Longevity is not found in one molecule. It is built through tissue, capacity, and recovery. In this conversation from Metabolic Health Summit, the useful thread is not novelty for its own sake. It is the way small physiological signals become practical guidance for a more resilient life.
Transcript from Metabolic Health Summit. Timestamps open the original YouTube video at the corresponding moment.
Welcome to the Metabolic [music] Link, a podcast that explores the common thread of metabolism in health and disease. This is where science meets society. Welcome back to the Metabolic Link. I'm your host, Dr. Dominic Degastino with a background in neuroscience, physiology, and metabolism. And today we are diving deep into mitochondria, muscle and metabolic medicine with someone who sits at the intersection of it all. Our guest today is Mark Tarnipolski. He is a clinician uh a scientist, an MD and a PhD and an exercise physiologist with decades of experience treating neuromuscular and mitochondrial disorders. He's published hundreds of papers and he's also done the real world work of translating metabolic and mitochondrial therapies into human application in the research lab and in the clinic. So he's worked on Pompei syndrome which is glycogen storage disease type two. Uh we also work on that in our lab and other genetic metabolic conditions associated with aging, performance and health span. In this conversation, we get into his personal path from high level sports kinesiology, then medicine, uh then neurology and mitochondrial research and how that combination shaped his uh whole system approach uh that he takes in the clinic. Uh so exercise plus nutrition plus very targeted interventions instead
plus very targeted interventions instead of more or less betting on a single molecule as a therapy. So we talk about why multi-ingredient strategies often make more physiological sense. Uh although these things other people are not studying multi-ingredient uh strategies and how exercise can meaningfully augment these therapies like uh enzyme replacement therapy for example. It's used for uh rare inborn errors of metabolism. and he really focuses on what actually matters most when we're thinking about function, body composition, and long-term outcomes. I know you're going to love this interview. Now, let's get into uh our interview with Dr. Mark Tarnipolski. Dr. Mark Tarnopolski, thank you so much for being on the Metabolic Link podcast. uh we connected our cro our paths crossed through uh our work on genetic metabolic diseases and shortly after talking with you I believe you know at the conference and also after at dinner I quickly realized that you had the broadest and deepest knowledge base of probably anyone that I had ever met on metabolic disorders and mitochondrial function and also you're truly moving really the science of mitochondrial metabolic therapies into human application. So, uh, you know, you are a clinician, a scientist, an entrepreneur, you have a company, you're, uh, in our conversations, you you're an elite athlete, a world record holder, I believe, a master formulator of
believe, a master formulator of nutritional supplements. So, I don't think I've actually met anyone that checked all the boxes there. And you've published like, I don't know, 400 or 500 articles on top of that, too. and you've also worked with Stu Phillips who is sort of a a very knowledgeable person on protein metabolism and we'll dig into that a little bit. But uh for our listeners, I thought we'd kind of just jump into a little bit of your personal journey and philosophy and scientific evolution to where you are now. And thank you again for being here. [clears throat] Oh, well, my pleasure. And uh far too kind. And I've never been a world champion. And I've been to world championships in the elite level with three different sports. But you know, sort of coming in the 30th and 40th is about the best I ever did in the world. But any was a a pleasure to represent Canada in some sports and stuff in the past. So I guess it really started with sports. So I was uh involved in all sorts of things in high school. Um people would laugh if you looked at me now. Um but I was actually captain of the football team and I thought I was going to do that and downhill skiing. Uh and then um you know I didn't make the national team for downhill skiing. So I became a little disillusioned when I was 16. They said I was too old. Um and uh I was also probably too slow. I don't have enough fast twitch fibers. And uh I also uh thought that I'd be a sprinter and a football player. But you know I could win when I trained really hard when I was in grade nine, but by time grade 12 people that never trained would just blow by me. Didn't know at the time that my physiology was not one for uh speed.
my physiology was not one for uh speed. Um so I was a little disillusioned but uh decided still to go into kinesiology and uh that's how I started my career. I was going to be a fizzed teacher. That was uh how I started out. I also got into endurance sports. Um so I was working up in Alberta uh disillusioned because of my failure to make the national team for downhill skiing. Started running a little bit and it became very easily to me. Uh I lost about 30 pounds uh and realized that I was a runner and got involved in a number of sports throughout university. So, uh, my university career was, uh, pretty much, um, training my face off, um, racing. Eventually made it to the world championships and ski orienteering and, you know, kind of paying some attention to school and, you know, ended up doing fairly well and got into medical school. So, my first plan was to be a sports medicine doctor and, uh, started going through and I got very excited and interested in nutrition, metabolism. Uh, my former supervisor, who's now no longer with us, Dr. Duncan McDougall had done a lot of work in uh protein metabolism and you know weightlifting and how muscles respond uh to to protein and exercise. And so I got really jazzed up during um at that period of time decided to do a PhD. So I did my PhD with uh Dr. McDougall and Dr. Stephanie Atkinson who was in a nutrition department. So, I learned quite a bit about nutrition and we did nitrogen balance studies and uh I was the first I think to show that top sport endurance athletes needed almost twice the dietary protein as sedentary people did and top bodybuilders actually didn't
did and top bodybuilders actually didn't need as much as they thought. Many of them were taking four and five times the Canadian and US daily recommended intake. Um but in fact uh you know when they're at steady state even training 2 hours a day they only needed about 50 60% more. Uh people said I was crazy. I was laughed at at conferences by the old uh old school British uh nutritionists and pretty much run out of town with the the heresy to actually say that endurance athletes needed more protein. So at the time they had done studies with people going for a little stroll on the British moss and thinking somehow that was top sport. So what was unique I think is that I did have one foot in the camp of you know trying to be an elite athlete and one foot in the science to realize it's a whole different kettle of fish. you know, you look at tour to France athletes, you look at, you know, the guys I was training with, um, you know, V2 max well over 75 mills per kilogram, training your face off, and you're not always optimal, you know, periods of depletion. And we showed, uh, you know, that people needed more dietary protein. Uh, and, uh, so anyhow, over the decades, that's now become, you know, pretty standard that top sport athletes need about twice the dietary protein. um you know and of course with uh weight training and as we get older we'll get into this uh people need more dietary protein and better quality protein and that's where timing and so many other factors come in. So any I did my PhD it was a little bit crazy too at the time because I finished my MD all my uh buddies were going off and doing residency and here I was going to do a PhD. During that time uh I spent a day
PhD. During that time uh I spent a day and a half working in a neuromuscular clinic. So I got very excited about neurology and uh when I finished I had to do internal medicine for a year and then went into neurology and also trained in something called physical medicine. Uh so all of this sort of culminated in my interest in trying to help people who have muscle diseases and in general muscle disease causes weakness. uh and the other aspect of my uh care and stuff I was interested in was the mitochondria. So I was very interested in how the mitochondria process food and energy and uh we have a number of patients that have genetic mitochondrial disease which gives them profound reductions in their V2 max. So collectively I was saying well how can I take my sports experience, my nutrition experience, my neurology experience, my physical medicine experience, put it all together and help people. Um so I started off in 1996 uh seeing patients with nerve and muscle disorders and really trying to find ways with exercise and nutrition to increase strength and also to improve endurance by improving the mitochondria. And uh you know even then people thought I was crazy. Everyone said we're going to cure duchandrophe with you know gene therapy. um you know we need a drug for mitochondrial disease and here we are you know 30 years later and we definitely don't have a cure for duchand distrophe uh you know almost 40 years after the gene was discovered and for our mitochondrial patients the only randomized double blind trial that's
randomized double blind trial that's ever shown to improve mitochondrial function and lower oxidative stress was a multi-ingredient nutritional supplement that we uh published in a clinical trial in 2007 to be beneficial. So, we could talk about a lot of those different things, but in a nutshell, that's kind of, you know, how I got to where I am now. Yeah. Uh, what you really instilled in me and what I've learned from you was, uh, it seems like everybody's out there, maybe it has to do with like certain patented molecules that everybody's studying things like a monotherapy of a single agent, antioxidant. So what you've you know the work that you've done is really showing that formulations are the key especially with redux balance and and the understanding that some antioxidants can be prooxidant and some can have negative effects of you know uh attenuating or abolishing adaptive responses to exercise and stuff. So we'll get into that a little bit. I have some deeper questions on that. Uh but in regards to your training, if you could rewrite your early sort of uh training knowing what you know now, uh what would you change about how we train future physician scientists? You know, with that background with the appreciation of understanding, you know, metabolic medicine and mitochondrial function, do you think that is, you know, should be incorporated into uh the training of future scientists? And we we actually have a a nutrition uh scholarly concentration of nutrition
uh scholarly concentration of nutrition that's mandatory for our medical school, but that's pretty rare. Uh and they get, you know, an appreciation for, you know, nutrition and metabolism. uh but curious of your thoughts on this. Yeah, it's an interesting point. Uh I think when we look at most medical schools, uh you're lucky to get a one-hour lecture on mitochondria if that um and uh to understand the complexities of um you know carbohydrate, fat, protein metabolism and how it integrates uh with nutrition. Uh there's so little training. Uh I mean there's almost nothing on nutrition. you know, if you go through gastronenterology, you know, there's a little bit more emphasis on learning something about nutrition. But I think doesn't matter if you're a family medicine doctor, um, you know, if you're a geriatrician, think how important it is. I mean, I would guarantee that 95 to 98% of geriatricians wouldn't know that there's something called anabolic resistance as we get older. they wouldn't know the seinal work of Stu Phillips, the work that we've done and others uh to show how we can optimize uh protein to prevent an important thing which is affecting society which is sarcopenia loss of muscle and bone uh and you know issues like taking vitamin D to enhance natural calcium absorption versus you know taking a calcium salt and getting these pulses which can contribute you know to issues with aththeroscerosis. I mean all of the complexities of nutrition you know we really need to understand them and then unfortunately when someone goes to a family doctor
