201 - Deep dive back into Zone 2 Training | Iñigo San-Millán, Ph.D. & Peter Attia, M.D.

hey everyone welcome to the drive podcast I'm your host Peter [Music] AA in you go it is so great to be sitting down with you again uh last time of course we did this in person but these days I've become too lazy to travel around and do podcasts in person so do it by video but that said I really hope you can get out here to Austin so we can train together and do some cool X Fizz and and also I need to get out there uh to to sort of do some of the x-

Fizz stuff we we've talked about but you know I almost don't know where to begin because there's so much stuff we talked about last time that we want to double click on this time there's so much that has changed in the interval from when we spoke uh gosh probably two years ago a little over two years ago I thought one place we could pick it up uh something we didn't really talk about last time uh was your work with uh Tedd pogacha because of course I don't think anybody knew who he was two years ago

or two and a half years ago and of course now he is um I don't know I mean I think it's safe to say he has the potential to potentially go down as the greatest tour def fron cyclist of all time given how young he is not to put that expectation out there but to win the tour at such a young age to not just win the yellow Jersey but the white jersey polka dot Jersey repeatedly um he he looks like something of a of a different uh species almost and I say that not in

the way that people typically say those things of cyclists in a in a way that's suspicious of anything so I don't know maybe for for the listeners who are not familiar with the tour to France not familiar with with your work with uh the UAE team and your work with uh Tedy poacher maybe give folks a little bit of an update as to what you've been doing with in professional cycling over the past couple years yeah well uh first of all thank you very much for for having me here uh it's it's an honor and

uh really excited for this and I appreciate the opportunity um I had a lot of fun last time and yeah hope to have fun again um yeah my work with with t started um in um late 2018 when he signed up for the team and uh yeah I was introduced to him by our CEO janetti and our general manager uh Machin um and they told me hey just start working with this guy and he was what at the time 19 maybe um uh yeah yeah 19 he was 19 uh at the time uh just turned

19 in fact and yeah so I started to to work with him and right right away I realized that uh he had very good potential and I think like a you know a couple months earlier no or later I forgot when we had that podcast I already told you about him right uh and uh yeah and I told her like yeah we have a guy that has good potential uh and yeah that was that was today and to put it in perspective I mean has good potential is one thing to then go and do what

he did is would make that statement the understatement of the century um for folks who who maybe don't don't follow cycling as as closely right yeah yeah I mean I try to be cautious right I don't usually say that out loud of people uh who has who have we talk we talked about it over dinner that night yeah yeah yeah when I say someone has potential is very is good potential I don't usually say that lightly of anybody right what did you see in him in 2018 2019 that led you to believe that even amongst

that class because professional cyclists you know from a physiologic standpoint are all very special individuals what did you see in him that made you think he has potential in your understated way well first that the physiological testing that uh we we started doing right off the bat I saw like that he had amazing uh capabilities you know at the uh you know oxidative uh capabilities like ability to clear lactate and uh uh and to put out great amount of power output for a long periods of time so when you say that was it specifically his

um FTP that impressed you or was it his is as you said lactate clearance was it shorter bursts of power that were higher than FTP but the speed with which he could do or the successive repeats that he could do I mean tell me some of the testing you were putting cyclist through and and how he stood out so it it's kind of like similar test that I did to you right and uh and this is kind of like a where I I saw that um at a given power output his lactate levels blood lactate

levels were extremely low and since I've been doing this specific protocol for 20 years with professional athletes uh professional cyclist in this specific case that's where I have my U my um U cheat sheet right where I know I can categorize where people are and I was like he was like whoa wait on the other side you know way above almost everybody that I had tested or around the same category and for that age that's what I saw like whoa first of all he is at a different category and he's his first year Pro he's

uh pretty much a junior um and uh and then that's where like I could see he could sustain high amount of Power with very low lactate compared to the rest and then throughout the trainings looking we use training pcks the software uh looking at training pcks that's where I would see uh his different abilities to sustain um a given power output for for the whole day or for specific effort a gtic effort on a clim and and would see the power output that he would be putting out and and and so altogether then I saw

his trainability how easy he would U get the concepts um how easy he would uh um comfortable uh with with the training how he he would recover I I I you know I like the feedback I talk to him once twice a day and uh you know over WhatsApp too you know how the feed back and and and and you know I know very well when when a a hard week is or what a hard week is and when you see this kid telling you I'm pretty good I'm recovering very well when other ones are

telling you woof I had to take it a little bit easier today because I couldn't this effort and we're talking about high level pros and you see this kid telling you like yeah there no problem that's where you start putting together things um and also around the same time uh with my two colleagues at the University uh uh um Angelo delandra and Travis neov we developed we started developing a platform for metabolomics where we can look at um you know hundreds if not thousands of of metabolites um in the human body uh and we did

it the T California in 2019 which was like around April um that's where uh and he won it and and that's where when we analyze all his metabolites and we did already at the training camp in January 2019 and we already saw wow this guy has different metabolites you know at the glycolytic level aced level um um recovery level and we confirmed that at the Tour of California uh and this is where putting all together you know I saw like yeah this guy is different so going back to what you said about lactate I assume

that one of the data points that is most telling of a cyclist is if you plot on the xaxis watts per kilo and on the Y AIS lactate production uh that would be a very I mean that might be one of the most telling graphs you could generate yeah to predict success in the in the tour correct absolutely absolutely you see someone at you know for example a normal Tempo climbing in the to France Tempo a that is the whole Pelon going up it's got to be I was about to say wow I was going

to say four and a half okay so wow the whole is going up at Kil yeah something like that and that's what you see like someone at that intensity might have already six milles yes so you can tell it's going to be very tasking and and and and others might have one resting levels you know and this is where like this is it really really predicts performance um and you can really predict performance in in in in a in an incredible way in fact when we go to the Str training camps like I'm going to

go next week for the first training camp of of of the year with the team we do this um um physiological testing and I do this protocol and and I get this data so right away I tell the uh the team managers this this guy is way about the rest these three guys are really really good immedi immediately behind it these two guys are the or the the third level and then we have all these guys that they're like really really bad form and it and it pretty much works you know then we do different

training um uh racing simulation and uh and they tell boom right away this is this is how it is so this is why it's very predictive and the same thing too moving into the season you see okay all these three guys are going to be at a very good level when we start the season this guy who we thought that he was going to be a very good level he's not there at all so uh and that when when the season starts you see that it reflects very well what's going to happen yeah it's one

of the things about cycling that I really love I mean I don't know if you saw but I interviewed Lance Armstrong back in oh gosh probably back in June or maybe it came out in September but you know one of the things that we talked about was both on and off EPO or blood transfusions you sort of knew where you stood Before the Race based on your FTP in watts per kilo so you know when he was he talked about when he was off EPO he could hold 450 Watts for 30 minutes so that would

be slightly below ft that would be slightly above FTP at 70 I think he was 70 to 75 kilos but it was in the ballpark of six watts per kilo and then of course on EPO it was 7.1 watts per kilo a huge difference but you knew that number going in and you sort of knew like only the GC contenders could do that I think that's the thing that a lot of people don't understand about cycling which is there's relatively few moments in the tour when you need to sustain that level but they always occur

at the most important strategic times right and and that's sort of where the race is one and lost because the race is one and lost by minutes it's it's for a race that is how many hours does it take to complete the tour a 100 hours or something that's a good question um um yeah an average about five four and a half five hours a day yeah so something like that it's about a 100h hour race and yet the difference between the first second third guy will be in some cases seconds in some cases a

few minutes for someone to win by five minutes is considered a blowout and it and and so what it really tells you is that there are a handful of minutes in that race there were a handful of climbs and time trials that set apart the winners from everybody else and that's to me that's one of the beautiful things about cycling physiology is you have these metrics and now I think it's not just FTP it's watts per kilo with at lactate production so it gets even more into kind of the the critical physiology of recovery yeah

and in fact we use this metrics a lot um uh for the competition and we we did it this year the through the France so knowing uh the power output that he could sustain for as as you very well said for specific times um um and climbs we knew his capabilities and one of the things that uh we we we knew was that uh in the Alps he was at a very very high level so uh you know like that famous stage where he broke away in cold the Rome uh 35 kilomet to the Finish

Line we were seeing not only his data but we see by knowing our writer's data you can also guess the other writers data too right um it's not rocket science so we knew that he was at a very high level And discussing the tactiques you know because this part of the thing that we do we we observe the data that we have the data that we think the other ones have and we we we structure a a strategy for the next day and hey does he have the legs to attack I should be holding back

or what should we do and clearly it was like well tomorrow if he attacks 35 kilom to the Finish Line he's going to get there with three minutes because the other guys they're not at that level you know so white wait to the end of the tour when we can try to solve the situation so we knew his capabilities very well and discussing this with him and the and the manager um yeah that was the the the the strategy first test the legs and like if you had in fact good legs boom try go go

fore and that's exactly what he did now how much of that are you going to determine after a night of sleep right where you say we're going to look at his resting lactate first thing in the morning we're going to look at his heart rate overnight we're going to look at his heart rate variability overnight so in addition to the subjective for example how he felt during the previous days attacks coupled with some of that objective data does that partially formulate the strategy also or is it mostly based on historical data from training where you

say I know that when he's at this many watts per kilo for this many minutes he has the capacity to recover yeah I I think it's more the the ladder right where we have U um all that physiological data that that the trends and how it how is and and what we see at this level um these guys they're so good at at knowing their feelings you know um sometimes it's just kind of how they wake up if if if you know his capabilities so if he wake wakes up fresh and say hi how you

doing today like oh yeah I S like a baby like boom then you're you're already you know uh um and sometimes yeah it's just we try not to focus on many other metrics the day off because we have already things and and and sometimes you know har variability um you know it might not be very precise uh and we don't want to get then put some ideas in the head and in fact speaking with him you know and I'm not going to mention any brand or anything but looking at high variability someday you say like

look today it told me that I was fatigued that algorithm and I went out there and beat my record right and um and the clim obviously I'm not fatigued you know and other other days it tells you you're in top form and and ah I feel a more fatigued you know so this is what these algorithms we we need to be careful sometimes and and might work with maybe general population but with this type of athletes um um I I at this level I really feel that it's better once you have all the work done

and uh and they know you know you know their capabilities like are you ready to go you know it's like it's like a top uh performing perfor performer at a theater right is like you have worked very hard now it's up to like are you ready to go you know do you have a good night sleep are you ready to perform and a good performer would say yes I'm ready to go I agree with you completely even for me and I'm not a top level anything I have not found the predictors of you know Readiness

to be very accurate or to necessarily reflect how well I'm going to perform I've had amazing performances by performances I mean workouts right like that's that's the only metric I'm performing in I've had amazing workouts um when my prediction was that it would not be good and I've also had the prediction saying you're on top of the world and I've not performed well so um you know I wish I could say with more clarity what the frequency of those deviations or discordances are but I can agree that putting the wrong idea in somebody's head when

the predictive when there's nothing you can do about it I mean that's the other thing too it's sort of like at best if if it was perfectly accurate it would be great because you could say look today maybe we shouldn't attack today it's damage control day you know one of the things I want to ask you about here and you've spoken about this publicly so it might be that you're just going to restate the views that you've shared publicly um but I've always felt that now that we have such great transparency from the sort of

that high octane era of sort of the maximum probably cheating in cycling which you know in my view was kind of that two decades of the 90s and 2000s and we we pretty much know now what kind of numbers cyclists were putting out when they were being assisted by EPO and blood transfusion and we sort of know that the best of the best we're able to put out somewhere between about 6.8 and 7.1 watts per kilo uh at FTP we also know today that cyclists are not doing that right those numbers are nowhere to be

found in the pelaton now that's that's information you and I share confidentially right that's not public knowledge but I know it you know it and anyone coaching people at that level know that nobody's putting out 7.1 watts per kilo you don't need to be at 7.1 watts per kilo to win the Tour today you could probably win the Tour today at 6.1 watts per kilo do you think that making that data public would put to rest a lot of the criticisms that say the sport is still you know it they've just found new ways to

cheat but it's still basically a dirty sport because I I think when you look at the data objectively it would be very hard to say that today based on what we know from the era when drug use was rampant no I think you make a very good point uh and and it's something that uh yeah it it frustrates me right when when people think that they're doing seven watts per kilogram you know or 7.2 you know um and then you have the real data from the day um and this is way lower you know you

see like you know for example like the short climbs where they would do maybe 7.2 now they're doing 6.3 maybe and the longer climbs uh they're doing 5.5 5.8 um so it frustrates me because I see this data and like and I always like gosh I wish I could just boom release it um and I I that I have I have absolutely no problem uh I know T has no problem with that it is more that uh and we debated it with the team let's do it you know like why way keeping all this at

the end of the day people can figure that out uh and some people what I when I see on internet because you can see the you know like the weight of the cyclist uh the um the grade of the CL grade when it starts the time um and the wind you know you can be very accurate at knowing that and and and I see some people they're quite accurate internet but I see other ones are all over the map you know otherwise they say I did the formula in a 7.2 like my gosh I wish

