you know, we're talking about trials. And we need to start thinking about the regulatory landscape that's supporting all of this. So, you know, 12% of US adults now are on these drugs. You know, meanwhile you got companies like Weight Watches, you know, filing for bankruptcy. You know, I guess as a as a scientist, you know, but you must get asked a lot of questions about what's happening in this space now. So do the perspective that we have on the industry as it is now from a pharmaceutical perspective? Do you see that we are starting to move towards medicating lifestyle rather than disease? So to me, the most important of all of all this, and also the entire history that we're in, has been the attempts to prevent complications of obesity and diabetes. That's from the medical part of you where I'm standing. That's the most important. And you know, the problem is huge because we see we say that about the quarter of the the adult population in our societies have this what we call the metabolic syndrome. And with that follows a importantly increased risk of cardiovascular disease and stroke and death. So this is what and this is what you can demonstrably affect with these medications. This has been beautifully demonstrated in something like the select trial with somatotide over in 17,600 individuals over four years. An amazing trial with a lot of information in it. And you know, what comes out of that is that you can actually interrupt this problem. The the semount one trial, the extension of that trial with the serratide showed that the diabetes that occurs in obesity can be almost completely eliminated with chusepotide therapy. It was a 94% reduction during this three year follow-up period in the occurrence of new diabetic diabetes. So I mean, that's a lot you can do. And I think this is hugely important. And I was so thrilled to see that the WHO now recommends the OP1 therapy for obesity and obesity related problems. But there's also they also discuss and this is of course extremely important how do you organize this? And that's going to be the real problem because it has had a lot of implications. First of all, who's going to pay? But to be perhaps the most important is the political aspects of this because now it's actually almost directly written in the paper. Now it's up to the government, to the countries and the governments to take to discuss this and find out how do we do it? How do we do it? Because now we have kind of a responsibility to help these people in our societies that are under an increased risk of developing the complications because there is a cure. I mean, I have been following this so closely and back in 2015 or 2013 when we started using the OP1's for obesity that was directly tied in with sex sender, you know? Everybody said, "You're crazy, you're out of your mind." This would never work. Nobody wants to pay for it. But that has completely changed, you know? So now it's now it's a really important societal question. How do we deal with this? Because it's there. You can do it. But it will require some real severe activity from the public. We're seeing from the US side that Medicare is just started covering the GLP1 Agnes for obesity. So, Eric, what do you think? Do you think that the shift is being driven by the drugs themselves and their popularity or a policy shift or, like Yen said, just that we really need to give more access? There's a great agreement with everything Yen said. I think there is an incredible shift happening and I would like to add another dimension to this is that quite often obesity has been sort of judged on the moral basis, on sort of a moral weakness. If you just stop eating, if you would exercise more. And I think this is a self-defeating approach because we see the results. Or visit the, no matter how much we try to shame someone who is a beast and suffering from it, it just doesn't work. And it's been we see the numbers going up. There's a role for the food industry. Everybody recognizes this. There's the degradation of food, and it creates ultra-process food. There's a decrease in physical activity. All of those things, I think we need to continue pushing for increasing lifestyle quantities to educate people and create cities that are walkable. So, all of these things are still true. That being said, there's still no matter how much we try, there will still be a group of people who will become a beast because the pressures that they're feeling are too hard. And I think none of us are in a position in my opinion to judge whether this is sort of a sign of moral weakness. And I think by medicalizing this and showing the incredible efficacy of these drugs, we essentially bringing your solution to something that's been an incredible problem. Not only, people always talk about the cost of obesity, but I always like to remind people the sort of personal cost of loss of motility and the disease burden and the shame. Everything that comes with it. So, the response quite often that I hear from people when I talk about my application of these drugs is, what does that mean? We're going to have 25% of the population on these drugs forever. I have absolutely no problem with this. We use a whole series of medicine forever without any shame. Again, it's linked to the fact that it's linked to obesity. We also assume, I think, wrongly, that