when someone goes to a family doctor geriatrician whoever it may be and they really don't even understand the basics of nutrition um you know many people with not too much insight can realize that the person really is not very knowledgeable and then you know nothing against you know naturopaths or anything but sometimes you know even those individuals think they know a lot about nutrition but they really don't often have deep understanding of the uh importance of nutrition and the fundamental biochemistry. So I uh unfortunately um you know I think a lot of the programs don't really get into the really hardcore biochemistry and maybe I'm old school but I still think you know you really have to understand uh all of the biochemical pathways to really understand the complexities of physiologic nutrition. I mean that's kind of a term I just came up with but the interplay between aging physiologic stress exercise and the complexities of nutrition require a deep understanding which is just not being uh taught to most of the uh folks in medical school these days in Canada and uh US in particular if you're serious about metabolic and cognitive optimization potency purity and delivery method really matter so that's why I've been very impressed with transcriptions So tro transcriptions uses a bugal troy which is a small lozenge placed between the cheek and the gum and this delivers the compounds in a way that bypasses first pass metabolism through the oral mucosa. So you get faster onset and
mucosa. So you get faster onset and higher bioavailability. These formulations are physician designed. They're pharmaceutical grade and they are tested for purity and potency. So these include things like methylene blue cordiseptin and B3 GABA and others and they are I want to emphasize precisely dosed. I've tried blue cannotine and trocom and can say that these are powerful supplements and they have true effects that you can feel for sure. So all these products are from prescriptions are made in the USA. they are aligned well with what we talk about here on the podcast, which includes metabolism, mitochondria, and mental performance. So, if you want to try a genuinely different delivery system and clinical grade standards, check them out at transcriptions. com / taboliclink or use the code metabolic link for 10% off. Thank you. Yeah, I think that's a really important message that you know the majority of uh patients that that are residents see they tell me you know 80% you know or more can be treated with nutritional you know intervention and uh and one area of nutritional metabolic mitochondrial sort of based therapies is uh and how how we met is through glycogen storage disease type two or Pompei disease and u po pump disease or Pompe disease uh is a therapy that has
Pompe disease uh is a therapy that has advanced pretty uh dramatically, I guess you could say, yet many patients still experience this progressive weakness over time. Uh what metabolic or mitochondrial pathways do you think remain uh untouched uh by current treatments and the work that you're doing? Where do you see that fits into advancing uh as you work on the science too? And I'll have to say that I I've met patients that uh were, you know, treated under you and I think they're very very fortunate to be able to have, you know, your expertise and and I think the outcomes of the patients that you're treating are probably much better just because you have that knowledge base and you can kind of convey that in their and nutrition and supplement therapies too. Yeah, there's many parts to this and it it does relate I think to some level uh to your first question and that is why is it that exercise and nutrition uh really aren't taught in medical school. I think it comes from pressure from drug companies. The drug companies for the last 50 years uh have the same mantra and that is identify a patentable single molecule. do, you know, in vitro work, do your animal work, all your what we call pre-clinical work, you know, do your first inhuman studies, uh, see if it's safe, then try it in the patient group, see if there's some evidence of efficacy, and then we go to what's called a phase three trial where, you know, neither the doctor nor the patients know what they're on, uh, and, you know, you give the drug. Now, every
you know, you give the drug. Now, every person who optimizes their nutrition and exercises and does not become obese and does not become diabetic is a lost client. And so the there is strong downward pressure and you know people may think you know I'm uh I'm a little bit crazy but I do believe that this is the case uh to to not promote exercise and optimal nutrition or to poo poo it and say well okay you know that's just that's that's not real science that's not real medicine. a drug is the only thing and I get this all the time you know when we say exercise and nutrition is really important but as I say the classic example duchen you know when I first saw that the gene was discovered back in the 80s we were supposed to have a genetic cure within 5 years we still have nothing and my patients who do best my one patient most boys with duchen for example uh will end up losing ambulation around age 10 to 12 little bit of benefit from one drug called a corticosteroid um but the only person I have walking still over at the age of 20 did not take any of the standard therapy, the corticosteroids, but had two hours a day of stretching and exercise with his grandfather who was a yoga master and optimized his nutrition and he's in university still walking. Uh so any just that's an anecdote, but we have innumerable examples uh how proper exercise nutrition can have a profound benefit. Now keep in mind that these are not exclusionary, they're not mutually exclusive. So uh I am all for and I I am the regional center for gene therapy for spinal muscular atrophy where it does
spinal muscular atrophy where it does work really well. I just saw a little kid who received gene therapy. But in addition stretching, exercise, um optimizing nutrition, we mom just asked me about you know is he getting enough protein. Uh we added creatine and we added a little bit more than what we use in muscle disease because we know that loading nerve takes a little bit more. Um there is oxidative stress and mitochondrial dysfunction. And you know we're giving a little bit of co-enzyme Q10. Now again anecdotal but our kids treated with gene therapy tend to do better if they you know do this intensive physiootherapy program stretching every single day with good you know inter intervention with OTP PT and the parent stretching every day and optimization of nutrition. So again, I think we need a holistic approach and you know, nothing against drugs. I prescribe them all the time, but I think we can mitigate some of the side effects of drugs with exercise and nutrition optimization. And you know, probably the the best example that people would understand is ompic or all of these so-called GLP1 medications. So we know that you know upwards of twothirds of individuals uh have obesity or overweight and so there's huge popularity of these drugs which pretty much work by suppressing your appetite and decreasing your your stomach's emptying so you feel full and therefore you don't eat as much. Now great drugs and for many people these are revolutionary and I'm fully supportive uh when a person needs them of taking these medications. However, they're known side effects. Uh and the side effects of these medications are there's
effects of these medications are there's bone loss and there's muscle loss. And it's no surprise uh people have known if you staple the stomach, if you just decrease your caloric intake, you're going to lose muscle and bone. And there's some folks and push down from the drug companies to say don't worry about it because if you're a little bit lighter, even if your muscle mass is lower, your function is probably not impacted or maybe even better. But I think everyone would probably agree that why don't we get the best of both worlds if we can optimize nutrition, optimize exercise and work with these to give people a loss of fat but preservation of muscle and improvement in function. You know, it's going to be a better lifelong strategy because we have to think 10, 20, 30 years down the line. You don't want to end up being a boneless chicken farm and having osteoporosis and being so sarcopenic you can't get out of a chair. So you know again it's just one of many ways in which I think we can optimize um people. Now you talked about pompa disease. Um pompa disease [clears throat] is a loal storage dis uh disorder. So the lo essentially is like a Pac-Man garbage disposal unit. So as we age as we exercise as we get you know ionizing radiation from the sun we get damage to some of our proteins. uh we get oxidative damage, dennaturation of the proteins and we have a process where that can be identified and we can remove those uh damaged proteins through a process called autophagy and uh when the autophagy engulfs the damaged protein, the lysosome really is this bag of
the lysosome really is this bag of enzymes which breaks it down and spits those components back so they can be reassembled. The diseases are different enzymes which are genetically encoded. If the gene is mutated, you don't make the enzyme and so it builds up in the loome. The problem there is the loome 1 can't do what it's supposed to do, which is clean up the cell. And in addition, in the case of Pompei disease, it's the glycogen that builds up and eventually they can burst out. [clears throat] The problem is that loss contain all of these proteolytic enzymes which start to damage the cell. But in addition, the second component which uh a very famous researcher Nina Rabin has shown is that it's not just the bursting and displacing the muscle. It's that they're not doing their job, you're not cleaning up the muscle. And that's where, you know, some of my hypotheses came in that if we don't clean up the mitochondria, if we're getting oxidative stress building up, we get all these epipenomenon, which is inflammation, oxidative stress, mitochondrial dysfunction, uh due to this impaired autophagy. And so what we've looked at is yes, our patients are treated with an enzyme replacement therapy and there's talk about gene therapy, but if they sit on their butt, they don't eat well, and they're not moving, they often become overweight or obese, which then further impairs their generalized function. So our point's always been, well, let's optimize everything, exercise, nutrition, and give them the uh the ERT. And in addition, we've now started to look at these epi phenomenon. Can we improve the mitochondrial dysfunction? Can we lower inflammation? Can we lower
Can we lower inflammation? Can we lower oxidative stress? And we've come up with a variety of multi-ingredient supplement approaches to target. Now, the hypothesis of multi-ingredient supplements we put forth in 2001 in a paper in analysis neurology that to treat these complex neurologic disorders, you can't just throw a single molecule at oxidative stress and you can't just, you know, try and improve autophagy. Um, mother nature really, uh, you know, has all of these processes going on and we think the best way to approach it is to target multiple final common pathways. And we proved that in 2007 in our mitochondrial disease patients that with a four ingredient supplement specifically designed to work in the mitochondria where the problem is, that we can lower oxidative stress and improve mitochondrial function in our patients. And we've now spun that out to different things like improving skin health, um, obesity support, pompa disease support, uh, musculardrophe, etc. On the metabolic link, we talk a lot about being intentional and what we put into our bodies, but what about what we put on our bodies? Your skin is the largest organ, and most of the quote unquote clean skin care products are still filled with ingredients that are potentially harmful. As an example, if the ingredient list says fragrance or perfume, like about 70% of them do, that's an umbrella term for phalates. And phalates are endocrine disrupting chemicals, especially for kids. Don't want to be putting them on your skin, especially for kids. That's why we've partnered with Tups and Co. Organics.