I could show him hey this is the real data that we're seeing but I guess like two two points there is like one uh um it's um um private data that the team considers like not release it that's that's team policy but the other one too is like you know even if you release that data there always going to be people that are not going to believe you or they might say oh they they probably altering the data or or they're tricking it somehow you know or putting more weight to the data so it looks

like there's less power output and I know I don't know if it's it'll be an endless fight you know um uh but I don't know it's I I don't have the answer I just I just have that frustration that I wish that I could really show the data and and people can can see it you know but but but I'm there's always going to be someone who is not going to believe it and going to make a lot of noise out of that um but yeah but the that's the other thing too is like other

teams and other writers are are releasing their data right so by releasing their data you can see pretty much where where pachar is you know like okay if it's a minute ahead or 30 minute seconds or sometimes with the same time you can see you know like whoa if whatever the writer has done and has entering Pat's group or or 30 seconds later and has done 5.9 patar is going to be in that neighborhood right not going to be seven you know with 30 seconds ahead you know in the spirit of releasing data the other

thing it would potentially do especially if you could see it in real time I don't know if you watch Formula 1 but one of the things about Formula 1 that I think the sport has been able to do because of the advances in technology is make more of the data available to the viewer so if you're watching Lewis Hamilton driving a lap you know you see what he sees now you can see see and it's not like the end of the world data but you see his speed you see what gear he's in you see

the difference between throttle and Brake pressure uh they could show even more data certainly and someone who drives would appreciate it if you really saw break bias and if you saw break pressure and lockup and things like that and you can hear the drivers speaking with their race Engineers so you know it basically allows you to come more and more into what they're doing this year they introduced a new camera angle which is what the driver sees and I think it's fantastic because historically you see above them and it looks so smooth but that's not

at all what it feels like to be in a race car so now they just literally put like a camera at their shoulder and now you see how restrictive the Halo is you see the bumps and it looks a lot faster you know I've had this discussion with a number of people which is if you could show the same sort of information in cycling if every time the camera went over to a cyclist you saw their heart rate their watts per kilo their speed you know all of these other things and you could hear some

of the communications back and forth with their teams yes that changes the sport strategically now you have to be careful what you say on the radio but it also allows you to see kind of the human element of this sport a little bit more do you think that will ever happen where you'll be able to flip on the tour to France and you'll be able to actually see real-time physiology I would love to see that that day I would love it uh because I I it will be so much fun right for the for the

viewer and and as you see I mean cycling has so many possibilities you know to engage people more and and and and be fascinated by the physiology and looking at these numbers um you know there there's this um it's already in a way you know you see some cameras already installed in the front in the back so it's called with Von right so you can see really cool when that I mean images when they're preparing a Sprint that is like what what feels inside and you can see it's really scary sometimes you can appreciate how

difficult is to to be at you know like a 40 m an hour U sprinting or or 35 miles an hour leading to a Sprint or or in a descent or 70 M hour descent 70 M hour descent exactly and then you can see the power also output in real time uh um it's still in that I think it's a great step um uh you don't see all the writers uh uh but it's estimation only the writers who wear that velon or the velon decides to do that and I think that they're still not doing

that with all the top contenders but I think it's a first step and and and obviously haven't spoken with them but maybe it's like hey let's let's see let's see what's what's the feedback and I think that people are loving it and I and I would expect that this will increase you know and and I mean I would love at some point you know and as you know very well in the world of biosensors right it's going to revolutionize Sports where we're going to be able to see you know so many different parameters of Imagine

You Could See lactate and glucose in real time which of course is technologically feasible already so it's just a question of yeah yeah so that this I I think that would love for all sports too right imagine you can see an NBA basketball game right and see that the lactator of of LeBron James compared to the other ones right I mean I would love to see that as as a spectator and I hope that someday we we were able to see these parameters so last thing on the on the tour um talk to me about

vtu this year what that was a that was a tough stage um also I mean kind of showed it looked like his toughest stage was that is that a fair assessment yes probably yeah and and what's amazing I think is the Poise on that stage um it it's hard to tell if he was really struggling on the ascent of Van 2 or he was just deciding strategically I'm going to conserve a little bit of energy here what was your take on that or what can you say about that well it was it was a very

uh difficult climb um and and a very long climb so um you know T his mentality is wired you know like a champion and and and he when someone goes and they were full gas in the last part when uh wiar attacked and and you know T know that okay this is this is not going to be the the top of B two is not going to be the uh the end of the stage right I have a long desent very long descent and and I have some partners with me you know that they can

help me out uh so I'm not going to panic at all but I'm not going to also try to uh waste a lot of energy um because I need to now I have and he also had a big gap you know a whole different thing would have been if he had 20 seconds but having a big gap and knowing that you have a big descent and how calmed he is uh that's one thing that um it's a very important strategy and this is pro this this is what happened um I have you know this reminds

me in a way what happened the first year that he was Pro when he was 19 at the Tour of California um uh it was the the previous stage before um um what's called burlake no what is the mountain ber I think it's Berle yeah is is the top mountain right in in the T California uh where is going to be decided so the day before two cyclist George Bennett and nigita attacked in a in a short but very steep climb um and they were only like 12 Riders left and Nita and Bennett attacked uh

then there was like a descent and a long Highway all the way to the finish line so there was plenty of time to to cat to catch him out but um T didn't follow them up you know another writer would have just followed their will and T had it no I'm not going to follow them we have time and I'm going to take the chance uh uh because I'm confident for tomorrow and and and and when I asked them like as soon as he crossed the Finish Line I asked him are you okay uh why

do you why you didn't um um follow the their attack and he said well I I just wanted I wanted to know who is going to be good tomorrow so I know those two guys are going to be good tomorrow but I wanted to take my time and see the other 10 guys how they're breathing what's their body language and uh take my time to observe uh to to start preparing my strategy for tomorrow and in fact that's what he did um so they were then caught up you know like 2 three kilometers to the

finish line so all those 12 13 guys whatever they were they got together and the next day in fact he knew this those two guys attacked he just follow them and he just eliminate it one by one but uh uh that that's what that's how this guy thinks you know uh his strategy like no Panic plenty of time today I have a good Gap in the GC why am I going to go full gas uh when I know that he's going to go full gas and and he might lose energy for tomorrow uh because he

might pay for this at this time of the of the to the FRS and we have plenty of time to to to catch him up um so that's kind of the strategy that he had too how much time does someone like teddi spend in zone 2 which we're going to talk a lot about right so um and let's do it more as percentage of training time because I think absolute numbers will be very large given that that's his job but when you think about the percentage of time he spends in that energy Zone how does

it change over the course of the year so presumably during the winter months a greater amount of his time would be spent there as he's Base building uh right before a race when he's kind of sharpening maybe less but what would be the range of time yeah perent rather very good question so yeah when and you're right when when we talk about percentage is is more I I like to to put it this way more like a percentage of days dedicated you know to cultivate that Energy System right um obviously if you put in in

just every single minute together right the you know like the majority is going to be that right but I would say more in days um uh so and then the you know so yeah in the winter months might be about 80% wow of the of the of the 70 to 80% of the days as the season gets closer he starts increasing more the intensity days and sessions and then you you have you start the season so uh when they start the season racing and you have it depends right you might have one one stage rates

of five seven days and then you have a five day block or one week to recover and then you have the next stage rate so in that week we do a lot of recovery we might do some sessions here and there um and then after a few blocks of uh uh races that's where you have another long time to train period to train uh going to altitude towards the T of France or or towards the next goal and that's where you may revisit you know uh those those this different Energy Systems and uh and train

specifically but uh but yeah we we we alternate and and and I think each each each Energy System has a time in the year and uh in the calendar where it's built um in order to try to achieve what we want so let's remind people now W with this you know uh I've put out a few posts on social over gosh the past year and even in the past little while and anytime I'm talking about Zone 2 it's really one of the topics that generates the most curiosity the most the most inquiry from people I

think people really intuitively kind of resonate with this and then of course a million questions follow because there's there's so much minutia and detail around it and a lot of that we're going to cover today but let's start from a place of maybe someone hasn't heard the first podcast where we go through some of the semantics of this Define zone two okay okay okay so um Zone 2 or Z2 right um I started using it about 25 years ago um and I just have a very simple um name so to um it is from my

um point of view it is the exercise intensity at the one you are stressing mitochondria and oxidative capacity to the most uh this is where you're recruiting mainly type one muscle fibers this is where you are mobilizing the highest amount of fat um both from lipolysis from mipos tissue as well from fat oxidation inside the MIT the mitochondria and this is also where um uh you stimulate all those uh energy that that b energetics which is um oxidative phosphorilation this is where you burn uh both the FX The Fat inside am country as well as

the glucose inide the mandri there's not a very high glycolytic flux that um it's going to be transformed into pyate and reduced to lactate but that flux still is oxidized inside mitochondria and uh uh this is looking at from B energetic standpoint this is what I would consider the zone two and what I have seen is that throughout the years is that this is the exercise intensity that um um achieves or stimulates that mandri function and F oxidation and lactic CLE capacity the most because um that's the other thing too this is where uh there

are other things involving lactate so lactate is a great fuel to cells it's in fact it's probably the preferred fuel for the cells for most cells in the body this is a work that my colleague and mentor and friend uh George Brooks discovered right um could you should have him someday in the podcast because he's fascinating I mean he he I mean I I would not be surprised if someday soon we hear that um um he he he will he wins it the Nobel Prize he's amazing guy I and every time I talk to him

I'm still learned a lot of things and and I've been translating a lot of of his research but um yeah that's how I see that yeah you know you you have um within the M kind function you see how lactate is oxidizing the m pandrea back to energy right so um and that happens at that uh in those muscle fiber types those muscle fiber types and the mandra of those F fiber types also develop um these Transporters which are MCT ones which are the ones is that transport lactate inside the cell and inside mitochondria so

when you stimulate that training Zone you stimulate all these Energy Systems and the components that come with them so let's talk about the difference ways that one can go about estimating this based on the definition you've just given it seems to me that the purest way to estimate this would be via indirect calorimetry because that will actually tell us the fat oxidation is that is that a fair assessment yes it's a very good assessment and and and and that usually exactly that that that usually correlates with the uh the fat Max that's how we we

call it too right uh with with fat AC o and when you see that you start oxidizing fat and my increase in many cases and gets to a point that is uh it max out which is the fat Max and then it it starts going down sharply right as exercise intensity increases so so let's tell people how that's measured because I think it's um we do this with all of our patients um and I find it to be not that easy to explain because there's some physi ology involved and there's some math involved but let

me try to see if I can explain this to folks so uh you know you you hook me up to an indirect calorimeter so you're going to put a a a little plug on my nose you're going to put a um a mask over my nose and mouth that mask has the ability to measure the amount of oxygen that I consume because it has a sensor for O2 so it knows that the O2 that's coming in is at 21% % the air is coming in at 21% O2 and whatever I exhale is the difference between

that so you can now tell how much O2 was consumed and you can have a similar sensor for carbon dioxide so you know how much carbon dioxide is produced so it's very easy to measure consumed oxygen and produced carbon dioxide provided you can completely isolate around the nose and the mouth yeah as you hook a person up to some form of ergometer usually a bike but could be a treadmill a rowing machine or something like that you can increase the demand on the muscle so you increase the wattage or the speed or the something you

then get out these numbers V2 and V CO2 which are what we just talked about so consumption of oxygen production of carbon dioxide these numbers fit into a relatively straightforward linear equation called the Weir equation and it tells you three things it tells you total energy consumption in uh kilo calories per minute and then the ratio of V2 and vco2 tell you how much of that energy is coming from fat oxidation and how much of it is glycolytic yeah so at any moment in time you can look at a vco2 and a V2 which are

usually measured in liters per minute and you can convert that into a total grams of fat oxidation and a total gr of glucose oxidation per minute yeah and so you could then plot on the xaxis work or power and on the y- axis you could plot fat oxidation M so again describe for people what the shape of that curve looks like and what differentiates Pacha from the average human being yeah so again I mean you explain it very well and and yeah those are based on uh stom metric equations based on the uh how uh

the combustion of carbohydrates and and and and and fatty acids are are done in the body um this um um already in the 1920s uh Francis Benedict Was the the one of the first ones who probably probably the first one who started to to look into this at this level um and obviously we have evolved uh into um do it in a more automatic way right with this indirect color imageries machines are called also metabolic cards right so yes uh um as extracise intensity increases you start um you you oxidize I mean you need more

oxygen right so your V2 increases and then you produce or give up more CO2 um so this is kind of what it shows uh when you're in a more um lipolytic state more more fatty oxidation state uh you you you still consume oxygen but you do not produce as much CO2 right uh when you are more into a more glycolytic State Which is higher exercise intensities uh when you're um recruiting the type two muscle fibers and therefore using more glucose for energy purposes uh you're going to consume more oxygen and you're going to produce more