we are sort of perfect evolutionary product. And I can tell you that what these drugs are highlighting is the fact that we are not. And the obesity epidemic is a reflection of the fact that our genetic blueprint is that of creatures that lived in an environment where food was scarce and where a movement was constant. And so now we have been transplanted in an environment where we're not moving and food is abundant and it's being engineered to actually appeal to our lowest instinct. And no wonder we have an obesity crisis. So, in some way, the drugs actually are offering for people who have the biggest problem maintaining their weight in the face of these pressures, the ability to live a much more normal life. And I think it's quite interesting for my experience sharing patients' experience with these drugs. They really decrease that food noise and allow people to focus their lives on what all of us want to focus on. So, I think there's a big shift in mentality. Stop blaming and shaming obesity. And let's treat it as a medical condition which has always been. This episode is brought to you by The Long Gevity Show, the global event empowering everyone to live longer and better right now. So, Fel, you're one of the founders. What makes this show different? Great questions always need up well. Unlike other events, The Long Gevity Show is open to everyone. We're running two tracks, and a shared experiential exhibition. It's international, it takes place in London in June this year. What great timing! London is so much fun in the summer. 100% and there's the public, festival style experience packed with evidence-based talks from world-class experts on nutrition, sleep, cognition, metabolic health. And then there's the full business track for those executives, investors and innovators shaping the longevity economy and for those newbies looking to jump in. So you're saying it's part science, part business, part experience and part celebration? Exactly, Nina. With inspiring speakers, networking, amazing visitor experiences, and even an after-show party. The event is for the longevity innovators, experts and community all to come together. So how do people grab their tickets? Well, just head over to longevityshow.com, tickets are on sale now, and the early bird offer is still open, but not for long. So don't miss out, head over to longevityshow.com and grab those tickets today. Yes, I wanted to hop in there. I'd like to add a complete degree with what you said, Eric. And I'd like to add, you know, the question of the imperfectness of our physiology. There are many things that it doesn't work too well when as we grow up, and one of the things that doesn't work too well is our appetite regulation. But another thing is, for instance, the eyesight, right? We almost have almost all everybody has a pair of glasses. And you know, nobody questions that we should improve our eyesight by putting on some glasses. So now we are improving our imperfect weight regulation because the GOP won at this, right? I love this analogy and it's great. I will add it to my speech. Well, I guess reflecting what you were saying, Eric, and you know, my extrapolation of where we are talking about GLP ones and obesity, you know, within the context of lifestyle, for me, you just changed the words obesity and put in aging. And then you can be making the same arguments. And I guess, you know, we've seen the biotech shares really starting to behave like text stocks, right? You know, no, but notice was obviously at its peak, Europe's most valuable company. It's gone right back down now. Obviously, we saw Eli Liddy hitting a one trillion market cap. So do you see in the context of all of this and the framing of the argument that a GLP ones and farmer and the investment appetite around prevention is starting to drive up a new context for biotech investing. And you know, are you seeing any evidence of the biotech winter that we've been in for the last three years starting to thaw? Yes, I do see it. I'm not the only one seeing it. There clearly seems to be some novel degree of optimism in terms of biotech. I mean, we should also be sort of realistic in terms of the longevity space is still a very small sliver of the whole biotech world. I deplore this because I think it offers incredible opportunities for growth and for tackling all of these chronic disease of aging. So I hope that along with the freezing, the unfreezing, the thawing of this nuclear winter in terms of biotech, there will be renewed interest. In some way, you know, we had the ARDD meeting in Copenhagen, which is the largest meeting on aging research organized by a friend of a colleague of Jens Morten, Shibian Nutsen and Zorongkov. It's a great meeting. We had two two talks there, which I never dreamt of seeing. And there was the CSO of Eli Lilly and some high level scientists from from the Vernortis, both starting their talks by saying GLP1 agonist are longevity medicine. I should say one of them had a question mark. The other one made statement. It was remarkable because frankly, I mean, the big farmer has been staying at a bit of the distance from the longevity field. For good reasons, it's a new field. It is populated by some serious people, as I hope we continue to be, but it's also populated by some fringe individuals, which, you know, create