partnered with Tups and Co. Organics. Their products are made with ingredients that actually support your skin's natural biology. If you're ready to simplify your routine and avoid parabens, avoid phalates, and avoid any of these hormone disrupting chemicals, go to tupes andco. com / tabolic and use the code metabolic for 25% off of your first order. Yeah, I I think you may have answered the next question which is you know uh do you foresee in the future precision nutrition or metabolic enhancement of uh meaningfully augmenting enzyme replacement therapy in pump and I know I mean everything that you do is really uh it's like exercise enhanced you know X so you're using exercise to like enhance and with with uh enzyme replacement therapy uh I think there's a discussion about just exercising to move the enzymes to where they need to be. Or maybe some of the formulations you're working with could maybe get them into tissues better or preserve uh you know prevent it from being uh neutralized or augmented by the immune system. So maybe talk about uh if if you think this is you know important the the therapies you're working on including exercise and your um the formulations that you have augmenting and further enhancing the therapeutic efficacy of ERT. Yeah. So uh ERT is enzyme replacement therapy. So essentially we infuse the
therapy. So essentially we infuse the enzyme that's missing because of the genetic defect. Fortunately with the pompa disease that enzyme can be taken up by a specific receptor and go to the loome. So people thought, okay, it's a cure. Don't worry about anything else. You know, we've got our one molecule. We've got our patents. We're paying $ 700, 000 to a million dollars a year for this. Uh drug companies are happy and patients think that this is the only thing that works. Um however, it's pretty clear. We showed in 2012 uh with the mouse model that by adding exercise to ERT in the mice, we could more than double the benefit. And part of that is clearly just increasing muscle strength and function is important. But part of the way that that works and how we showed is that we could increase uh uh this autophagic process. So the best way to activate autophagy uh we can activate it with fasting which you got to be careful. You don't want to go too much for too long because you can start decreasing your calories and your protein. So fasting is one way but exercise is mother nature's way of turning it on. And we did show that we could activate autophagy with exercise and the mice who exercised plus ERT did far better than the mice that just had this ERT or this enzyme replacement therapy. So that's uh where we first hypothesized this would work, but now there have been multiple studies. a study coming out of Greece where they use combined endurance and resistance exercise, a study in the Netherlands and we've just finished a study um which I um presented some of the data at the Minneapolis meeting where the improvement and these are patients who
improvement and these are patients who are stable on ERT already. We then added four months of targeted exercise which was a combination of endurance and resistance which we think is probably the best for all muscle disease and for you know most people for health span. Um, and what we found is a better improvement in the six-minute walk test than has been reported for the ERT in any one of the three main studies. We found dramatic improvements in uh the breathing strength. Um, we also did a really cool thing where they did a plank uh and that increased by 100%. And why that's important is these patients get a lot of weakness in the core and that core weakness really impairs their gate and we could double their endurance time uh with a plank type of activity that they were doing. So uh absolutely showing that you can add to the benefits of ERT and importantly what we're now looking at is can we also add some of our nutritional supplements. We have data in the mouse model where we've said okay we've now shown that exercise works. What about targeted nutrition as well? So in that study, what a lot of patients were doing was going on the ketogenic diet. And so uh you know, you've done work on this and you were the one who uh the pennies dropped thanks to your work. So uh again I remember uh we met down in San Antonio and uh we had [clears throat] done this study in our mouse where we gave them a ketogenic diet very similar to what we use when kids have bad seizures and we didn't see much benefit and I couldn't figure it out. I was thinking this just
figure it out. I was thinking this just doesn't make sense because we're we should be activating autophagy. We are also reducing the amount of sugar in the diet. So we're reducing the precursor to this glycogen accumulation called substrate reduction. So I thought for sure it was going to be amazing. However, it was your work that got me thinking and we talked about it afterwards. We had the traditional uh anti-epilepsy diet. We didn't have enough protein and duh, the person that first looked at protein requirements, I didn't even think about that. So really, a ketogenic diet with adequate protein almost certainly is going to work amazingly and I know your work shown that and I totally agree with that. But then what we did is we uh used a precursor to ketones called 13b butane dial. The way and reason why I think that worked is that it allowed us to give the animals enough protein, but then we gave them the benefits of the ketone. So again, if you had a ketogenic diet with adequate protein or, you know, we had the ketone precursor. So that worked on its own as you would expect because, uh, you know, you're more of an expert than I am in the ketones, uh, clearly there's benefit increasing autophagy. You know, we get some substrate reduction. There's many other benefits. And then we also added our mitochondrial cocktail to try and lower oxidative stress. and it was sort of icing on the cake. So, um the 13 betain dial, you know, worked really well. Uh and then when we added our other uh multi-ingredient supplement, it was just even further benefit. And we're now studying uh this uh in our Pompei patients. Next week, actually, we are going to break the code. Um so, the data is what we call locked. an independent
is what we call locked. an independent third party holds all the the codes and then we'll know who was on what and then we'll really see in humans as we showed with exercise the benefit exercise plus nutrition or we're going to get an added benefit and we'll find that out next week. Yeah, no doubt that exercise is such a big lever you know in muscle and also probably in brain and the CNS too. Uh I was wondering is there sort of a metabolic signature or a specific biioarker I guess that could be blood or functional or maybe even dexa that you believe could predict the neur in neuromuscular patients or how they will respond best to the intervention. um and is you know I guess I mean you're looking at the functional outcomes the plank I mean that's probably I don't know who else used that uses like a plank but it's probably one of the most important you know the six-minute walk I guess is pretty pretty uh important too but u I was wondering if there's like a a blood biioarker and I've often thought about this for things like hyperbaric oxygen therapy or other antioxidant therapies is there a redux you know marker that we can look at to to know if we're shift ing things and you know shifting things out of balance. Yeah, I think that's an important uh um question and there's so many aspects to that. So it depends on the disease of course. Uh I mean we have for me the most important thing at the end of the day is function. Uh the other thing that's critical is body composition. Um because you know if we have an intervention and we're losing bone mass
intervention and we're losing bone mass or we're losing muscle mass, you know that's not optimal. We want to optimize the ratio between muscle and body fat. Uh we want to make sure that bone health is is adequate because we're in it for the long run. Uh we're now, you know, saving our kids with SMA. Our kids with duchen are living 10 years longer. Our patients with Pompei disease are living longer and we need to think about the full metabolic health. Um you know, unfortunately um again with this push towards um you know, single molecules and drugs, uh we're forgetting about the holistic metabolic health that's important for someone's health. So, for example, in the cover of of uh The Economist magazine for Ozmpic, essentially it says, "Eat, inject, repeat, and they've got a big hot dog with all the toppings on it." I I can't think of a worse public health message. So, don't worry about what you eat. Don't worry about exercise. Don't worry about anything. All you need is a drug and it's going to cure you. It will not. What people forget is that every study and know I keep going back to the obesity thing but it's just a classic example uh that every study whether it's beriatric surgery whether it's ompic or one of the new dual aagonist it is exercise and nutrition are very significant components but it's always sort of poo pooed but you have to have that in there and if you read the fine print on every one of those you know they're they have a nutritionist that tells them how to eat better they have an exercise physiologist that puts them through the ACSM guidelines. So they're usually 150 minutes of exercise per week. So it's not in isolation. And again, we have to always be thinking about our sort of mother nature
about our sort of mother nature biological defaults. And that is number one, the only thing that's ever been shown to increase human lifespan is what? Exercise, right? Exercise. So all this handwaving about these not even caloric restriction you know maybe just in in you know small mammals and uh you know there's some non-human primate stuff and sea elegance and you know but yeah it's exercise just it's a massive lever and it's just we do not pay enough attention to that or teaching that actually in medical school but we do have a lifestyle medicine residency now and then uh we have like student groups so the stu it comes up from the bottom up not from the top down, you know, administrative level, but the bottom up. Students start their own groups on exercise like in lifestyle medicine. Hair loss is fundamentally a bioenergetic problem at the follicular level. So over the last year, I've consistently used the eye restore elite helmet and here it is. And I can confidently say that I've noticed zero hair loss. My wife says it's getting thicker. The system combines lasers. It combines LEDs that are engineered at very precise red light wavelengths to stimulate mitochondrial activity and help reactivate dormant hair follicules. So we know that food is medicine and also light is also medicine and light can stimulate the mitochondria in ways that can optimize the bioenergetic
that can optimize the bioenergetic effects of the follicle and also stimulate blood flow. The aluminina face mask uses red, infrared, and blue light simultaneously to support collagen production, circulation, and also skin clarity. It's clinicalra photobiomodulation that you can use at home while you're working, while you're reading. I pop the hat on, you know, first thing in the morning when I get to work at the desk here. So, right now during our spring savings, you can get the elite and the aluminina bundle at an exclusive discount with the code metabolic link at i restore. com / medaboliclink. So, that's metabolic link at i restore. com / taboliclink. Support the show and give your hair and skin the upgrade it deserves. The only strategy that's been proven in humans to extend lifespan by about four years is regular endurance exercise. Now uh you know and you can hand wave and I'm going to be dead before anything ever could be proven. So all these single molecules that they're trying you know rapamy and metformin we can talk about all these things um probably not going to work. Uh but they've never been proven and yet people are you know suggesting that they're improving people's longevity. It's complete heresy and garbage. Now the other important point is health span and part of health span is strength and so I'm a big fan and even though when I was an elite athlete I was only doing endurance stuff then I started to get older you have kids and grandchildren
older you have kids and grandchildren and you know you start to get a bit of sarcopenic can't pick them up and you can't lift what you used to I'm so much more of the belief that you really need both endurance and resistance to get optimization you get the metabolic benefits the lifespan extension from the endurance uh but in addition we can't forget about uh uh weight training. And for those of people that know me as a endurance athlete, but might think it's crazy, but all of our research in older adults and our patients clearly show you've got to be doing at least three times per week of more resistance type training to keep the muscles strong. Uh you know, get you off a toilet. Um even the work by the great bank saltine showed that top um marathoners uh in their 70s were no stronger than sedentary folks if they didn't do any weight training. Uh and I was you know classic example of that. And so now you know three times a week I'm doing leg press you know knee extensions hamstring curls um you know arm weights and the whole nine yards. And I really think that that's not just important for our health span but it's also important for our patient groups especially as we get older. It's just critical. Yeah. I think about it is, you know, from a financial, you know, analogy, I guess. So, you want to deposit as much as you can early in life into, uh, your bone mineral density and your muscle. You know, deposit as much muscle as possible into that because after 50, I tell you, you know, after turning, you know, 45 and 50s, uh, it becomes harder to keep that, but it's so much easier to keep what you have built, you know, if