CO2 right so plug it in all these numbers into these stereometric equations it's going to give you that profile right in the X uh and the Y AIS and it's going to see what is the um the fat oxidation throughout a ramp State a ramp test and this is where you're going to see that um Elite athletes like bachar they have an amazing fat oxidation capacity compared to other competitive athletes or recreationals or or people with even um um um type two diabetes or metabolic syndrome or in the recent study we we have published with

a covid patient so so it reflects in a way uh uh ultimately what happens in your mandria and how the mitochondria oxidizes those fuels at different exercise intensities so for example let's say at at an intensity of a 200 let's say 200 Watts like athlete um doesn't need to incure in that glycolic capacity as much as someone who is not very well trained so the lead athlete they can still recruit the slow twitch muscle fibers and rely a lot on fat you know to produce ATP because they have an amazing mandal function and they don't

and they're very efficient metabolically speaking uh therefore they're going to be oxidizing a lot of fat however someone whose mitochondria are not working as well uh whether you are like a recreational affl or or sedentary individual or someone with type two diabetes which is one of the Hallmarks of the disease that might handle impairment or dysfunction at 200 Watts uh uh you fully rely on on glucose pretty much because you know you cannot sustain that effort uh with with with fat alone and and this is why you're going to be seeing this gas exchange the

CO2 and the V2 you can just plot it into the equation and it's going to give you all that um um what I call metabolic map where where you see the the fat oxidation the the carboh hydro oxidation and then I plug in also the lactate and that's where everything comes together quite well and you can then first in an indirect way calculate the mitochondrial function and metabolic flexibility how flexible they are at using fats or carbohydrates and also you can determine training zones and this is this is what I I I've been using this

methodology for about 16 16 years 17 something like that I didn't think to ask you this earlier but if you have it handy do you want to pull up a graph of what fat oxidation looks like versus Power so that people can see the difference between a highly trained individual you know reasonably trained individual an untrained individual and at the other end of that Spectrum somebody would type two diabetes sure so uh let me share a screen then right and hopefully this works okay so this is from a a publication right uh that my colleague

George Brooks and I published in 2017 so this this is uh uh the formula and and we we have realized that this is flipped so we need to send an we working out the to change it because the formula is flipped here in the meth in the method section which is so funny by the way I like seeing that I I you know I'm embarrassed to say when we do this for our patients we do it in two steps which yields the same result but we in we first calculate energy expenditure using the Weir coefficients

of 3.94 * V2 minus uh or 1 plus 1 point I think it's two * vco2 and then we convert that to Fat ox and carbohydrate oxidation using the ratio of uh V CO2 to V2 and I never even thought to do what you've done here which is so much more logical which is combine them into a single equation for each well we use what what fryan observed already in 1983 uh and this is It's Fran's equation um and and it's been validated with the tracers with the stable isotope tracers and uh yeah and and

and that's what it shows there's a very high correlation now furthermore in um in study that we we were going to be publishing soon we have validated this um um fat oxidation and carboh hydroxido condrive biopsis we inject um uh directly fatty acids pyate representative of carbohydrates right and glutamine representative of amino acids and then we can see that there's a very high correlation between this this indirect methodology uh to look at mandal function and the direct methodology which is through muscle biopsy and injecting the substrate and see how it's oxidized right so so these

two graphs are really powerful so let let's let's talk about what the first graph is showing us the first graph is so both of these graphs it's important to Note have the same X AIS in other words the independent variable here is is the workload in Watts that's the metric that matters in cycling which is I think the easiest way to do this test and so you're increasing wattage this is a progressive increase in workload yes and and what you're plotting on the y- axis your dependent variable here in the first graph figure one is

blood lactate so um what stands out to me is a couple of things so you have a the triangles represent metabolic syndrome the squares represent kind of a modestly trained athlete and then the little diamonds represent a professional athlete the first thing that stands out to me and we're going to talk about this later so I'll put a little pin in this is that the people with Metabolic Syndrome have a resting lactate that's almost 2 Millo yeah yes we see we see already this and it's a it's it's I think that it's going to become

more and more as a biomarker like like resting BL glucose levels yes what what is your resting lactate and I you can see already in patients with type two diabetes or profound metabolic syndrome that yeah I you say perfectly yeah resting levels are you know in the neighborhood of like a 1 point8 1.5 to even three right uh yeah so so one of the metrics that we've discussed at length and we'll Revisited of course is using this lactate level of about 2 Mill as being that the that threshold so once lactate exceeds 2 MMO the

individual is now escaping out of Zone 2 and they're actually now into Zone 3 so when you look at these data here you can see that the individual with metabolic syndrome is basically tapping out zone two initially so any incremental workload that is placed on them takes them right out of Zone 2 so they're for all intents and purposes by the time they're at 100 Watts they're already at the threshhold of their Zone too now conversely when you look at that sort of medium Tred or reasonably well-trained uh individual um or what we I think

it's referred to as moderately active healthy individuals you know they start out with a lactate of about one and it's not really until they hit about 175 Watts that they pass that inflection point and then when you look at the professional athletes the professional endurance athletes specifically you know they're starting out at a lactate level of .5 Millo and they stay relatively flat until they hit about 300 watts is when they finally cross over that threshold now what's not captured here is that as you move from left to right the athletes are getting lighter so

this graph if I'm going to be critical of it in you go I would would say it should be done in watts per kilo and that would show a much Starker difference between these and in our patients when we Benchmark them we Benchmark them in watts per kilo yeah for this reason so that you normalize by weight and yeah and and I and I'm sorry to interrupt but you're absolutely right it is that um and that's how we do it also yes of course it is like the one of the reviewers didn't allow us to

use what's per kilogram so that reviewer was an idiot so that's fine I won't I won't hold it against you because you have an idiot reviewer but yes you know how it is in review papers you want to show something and and and eventually it's change and it's not exactly sometimes what you want to show you know because otherwise they don't allow you to publish it but anyways so but what's amazing here is that person with metabolic syndrome is probably about one watt per kilo easily right or you know 1 to 1.3 watts per kilo

is their Zone to when you look at the modestly trained individual they're about 2 watts per kilo mhm right they probably weigh maybe 2 to 2.1 2.2 watts per kilo that professional endurance athlete probably weighs in the neighborhood of 70 kilos yeah exactly so you know they're in the ballpark of four watts per kilo uh for our patients in youo we typically want we set the aspiration at 3 watts per kilo so again our patients aren't professional athletes but we think that three watts per kilo would be kind of the elite level that we would

want to see people uh and then of course we stratify from there okay let's let's look at the lower figure um figure two just beneath this so here we're looking at the same group of individuals we have the same independent variable which is work but now we're calculating fat oxidation as a function of that work so now you're dependent variable is fat oxidation which again very easy to calculate via indirect calorimetry two things stand out again the first is the obvious which is the fitter the individual the higher their absolute capacity for fat oxidation but

something else stands out to me in you go and I have now seen this repeatedly across multiple data sets which is a fit individual actually increases fat oxidation to a local Maxim before beginning that decline whereas most Mortals begin at a maximum and decline from there can you explain why that's happening yes um yeah it's it's something that I agree I I I see this all the time right um I I think that on one hand is how you start a protocol right um in this case we we start like at one we start about

1 to 1.5 watts per kilogram mhm um and that obviously for an elite athlete is is low resting level so this is what they're very low and and and they don't need to use much fat for energy purposes until you push them more and that's when you get to like two 2.5 3 3.5 watts per kilogram right and and and and again this protocol comes originally from from the work that I've been doing for 20 years the same protocol with Elite athletes now when you do the same protocol with other pop ation especially people with

metabolic syndrome or not very fit and you start at 1.5 watts per kilogram that might be too much yeah right and and I'm sure you have observed that if you start at 0.5 watts per kilogram you might see a higher fat oxidations and then you might see the same phenomenon so on one hand is that protocol but on the other hand yeah sure it like 0.5 watts per kilogram it's like nothing you know uh it's close to Res in levels almost so uh it will take you for a long time but that being said I

I think that one of the thing that we're doing with with populations more clinical populations is really start at a very low level even up to 50 Watts or or 25 watts sometimes you know so we can stall these points because if you start at 2 watts per kilogram or 1.5 watts per kilogram with someone with a significant metabolic disregulation they're already you're going to miss the fat Max yeah I agree with we we have been struggling to tune our algorithm to exactly that because I actually think that and I had this discussion with our

team a week ago which was the physiologists who were doing this with our patients are probably overcooking the uh people who are not fit during the warm-up so they do a warm-up and the warm-up is actually too stressful and it overcooks them and then we're missing kind of the true max fat Okay so the the the next thing I want to point out here is that the and let's just look at the fittest person but it's true for all of them but it's most it's it's easiest to see here fat Max so fat Max Ox

right so maximum fat oxidation is occurring earlier than lactate is two and that's true for all of them except for the Met sin person because it's it's so low but if you if you look if you look at the moderately fit person they're hitting maximum fat oxidation about 130 Watts but they're hitting lactate of two at 175 watts in the upper figure and the uh professional athlete is hitting an absolute um fat oxidation Maxima at a little shy of 250 Watts but they're hitting lacta of 2 closer to 300 watts so I guess the question

then becomes which one of these do you think well you've already answered part of the question which is we're really defining Zone 2 as the place where maximum fat oxidation occurs but I guess this would suggest that using a lactate level of two is maybe overestimating where that is and should we be using a lower level of lactate such as uh you know 1.5 or something like that yeah that's a excellent question and this is what I've been learning all these years is that uh um um the blood lactate levels might change between different groups

and it's everything related to the lactate kinetic kinetics and LAX oxidation and lactate oxidation uh in the mitochondria so for example um Elite athlets uh to uh and and I did this was part of my doctory thesis and some of this that never published it 20 something years ago um but the same blood lactic concentration does not correspond uh to the same in an elite AET does not correspond necessarily to the same lactate concentration in a recreational athlet uh the metabolic uh stress so for example um two milles or two millimolar right of lactate in

in in these Elite athletes uh might be uh a higher metabolic stress than 2 milles in a metabolic patient yeah so this is why uh and it would be very difficult for example you can have a a a let's say 2 and a half milles you can have a metabolic syndrome patient exercising for a couple hours without a big deal you try to do that with a professional athlete and they're going to be hurting right and in fact one of the things that I observe is like a I I used four Millo or Millar which

is kind of that that gold standard has been forever like the lactate thres Etc yes and if you put a worldclass athlet at four milles of lact at the intensity in power output that elicits four milles and you put a um a recreational athlet at the power outut at least it's also four milles and you say now go right and see who lasts the most intuitively we're going to say obviously it's going to be the professional athlet it's the opposite and this is the data that I that I saw 20 something years ago where U

the recreational athlets at the same blood lactic concentration would go about 30% longer period of time and that's because metabolically it's not as tasking and the main reason is that um the lactate um um uh that we see in the blood it reflects the mitochondrial oxidation so someone who has uh obviously when we're talking about you know high power output when you need a lot of glycolysis to produce energy uh you're going to produce lactate lactate is the mandatory obligatory byproduct not waste product but byproduct of glycolysis so the higher the glycolic is the higher

the lactate now that lactate has two routes mainly one is going from the fast twitch muscle fibers to uh the the the slow T each muscle fibers is the lactate shuttle that George br discovered and is oxidizing the mitochondria of those uh um um low twitch muscle fibers if you have a very good lactic clearance capacity right you're going to be oxidizing it very very well for fuel therefore you're not going to incure in the Second Step which is exporting it to the blood right when you have a poorer mandal function uh it's going to