a bit of a problem for farmer. And so I think the combination of the two, the, you know, renewed the success of the drugs. And the fact that they are actually joining our fight, I think it could mean really great things for the longevity research area. That's my tradition, my hope. I agree with you there, especially opening up GLP1, obviously, as opening up a talk, saying GLP1 could be longevity drugs is a huge statement. And leaning into that thinking, that also means they could be preventative. So do you, yeah, and do you think from a research perspective that big farmer is going to start swinging more into that prevention space, rather than just disease management? Guys, camera for you. So right now, we all across our fingers. So right now, the way I see it right now, what has been uncovered is that these huge diseases of the civilization, we talked about the metabolic syndrome, the obesity and all that, that this is something that is preventable, that was on outside our reach and thinking of just 10 years ago. Now it's preventable. So I think there is plenty to do with keeping people alive, you know, rather than prolonging their, you know, their healthy lifetime, even further, because I'm not so sure that this, this is what is, is this, that they will really do this. So that's one reservation I have. The other one, on the other hand, and think, if I have the stock exchange, you know, we usually call these stock dealers for steric and bitches, that's why. So I mean, the number of lawyers were selling more than it ever had been selling ever before and making all this money. And that continued completely on its interest. It's still the stock value failed to get rid of this low. Okay, that's a different matter. But I'm also waiting for, and Eric also mentioned this, the Amix age. So I'm, in all those fortunes have now been invested in the Amix. And we know more and more and more about this. And people are now talking about creating a virtual electronic mouse. So that containing all that we know. So, so if that is true, then it also means that we know things about aging. We know things about longevity and all that. So when is the industry going to look into this? And, you know, when do we harvest all that work? All this knowledge that is accumulating that should be able to in principle tell us exactly what knobs to turn in the future. That's what I'm expecting. I agree. I agree. It's happening. And you know, I used to say that we had to reform medicine because both you and I were trained as traditional physicians where I did not have a single class on nutrition, on sleep, on prevention, on anything. We were not trained about preventing disease. We were trained about treating them and curing them. And I used to say we should reform medicine. I've given an up on this. I think we have to invent a new form of medicine that will function with the different goal. And, and hopefully my dream would be to put the rest of medicine out of business. On the other hand, you know, there will still be cancer. There will still be heart attacks in the future. There will never be immortality. I think this should never be part of the discussion. But hopefully there will be a lot less or very for a very short period. I think that's really the vision that we have is that most of us could live, you know, to 1995 in good health and then a short period of compression of morbidity and then past. And maybe in the future, who knows what's going to happen? I mean, I think I'm sort of more focused on what we can do today. And these drugs, you know, I'm skeptical by nature. And these drugs are giving me hope that we're going to be able to make much more rapid progress than I thought, you know, five years ago. Yeah. And Eric, obviously, you know, with with the buck, there's a lot of, you know, IP being created there. We're seeing these companies being built, seeing quite a number of smaller, earlier stage biotechs partnering now with Big Pharma, you know, we've seen deals with Novartis and Eli Lilly. And obviously we've heard of Erundz law, you know, the diminishing returns for Big Pharma. So do you feel that there's an opportunity for, you know, the smaller biotechs to be bringing through the next generation here? Absolutely. And I mean, this is not something that we've invented in the longevity field. This is how it's worked. This is how biotech has always worked. You know, biotech very rarely becomes a full flat pharma. I mean, the fate of most of biotech is ready to push the technology that's invented, by the way, 95% of the time, at least in the US and NIH supported labs, to bring it to a point where it is proven and supported enough for Big Pharma to pick up this lab and to actually push with the really expensive and long-term, you know, long clinical trials. By the way, I think one thing we really hope to do in the longevity field is also to, by bringing your personalization. And Yens talked about the omics. I think this is a big part of the effort at the buck. You know, we have a long-standing collaboration with Leigh Hood and Nathan Price building on the effort with Phenome Health, which is really to bring all of the The omics to bear to designing clinical trials that are much more precise and therefore much less costly and much faster. And I think Nathan Price at the back in a long term