keep what you have built, you know, if in in younger age. That's something to this muscle memory. Uh with that in mind, especially with you know uh the crazy sort of endurance stuff that you've done and I know uh you know well one point I want to you had mentioned uh AIB that you had AIB and I know and I've heard this from elite level athletes you know they've reported that AIB and and there's something going on with AIB. Is there a point more of a broad question? Is there a point where exercise becomes pro-aging? And you know, and what are the early warning signs for for athletes or patients who are unknowingly sort of overtraining their way into metabolic dysfunction or a pro-aging? Uh because I just I I know people in my sphere [laughter] that are working out three, four hours a day. I'm a minimalist when it comes to workout. Uh, but I should do more cardio stuff. But yeah, so where does exercise become pro-aging? Yeah, it's a good point. I I think everything, you know, there's a U-shape curve and it's very clear with endurance exercise, uh, that you can cross a threshold. Um, now, you know, forget about doping because we know that some of the top, you know, tour def France and other experiences with orienteers and skiers, people were dying from, you know, probably hyper viscosity from taking too much EPO. um you know real tragedy that people would push to that level. Uh but you know that aside from a normal physiology uh there is clearly a um threshold that can be passed. I know
um threshold that can be passed. I know myself I've never doped you know I know cuz it's my body and I've never done anything but I clearly developed issues and this is well known that top endurance athletes and you know some of the stupid things that we did too. I mean, you know, I've run a race where uh my vision tunnneled down to just a little speck and I just made it over the finish line to beat this guy who was drafting behind me for 25k. You know, I've crapped blood many times. Um like just pure blood. Um I used to have such bad stomach pains for usually 24 hours after the endurance races I did. So, I mean, these are, you know, you're really pushing yourself not just for physiologic adaptation, but you're dipping into pathology, you know, and there's a recovery period. No question about it and you still can compete well. But at some point, quick question. Have you done blood work after that? I think of rabdomiolyis, you know, and I know some people I wonder if you've, you know, ever gotten blood work shortly after and what that looks like. I don't think I've ever asked anyone that question. Oh, absolutely. Yeah, there's just no question. Uh, you know, and I'm very prone to ravdo, whereas a guy I've trained with is not. And there's a huge variability. Uh we did a study uh where we did a relay run um 800 km sort of relay run down the Bruce Trail and we published it where we did blood samples uh and on average this is you know some people were higher some were lower but on average the CK was under 200 which is normal to start and it was over 2, 000 by the time we finished uh you know six legs which is not that crazy. I mean I've seen some people up to a million but nevertheless clearly there's damage. So, what was interesting is I didn't
So, what was interesting is I didn't know the literature on damage to the heart because it really hadn't been uh published very much at the time, but I ripped all my hamstrings off when I was 42. Um, you know, went through surgery, reattached them, fixed my sciatic nerve. And then as I was recovering, I started biking again and I was going up a hill and my heart rate all of a sudden went from 100 to 200. And I said, "Well, that's not good because it's an exact multiple." And then it would go to 150. So, I knew that was what's called atrial flutter. So, I went to see my cardiologist. I got an ablation. Um, you know, got back two weeks later ran another race. Uh, you know, won the race and then two weeks after that tried to do another race and went back into atrial flutter. Had another ablation. Then I went into fib. Tried to deal with it with three different medications. Um, you know, couldn't drink even one sip of I mean one beer would would trip it. It was so bad. But then the literature was starting to come out that there's almost a five-fold greater risk of atrial fibrillation in top sport endurance athletes. um that alone you know wasn't shown to you know alter the mortality and there still is benefit but that's such a narrow window of the population that you know I'm not sure we know exactly what the delterious consequences are there is data now and uh I won't say the person's name but I was with you know a world record holder in the marathon and uh you know he has a really high calc coronary calcium score so that's the other thing that we're seeing in some of the top sport athletes coronary calcium buildup uh and that's been well documented now. What that means and the consequences is, you know, a little bit unclear, but it's probably not a good thing to have this uh calcium
not a good thing to have this uh calcium in your coronary arteries. And I suspect I probably have it as well. I know when I start running now, it takes me about half an hour just to warm up. So, it's probably that, you know, there's there's decreased compliance in the vessels, but I've now had three cardiac ablation surgeries to get rid of my atrial fibrillation. I mean, fortunately, it worked and I'm on no medications, but uh it would have been nice if I didn't do that. Now it's more common in men than women. That's been shown and that's probably an oxidative stress issue. So again when we exercise we get oxidative stress. We get muscle damage as you say CK comes at a muscle and then we get hormetic adaptation. So the body responds to it and say I don't need this stress. So we upregulate proteins and we we upregulate antioxidants inside our body to bring down oxidative stress. But I think too many crosses over into pathology. we start to you know accumulate some damage probably some scar tissue in the conductive system leading to the atrial fib and calcium deposition in the coronary arteries probably driven by inflammation too right and that's like another topic I was wondering have you gotten a CT angiogram or like a corateed in inima thickness or look at soft plaque and heart soft plaque or and calcium I've not because I figure what am I going to do about it I do everything right I mean I'm an optimal nutrition um you know, I'm exercising, but what I've done is I I I've given up and you know, I'm old and slow now. So, it's it's too much for my psyche to to go out and say, "My goodness, I can't do three-minute ks on the trail anymore." Um though, I I just totally don't go out and push
just totally don't go out and push myself. I still do long duration endurance things. I'm still adventure racing. My wife and I have recently won a master's division adventure race, but again, it's a much lower intensity. So, I'm just for the rest of my life, I'm not going to push to that, you know, pooping blood or going blind uh level of uh of stress. Just not worth it. If you're relying on highdosese caffeine, coffee, for example, to power you through your day, you're probably riding a dopamine spike and crash cycle that drives irritability, poor sleep, and even compensatory behaviors like going for alcohol to take the edge off at the end of the day. So, I've been there. that too much caffeine is definitely a negative thing in my life. I've cut it by half and I feel better, have more energy. So, Mudwater was part of that process. MUD / WTR Mudwater offers a a much smarter approach. Their new low caffeine blend delivers just 45 milligrams of caffeine. It's also paired with elenine, the amino acid, has a gabaurgic effect. And it's also paired with functional mushrooms like lion's mane and cortiseps to support focus, mitochondrial energy, and also cognitive performance without stimulation. So the original blend combines cacao, it combines chai and adaptogenic mushrooms uh for a polyphenol rich USDA organic zero sugar
polyphenol rich USDA organic zero sugar drink. So, it's really if I had to come up with a lower caffeine optimized uh drink like this would be it. So, head to mudwater. com that's mudwt. com / taboliclink and get up to 43% off. Plus, you get free shipping. Plus, you get a free rechargeable frother with this deal. So, you're not going to find a better deal than this. So, use the code metabolic link at checkout. That's m u dwtrmudwwater. com / metaboliclink and use the code metabolic link for 43% off free shipping and also a free rechargeable frother and uh just curious have you looked at things like C reactive protein like in in athletes and as and just like the baseline level of systemic inflammation just wondering. Yeah. So people were worried when we first started exercising people with muscle disease and in aging. I remember talking about exercising older adults and some Europeans at a conference were saying it's crazy you're going to increase their oxidative stress. You know we know they have elevated oxidative stress and it's going to be bad for them. What people don't realize is there's a difference between pulsatility and chronic lowgrade. Chronic lowrade is never good. So that chronic uh low gradede elevation of CRP chronic increase in oxidative stress is not a good thing. But the pulses are a good thing. Every time you exercise, you know, IL6 is going through the roof. Um, you know, many other inflammatory markers go up. But then that's part of
markers go up. But then that's part of the horatic adaptation. And what we found u many years ago, Johnny Perez was one of my PhD students and we showed that older adults after they did an exercise program actually had lower levels of oxidative stress and that was due to the fact that they horatically would upregulate their endogenous antioxidants. So you know exercise is always a a great strategy and again it's our biological default uh much in the way that multi-ingredients essentially is how we evolved. We evolved with food which is a complex matrix of so many different you know protein and carbohydrates and v vitamins and minerals. It's not isolated single nutrients and almost every epidemiology study uh really shows the benefits of eating you know uh colored vegetables for example and you know a variety of different colors eating close to nature um and yet single ingredients often fail like you know just giving highdose vitamin E for example it's failed miserably in trying to prevent cancer actually made people at greater risk of cancer who were smokers um so generally and that's part of our philosophy is you know biologically we ate mixture of foods. Uh, and that's how we evolved as homo sapiens the last 300, 000 years. We also evolved to do endurance exercise. I mean, it's probably what allowed us out of Africa 80, 000 years ago was the ability to perform endurance exercise. So, those two things, we've got to support them, I think, for optimal health. Yeah. And it's really that adaptive response to the periodic pulse of oxidative stimulus which could be
oxidative stimulus which could be blocked uh conceivably by uh not conceivably factually by antioxidants and that's a direction I I kind of want to go in now uh because I was fascinated with antioxidants as a PhD student and as a post-docctoral fellow and found certain antioxidants my in vitro experiments whether [clears throat] they're patchclamp electrphysiology or measuring mitochondrial superoxide production or oxid, you know, membrane lipid peroxidation. We did tea bar tests and things like that. Antioxidants always worked really great in a petri dish, but uh but they largely were unproven and they did not work for what I was studying, which is central nervous system oxygen toxicity seizures, which is manifested, you know, by uh which the theory was oxidative stress would overwhelm and and you know, oxygen's a stimulant. Uh so so this idea that you know antioxidants um I know you're using combinations of antioxidants. So one of the questions is which antioxidant combinations or doses do you consider most potentially uh you know harmful for longevity? formulations might actually be promising when you strategically in the and and when you do the formulations, I know you you just you draw off a lot of your experience and knowledge that you probably have greater knowledge of this than anybody in the world. Uh but are you using now like AI uh AI algorithms and things to like generate uh you know things for specific