get to a point that that capacity is going to get saturated at a lower power output and therefore you're going to be forced to export that to the blood so that's why looking at blood lactates might not mean the same I'm not saying that the parties are huge by no means right but as you very well said those two milles might not correspond in an elite athlete with a fat Max but might be more maybe towards 1.5 whereas maybe in someone with a more recreational or metabolic syndrome it might correspond there I don't know if

it it completely makes sense and this is definitely the level of nuance that I I don't think we captured in the first podcast and I and I want to now ask uh a more telling question specifically for the middle person here so the the one that's called the moderately active individual where again we have a disparity right so based on these data the moderately fit individual hits a lactate of 2 Millo at 175 Watts but hits a Max fat oxidation at gosh 125 watt so it's a 50 wat difference so now the question for you

is when that person comes to you and says in you go I want to improve my metabolic function I want to improve my mitochondrial performance I want to improve my fuel partitioning my flexibility all the things we talk about are you going to train them as a zone two of 125 watts or as a zone two of 175 Watts as represented by these Deltas that's a very good question and normally I would try to do something in the middle normally and again this this uh um yeah it it might not coincide perfectly but normally they

they they they do they do quite well and and and another parameter that if if if you alow me I can show you in this paper this is what when decided we see individually right the lactates yes and then we see the fat oxidation but then where I decided to to cross them over right and this is this is what we saw in this graph over here uh I'm going to so this is can you see it okay yes so this is where you see the the lactate versus I mean sorry the lactate versus the

fat oxidation M right in the uh Elite athlete and the r is 0.97 um this is true Bon foron equation so this is is an average right of all of them um and this is where you see the same uh pattern uh the same graph for the modally active and this is also what you see in the um people person with metabolic syndrome the correlations are very very strong they're almost perfect right so this is what normally fat oxidation and and and and and and lactate they go together right so for people who are going

to be listening to this in Yugo and not able to see what we're seeing can you describe the differences between these graphs these are obviously showing the same data that we discussed earlier but now we're using two Y axis so let's even just talk about it as looking at the elite athletes so you're basically plotting the decline in fat oxidation or in their case the initial increase in fat oxidation followed by a decline in flat fat oxidation and on the same graph you're showing the increase in lactate production again both plotted to the same xais

of power does the does the Cross Point here indicate any significance so they're Crossing at about 325 watts is there anything about that that means anything I mean to me I think it's an artifact of the graph because it's really just a function of how you scale it correct yes yeah exactly I mean it shows to me that yeah the crossover point for blood lacta and F oxidation it's a very high or usually in the elite athletes very far to the right um right so and then of course in the moderately fit people it's looks

like it's closer to maybe 80 Watts EXA and in the unfit individual it's about 125 watts person with metabolic syndrome yeah and again I mean if we if if you started and I'm sure you have seen this but if you started with the metabolic syndrome for example at at 25 watts you might see or or in even in the recreational athlete even earlier you might a similar pattern as you would see in the elite athlet but a much lower wats obviously it is that um we just did the same protocol for everybody uh just to

show the concept right um that um you know both F oxidation and and lactate go together and also when we look into and I'm sorry I should have gone this to this directly when we look into F oxidation and carbohydr oxidation we see the same concept right so we see as exercise intensity increases you need to oxidize more car carbohydrates um and then as exercise intensity increase you may get to the fat Max and then in the moment you switch to the glycolytic fibers uh you cannot use much fat for energy purposes so you see

a a sharp Decline and eventually fat oxidation disappears um and it's all full glycolytic and the same pattern we see in the rest of populations with also a very high um statistical significances and correlations um so that that's where like all these elements fat oxidation carbohydrates and lactate they're very well connected um if we look in the other graph this is the correlation between lactate and carbohydrates right we see that overall the correlations are quite good because yeah lactate is the byproduct of of of of um um glucose utilization right you may see that that

in the elite athletes though the Gap is wider here and this is for the same reason I was saying earlier they use a lot of glucose they're using so much of they're using so much fat there as well is really the point right so the bigger the gap between the blood lactate curve and the carbohydrate oxidation curve the more efficient the individual is the more they're able to oxidize fatty acid then they have to require glucose and clear lactate uh again the mandatory byproduct of of glucose oxidation is a a lactate so here the lactate

doesn't show up in the blood if yeah that's interesting it's it's it's it's hard to disentangle those two because you mentioned a good point that I omitted this in part reflects the lactate shuttle this in part reflects the ability for them to reuse lactate as a fuel as oppos to just letting it get out there with hydrogen and start to PO poison sarir so let let me see the the other slide that you you wanted to show that explains I think how the um MCT Transporters work yeah so this is a little bit more of

the the B energetics of the cells of the main two uh um um substrates which are fatty acids and lactate I mean and pyate and also lactate right so normally glucose goes through glycolysis and ends up and this is this is the cytool this is the outside of the mandra the inside of the and glucose once when it enters the GL the cell it's oxidized to pyate that pyate needs to enter the mitochondria through What's called the mitochondrium Pyro carrier and it's oxidized to a Cil COA which enters the crep cycle right this is a

complete oxidation of glucose through oxidative phosphorilation in the CB cycle and electron transport chain then F acids have the same mechanism seems to uh I mean I mean they also get converted to acety COA but through different mechanisms fatty acids are transporter uh through cpt1 and then cpt2 go through better oxidation acet Co and enter the cell right but every time that you use glucose um um you produce pyate and every single time that pyate is going to be reduced to lactate always right and uh and this is the key concept so uh when you

have a a constant glycolytic flux right uh you're going to in in one of the steps of glycolysis you're going to utilize NAD right um and it's going to be U transformed to NAD h plus um hydrogen so if you use this mechanism a lot you're going to replenish NAD I mean you're going to deplete NAD the only way that rescues Ned is the reduction of pyruvate to lactate which replenishes NAD going back for glycolysis and this is absolutely necessary for the continuation of glycolysis but anyways and this wasn't a side note but this lactate

enters the cell right through a specific I mean the mitochondria through a specific transporter mct1 and has a specific enzyme LDH that uh um um oxidizes lactate back to pyate and going back to the um C cycle so again this is an extra fuel but for that you need to have these Transporters very well developed yeah yeah let me let me try to explain this to people who aren't able to see the graph because this is such an important point right so you're showing a picture of uh the mitochondria and you're we're looking at the

outer mitochondrial membrane we're talking about three Transporters three things that let substrates from the outside to the inside where they will undergo the most efficient form of ATP production so the first is we have the fatty acids they enter directly and they undergo uh an oxidation where they get truncated into little two carbon chains and they enter the kreb cycle we we get that one and we know why that one's very good uh what I think is very interesting here is when you contrast the two different fates of glucose byproducts so the traditional way that

we think about this glucose being reduced to pyruvate pyruvate directly entering the cell through its own carrier and then being converted to acetal COA which follows the same fate as the fatty acid now when energy demand increases and we just looked at graph after graph that demonstrate that no matter how fit you are at some point you have to produce more lactate so you now don't have sufficient cellular oxygen to go down that first route so you start making lactate but if you have enough mct1 Transporters on the outer mitochondrial membrane you can now bring

that lactate in the cell and actually do the reverse of what just happened turn that lactate back into pyruvate pyruvate becomes a cetal COA and everybody wins the game again the game being won of course because now you're making 32 units of ATP instead of just the two units you would make converting pyruvate to lactate so it begs a very important question which is earlier when you spoke about what makes pachar so remarkable physiologically one of those things is he must have a boatload of mct1 Transporters on his outer mitochondrial membrane and that must explain

in part why his lactate levels are so much lower than everybody else's at a comparable work level how much of that is genetic and how much of that is a result of is training exactly so you're right uh he has a much higher level of to oxidized lactate right so there's a genetic component no doubt about it but uh there's also an epigenetic component right um and as we know nowadays right the genes are not your fate necessarily right um um from the genes to to be um um able to to to be transcribed and

and you know and and form of protein with biological action uh the the the the probability is is is less than 20% that's kind of what the science is showing roughly right this is the whole from um uh genetics to U transcriptomics proteomics and metabolomics right it's about 20% chances that one gene is going to be ultimately expressed obviously we're still trying to understand all this so these Elite athletes probably they have a much higher possibility right but there's a long journey and this is where epigenetics occur right it's like what you eat how you

rest how you train and I think that the training is also an important component of this uh this is for example why we train train very very specifically this Energy System and we try to dial in as much as we can specifically to try to stimulate this by energetics system and increase the the MCT ones the transports for tape as well as all the components in the CP cycle right which is the mitochondrial respiration and also to to increase also the M kind of P carrier because as we might discuss later this is already disregulated

in people or downregulated in people who are sary right but um but the the thing is like if you see this next slide can you see it okay yes so this this is what you know makes the difference in this athlets right so this is a fast twitch muscle fiber and they use glucose so this is when you're like a high exercise intensities climbing or running at a high intensity or swimming or whatever the activity you do you need glucose because uh glucose is it's it's as you said very well it yields less ATP but

it does it much faster right than than than than the diesel gasoline which is the the the fat so but when you use glucose uh you're always going to produce pyate so that pyate you know the higher the intensity the more glucose you need the more pyate you will need and the more lactate that you will produce so that lactate has as I said earlier two routes one route is like is exported through the MCT Force which is the transport of lactate outside the fast twitch muscle fibers uh something that also is trainable right the

capacity to export lactate through high intensity exercise and then it travels to the adjacent uh slow twitch muscle fires uh and uh if we blow up this uh mitochondria in the slow T muscle fibers this is what will happen uh the entrance of that lactate it goes through another transporter mct1 is the same family but instead of four it's called mct1 and as I mentioned earlier that lactate is converted to pyin a CO and goes into the CP cycle so so in these well Tred athletes like patar for example um they have an amazing ability

to oxidize the L inside mondria right at some point every single human gets to a point that they cannot sustain the effort anymore right but what makes the difference is obviously is like these guys can do 400 watts for a long time versus a mer moral who canot even do two strokes at 400 watts right so what happens is like when you have a lot of when you don't have the right mct1 and mitochondrial function uh this lactate is going to increase and accumulate right and it's not lactate per se but the hydrogen ions Associated

to lactate elicit an um um acidosis of the micro environment of the muscle which is something that we know and we have learned also from cancer the famous cancer micro environment which is very acidic and that's going interfere with different functions in the muscle with both the um the uh uh the the contractual the contractive force and the velocity of the muscle fibers uh I'm not saying that this is the cause of fatigue by no means because there there are multiple theories and we still try to understand it's the central fatigue as well and everything

probably is interrelated or it must be interrelated but the bottom line is like when this lactic cannot be oxidized it is exported to the blood and this is what you see that people with metabolic syndrome for example or type two diabetes who are characterized by having a very poor mandal function they cannot during exercise oxidize this lactate in the moment they start using glucose which is very fast also because they don't have the fast twitch the slow twitch muscle fibers Mand to use fat they need to rely on glucose that's that metabolic reprogramming or partitioning

they have they produce lactate but they cannot oxidize the lactate that's why this lactate chooses mandatorily the route of being exported to the blood and in the blood then it goes and to any tissue in the body so this is what I meant earlier about what is 2 milles versus one mill whereas patar for example uh he oxidizes a lot of this lactate so by the time the pachar saturates this transporter and this mandri capacity to oxidize lactate it's a tremendous amount of uh Power output and a tremendous amount of glucose that he puts out

so this is why that the 1 M or 1.5 m in in in in in a worldclass athlete doesn't necessarily represent the same metabolic status over 1 Mill 1.5 or 2 milles uh in the blood of a normal person does it make sense it makes complete sense this is this is a fantastic tutorial in in muscle physiology um and again this very important distinction between uh lactate production at the at the local level and lactate that we measure at the global level right that's the challenge we have when we are measuring lactate we cannot impute

lactate clearance and lactate production we can only impute the sum of those exactly and we think I mean or it's originally thought right that this athletes they don't use as much glucose right well in fact the Richard shows and Brooks and his team showed it that uh and others too that the well- trained athletes in fact they use more glucose because they have to you cannot do 400 watts without massive amount of carbohyd oxidation and this is what we also see in the indirect colorimetry that you know you see people recreationals or people with metabolic