colleague of Lee Hood as well has a whole program program at what we call the digital twins or where he calls also the end of one analyzer which is the idea that conducting clinical trials on a one person at a time and really looking at the changes in parameters. So we're really excited to be pushing this technology and I think it will change the way we do clinical trials and hopefully empower many people to actually conduct more clinical trials because everyone recognizes we have this incredible basket of technologies and we have a bottle neck at the level of the cost of these clinical trials which are long, expensive and can fail. So I think we have to really rethink the whole process and do it better. Yeah. And I guess thinking about we're talking about the future and where that's going to go. I mean, we're looking at where we are with GLP ones, yes, thinking about, you know, microdosing, obviously that's become a bit of a tick tock trend, you know, people stretching out their prescription pens, you know, even people taking tiny off label doses, you know, buying from online research supplies and so on. From a regulatory standpoint, you know, should we be worried about this? Yeah, I guess so why was very amazed to see that we do know the compounding problem in the United States because the question I asked myself, where does it come from all of it? Because we usually consider the production of the peptides, you know, as a kind of a complicated process, there's, you know, I think it's kind of a biological. So it couldn't be possible to, for everybody to do this, but apparently they found some people that could synthesize chemically these compounds and then sell them at much lower prices. Of course, quite smart. But I mean, they're not, they are not originally quality, the quality is not controlled in a good way at all. So there must be problems, so there has been problems. And actually in the UK, they said the major complication of the T-1s was a compound or fake production of it that had killed several people. So of course, it's important. On the other hand, the industry has not been, so we are touching on a very interesting problem. That is also the dosing in the long term. And that's where I find the micro dosing problem very, very interesting because obviously people are having benefits from this. I mean, it really helps a lot of people and solves some of the problems. And obviously the pharmaceutical industry has not been the far runners of lowering the doses and low-worth in the prices because there's not how they do it. So it's very nice to see that people have taken the mattress in their own hands and do it and have apparently good results. So we really need some studies that look at this and see how good it is. How far does it go? Have you seen any actual studies be done at the, well, I guess referencing back to what you said at the very beginning with the Noven Nordisk Alzheimer's, that they used a sub-optimal dose. So have you seen studies that have been done at, let's say, instead of these micro-doses or very low doses, this sub-optimal dose that have benefits? Oh, actually, actually, so there's an interesting observation here that the redefined studies with the CEDC research center, which was really very recently publicized. They actually saw something about this because the lesson we learned here is that the optimal effect was not necessarily achieved with the highest dose. The essential problem was to find the doses that fit the individual. And once that, you find that balance, that's when you get the optimal effect also. So it turned, you know, this relationship between those and effect is an individual thing that needs to be looked at. So the usual way of, you know, everything, all those fits all, doesn't work in this. So there's a lot of work to find out how we do this. I completely agree with this. And you know, another aspect that has been discussed a lot is the sort of muscle wasting effect of these drugs. And I recently saw a study where, so the idea is that if you, you know, go on these drugs, you will disproportionately lose more muscle mass. And since we know that muscle mass is critical for your longevity and your metabolic health, you could actually be doing yourself some trouble, some harm. And so the study I saw recently actually compared the rate of muscle loss in response to different interventions, including bariatric surgery. And there was nothing unique about these drugs in terms of muscle loss. It's just a reflection of the rapidity of the weight loss. And one thing that I would highlight is the fact also from discussing this with patients and so on, that the pharma industry encourages very rapid weight loss. And I would argue that, you know, for someone to lose 20% of their body weight in six months to a year is probably not healthy. And I would, I would, you know, I would say that probably there should be a lot of work to be a second look at doing these trials, which much more significant lower doses, which, you know, over a two year period could actually yield the same results, but with less, less metabolic consequences in terms of muscle mass. And I think from what my conversation with people in the industry, there is an interest. And, you know, the public are voting with their feet if they have the higher dose, of course, the