uh you know things for specific disorders because everybody is a unique metabolic entity and I was wondering if someone's metabolic profile or specific mitochondrial disorder would necessitate sort of a different formulation. Yeah. Number of boy it opens up a whole bunch of different things to think about. Um first of all uh I think what we have to do is always test in humans. Uh first a mammal preclinical work uh as you pointed out petri dish my goodness we can cure duchenand distrib cure anything in a petri dish and we even started a company and went bankrupt uh looking at gene delivery with exoomes where we had great in vitro work uh some you know okay stuff in in animals but then we had a patient who proved that it could never work. Uh so the wonder of biology uh you know completely tanked our company. Uh but the point there is um you know even in clinical trials things can look really good but you fundamentally need to be in a randomized double blind trial to see placebo versus the active. Do you actually do in the human matrix what you expect that you're doing? And uh you know where I uh where I'm going with this is we did a study uh based on some interesting work that came out a few years ago by Risto in PNAS and what they found is when they gave vitamin E and vitamin C to middle-aged individuals who are exercise training it blunted the benefits and the theory there is hormmesis right you need the pulse to you know lead to the upregulation then of the genes which
upregulation then of the genes which give you your endogenous antioxidants and also So there's good uh evidence that pulses of oxidative stress lead to mitochondrial biogenesis. Bruce Spiegelman with the whole PGC1 alpha and some of his posttos worked on that whole signaling. So anyhow that was the concept that if we blunt our signaling too much uh we don't get hormetic adaptation and you know certainly that study did show it. So what we wanted to do was to look uh with muscle biopsies to see if that would blunt the pulsatility of the mRNA uh that's used for adaptation. And so uh we gave an antioxidant combination and again if AI generated this which is what it would do it would go out and say you know uh and and problem with AI is that it doesn't it can't evaluate the literature properly. So you know if a person who's never published a paper but they've got a lot of social influence that's going to drive a lot of what you get. Um and so what it would have done is just what we did is we went and said okay here's 10 antioxidants. they're called antioxidants. Let's throw them into a mixture. Let's give them to the humans and which we did. And then when he showed me the data, I said, you know, you must have mixed up your columns because it looks like it's the opposite. And uh I said, you know, go back, you know, recheck everything. There must be a mistake here. So what happened is that these antioxidants when we gave them in a petri dish were powerful antioxidants. We couldn't even generate free radicals. But when we gave them to the human as it went through the physiologic matrix of a human, it became a prooxidant in the human. So my point there is everything
human. So my point there is everything that is a quote antioxidant listed and stated as such doesn't always function that way in a human. So you have to show whatever you're uh giving and you think is doing X Y or Z you've got to prove it in a human that ultimately it's doing that. So that's what we did with our core which we call which is the alphalapoic acid co-enzyme Q10 vitamin E and creatine which we studied in 2007 in a randomized double blind trial in patients who had increased oxidative stress increased inflammation and poor mitochondria. The V2 max for example in our patient with mitochondrial disease the average was 8 milliliters per kilogram per minute. So all of us sitting here were around four ms per kilogram. Top sport athlete. I mean at one point mine was over 87 ms per kilogram. Um but you know eight is below the estimated threshold for independent living. People say you need about 12 ms per kilogram per minute for independent living. That's how poor their mitochondrial function was. And yet we could lower the lactic acid which was reflective of mitochondrial function and lower two markers of oxidative stress. So we know that that's working. And so what we've done is we've taken that as our core and then depending on what we're working on uh we add things to it. So we've shown now uh first in two pre-clinical studies independently done by a third party that adding a few things green tea extract green coffee bean extract um and forcolin which is a mint extract uh that we can lower body fat lower um fatty liver disease in uh
fat lower um fatty liver disease in uh overweight and obese mice. uh and that was shown by an independent third party uh who didn't believe me so we sent them the stuff blinded. We've now done a randomized double blind human trial showing that that works and that's just one example. Then we also use that core and we've shown that we can improve skin health. Um we've also used that core and an individual who is a radiologist was worried about ionizing radiation. So we added certain things to it to focus more on on ionizing radiation and showed again in pre-clinical work that we could uh we could lower it. So um you know depending on the disease we're treating um but pregnancy for example you know start with the core and then you know what other things are important folate to prevent neural tube defects you know and we've shown that we can improve fertility in the overweight and obese mouse model and also in an aging mouse model and if you look at fertility or infertility two most common causes in North America are being overweight or obese uh andor aging ovaries um you know a 35-year - old woman's ovaries mitochondria don't function very well there's ox state of stress and inflammation and that limits fertility, but we could show that we could improve that with a targeted supplement. Wow, that's yeah, that's really interesting because I've I've heard different, you know, dietary therapies and other supplements out there uh or people claim that, but you actually are doing the RCTs to kind of show that. And I guess there's, you know, where do you draw the line between helpful hormesis and harmful oxidative stress? And I was wondering is there a practical way for people out there to like uh measure the
people out there to like uh measure the balance like in everyday people and and is it uh I know that's hard to do from I don't know if there's you know an at home kit that you could do. I just kind of use subjectively sort of how I feel. Uh you know 20 years ago I could like you know work out really hard deadlift squats and and in 24 hours I'd be okay. I but but nowadays it takes like you know two or three or four days to recover and I just feel almost like brain fog like the day after like if I have to do something and that involves a lot of mental thought. I don't work out. I'm almost like useless the day after if I do a really hard workout. It's just I'm kind of in a fog and I'm just feel inflamed and then maybe that's just the consequence of aging. But I was wondering like is there a practical way to measure sort of the the balance and just you know elite athletes are always pushing that edge and we have wearable devices that look at heart rate variability and and different you know continuous glucose monitors and if you're really inflamed I guess from the maybe you'd be trending a little bit high with your glucose levels or you know anything out there that you think that could give people insight into their yeah that balance. Yeah, it's a tough one. I mean, you know, biologically, uh, you know, we know all sorts of stuff. Doing muscle biopsies and gene expression, all these things that we can do. There's a whole host of things I, you know, could could rhyme off that we could look at in blood. Uh, you know, as you mentioned, Ta bars, you know, you can look at the ratio of oxidative and reduced glutathione. There's many many measurements we can do. 8 hydroxy 2 deoxxy guanazine blah. The
deoxxy guanazine blah. The list goes on for oxidative stress markers. But it's not practical. um you know even most labs like our lab here if I went down there and said you know can you measure oxidative stress they'd look at me like I have you know two heads we just don't measure them clinically it's only through a research lab and even with that too you'd have to contextually say what is the baseline how long after exercise so if you start going too far down that wormhole I think people become too um you know obsessed and uh and you know you're never going to get the right answer it's going to be too complex you know I really like what you're saying and that is how do you feel at the end of the day? You know, I think a wearable device is is a good thing. You know, is your resting heart rate trending upwards? You're probably overtraining. Uh you know, some of the heart rate variability stuff that you can get the feedback on the watches. Uh those things I think are helpful and they're inexpensive. Uh and the the um you know, the feedback that we're getting now from some of these wearable devices is is quite helpful. Uh sleep is critical. So, you know, if your sleep is messed up, you're not going to get that restorative sleep. We still don't know what sleep does, but we know it's essential. The if you don't sleep, there's a fatal disease where you will eventually die. Uh I'm sure everybody knows when you don't sleep, you feel trash the next day. And there's now a link between good sleep and these things called clock genes which can activate your mitochondria. So, you know, good quality sleep is important. Uh optimization of nutrition, um you know, timing of your nutrition, for example. I mean, we're going all over the place here, but one important thing that we found was a very simple
thing that we found was a very simple strategy, and that was taking your carbohydrate and protein and a little bit of fat immediately post exercise versus taking the same amount in the morning during a simulated oneweek training camp. We found at the end of the week, these women that we were overtraining a little bit for that week had better nitrogen balance. So, they held on to more of the protein and they performed better at the end of the week just by same amount of calories, same amount of protein. We just gave it immediately post exercise. So I think for a lot of folks was that Mark, sorry to interrupt. Uh that post exercise was that later in the day instead of a morning feeding and they would exercise and then do that later in the day. Yeah. So what we would do is we either gave them essentially a defined formula diet like you probably heard of insure and boost and these sort of things. We gave them that add added on to their breakfast or immediately after their workout. So if their workout then was like at 9: 00 and they finished at 10: 00, they would take the exact same amount. So they had a placebo in the morning and they had the boost right after exercise or they had boost in the morning, placebo afterwards. Just changing that around even though we kept the protein intake all week and the calories the same uh people perform better uh and you know they felt better at the end of the week. So I think how you feel is an important thing. Uh but there's a lot of really uh you know simple things I think that uh that people can do um from health span perspective. Mixing it up is important. Optimal uh recovery so you're not exercising the exact same muscle the exact same way you know seven days a week which is what we tried to do when we were younger and you know you can get
we were younger and you know you can get away with it when you're young. You can get away with not the best nutrition. We were just talking about this yesterday. Some of the mistakes that we made and we still were performing at an elite level. Uh but as we get older the importance of optimal nutrition, improving sleep, optimal time for recovery become that much more important. And uh you know for some people uh tracking it is important. People like you and I that have done this our whole life you can kind of feel it a little bit. But I think for some people they may not be as in tune with their body and having some sort of a wearable tracking device is important. Now I know there's all this stuff about you know we can take your blood and do AI this and AI that. I unfortunately I've been around for too long to believe that that's going to be real. Uh the problem there again is that when did you take it? Was it 1 hour, two hour, immediately post exercise? What did you eat? There's so many factors that can influence you know metabolomics for example in in your blood like you need it's really hard to interpret metabolomics. Challenge too is a lot of these things just go into some AI generated thing which I've seen so much crap come out of that stuff and so many hallucinations. I'm I'm sorry, but I just I don't believe that AI is going to replace human intelligence. Human intelligence with lots of smart people putting their heads together uh and mimicking mother nature. I'm sorry, but I don't think AI is ever going to be smarter than mother nature. You know, we've evolved uh with mitochondria for the last two billion years. We've evolved as mammals, you know, for the last 200 million years. We've evolved as homo sapiens for the last 300, 000 years.