syndrome they have like four grams per minute at Max carbohy oxidation whereas Elite athlet they can get to six and a half right GRS per minute it's massive amount of glucose and they produce a lot more lactate but the key is like they it doesn't show up in the blood is the rate of appearance in the blood because it's oxidized in the muscle so it doesn't show up in the blood it's the is the balance of of of lactate production and lactate oxidation without getting to the blood and this is what it correlates a lot

also with with the fat oxidation as well uh and the graphs that I was showing earlier so one of the things I want to ask you about here that is a bit of a confounder when we do this type of analysis is the carbohydrate content within the diet so I'll share with you my data but I've now seen this with multiple people including uh one individual who's remarkably fit so uh God it's how many years now 10 years ago I was on a ketogenic diet for three years and part of that three-year window overlapped with

the the very end of that three-year period was when I kind of got back into cycling so um at my fittest as a adult cyclist I was back eating a lot of carbohydrates but there was about a 6 to 12 month period when I was still in ketosis and I was kind of getting back into cycling shape and I do have one V2 Max test from that window of time probably 6 months after getting back to cycling uh and still on ketosis I've gone back and looked at the data and they're very interesting so what

what I would observe is maximum fat oxidation was 1.3 G per minute and that occurred almost immediately and it sustained until I hit my well let me think I it was sustained until about so at the time my FTP was about 4.1 watts per kilo this would have been SU stained until about 3.5 watts per kilo so at 3.5 watts per kilo I was still oxidizing about 1.2 gram per minute and then that sort of fell off and glucose become be became then the dominant fuel source at the at the at the completion of the

test when I was done you know when I failed I was obviously not oxidizing any fat um and glucose oxidation was just under six G per minute uh yeah about 6 G per minute about 24 KCAL per minute so um I've also seen this with another athlete who's been in ketosis for 7 years uh is a very fit cyclist actually he just sent me his data um and it's it's comparable right so he's in fact he's much fitter than I was so his FTP his 20 minut FTP test is about 412 Watts for 20 minutes

um and surprisingly he has decent glycolytic power so that's the other thing is I never really had good power at the low end because I only cared about time trialing so it didn't not it didn't matter how much I could hold how many watts I could hold for 2 minutes or 3 minutes I only cared about 1 hour but you know this guy could still hold you know 1,200 Watts for 15 seconds even for 3 minutes he's north of 500 Watts 600 watts um and again fat oxidation is well is you know 1 1.5 gram

per minute so it becomes a bit confusing because you it would be very difficult to Define Zone 2 by maximum fat oxidation so ketosis is an extreme example but given how much RQ respiratory quotient the ratio of vco2 to V2 depends on Baseline carbohydrate intake how do we make the adjustment so that we understand and we're not being misled because if you just looked at my data you would dramatically overestimate my mitochondrial efficiency is is is that a situation where you say well actually the lactate might be the more and unfortunately I don't have lactate

data from that test so I can't tell you what my lactate levels were doing but um again it might not be a problem in the pelaton because you're not going to be in ketosis if you're trying to win the Tour to France but uh we do see a great degree of carbohydrate and fat variation in the diet amongst people that we trying to test so how how do you make that correction yes so I I my humble opinion uh what we see in these cases because I see them all the time too is that there's

an artifact in the uh uh metabolic heart um the metabolic heart measures uh gas exchange and and then through the equations it it it kind of says okay this got to be or this person must be burning fat or burning carbohydrates right um uh but it was calibrated the the equations are calibrated on high carb diets presumably yeah and so the thing is like as you exercise no matter what fuel you're using you you keep increasing oxygen consumption right but if you don't have much carbohydrates you're not going to produce much CO2 so that's going

to uh tweak you know uh um um Mis or mis mislead that uh um stom metric equation because the uh the algorithm is going to think that oh W he's using a lot of oxygen and not producing enough CO2 so he's got to be burning a lot of fat that's when you see fats in north of one gram per per minute right so th those are fat oxidations that I think they're an artifact and I see this because 3 days later you know when you change the diet of that person uh 3 days later uh

that person's fat oxidation might be 0.35 right so there's no way that the mitochondria adjusts you know first like it reflects a very high flat oxidation capacity in someone who we know very well who is not an elite athlete whose matter candle function is not incredibly High to be able to oxidize so much fat right and in three days um reduces like by three or four times right so I I I I attribute this to an artifact of the gas exchange and this is where uh um uh looking at lactate uh it should give you

those parameter you know normally what I see in this in this individuals is that you see maximum lactates of two three milles right because simply they don't have carbohydrates um also the thing when you see that yeah my maximum grams per minute of of carbohydrates were in the six but you're in ketosis right so how can you have enough glycogen or glycolytic capacity to elicit such a high carbohydrate production well I mean I think even when you're in ketosis you know you're you still remember my blood glucose is still you know four to five Millo

right I mean it's it's it's uh so so I would really like to see this studied because again even if you're only eating 50 grams of glucose a day think of how much glycogen you're making from all the glycerol from all the fat that's being converted to Ketone so I mean I think Jeff volik and Steve finny have looked at this and when they put people into very very strict ketosis but do muscle biopsies they're still seeing 60% of the glycogen content in the muscle that was there under high carb conditions yeah so I I

I mean I think my capacity to oxidize five and a half to six grams of glucose per minute was still there um it just wasn't you know it just took a long time to get there I think is the difference um so I guess the question is if the vco2 estimation is off because of the stochiometric coefficients do you think the V2 estimation is off also I don't know I don't think so because you know as you said very well you know like are you know like ketones are used for energy purposes and then we

have a third element which is absolutely key in B energetics which is glutamine right uh glutaminolysis it's highly expressed and utilized we have learned that from ICU patients ICU patients is a great model to study metabolism or stress metabolism ICU patients um they utilized for wound healing about uh three times more glucose at rest um than what we have right um and it's part of the healing process glucose is is instrumental for self proliferation W healing and part of is lactate too as a byproduct in singular molecule but um but we see that um um

and this is a study that we published looking indirectly a methodology to look at glycogen and we did it with a with a it's it's a pilot study we did with the ICU patients they don't have glycogen and it makes all the sense in the world because if you enter ICU first of all normally sorry when you say they don't have glycogen you mean liver glycogen muscle glycogen are depleted by how much and and depleted to what level yeah so let's say that let's say that you have 500 grams you know of of of glycogen

um if you have a full High carbohy diet so that might not be the case of someone entering the ICU first because they might not be elite athletes or they might have maybe 300 grams or they might not have that adaptation to home more glycogen so let's say they have 300 grams or so uh and then uh by the time they get into that condition the body uses about three times the glucose at rest now an athlete uh use that same glucose but a higher intensities but only for a reduced amount of time 2 hours

3 hours for hours whereas the ICU patient is 24/7 right So eventually the body is going to run out of glycogen in the muscle or it's going to be under huge stress so the body has evolutionary mechanisms this is a wonderful machine and it needs to continue so it increases um another route which is uh glutaminolysis so glutamine is an excellent source of fuel it enters directly the mitochondria uh we have seen in in in in the publication that we're going to show um now that um when we publish it is that when we when

we uh inject mitochondria with h with glutamate uh it's incredibly well oxidized and what's the source of of glutamate in these ICU patients are they breaking down muscle exactly so this is this is where CIA comes into place we know that pretty much every single ICU patient becomes um CTIC or suffers from muscle muscle waste and this is the syndrome right post IU muscle waste syndrome uh and this is where like where why do they get CTIC or catabolic right and and and why they overexpress tremendously levels of glutamine because they need it for either

uh enter the the CP cycle for energy or for glucono Genesis so this is one of the things that uh we learn a lot from ICU these ICU patients they have hypoglycemia right yet they're not given them usually because they have hypoglycemia it's true too that in the acute ICU phase they also have insulin resistance right but obviously this hyperglycemia and ICU doctors historically have seen this it's like whoa this patient has hyperglycemia of the chart so obviously we're not going to give them IVs of FIA of glucose we're going to give more protein and

glucose I mean and FAS and in fact glutamine has shown that increased survival rate in these patients right uh but where is this hyper glycemia is coming from when you do not have glycogen it comes probably from proteolysis right where you break down protein from your muscles to release glutamine but I mean I think we could we would only know that if we understood hepatic glucose stores because regardless of how much glycogen is in the muscle it's never going to make its way into circulation because the muscle can't fully def phosphorated so do we have

a sense of what the hepatic glycogen content is cuz I can't imagine the body would ever let anything compromise that given that if the liver can't produce glucose continuously the brain dies so it might be that this is true true and unrelated right it could be that the the the muscles are depleting glycogen because of high utilization but the liver through glucan Genesis has plenty of glucose that's what's making it into the circulation because of hypercortisolemia because of other acute phase reactants and so we have hypoglycemia but it's all being mediated by the liver which

has no trouble maintaining glycogen levels and again from an evolutionary perspective you much rather air on the side of hyperglycemia than hypoglycemia under period of stress absolutely and is and is necessarily and that's I think what's the source of that gluconeogenesis right so it's probably glutaminolysis right coming from the muscle so this is what um this is my hypothesis right that those muscles they eat themselves to feed themselves or to feed the rest of the body right uh this is why so it would suggest that exercising ICU patients would be important right so getting some

loadbearing resistance even of course they're in a bed but you know sort of moving their extremities against a load supplementing with amino acids absolutely could actually improve outcomes absolutely there's there a lot of research in this area my colleague uh Paul wh Meer who used to work here with me at the University now he's in Duke he's doing a lot of research and uh and practical work with that but with the with this is like uh yeah this hypoglycemia probably comes from glucono Genesis um uh and again this is this is what to to going

back to where we started um um yeah could be that there's a lot of um glutamine released you know when you're also in know keto acidos State as well especially in the first phases of that right we know cortisol is very high at first the same thing that we see in ICU patients that that the two main parameters that are predict predictors of mortality at the ICU is a hypercortisolemia high cortisol levels and high lactate levels right they both are completely related right um anyways um um yeah I think this is this is fascinating there

this a great model to understand um metabolism stress metabolism of these patients in the ICU patients and and that's the other thing too once once you exercise and this is a very important concept for people with type two diabetes with type one diabetes um uh and hyperinsulinemia is that you have insulin resistance right um and and and and you have difficulty to translocate therefore to translocate the glut for Transporters to the surface of the muscle the ccma and we know that prob probably the first tissue or organ where diabetes uh debutes starts is the skeletal

muscle absolutely because about 80% of the carbohydrates that we have they're oxidized in SK in skeletal muscle and and because we're at R are should be oxidize with the mitochondria of skle muscle that pyate right this is what we're doing research I seen it clearly but um but uh when you have insulin resistance you cannot translocate those transporter now we have a second um way to translocate those Transporters that not many people know about and that's muscle contraction right this is the this is the insulin independent glucose uptake which which also seems to be heavily

dependent on Fitness right the fittest athletes here require virtually no insulin to translocate glucose into the muscle through the insulin independent pathway and actually this I think we may have even discussed this I don't know over dinner one night but you look at the type one diabetics who are highly highly active require very little insulin exactly and and this is because they have a and this is this explains um uh the hypoglycemia in these patient shortly after they start exercising right they might have some something to eat and they inject themselves with insulin and and

there's nothing you can do once you have insulin on board right so that insulin is going to translocate those spers and it's going to start bringing insulin inside but in the moment I mean sorry glucose thanks in the moment you start exercising you do the same function through contraction of exercise of of the muscles so you have two mechanisms acting at the same time pulling more glucose inside the cells leading to hypoglycemia so this is what we we learned a lot with type one of persons with people type 1 diabetes in exercise but this concept

and and then we can prevent them so for example do not inject yourself before exercising right because exercise alone is going to take care of that glucose right but we can take these Concepts also with people with type two diabetes uh that that they have insulin resistance or pre- type two diabetes like why not exercising right after you eat right because that that that carbohydrate you have uh you know like you don't have that you have insulin resistance already but when you exercise you you're not going to need that insulin and yet you can translocate

those Transporters and you bring glucose levels down and I'm sure that you you you see this all the time where your uh glucose sensor with your Tex come right yes and and and there's I've gone periods of time when I've done incredibly frequent lactate testing so you know lactate testing every 30 minutes for a day or something insane like that which is incredibly expensive and incredibly painful on your fingers but you learn how much for example a meal in impacts lactate so um when I wake up in the morning my my resting lactate level varies