more side effects you have in terms of nausea, and, you know, hard burn and so on. So people are automatically lowering their, lowering their dose. So there's a lot of, we live in an interesting period that I call the empowered patients, which is patients are reading about what drugs they can take. They go see their physicians, they're asking for the drug, they're adjusting their doses. There's a lot of the whole biohacking movement, despite its success, as I still view it as a positive force because it means the patients are, you know, are pretty becoming part of the solution, which is the only way we will reach optimal health. So, so that's one of the reasons that I also think that these drugs should still be prescribed. And that's because there's so much advice that should be given to the patients, and one of the pieces of advice is to go slowly to, you know, take it easy, use one and a half two years to obtain the desired weight, and use that period, that's the important part, to adjust your lifestyle, because you can do it. Just of the effect on the appetite and the reward and all that, you can actually, you can determine what you want to eat. I mean, you're in power again. And the other extremely important thing is to start exercising a little bit, and it doesn't take a lot, it only takes, you know, 30 minutes of WHO recommendations, and walk this enough, many of these people have an important low oxygen reserve, you know, capacity, and this needs to be rebuilt. So that is really much more important to maintain them as well as, but you can also do it, it helps you because of the lower inflammation, the joints are better, the physical exertion, the probability is a better, everybody reports that very nicely in the study. So, this is the important thing, and this is where the doctors, you know, should really do something, and also recommend a healthy diet, enough protein, enough vitamins and all that, just like after a very hard surgery, it's as important here. I love this, I love this, because I think it really, you know, speaks to, you know, our interest in the lifestyle factors, but quite often we don't recognize as much how being obese actually interferes with the ability to, you know, to exercise, to move. So as you lose weight for people to really adjust the two together, for me, you know, this is not a sort of a patch onto a poor lifestyle. Eventually, and the same for bariatric surgery, I mean, we know in some cases these therapies fail because people go back and they start increasing their intake of rapidly absorbed food that don't need a stomach. So the same thing I suspect will go for these drugs. I think the combination with the change in lifestyle is going to be really important in the long term. So can we just, just talking, extending that a little further. So Eric, you mentioned earlier that you had a period of time taking a low dose of a GLP one. You know, I've met people at conferences that are talking to their doctors so they can access it. They're perfectly healthy people. And I always remember Yens, the article that we were on with you, which is saying, you know, they may be longevity drugs, but healthy people shouldn't be taking them. I guess, you know, reflection what Nina said about the microdosing and the appetite for people to consider jumping in early on this. Do you feel that there is a societal change coming about, or is this just like the experimental biohackers coming through? I'm still on, on tersepetite, 2.5 milligrams. And I'm not saying this in a way to endorse it for other people to do this. I'm in the longevity field, so I'm curious. I do a lot of self experimentation. Even at that very small dose, I have seen profound metabolic effect. My fasting blood sugar is to give you an example when from 97 to 85. That's, you know, that's the blood sugar of someone from Sparley 20, 30 years younger than me, my fasting insulin is lower than two. It used to be higher than five. So there's, you know, there are an inflammatory markers as low as you can possibly detect them. So for me, in my case, it's more self experimentation with the low dose, no side effect. I find that it has a profound effect on my taste for alcohol, meaning decreasing it. It used to be a glass of wine or day, and I've completely lost interest in this. So we see, you know, on a population level, actually massive changes in people's interest in fast food. So again, I just want to make sure that your audience does not misunderstand what I'm saying for sort of recommendation that everyone should be on this. I'm a physician. I follow all of my numbers, and I view this as a self experimentation. But, you know, I get an increasing number of people who approach me, ask me, should I do it? Now, if you are 25 years old and you're exercising and you're in good health and you're doing, and you're lean and you're sporty, and all of this, I would say no way, you know? If you're, I'm 68, so it's a different kind of ball game. I'm getting to the point where I'm thinking, okay, you know, I feel good, I feel wonderful. I want this to last as long as possible. It's the same discussion that we had with people about metformin. You know, if you're 65, you have some mild degree of glucose intolerance, and you want to go on metformin because as GRT to inhibitors, because you think it might do you