homo sapiens for the last 300, 000 years. If we understand what works and allowed us to be where we are, [clears throat] which is what we do at our company and what I've done with all my research, understand exercise and nutrition and how did we get where we are and how can we mimic that to optimize health and performance. That's kind of our philosophy. Yeah. I mean, you talked a lot about um we're longevity and health span in particular. And uh one thing we didn't talk about which is a bit controversial but gets a lot of uh attention is drugs. So uh and now you have metformin rapamy NAD boosters SDLT2 inhibitors uh and also peptides. Uh so do you think maybe just focus on like uh peptides right now because I didn't I just popped into my head. Uh and these are heavily marketed. there's whole like you know at the American Academy for uh longevity or A4M or you know that's going on and that takes up you know a lot of people's bandwidth when when just the discussions about longevity and health span uh and I don't think I've ever talked about this to you and what what do you think the the current state of the use of peptides and the explosion and the emerging science I guess or maybe lack of science on peptides what do you What's your opinions on there? Yeah, it's it's a tough one. There's a a lot of extrapolation I think uh with this and uh again if we don't look to the past we make the mistakes moving forward. So the most logical things are testosterone
testosterone testosterone um and growth hormone and IGF-1. So uh I think the data is pretty clear. There's been great work by a fellow named Basain who's done a lot of work with testosterone and it's pretty clear that if you're hypogonatal uh you don't get the same adaptations and you're associated with lower muscle mass. So I think for men it makes a lot of sense to you know have your testosterone levels checked both total and free and bringing them into the normal range of your hypogonatal will allow you to optimize. So I think that's you know that makes sense and there's strong strong data for that. Now, of course, we have to be careful about, you know, prostate, but remember, you're not super compensating. You're just bring it to a normal range. So, your risk of prostate cancer in the normal range is no different than anybody else who's in the normal range, right? Um, and maybe it's a little lower if you're hypogonatal, but you know, who cares if your prostate risk is down a tiny bit, but you're, you know, sarcopenic and you're not getting the optimization. So, I think that's one peptide. Well, it's a hormone, steroid based hormone that makes sense. The other one is growth hormone. So uh with growth hormone, Kevin Urasheski at Wash University published data and with IGF-1 which is sort of growth hormone causes IGF-1 to be released from the liver and can help us to build muscle and those you know pretty much failed in sarcopenic older adults in those studies. So it it makes a lot of sense. It sounds really groovy but um you know with those not working it just raises a question as to what that efficacy is. So then one of the interesting stories is growth hormone.
interesting stories is growth hormone. People think growth hormone, okay, bigger, stronger, you're going to get more muscles. Uh, and there was an anecdote, Mike Renie, who's uh, one of the top protein guys in the world, uh, was doing a postto, not a posttock, a sabbatical with Bob Wolf, and uh, he was at a local bar talking to some of the bodybuilders, and they were saying they take testosterone to build their muscle and they take growth hormone to toughen up their connective tissue. And Mike said, "Ah, you're full of you know, blah." And so he went back and actually did the study with stabilizes. Lo and behold, it was true that the growth hormone [clears throat] seems to increase the fractional synthetic rate of collagen. So, uh it actually, you know, just through trial and error, the bodybuilders seemed to realize if you just take testosterone, your muscles get big, but your connective tissue doesn't keep up. So, they were hardening was the term they used with the growth hormone. So, I think for people with muscularkeeletal injuries, there may be some benefit to to some growth hormone. again, you know, not for performance because that's cheating and that's performance-enhancing drugs, but when you're older and you know, if you're getting muscularkeeletal injuries and you want to optimize, I think there's there's some evidence that that might be reasonable. And there's a whole host of other ones that are coming up, but the problem is they haven't stood the test of multiple randomized human clinical trials to show are they doing what they're doing. And I would also state and this is the same for nutrition. It's the same for any drug. Show me that it works on top of somebody doing proper nutrition and exercise because if you are just saying look I'm going to sit on my ars do nothing take
going to sit on my ars do nothing take this. Yeah maybe you'll get some benefit but it's not going to be proven to extend health span and lifespan in the way in which optimized exercise nutrition is. So that's an important thing too because we get back to the hormmesis where you know certain highdosese antioxidants have been shown to blunt the benefits of exercise. Anything that uh negates or attenuates the benefits of exercise I don't think is going to be uh you know appropriate and it needs to be everything needs to be studied in that context which I hasten to add we do in our pre-clinical work and all of our clinical trials we always have exercise as your sort of baseline and can we optimize the benefits of exercise and even with obesity I'm sorry but every study in the world has to have exercise and nutritional advice and then you layer the ompic so all the results that you see, you know, with 16% body fat drop in Ompic, that's not Ozmpic alone. That's OMIC in an ideal situation in a clinical trial with a nutritionist telling you how to eat properly and with an exercise physiologist getting you to exercise 150 minutes a week. So, yeah, again, same thing's true of all of the new peptides that are coming out. And there's too many of them even to name, but I think they're all going to, you know, but the thing is, who care? These guys don't care. They just want to sell as much as they can, make a profit, and they don't care if it helps you or not. Um, you know, in 10 years, 15 years, if if it's proven not to work, they've already made their money and and moved on. And the same's true, I mean, I'd love to talk about rapamy and all these other things, but like rapamy, oh my goodness, are you kidding me? Immune
goodness, are you kidding me? Immune suppressant. And in addition, it's been proven black resin showed in two studies that giving rapamy does what it's supposed to do. It blocks mTor. And so in animals and in vitro, you know, there's this stuff about blocking mTor expan extends lifespan. The problem is what we just talked about is we need endurance, we need resistance. And if we're not building muscle, then we're not getting the optimal benefit from, you know, our health span. And so what mTor does, mtor blockers do, rapamy, mTor signals protein synthesis. If you block it, you decrease protein synthesis. So what you're going to do is you're putting everything into the mitochondrial side of things, but you're not doing anything for protein synthesis. So these people are going to be shown to be, you know, sarcopenic old individuals taking rapamy disserate. Not to mention that we're worried about immunity as people get older and then you're giving this immune blocker and then there's all this handwaving. Oh, we're micro doing and all this kind of garbage. But, you know, even then, show me the data that that's doing anything and show me that you're not blunting the adaptive benefits of resistance training, which is critical for older adults to do, men and women to keep your muscle and bone healthy. That's the most effective countermeasure. So, that's a rap, you know, and metformin. How does metformin work? Metformin, oh my goodness, it's a complex one inhibitor. So, it inhibits the first enzyme in the mitochondria. And so how it works is that if you're just sitting there doing nothing, you block your mitochondria a little bit, inhibit
mitochondria a little bit, inhibit complex one, you get hormesis. The body says, "Oh my goodness, I'm running out of energy. Let's try and make more mitochondria." So you get this adaptive benefit. But show me that giving metformin to an exercising human and blunting their complex one that that makes logical sense. I mean, it's it's disarrant. And yet, you know, people would love to take a drug. Um, but, you know, they don't want to put in the work to do the proper exercise and to think about optimal nutrition. You know, every day I want a bag of chips. I want, you know, uh, licorice, I want chocolate, I want two beers, not one, two beers every day. But I have to think about it and I've got to, you know, yes, in moderation, but I've got to really think about timing my nutrition, good quality protein, eating as close to nature as I can, you know, whole foods, um, you know, avoiding ultrarocessed foods. It's not that complicated, but people always want to come up with something fancy and, you know, a quick fix. Yeah. So the next question was and maybe you answered it. If you could uh if you had to bet on a single class of therapeutics that would meaningfully extend human health span in the next decade uh which would you choose and why? And I I know you do work in in genetic therapies too. uh and maybe maybe we extend this to some of the genet some of the uh genetic disorders and maybe just the general population to a single class of therapeutics you think and that might be a different answer for those two. Yeah, it's a tough one because
Yeah, it's a tough one because [clears throat] well the reason why it's tough is that you know a single class means uh a drug uh and you know no drug is going to you know ex extend lifespan and health span um and enhance the benefits of exercise nutrition. So you know our approach and again you know full disclosure that we started a company based on my 30 years of experience is uh you know what really works. I think there's pretty solid evidence that creatine monohydrate is helpful and I think creatine is something that uh you know we probably evolved to have higher creatine in our diet because of a higher meat intake. So I think we're relatively creatine deficient and the studies are pretty strong that creatine has benefits you know to brain and to muscle. Um, so I think creatine is always part of uh what we're looking at for mitochondrial patients and for muscle patients and for aging and we've published many studies in the area. optimize protein and again uh when I think about protein there's all this BS about you know lactumin here or some other and there's even lactalumin they're saying it's you know health savan protein and they've got a bunch of AI generated crap where they're actually lying and attributing Stu Phillips's work who was my first postoc to studying lactalum and I just talked to Stu he's never done a study on lactalum in his life and yet AI you can tell it was generated because I checked all the references and they don't actually fit but anyhow there's so crap out there. But if you think about it, what we've done is we've said, "Well, what did mother nature do?" So, what happened is 200 million years ago, we split from reptiles and birds. And what did they do? They chose egg white. We