between and this is I've been tracking this over a period of uh probably 40 days so 40 days of tracking what what range do you think my morning resting lactate level has been over a 40-day period how much variability in the morning first thing in the morning I would say I would say you know like in the neighborhood of 0.8 to 1.2 1.3 I'm pretty good guess so 0.3 to about 1.1 okay but that's a pretty big variation yeah um and probably median level of about 08 yeah would be the med neighorhood of wine which

is normally in a fit individual right yes so then what I can do is I can eat a very high carb breakfast and go and do a Zone 2 ride or don't eat anything at all and go into a zone two ride very different lactate performance curve absolutely so the high carb meal raises lactate absolutely so it becomes a bit of an artifact in a way which now gets me to some of the the we we've talked about this at the level of the most Precision possible the way in which I would measure it in

a patient you would measure it in a worldclass athlete where we have the ability to do indirect imetry and lactate testing but now I want to talk about it in the way that we train people normal people so we've talked about this um call it you know difference right between the lactate level that you measure in the blood which is now heavily influenced by production and clearance and then we've talked about the gold standard which would probably be fat oxidation but even that can be confounded but let's take off the table the people who are

consuming a high fat low carbohydrate diet because that confuses things a bit if I have a patient and I'm looking at their Biometrics and we do a Zone 2 test based on looking at their fat oxidation during an escalated test of part of a V2 Max test and it comes back that their maximum fat oxidation which is you know3 g per minute occurs at a wattage of 1.5 watts per kilo that's a pretty average person and I say I want that number higher both the absolute number of fat oxidation but where it occurs on the

graph now I want you in a year to be 2.5 watts per kilo let's talk about two things one how they should train and that means duration intensity frequency Etc and secondly what we should use as the readout to know we're in the right training Zone given that they won't be able to train daily or weekly or Whatever frequency with indir calorimetry and by the way let's assume that some people will want to use the point of care lactate meters and some people will not so let's start with what's our surrogate for training Zone and

starting with what we knew so we learned that uh 1.5 watts per kilo was maximum fat oxidation but we want to increase that to 2.5 so what metric do you use to train them so yeah so normally what I do is like starting with the metabolic test I translate that information into whether it's Watts uh or or speed or heart rate uh all of them normally they correlate quite well um and you can individualize it there are people that don't have a power meter okay you can do heart rate for example um or or people

that just obviously they run or they walk uh you can do speed or or or heart rate as well right they're very good surrogate so that's that's a first metric the surrogate right then it's about at least from my experience uh the three main principles that I've learned over the years on how to apply this uh so first is a frequency how many before we go to the frequency and the duration I do want to go back and ask you another question we have some patients who don't want to use a lactate meter uh either

because it's cumbersome or somewhat intimidating we also add another metric which is relative perceived exertion RP um I'll tell you what my rule of thumb is but I'd like you to sharpen it refine it throw it out make it better whatever I tell patients based on my experience so I don't know how extrapolatable that is when I'm in zone two as confirmed by lactate levels so call it 1.7 to 1.9 which is what I Target mhm I can carry out a conversation so I can spend my entire cuz I do most of mine on a

on a wahoo kicker I put my bike on a wahoo kicker ni I can spend the entire 45 minutes on a phone call yes absolutely but it's not as comfortable as this discussion here exactly I'm a little more strained yeah but if I can't talk if I feel like I can't talk I'm too high in the intensity yeah do you think that that's a reasonable surrogate for people to use across the spectrum of not particularly fit all the way up to pachar 1,000% and and I use the C metrics also with people who like you

know like you you mentioned they they don't want to do a har um lactic meter or they don't have access or or they I get hundreds of emails about where can I do this test you know and I or or is there anything that I can do right um so and I agree 100% you know that um with everything that we know at the at the granular cellular level by injecting fuels and SRS directly into the Mand we cannot get more cellular level and scientific that that the surrogate of the pafic exertion it works beautifully

you know I know that people are coming out with different algorithms based on har variability or the DFA 1 Alpha you know Etc but honestly I agree 100% with you um uh if you if you can I always tell people if you can exercise whatever the exercise you do and maintain a conversation like you and I are doing you're way too easy you're probably Zone one yep um um if you can talk but is some form of strain you can talk for two hours right um uh but we're talking yeah you're just at you're just

at that threshold of the per put it this way the other litmus test I tell people is the person on the other end will know you are exercising exing exactly you will not be able to mask from them that you are exercising exactly and in fact I have I have many conference calls with you know like um people that I know to be respectful but I do it on the bike you know uh work as you said you know they call me and I'm on the bike uh either outside or in in the trainer and

and they tell like you're exercising right because you can feel it but yet I can I can maintain a full hour meeting on the bike right um uh and and and without bothering the other person because they can understand me but you said if you cross to the point where you cannot maintain that conversation that's where you you is because yeah you're you're you're you're you need to breathe much faster because you're producing more CO2 and that's probably because you're already transitioning from the slow twitch mle fibers to the fast twitch mcle fibers more glycolytic

more lactate more CO2 more buffering capacity so it seems old school but it works beautifully agreed and and the other thing I do because I really like people to triangulate and give them a starting point so if someone has not done a metabolic test yet and we're just and that's usually the case by the way is that we're starting with just a Zone 2 training protocol I also give them some some ranges on heart rate now here I have found much more variability so the first thing I say is for to do this you do

need to know your maximum heart rate not your predicted maximum heart rate but your actual achieved maximum heart rate in my experience personally so this is I don't know how much I can extrapolate this my zone 2 is actually at about 78 to 81% of my maximum heart rate but I know that for Less trained people it's lower so I tell people a broad range of 70 to 80% of your realized maximum heart rate is a good place to start and then make adjustments based on relative perceived exertion yeah I agree what do you know

about heart rate and I I would agree that I usually also say the same thing somewhere between 70 to 80 that being said right if you want to beis it's a big range exactly so you can be at 70 let's say at 1.7 milles and then at 80 you can be at five milles right so you you're you're completely away from one some but as you said it's a good starting point and then as you very well said and I agree 100% with you it's like yeah then you you you you tweak it with your

perceived exertion um I I agree the other thing too with the heart rate um and this is where you know the har variability you know uh there there are different interpretations you know so the modern interpretation of heart variability is the differences between bit to beit right um and that's where there are different algorithms right for me the har variability har variability is it's more at a broader SP spectrum and it's more on the um you know the um uh adrenergic activation that you have so for example uh you're fatigu today right uh first of

all normally you're going to wake up with your resting heart rate a little bit higher than normally um so that that that if your normal heart rate let's say it's 50 and you're being fatigued you might wake up with 65 so that alone is a hard variability concept it it varies from from the norm to one day so that's a red flag that you might be tired that day might not happen all the day all I mean might not be super sensitive but it is very sensitive for elite athletes without a doubt the second aspect

is like when you go out there and exercise as you might see there are days that you were like 130 bits per minute whatever you think your zone two is 13038 for example um but some days it's really hard to get that hard rate right extremely hard and and you're already struggling at 110 bits per minute or 115 bits per minute where that's not the norm that's another deviation that's a variability of the heart right so this is what I've been historically used for hair heart rate variability which tells me a lot more information this

is what all the athletes also tell you like man my heart doesn't get up today you see on training pics you know you see when someone is fatigued they they do an interval and they know they always 100 80 185 let's say the lative threshold and today they cannot get up until more than 170 you see in the competition the first week of the two the France their maximum maximum heart rate let's say it's 195 last week the maximum heart rate is 170 right that's that's what I interpret by har variability and I know that

a lot of people might criticize me because all that has nothing to do well I respect all that no I think it's macro versus micro I agree is how I is macro versus micro I I'll share with you an interesting self- experiment I've done a couple of times it's not pleasant but it's interesting if I take a huge dose of a beta blocker and the only beta blocker you can do this with if you if you have low blood pressure as I do you have to be careful but Propranolol is is fine because it really

it disproportionately lowers heart rate but not blood pressure but I've done this experiment a few times to test an idea which is would taking all of the gas out of my heart rate allow me to push harder and generate a higher Zone too and it turns out it does so if so my zone two is you know just under three watts per kilo I really want to talk with you about getting over three watts per kilo I'm still Furious because in July remember I was at 2.95 I was just kissing on the door of three

and I've actually come back a little bit I've come back you know I'm now at about 2.75 to 2 85 so I've lost a bit no I I think it we're going to talk about training in a moment so but what I notice so and for me I'm at that upper end of maximum heart rate so so I'm going to be doing that at about 80 81% of maximum heart rate but when if I took Propranolol you know 60 milligrams of a Time relase Propranolol I will be able to get over three watts per kilo

and I'll do it at a heart rate of 68% of Maximum yeah but it feels horrible yeah I feel like I'm going to die yeah it is the worst feeling in the world it is like somebody has and it's not pain it's it's not like I don't know how to explain it other than it feels like what it feels like when you're overtrained it feels like you just can't you can't get moving it's like an engine that's being taken from 9,000 RPM to 6,000 RPM yeah but yet somehow is able to generate the horsepower but

it just doesn't feel right so you know that that's sort of my um uh that's that's my drug cheating way to ramp to get over three watts per kilo but more to illustrate the point right which is when you put the governor on heart rate you can you can get there um at a lower heart rate but it but but there there's just subjectively it's a miserable feeling yeah no absolutely it's uh um yeah and this is kind of in a way what happens when when you're fatigued when you don't have enough fuel right so

uh again going back to like my heart doesn't get up today and I'm struggling kind of like you know it's like if you were taking some better blocker right yeah uh but the thing is that it has to do a lot with fuel uh and and and and for example and I experiment this a lot too I I I I try to understand how this works so I do maybe the intermittent fasting for a few days and I go out there and I'm not good at adjusting at that and and I I cannot do that

I know others can do it and I admire that uh but I can see my heart rate right away right um when you don't have enough glycogen storages um um um it's very possible that adrenic activi decreased you need to break down glycogen and we know that um what takes to break down glycogen is foror a right in the in the muscle and that's directly regulated by um um um um CAC colines right so when there's um a decrease in glycogen this is my hypothesis right when there's a decrease in glycogen storages um because of

the evolutionary mechanisms that humans have the brain is the boss right the brain says like I don't care about your legs but don't don't use up all the glycogen because you have to give me and the liver has to give me glycogen as well so I'm not going to shut you down completely of breaking down glycogen but I'm going to slow you down so I'm going to release less camine so that you break down glycogen now um um the collateral effect of that is the heart because the heart contractility is regulated by catac Colin as

well so this is why using that my version of heart rate variability it's quite useful I've been using it incredibly successfully for 25 years with my athletes uh where I see that hey your heart R is not going up today you know usually it's 185 190 for example when you do a active threshold for example and today it was 170 so tomorrow take it easy or pile up on glycogen I mean on carbohydrates or take an easy day and you'll see how you're going to be very responsive the next day the following day and in

fact that's what happens I would say 10 out of 10 times but let's say nine out of 10 times right but I do that with myself as well and and I see is also uh um uh that I don't I mean I I work a lot with the head you know so you know you think a lot and the brain uses about 100 to 125 grams of glucose daily right when when you go and I don't know that fact you know but when you know when you work a lot of hours and thinking and thinking

and thinking and stressed um I'm sure that obviously that the brain might need a lot more glucose so that's that's training your your glycogen Estes from the brain probably and even from the muscles because the muscle can release glucose utilized as well yes yes muscle can the muscle has phosphor and can be a degraded gluc glycogen and that glucose can go to the to the circulation as well to feed other organs I didn't realize that we had glucose one phosphatase in the muscle I I thought the muscle glycogen fate was sealed in the muscle no

it's it's possible there there are a few studies I I'm happy to to send them to you I I cannot refer them out of memory but uh yeah the the the the the muscles can also release glucose to and Export glucose outside I assume this is a relatively small amount yes I I top of my mind yeah absolutely exactly but it's possible too but what I mean and and I don't know what say yeah so so those days were I'm thinking a lot and I'm very stressed uh and I'm not you know like dieting or

anything I just go out there and I'm dead and I'm sure that many people listening to this feel the same way like what the hell is going on today I don't have energy at all today you know so and you will see that your heart rate doesn't get up those days um um and and you can get to that by just training five hours a week or seven hours a week and sometimes people say like look I cannot be overtrained because I only train five hours a week yeah but you're overworked yeah and that that's

that that's a big artifact with your training that's what most of us are aspired to pre- retire before 60 you know so we can have more time to exercise right and less time to work but uh but yeah that's what I do this I I I I I I take a day off completely I I sleep more I I I I uh I increase my carbohydrate intake and the following day I I can even break my PR on a climb or something like feel like like a million dollars so resting recovery is key for that