good, I'm supportive. But it's an informed decision that has to be made with a physician that understands the longevity space that explains the risk. So every medicine has a side effects. And that's the number one thing that people should realize. And so I think we live in this gray world where there are physicians who will prescribe it to people who are not obese, not diabetic, who hope to get that little edge, to stay healthy as long as possible. I think we should be supportive of this. You know, after all, as some people say, no, I'm not hurting anyone. I can afford it, I'm lucky enough to be able to afford it. And I think we might learn something quite interesting at that edge. But I recognize it is the edge. And again, this is not an endorsement. It's more sort of a reality of the fact that there are a very rapidly growing number of people who are doing this and self-experimenting. And frankly, some of them I've come back to me and said, you know, I don't like it. It doesn't make me feel good. I've lost a lot of the joy of life. I've lost my appetite. I've lost, you know, there's a, you know, there are downside to this as well. I'm glad you bring up some of those risks or some of those downsides because we have been talking about a lot of the benefits of GLP1 agonist. But which, I mean, we've also talked about the effect of muscle loss, potential bone density loss. What are some of the side effects that, A, you think have been overblown in the headlines or be really haven't been talked about enough? Either one of you. So of course, we have this long list of potential side effects that we need to look into. And some of them are very real. There's problems with people that have a delayed gastro-gaming, if they have that already, then they may run into problems with these drugs. And that's something that you have to realize because this is one of the actions of the drug. So here we are. So you're interfering with something which is already impaired, then you may have a further problem. And the Gulf Stones is another problem that we also need to realize that's something that is increasing when you lose weight, that has been known for a long time. And this also applies to the GLP1 therapies. Maybe there's even more, but it's still a rare complications, but it's there. It's something that you need to know. Fortunately, the cancers have gone away. That has been, they were very much on the agenda some time ago. But that has gone away. And fortunately now we see, again, it's observational studies, but we do see that the obesity-dependent cancers and that there are at least 14 or maybe 15 of them, that they are generally improved. There's a fewer of them if you are on the GLP1. And there's a huge number of studies looking at these days. So that's something that what has recently been brought up and doesn't really seem to go away, that is nion. That is the inflammation of the optical artery. That can cause blindness in some very rare cases. Fortunately, it's very rare. But it's enough for people to have, it's there. It's on the list now. It's recognized in Europe. And people can get money if they can run into that problem. And then there is most recently in Australia, they are very concerned about suicidal ideation and think that this is something that should be brought up. It's again very rare, but it's probably real. And likely it's real also after very rare surgery. So there are a few, the very rare, but there are a few problems that we need to talk about. I suspect that many of those also can be mitigated by, or at least are those dependent. Absolutely. Are you on 15 milligrams versus 2.5 milligrams? Yeah, well, I guess my question really to both of you before we move on is, you mentioned years, of course, that these are very, very rare. Sometimes these things are blown up by newspapers and so on because they want a story. Do we see, just I guess, the momentum is so great now that people, although clinicians are studying these things, but from a public mentality perspective, that everybody's going to move on. I mean, do you feel that that's happening out there? Do you feel that we should be looking at the end of the day? And the rear view mirror a little bit more or is everybody just barreling forward now? I don't know what to say to this. I don't know. So, you're completely right there. The press will pick up these stories and you blow them up and I don't know how this affects people. I hope that they get other sources of information so that everybody doesn't think that the world was out. But I don't know what to say. Yeah. Okay. Well, I mean, maybe let's move on to a slightly different subject, which is in relation to, we've seen GLP1, you know, what is coming next. And Oppenheimer equity research, Rota Paper, beyond GLP1's erectile dysfunction as a harbinger of health. They identified PDE5 inhibitors, specifically Sedanaphyl and Tadalaphyl have been shown to have significant reduction of risks for mortality, cardiovascular disease, and dementia. What do you think about these being perhaps a next wave of longevity drug? Well, that's one for you Eric. You know, we are at a stage in the field of longevity where there are a growing number of opportunities. You've mentioned those two drugs. I mean, they do increase lifespan in animal models. They exhibit many of the