did they do? They chose egg white. We chose milk. But even further, as we evolved, are humans the same as cows? No, we're not. Humans are 60% whey, 40% case. Cows are 80% casein, 20% whey. Same with mice and rats. So what we've done uh with our company is we've uh tried to mimic mother nature. Pretty simple stuff. Forget AI. Let's figure out what mother nature did. And so we always use now this 60% weight 40% uh casing. What's interesting with that too is that I came across a study after we observed when we gave that versus collagen to older adults and to people with overweight and obesity. uh they actually consumed about 200 kilo calories less when we gave the humanized milk ratio when they got collagen they consumed 200 calories. So all that collagen just went on top and didn't suppress appetite. So then I found a paper in humans that they showed cow's milk ratio versus that humanized milk uh with the humanized milk you get a greater GLP1 and GIP response. So that's what you know the ompic and the dual agonist tepatide are are emulating. So, it it makes total sense, right? You eat protein. Uh these go up in your blood uh to tell your brain, "Okay, we've got food coming in. We don't need anymore. We're satiated." Uh and uh for some reason, mother nature knew that that was the right combination. The other issue, too, is you everyone says, whey, collagen, you know, all this garbage that's out there. Again, it's mother nature. Whey comes in quickly, turns on protein synthesis. Casein comes in slowly and attenuates protein
slowly and attenuates protein degradation. Again, mother nature knew best and you know, Stu and myself and others have shown that data subsequently that it really turns out to be the best combination to optimize what's called your net protein balance. Higher synthesis, lower degradation and then of course from a mitochondrial support uh you know I'm a big fan of our core which we showed in 2007 and then you know we tweak it depending on what indication. So unfortunately it's not going to be a single thing. I think it's attention to all of those details. good quality protein, creatine, proper mitochondrial support. And the other thing I think that um you know from an evolutionary perspective too with a lot of processed foods, we get a lot of omega-6 fatty acids and you know healthier diets tend to have more omega-3 fatty acids uh and not the ones from plants because they have never been shown to do anything but the uh DHA and EPA which come more from marine sources uh you know increasing that intake I think has been shown to be quite good. Stu Phillips um has shown too it improves mitochondrial function when you undergo immobilization and every one of us be it athletes or older adults you know break your hip break get a ACL repair there's periods of immobilization and Stu showed with highdose u um omega-3s it attenuates some of the um drop in mitochondrial function in young women who had a cast on their leg so those would be the things that I would pick you know and again it's it's conflict of interest because that's what we created but we created it based on 30 years of science uh by myself uh and others that have
uh by myself uh and others that have come to that uh you know point and we're using that now in our patients we have a study on myotonic distrophe we have a study in Pompei disease both completed all independent blinded uh by an independent third party people can access the data upon reasonable request and they can check to make sure we didn't cook the books and we're now uh have a big grant in to look at another thing called FSH muscular distrophe but all of them at the cell level are the same. Doesn't matter what the genetic issue is. Aging, FSH, motonic, duchen, whatever. At the cell level, it's really the same. So, studying what works in aging is almost certainly going to work for our patients with complex disease. Yeah. I mean, a lot of people talk about mitochondria or metabolic uh medicine and stuff, but I think I mean, you're kind of the only one physician, scientists, and athlete that's actually like doing the work, treating patients. I've had the opportunity to meet you know your patients that are luckily we're you know to have you as a doctor and uh and one one thing that comes to mind do you think in regard to just the the age related de decline in oxidative capacity and V2 max you said your V2 max is like 80 something or it was and it' be interesting to know what it is now and how that has changed over time. So do you think impaired [clears throat] metabolic flux or metabolic flux signaling uh rather than absolute mitochondrial content or mitochondrial efficiency explains age related declines in oxidative capacity? Do you think uh
in oxidative capacity? Do you think uh you know just some thoughts on that there if if it's and I know it's not one or the other but this kind of question about impaired flux signaling rather than absolute mitochondrial content uh associated with oxidative that's that's sort of a discussion in the uh upper level echelons of exercise physiology right now. Yeah know it's a interesting component there's no question we all know um that V2 max goes down as we age. Uh Justin Crane, one of my PhD students, uh you know, we did a study on younger athletes, uh older athletes compared to sedentary individuals, and it's it's pretty clear that V2 max of um mast's athletes over the age of 65 is higher than sedentary 20-year - olds, but the elite athletes who were 20 were much higher. And I' I've saw that as well. I mean, I've had my B2 measured at least 15 20 times, you know, in certified labs, uh you know, over 80 um on the bike. um 80 87. 6 I think was the highest recorded uh officially that I put into b2max. com um uh on on the treadmill. Now I was fortunate when we did that relay race I was mentioning before um did it again. It was slightly different protocol but you know it dropped to 70 but that's you know 26 years later um still training the same amount. Now what is it? Now there's a number of things. One is V2 is a function of delivery of oxygen and extraction. delivery is you know your heart's ability to pump uh and the I remember I was mentioning that we get calcium in the vessels as we get older
calcium in the vessels as we get older especially as top sport athletes and I can feel that I on my fingers and and toes are colder and I hurt my ankle and I got an X-ray and there's actually calcium you can see in some of my arteries so clearly I think there's a decrease in DO2 delivery so that's a component to the loss of B2 the second thing is mitochondria and that's you know our myarian what we've studied so the mitochondrial content goes down a bit for sure as we get older, but more importantly, the functional capacity of the mitochondria. So, if we take them out in their intact state and we use high resolution respirometry, um the mitochondria are a little less efficient as we're older, but really it's the total number that tends to go down. The other issue too which we see is if we look at our patients with mitochondrial disease, they have more mitochondria. They're just not working properly. And to some extent that's why we kind of when we look at a biopsy it looks pretty similar with the older adults in terms of the total amount but we see some damage. We see what things called paracrystalline inclusions which is due to oxidative stress crystallizing the mitochondrial CK. Uh we see cytochrome oxidized negative fibers which we see in our patients when they're in their 20s and 30s and that just means that the complex 4 activity is not being expressed properly. So all of these things start to accumulate as we age. Of course, we clearly can attenuate that by pruning the tree, I call it through mphagy. When we exercise, we're getting rid of the dysfunctional mitochondria, but that is not a perfect process. And as we get older, it's, you know, it's going to eventually attenuate, but you're going to be a hell of a lot better off if
to be a hell of a lot better off if you're going to be exercising your whole life versus sitting on your butt. And what can we do to uh to enhance that? Um, you know, it's it's difficult. Uh I think the um protein is important because we think of protein only for muscle mass but why do the top sport athletes need more protein? It's probably because we have to turn over our mitochondria and there's many other proteins that we have to build enzymes not just structural protein. So maintaining proper protein intake even for more endurance athletes when they're older is important. And again, when you're still pushing hard, I think some oxidative stress um supplements that have been shown to lower oxidative stress in a human uh can help on those days when you're pushing a little bit hard, like when my wife and I did the adventure race for six hours and you're trashed for three or four days. I always take, you know, my mitochondrial supplements, you know, for a week or so afterwards to attenuate that pathological increase that I've induced, you know, to try and bring that down to a more physiological level. So yeah, taking them kind of situationally when you need them. Uh sort of coming to the lot, I know we're kind of coming up on time, but a quick question. Do you look at uh and my uh friend and colleague Dr. Thomas Safe has done some work looking at sort of in cancer cells like this immature cardipin and he's sort of evidence that the in cancer there's the the structure number and function of cancer uh of the mitochondrian cancer is uniquely different. um some call it you know metabolic damage. Uh but I was wondering