yeah I I think that's a very important point and it's actually something I've only been able to pay attention to in the last year which is I used to judge my performance by training load so you know and we I used to use training Peaks when I was training I don't anymore but the concepts of acute and chronic training balance and and it was you know any day that was suboptimal could be explained by training volume in some capacity but now you know my training volume is relatively low it's 10 hours a week of total

training that's both you know cardio and strength so that's this is not a lot of training and yet when I'm under stress workwise you know I I'm just doing too much and I don't even use the word stress it has a a real negative connotation to it I just mean when I'm overworked when I'm doing too much my performance I have to either adjust my parameters for what I deem successful or I just have to sort of cut back on the actual training a little bit to make time for more sleep or more relaxation um

and so I think that's a very important Point uh that I that is easily lost so so let's let's now so we've got a very good handle on the metrics we're going to be using so now let's talk about two scenarios the first is the person who is new to this type of training so they've listened to this podcast or they're one of my patients and I've made the case convincingly to them that you really need to do this type of training I want to come back by the way to a justification for that so

let's explain why high-intensity training is not sufficient but we'll we'll park that for a moment but they really don't have much of a background in this type of training right they you know maybe they do some high-intensity training they do some weights they play some tennis uh but they really don't do the sort of steady state sustained cardio that we're talking about um how would you structure a training program in dose duration frequency uh for that individual and tell me a little bit about the choices that you would make if they're agnostic to running walking

cycling rowing swimming you know again I have my biases there but I want to kind of hear what you have to say about it yeah no think yeah that's a great um question and I also you know before that I want to apologize to many of your audience um um uh because I I I get a lot of emails you know asking me about these questions and it's hard to well that's why we're doing the podcast so you don't have to apologize it's easier to do appreciate it uh this way but still I get emails

um and uh and and before I used to see people here at the University but now at the University you know we don't have these services so I'm trying to convince them that these services are important to offer to to population but anyways I want to apologize because I cannot answer to everybody but yeah so uh my my my I have the three three main rules or parameters I have learned over the years so one is the duration right um we have in in mind sometimes that this is like endurance training long day like like

I don't only have six hours a week or seven hours a week at most right to do this type of training or less so there's no way I can do that it's usually less because they might have six hours a week for total exercise exactly and we're going to take half of that for strength training exactly because which is very important as you know uh um it's it's my it's where I fail because I should do more of that and I try to to get a little bit more of time to do that but I

it's not easy but I Aspire really to to to dial that in but uh but yeah you're right they might have less than six hours and they might think like well I I'm not an endurance athlete so you need to do four hours to do to accomplish this so therefore I'm just going to move to do just high intensity and just get out of the way well that that's not completely true right uh you can accomplish very important matter Cal adaptations and very important um um metabolic adaptations by exercising one hour right so this is

one is the uh uh um uh the duration let's start by the duration right so uh um if you try to do that one hour to 1 hour and a half range uh you're on target um and is that in one setting hours I'm sorry is that total or one setting what do you mean uh meaning is it one to one and a half hours per week or does that need to be in one continuous exercise bout yeah I'm sorry let me let me maybe go back to that the frequency right that the dose so

the frequency that I see is that uh this type of training uh ideally needs to be done between three to four days a week ideally uh um what I have seen and how can I know this U I know this because I've seen in the laboratory everything right the person who trains one day at this um zones or two days or three days or four days or high intensity low intensity and I see the adaptations how do I see the adaptations again looking at matter kind I mean that fat oxidation lactic cleans capacity both surrogates

of matter kind function right so I've been identifying that the dose of that training so if you train once a week there uh chances are that uh you're going to deteriorate over time and especially as we age uh something that I see for example in high-intensity exercisers and bodybuilders that they have a very poor mod candle function compared to people who do more uh a little bit of everything right so one day a week it's not going to work two days a week it might maintain what you have but if you're new to an exercise

program might not be enough three days a week now we're starting to to to to see for sure four days a week now we're talking ideally five days a week or six but not not everybody has obviously six days a week to train but I think that we all can I mean you are a very busy guy I'm very busy guy and we try to squeeze four five days a week maybe six in the summer but four to five days it's achievable for most individuals and and and put aside an hour to an hour and

a half right so I would say that four days a week is ideal right that's the that that that's the first principle the second principle is the duration going back to what I was saying right with with with one hour maybe Patra needs four hours five hours uh to keep increasing those huge mondria for a long time but a mer mortal and especially someone who might be pre-diabetic or might be out of Fitness or or has an exercise in a long time or or someone who coming from a disease or or or a mother who

just had a baby and has been out of safe for a while you know 1 hour um if you walk or if you run U might do might be very very good for you uh 1 hour walk you know you or run you might have to bring it up that's that's part of the plan too right you cannot start off the bat with one hour you might start by 20 minutes 30 minutes 40 minutes increasing it but maybe about an hour and if you bike for example about an hour 20 minutes hour and a half

that's what I see that if you do that for four days a week things are starting to move even even if you bike on a trainer where you can be much more efficient and you can really get straight to the wattage and stay there CU we we tell patients you know again it depends where they are in their cycle but if they're starting out I mean we'd be happy if they give us 30 minutes three to four times a week of dedicated exercise um so so do you see a difference between I don't I can't

do zone two on the road I can really only do it on the trainer I just can't stay at a constant level on the road with starting and stopping and wind and hills and stuff like that that's a very good point that's why an hour and a half on the bike it might actually be one hour or so right because you have all these artifacts but you're right when you're on the trainer you isolate everything completely and and what I also recommend is about an hour if you can get there but again you know like

yeah sure you might it's it's to me it's it's feels like a torture sometimes you know to be an hour and the trainer I hate it I like to be outside uh but we have have to do it I do it I I watch a movie or or just catch up on work I have one with special desks right where I can type or read articles or answers some emails low key activity because again you know you're not very sharp to think uh very intellectually but um but yeah one hour might do the trick uh

what I've seen is like yeah in those people who haven't done much at all even 30 minutes 20 minutes might start moving the needle but eventually it's not enough uh those right uh um uh it's like if if the body needs more right so if if you can get to a goal about an hour to an hour and a half that's that that should really work in my modest opinion in my experience so that's that's the um the duration um and the third is always the frequency which we have talked about which is usually the

zone two that being said I think that it's also important to stimulate other Energy Systems right like the glycolitic system um uh and again continue with the model that we do with Elite athlets people think that Elite athletes whatever the sport are all they do is high intensity all the time and intervals intervals and it's the exact opposite if you look at the workload of of an elite athlete where whether that Elite athlete is a especially in individual sports right it's easier to to to see this whether it's a triet or a cyclist or a

marathon runner or a swimmer right which is like a 100 meter swimmer is under a minute right it's maximal exercise if you you look at the workload it's very similar right the majority of the sessions are in the lower intensity they're not intervals intervals intervals and I always say we cannot be so naive to think that you know like the best coaches and athletes in the world haven't figured this out when they're always trying new things and they want to try the cut and Edge things obviously they have said like oh ours sport is swimming

it's under a minute all we need to do is like intervals intervals intervals intervals right well if you look at what swimmers do they train and and if you ask Michael Phelps you know hours and hours and hours and hours and hours is if you can travel through the competition in that under a minute with a slightly better function to clear lactate even if it's 1 Millo uh or less uh the muscle contractual Force might be improved so all the hours and hours and hours might be that just to improve a fraction of a second

but anyway so this is what I'm seeing that this concepts of of of of the gly of the G glycolytic capacity and high-intensity training they're necessary but they're not what the elite athletes do and if the elite athletes have the best metabolic function of any humans why not try to imitate their philosophy of exercise and so just to come back to the frequency duration question I think the answer to the following question is going to be the more frequent training sessions but if you compared four training regimens that were four hours a week each one

of them would be four 60 Minute sessions one of them would be 3 80 minute sessions one of them would be two 2hour sessions and then one of them would be one 4-Hour session so it's the same total volume is it safe and notwithstanding the brain damage of one 4-Hour session is it safe to say that the four 60-minute sessions because it's a higher frequency would be the optimal one there I would say so I I think from my experience that it it might be better because it's it's the frequency it's like it's like if

you take a medication right if you take a medication twice the dose and only three days a week might not work as well as if you take the right dose every day right uh because at the end of the day we're talking about the whole exercise is medicine right how do we prescribe that you know how what's the dose how what's the Frequency I'm assuming that you will have to take it as many days as possible right uh so that that would say that it's better to to to do that that being said obviously if

you have the weekend and you have the possibility which I don't have to do three hours go ahead right um and and another thing I wanted to point out is that you know for many people there they need that adrenaline right um for training so uh other people don't care right other people say wow I love this I don't like to kill myself into high intensity but I think you need to do some high intensity yeah so I want I want to talk about that so how do we bring in the other Energy Systems of

of the of the four pillars of exercise in my world uh stability strength lowend aerobic which I describe really as I talk about it as kind of mitochondrial efficiency and then high-end aerobic which is Peak aerobic capacity SL anerobic performance so anerobic power Peak aerobic low-end aerobic mitochondrial efficiency strength stab of those four I for some reason struggle to make the time for the peak aerobic in part because I one it's the least enjoyable truth if we're going to be brutally honest if you're doing it right it hurts the most yeah it's also no longer

as relevant because I don't compete at anything right like it was I actually really enjoyed that type of training when I competed because you have to spend time in that energy system and you see the rewards of you know repeating 60 Minute you know you know 60 Minutes of repeating 2minute intervals or something like that so if we're if we're really talking about this from the lens of Health maximizing Health the data are unambiguous that V2 Max is highly correlated with longevity in a in unlike there are not many variables that are more strongly correlated

MH so but the levels don't have to be that high right we're not I mean pogacha V2 Max is probably 85 you know or it's probably in the 80s at least in terms of milliliters per uh minute per kilogram but someone my age to be considered absolutely Elite which means the top 2.5 to 2.7% of the population which carries with it a fivefold reduction in Risk to the bottom 25% of the population uh my V2 Max requirement is about 52 53 milliliters per minute per kilogram so the question is can I use that as the

gauge for how much high-intensity training I need to do basically just enough to make sure I maintain that V2 Max or do you think about it in a different way well I think about it more again the by energetics energy energy systems right I think that ultimately and we know that longevity is also High related with mandra function and metabolic health I think that more and more and and and this is what you see in so many fields in in in medicine nowadays right that everybody's is stumbling upon mitochondria right um um and and so

there's an aging process where we lose mandal function uh and there's like a a sedentary um component right where we lose mandal function um I wish that we could have a medication a pel that you could take it and increase the mandal function because it would increase metabolic Health and Longevity but the only medication that we know is exercise and the medic and within exercise that the right the dose that we see that improves the most and and also it's sustainable in the long term which is another important concept you know uh very high-intensity training

is not sustainable very extreme diets are not sustainable if you combine both it's even worse and this is what a lot of people are doing together but you need to have some sustainability but this is what it we've seen this this is important to improve that mitoch candle function but going back to the that high intensity I think is necessary because we also lose glycolytic capacity as we age and it's important to stimulate it as you very well said for all of us who are not competing I couldn't care less about um being super high

intensity uh I'm not competing uh but that said I want to have also my adrenaline rush you know so like many people I but how much does it feed into it so for examp example if and I've often thought about this now as I just want to make sure my zone 2 is above 3 watts per kilo would I be better off taking that extra training if I have one additional training session per week should I make it an additional Zone 2 workout so then I do four now should I be doing a fifth one

or should I be taking that fifth one and doing a V2 Max protocol and that's that's what we'll typically prescribe to our patients is a 4x4 protocol of you know highest intensity sustained for 4 minutes followed by four minutes of recovery and and then repeat that four five six times uh you know when you put that when you put a warmup and cool down on either end of that you know that's a little over an hour um so you could would you spend that hour doing that in an effort to make your zone two even

better or would you just do an extra hour of Zone too no that's a really good question so what I what I I I I agree I agree that uh you can if you have a fifth day you can convert it into any type of high-intensity session structured all right what I can tell people so hey if you're a cyclist or a runner and you want to go with your friends that's your group ride yeah group ride go ahead and boom go at it or or or if you don't have that possibility what this is

my situation for example where I I don't have the time to train more than an hour and a half usually two hours max right so what I do almost on every session I do my zone to so it's clean and at the end that's going to do a very high intensity interval and tell me the duration so if you did an hour of zone two yeah so I do usually let's say an hour and a half right so uh and so you'll do an hour and a half of zone two three or four times a