hallmarks of things that you want to do increase, you know, nitric oxide in the blood vessel wall. So this is, these are things that we know are associated with health. Again, you know, who should go on these drugs? If you have some mild erectile dysfunction in the year, in your 60s, you know, this would be a good argument to say, you should go on it. There's not only, you know, you're going to get a benefit in terms of the ED, but you're also going to get potential health benefits in terms of health span and possibly lifespan. I mentioned earlier in the discussion as GLT2 inhibitors, guardians, family of compounds that are blocking sugar reabsorption in the proximal tubular dechidney. And having also very, very similar effect to metformin and these drugs, improving glucose metabolism, decreasing the spikes, has been, you know, has G-T2 inhibitors have been shown to increase lifespan in mice and animal models. They also exhibit some of the side effects that we mentioned for GLP1 agonist in terms of cardio protection. Kidney protection. So my prediction, you know, my good friend, Karl Flager, who has tabulated, you know, all of the clinical trials that are happening in the longevity space recently told me there are so many clinical trials that will be read in the next few months to a couple of years, that we will, I predict, we will, in five years time, we will be in a position where we will have at least two or three drugs that have the potential to increase your health span and lifespan. And I think, you know, who should go on what? That's the research for the future. Maybe some of these drugs will work in synergies. You know, all of us clearly aspire not necessarily to a long life, but to a healthy life. And I think this is what the field is really focused on. And now it's really decreasing this incredible burden of chronic diseases that we associated with. aging. You know, whether we live longer in the process, I think I suspect the two are really clearly linked, but clearly also what we've been doing so far, which is mostly focusing on increasing lifespan without any respect to the quality of that life is not working for people. If you ask people, you know, who wants to live to 120, I would say in an audience of 100 people, you'll have two raised their hands and the reason is they know what happened to grandma and to their parents, you know, who suffered from all the indignities of all these chronic diseases. So I think we are at a really moment in history where for the first time, you know, we increased lifespan along with it came this burden of chronic diseases that the grades, the quality of our later years. And now we are in the position for the first time to change this equation and help people live healthier longer. And it was beginning of a long journey. I think I could not be more optimistic about what lies ahead. And I think at the same time as responsible physicians, I think we ought to proceed cautiously. There's nothing worse that you could do to take someone who could live healthy until 90 and to actually make them sick by giving them a so-called longevity medicine. And this is where I've struck a somewhat conservative note, a tone in the whole community because the population will not tolerate that we make them sick with the hope of making them healthier. So the burden of proof for us as longevity scientists is higher than a farmer company doing curing a disease because we have to, we're starting hopefully with healthier people. We should try to keep them healthy and not give them complication. And that's why I'd like to return to the effect of the GLB1's on inflammation and the vascular system because that's exactly those problems that we have that we have with the extended life. That's where the the problems come from. That's how we get the cognitive dysfunctions of the brain. That's how we get the cardiac disease and all that because of these disturbances and you can you can you can demonstriply do something about it with the GLB1. You can delay this process and reduce it. So I mean, there's every reason to try to improve those complications of being old, right? And that's what I that's why I think it's simple. That's totally true. Yes. And you know, the chronic inflammation associated with aging that we refer to as inflammation is one of the big targets of these drugs. And we know chronic inflammation, razor roll and type 2 diabetes and heart attacks and stroke and Alzheimer's and Parkinson's. All of these diseases have a common proinflammatory terrain and and these drugs are targeting this. So it's hard enough to to be optimistic that they're going to have global protective effect. Exactly. I think we could do an entire episode with both of you just on inflammation. So we're going to have to save that one for next time, exactly because really that's that's our hours. So that's it for today on today's deep dive about GLB1. Should we all be taking them? Thank you so much, Eric. Thank you so much, Yens for sharing your expertise and your vision. This was really interesting conversation. Thank you. Thank you. It was pleasure. Thank you, guys. So if you enjoyed this show, don't forget to subscribe to longevity technology. Unlocked wherever you get your podcasts. Till next time, keep questioning the hype. So thanks for joining us, everybody. [BLANK_AUDIO]