metabolic damage. Uh but I was wondering if you look at uh cardiolippin composition or alossteric regulation of PDH or CPT1 is this something that you do in in that and and if that changes sort of um specifically in the context of pomp disease I was because we're interested in looking at that but and maybe in athletes and aging too. So just the cardiolipin and then uh pyuvate dehydrogenase complex uh and I know the alpha lipoic acid is part of that complex too and I know it has antioxidant function too but it it's lepoic acid I think is part of the PDH complex and and CPT1. So these these have been things I've been kind of interested in. So sort of like a selfish question but uh I know you're at the forefront of this. Yeah, it's a tough one. I mean um you know we definitely like alpha lipoic acid. I did. That's why I chose it for our first cocktail because alphalapoic acid we we if you have an antioxidant it's got to get into the mitochondria. So that's why I like alphalapoic acid as you point out it's a co-actor in PDH it's a co-actor in alpha ketogluterate dehydrogenase and it's a co-actor in branch chain keto acid dehydrogenase. So three really important enzymes involved in TCA cycle involved in bringing pyrovate into the TCA cycle and in amino acid oxidation uh which actually does go up with uh with highintensity exercise up to eight or 9% of your total energy can come from branch chain amino acid oxidation. So anyhow I like the alphaloic acid component. Uh cardipan is a tough one to study uh and to know exactly what it means. So the
exactly what it means. So the quintessential example is bar syndrome. So bar syndrome is a genetic uh disorder. It's an excellent disorder affects of course boys more than girls. Uh and there's a a gene called taz or tfasin is the protein uh which affects cardipen. Um so there's a a drug that came with great fanfare called bendivia. Uh it's now called lametide which works to improve cardipen. What's interesting though is you know all that interest in cardioipen theoretically that it's it's going to be beneficial. Unfortunately, in the first randomized double blind uh study, um crossover or sorry, not crossover, a double blind study in primary mitochondrial disease, the elameraide didn't work. You know, they're trying to massage it a little bit and maybe see if one subgroup works, but you know, it should be a perfect thing theoretically. Uh and there was some evidence in a phase two study that it looks all exciting. They went on to a phase three and it didn't work. So I'm a little less optimistic that just messing around with tfasin andor cardioipin is going to have a huge effect. Clearly, you know, with oxidative stress, you know, cardioipen is, you know, oxidatively modified and, you know, it's a component. But then I get back to the point, well, you know, proper multi-ingredient supplements to decrease the approximate signaling, not signaling, but the pathological consequences that are affecting cardioipin, you know, is probably the best way to prevent that from getting damaged and affecting the fluidity of the mitochondrial membrane, which is,
the mitochondrial membrane, which is, you know, what we think cardioypin probably doing. Um but again uh exercise what we get is mitochondrial biogenesis. So the total number of mitochondria we can double them in just 3 months of endurance exercise training. Uh so the mitochondrial mass actually goes up. So we think of biogenesis but it's actually more mitochondrial hypertrophy. We actually increase the total number and exercise really ends up being your your best way to keep that uh tree pruned nicely and functioning and and flowing smoothly. And I like the you know I've always said it's the quote tarno flux theory and that is I think the human body works best and this is handwaving based on some you know work from some British biochemists back in the 70s that a higher flux is always good for for an organism and that is food in energy out you know keep that flux moving uh rapidly so you can adapt to physiologic situations because you never know when you're going to slip on ice when I walked out this morning and rain fell and then it went down to minus 10 my wife and I almost wiped out, you know. Um, so you got to keep the flux high to deal with these little trials and tribulations that hit us as we get older. Yeah. And getting older. How old are you now? 60. Wow. Okay. Yeah. I think of you as kind of like my age, but you just don't look it. So, [laughter] so cool. Well, yeah. I know we're coming up on time. I have a lot more questions, but maybe we could do a part two some somewhere down the line, but I want to thank you for your time and sharing your expertise uh uh clinical and and scientific expertise
uh clinical and and scientific expertise and just wealth of knowledge on mitochondrial medicine. Uh how can people, you know, find out more about what you're doing? Uh your publications, you know, are all over PubMed and I usually I direct so many people to PubMed. Uh I have sent them your your work uh many times. So maybe share a little bit about, you know, how people can find find out more about what you're doing. Yeah, I mean I think for everyone it's critical in this day and age to look at PubMed because you know you go to AI and it's interesting you know you just put something in does product X work you just throw in AI everything works and it's social influencer crap that they pick then you say does such and such work quoting only clinical trials and then oh wait a second it's a nuance totally different answer so you got to be very careful with AI that's the first thing I would point out the interesting thing is that there are limitations on what papers they can select with AI because there's some leg legalities about going into a publication that you'd have to pay for. So there are open access journals and those that aren't the nonopen access journals technically AI can't go into those and use it. So, you've got a very biased selection and heavily influenced by handwaving because there's social influencers, I won't say their name, who, you know, I just read this morning, the number one health span person in the world, hasn't published a single clinical trial at all in nutrition or exercise. Not one. Zero. Not one. So, go
exercise. Not one. Zero. Not one. So, go to PubMed. if someone says something if it ain't published and it's not a randomized trial or with really solid preclinical evidence you know don't believe it um so that would be the first thing I would say um you know if people are interested in you know how we've taken all of this and put it into different uh supplements that we've created which we call neutraarmacearmaceutical approach doing the proper pharmaceutical rigor and right through human clinical trials uh our company stay above nutrition um so if you type in stay above nutrition you know you'll find that stuff and you know we're we're upgrading and updating that and there's you know some of the stuff that we're doing comes out there but again that's you know taking the the clinical trials and bringing it down to uh to an actual supplement. Uh but I would just say you know definitely go to the clinical trials. There are more and more podcasts uh like this lovely podcast and talking to such intelligent people is always a thrill for me and you know you can find some of the podcasts out there that talked about mitochondria and various other aspects of aging and nutrition. So, it's been a pleasure. Thank you so much. Thank you for being generous with your time, Mark, and thank you for treating so so many patients, too. And your expertise really spans across uh scientific research and clinical medicine. So, I want to thank you for your time and it was great talking with you. My pleasure. Have a good one. Thank you. That was Dr. Mark Tarnipolski and now you know why uh we really wanted to have him on. This was one of those conversations that ties together uh the mechanistic side uh the mitochondria, oxidative stress and protein metabolism
oxidative stress and protein metabolism and muscle strength with clinical uh reality of what actually helps patients uh in the clinic and and in real life function, strength, endurance, and long-term metabolic health. If you want to go deeper, check out Dr. Tarnipolski's work on PubMed. He's publish published hundreds of articles, research articles and clinical trials and he has a very interesting one coming out that uh I'm very excited about. You'll hear about soon. And you can also look up his company. It's called Stay Above Nutrition if you're interested in the clinical trial driven supplement approach that we discussed. And uh and one last reminder before you go, if you love this podcast, please leave us a review. it goes a long way in helping us share the science of uh metabolic health and therapy. And if you wanted an adfree exclusive episode of the metabolic link, check out our medical education platform where you can also find hundreds of videos. We have live Q & As's on that. We have an ebook that you need to check out. It's a comprehensive uh list of [music] everything that uh we've we've covered uh the essence of metabolic health research and more. So visit membership. mabolicinitiative. com to learn more. Thank you again for listening and we will [music] see you next time on the Metabolic Link. Do you love learning about metabolic health? So do we. It's why we created the Metabolic Initiative, an online educational platform providing
educational platform providing evidence-based education [music] on metabolic health and therapies for health care professionals and the general public. By joining the Metabolic Initiative, you'll gain access to hundreds of expert lectures, interviews, panel discussions, and even private episodes of the Metabolic Link. CMEs are available. Go to metabolicinitiative. com [music] to get started. And as always, thank you for listening to the Metabolic Link.
Transcript auto-generated by YouTube. Verbatim — duplicates intentionally preserved.
The modern wellness world often turns mechanisms into promises. A calmer approach asks better questions. What is the body being asked to adapt to? What dose can it recover from? What practice still feels intelligent tomorrow?
"Muscle is a metabolic organ and one of the strongest anchors for aging well."
Healthspan begins below the surface. Mitochondria, muscle, hormones, glucose control, inflammation, and repair systems shape how much capacity the body has available for work, recovery, and presence.
The strongest longevity practices are rarely dramatic. Training, protein, sleep, light, stress regulation, heat, cold, and metabolic steadiness compound because they are repeated. The advanced work rests on the ordinary work done well.
Use the idea as a ritual, not a performance. Start with the least dose that changes your state. Notice breath, sleep, appetite, training quality, and mood. Those signals tell you whether the protocol is building capacity or simply adding load.
Muscle is a metabolic organ and one of the strongest anchors for aging well.
Resistance training, aerobic capacity, protein, and recovery form the practical base of longevity.
Performance can build health or erode it, depending on whether adaptation is matched with restoration.
Choose one practice you can repeat consistently for the next two weeks.
Track the felt outcome: sleep, focus, calm, recovery, or energy.
Increase intensity only when the current dose leaves you steadier.