week yeah try I try I shoot for four or five but not all the time it's easy uh but yeah I shoot four or five and I try to be strict than that but let's say that yeah the last um and unfortunately that you know I where I live you know like U I live more in a it's Highlands area and uh so you have to go up so the last part I just I just go at it you know sometimes you you find another cyclist and you just compete you know to see who's the

the fastest in that short climb but I Tred to do like a good five minute interval roughly um uh where I really like kind like a go hard at it and and and and I I arrive home like man I I kicked my ass today or or this kick my ass today or or sometimes you try and you don't have the energy as I mentioned earlier oh my gosh I can barely move the pedals today I just quit and go home uh but when I feel fresh you know um that's what I I stimulate that

glycolytic system what we know well too is that you know that increases the mandal function it takes months or years increasing the glycolytic system it takes much muchow less amount of time you can do that in weeks or months uh and you can just if you stimulate on a regular base two days a week or 3 days a week uh at the end of that zone two that's where you can Target both um Energy Systems right the oxidative mitochondrial system and the glycolytic and we don't blunt it we don't we don't we don't um blunt

the benefit we had from the zone two if we immediately follow it with the zone five no because that's done right that's not what I see is like if you do the same things in the middle but you don't want to do the reverse order yes and one start with the high intensity exactly one of the things like because you start having all these hormonal responses and also you see you have high lactate levels in the blood and what we know very well is like lactate inhibits lipolysis so if you have a high interval in

the middle or the beginning and you don't clear lactate very well you might have high lactate levels for a while and it's going to inhibit Li policies right also another study we have under review lactate um the autocrine level yeah decreases the activity of cpt1 and cpt2 so interferes with the transport of um of fatty acids as well um so that's where like if you do all these you might change things you have high cortis cortisol enemia as well and that's an important point I I I'm glad you raised that because I explain this to

patients when they say um I went out and did a 2hour ride today and it showed me that I spent 45 of those minutes 45 of those 120 minutes we're in zone two so I did 45 minutes of zone two and I say no you didn't really do it because you were going up and down and up and down and up and down and so that's not the same as spending 45 minutes in the dedicated uh Energy System you're right and if you I mean when I look at training pcks you know like you see

the the elite athletes they're like what power output and heart rate this is like goes together incredible you know whereas yeah you're right up and down and down the average might be zone two but actually you're between ulating so one so three so four all the time right so tell me what's the difference between so so if you don't mind sharing what is your in wats per Kila what is your Zone to in Colorado where you're at altitude yeah so I I usually go and and I'm I'm I I'm not very good at um at

you know like understand I mean doing this but I'm it depends uh um uh what I'm saying is like I don't look so much into this I have done so many um test in my life I I I was since I was 15 years old I I was using a heart rate monitor I'm talking about 1986 um um when the first heart monitors came out so in other words you're what you're getting at is you don't like to have a lot of data when you're doing you're going off RP and you're not looking at your

power meter or a heart rate monitor and you're not poking your finger when you're done I do it here and there you know cuz I still want to look at this and I do metabolic testing here and there right uh but I've done so much me since I was 15 years old and I was obsessed by this now I I I got to a point that I know my by my my body quite well yeah uh where I I I can just go by the sensations and and and and but here and there I I

double check but it's hard for you to then get at what I've observed the few times I've tried to do my zone to at altitude like in Colorado yeah it's a enormous discount I feel like it's a 20% discount at altitude yeah I TR to go like around yeah mine is around 2.5 2.8 something like that wats per kilogram uh when when I when I do it um and I you know like about one so at sea level at sea level you'd be over three probably based on what I experience in going in the RSE

Direction I would say roughly um uh and and one thing that I'm very proud of uh is that um I have been doing because I do sporadically this testing I don't know my PRS because I know the thing we have climbs here and one day I go I'm going to go for this climb and I go full out on that climb right and in I'm 50 now uh and I have the same uh uh uh metabolic parameters that when I was 40 so um to me I'm very proud of of this because and when you

say parameters you don't mean times up the climbs which parameters are the same yes so I look at you know lactating power output okay I look at V2 I look at uh time as well you know the pr that I had it was similar in fact the other day I bat my PR what's your V2 Max now so my V2 Max now is uh 4 lit um um uh per minute you know so that's about 51 52 say that's I am you but you could easily you could easily raise that if you lost you know

three kilos which you could probably do yeah yeah yeah yeah and the thing this because I've obviously when I was a cyclist I was 141 143b and you were probably your V2 was 5 and2 lers or something it was it was 76.7 uh so that's um uh let me see it was 4.5 I believe between uh 65 yeah it was it was about uh 4.8 something like that now so now you know like 40 years L 30 years later right uh I have decreased only about 0.5 0.7 right which W I'm really happy about that

because I'm not training like I did uh um but this is one of the parameters but in a decade I haven't decreased my parameters so this is to me it's a proving point to myself at least that doing this routine um it it it it it helps uh to maintain you know that metabolic Health that you had a decade ago now can you do this 10 more years and when it turn 60 uh I I don't know but what I know is that from others I'm seeing it so I see the typical person who just

retired or or as we as I discussed early aspire to pre pre- retire at the age of 60 or little B before in the moment they and these are like people like us who are struggling to to to squeeze in time you know and do five hours here six hours a week here or 10 at Max um but then they have the whole time in the world and they can sleeping they don't have they're not overworked uh you know they can exercise it's unbelievable and super inspiring how much they improve in their 60s I've seen

people in their 70s with the metabolic parameters of of of people active morally active uh in their 30s wow I saw the the world champion in the cycling who's 81 in the category of 8 to 85 believe me there's a category of of that uh whose metabolic parameters were those of someone in their 30s healthy active so this is incredibly inspiring then I think that we're rewriting what's been taught to us in the books now In fairness was was that person of an elite athlete were they a professional athlete in their 20s and 30s never

and this is what struck me he was a a smoker hypertensive and he started uh cycling because he needed to change his lifestyle in his 40s because that's the same question like wow you must have been doing this all your life like no I started riding my bike when I was in my 40s I was a smoker I was Heavy I was hypertensive like what so it's incredible that 40 years later he's in a better health than he but but I'll tell you what I what I take away from that as well is the benefits

and the more the importance of compounding you see you alluded to it earlier and I think the listener could be forgiven if they missed this point you can make relatively quick changes in your glycolytic efficiency you you can take an untrained person with a V2 Max of 20 Ms per Mig um per minute um or m u Mill per kig per minute and you could take them from 20 to 30 in a period of months yeah with the right amount of training a 50% improve in a few months exactly it's very difficult to see a

50% Improvement in mitochondrial function in a few months exactly and and and you you've already made this point but I just want to restate it because it's important to set expectations and it speaks to why this level of training should be thought of in the same way that you think of accumulating wealth which is you got to you it's it's day in and day out day in and day out small compound Ed gains over years and years and years is why a 40-year-old overweight smoker can become a world champion at 80 it's because he probably

never once again got out of shape in that 40 years Absol absolutely absolutely and this is incredibly inspiring you know uh when I see these people in their 60s just retired and they come to do their first test and one year later they come back I mean it gives me the Goosebumps because it is like oh my gosh like how can you improve so much and and they're they're like and they're say like look I'm I'm 64 and I I I feel strong as as when I was in my 30s you know and like and

so this is where we're we're going to be you know like and of course no medications you know um really good state of mind uh which is absolutely key for longevity right um normal diet they can they're not strict with one this or not that they they they eat in moderation but they can have a little bit of everything right uh which is also in my modest opinion is part of the enjoyment of life um eating what you like in moderation as well um so it's incredibly inspiring to see all these examples and and and

and and a way where we're rewriting what we've been been thought for years that once you turn 40 everything is going down you can really really change and again you know your you know you're you're you own your own body and you can really you know take ownership of that and improve it at any age so what you mention drugs I want to talk about One Drug in particular and maybe some supplements um you and I have spoken so much about this and you know myself and another person are committed to funding a study that

we're going to be doing once the um uh once we get through kind of the backlog of of covid uh issues at the University um um but uh the question really arises around the use of metformin and whether or not there's sort of a true impairment of mitochondrial function or whether the elevated lactate levels we see in patients taking metformin is an artifact of the drug itself but says nothing of the mitochondrial function do you have any more insight into this question that that that we struggle with greatly because we have some patients who take

Metformin who achieve uh who who receive much benefit from taking metformin but it makes it confusing to interpret their zone two data and it makes me ask the question you know it's a more important in those patients it's maybe less relevant but now it becomes relevant when we think about using Metformin as a geroprotective agent an agent to enhance longevity yeah I that's a thing that um we need a lot a lot of uh um um research on that I think to understand this better now we it's it's a strange that definitely it seems to

work in many patients right obviously for those once in the pre-diabetic first stage diabetes uh is the it's a very good uh medication has been used for for a long time with good results but how about the longterm the long-term results right um we know that a metformin inhibits complex one which is key for mandal function in the electron electron transport chain um so we don't know the long-term effects of met forming right um uh in longevity this is where I think that we need more more more information as well uh we see or I

see like someone showing up with the lactate of 3.5 Mills at rest and the first thing I ask is like are you a metformin and many say yes and I'm sure you see the same thing right like wow so um so it's it's definitely an artifact and why do you see it rest 3.5 Mill for 3 m of lactate and by the way is their fat oxidation commensurately suppressed because when you when you metabolically uh test them on the cart do you see in that individual a very very low fat oxidation if if not it

might suggest that that that lactate level of two or three Millo is is an artifact but doesn't really speak to what's happening in the mitochondria right and that's a great question I haven't seen people taking metformine as a a um um um um uh um um medication you know for longevity for example or for health where I see people on forming are already clinical patients yeah so so in other words it's confound so of course they're low because yeah so they're taking metform in in the first place because of their clinical condition which is driven

by a mitochondrial impairment or dysfunction so it's it's difficult to discern but I mean I'm sure you you you you have more experience of people taking metformine we do yeah but that's why this study that we're eventually going to get around to doing is going to be so important because it will answer this question directly yeah and we can do the muscle biopsis and as you say is like is it does it really mess up with the whole M CLE function or can even like the M kind function overall override that inhibition of complex one

and and override other Pathways I I don't think we know the answer to that do you have an insight into any other uh supplements there's no no shortage of of supplements that are out there that that are touted as sort of you know longevity boosting agents and mitochondrial Health agents so so the most talked about of all of these I think is the precursors to NAD so the most common of these would be NR or nmn both of which are uh pretty clear that they are precursors to NAD there's certainly some debate about how clinically

relevant it is do you have a point of view on whether or not taking a supplement that boosts uh NAD at least in the plasma I don't I still don't know how well it's boosting NAD in the cell but um nevertheless do you you have a sense of if that is beneficial to the mitochondria um both theoretically but more importantly experimentally yeah well that's that's a great point and this is like I I don't think we have the answer but I think we need to be cautious about how we we interpret this data um um

it's definitely been shown multiple times that um NAD levels at the cellular level are and even M candle level decreased with aging right therefore the whole thing wow if it's low let's take it right but it's not only NAD um I mean if you look at so many metabolites you know in at the cellular level in Mand level they're done regulated with aging right the question is why are the they are they down regulated uh is is because mitochondria per se to start up with is downregulated so doesn't need so much NAD because cannot take

it right or other supplements or other metabolites right so this is this is at least how I think of um n it's as as we mentioned earlier it's very important in glycolysis it's in Redux St status right to maintain Redux and is very important in the in in glycal 3 phosphate 2 to three by phosphor glycer phosphate where n is utilized uh to convert um glycerate three phosphate to three phosphoglycerate uh but it's depleted and this is what the only thing that rescues that is lactate right as we mentioned now taking n is that going

to increase longevity I don't think so that's my opinion because longevity is not just one supplement or two or three or four or five it's a compendium on on an incredible amount of things that happen at the C Level and I don't think that One supplement I remember those days where Resveratrol was the thing right for longevity and everybody was not everybody a lot of people were buying R virtual and there studies with mice showing that increased 50% longevity in mice so therefore forless do it in humans well as you probably know a lot of

people started to take in ver virtual when they were 50 and they're dead now you know it didn't incate it doesn't increased longevity in humans right yeah I mean and I think you know I think the data in the in the mice we can debate the merits of that I want to ask you about a theoretical risk though you you kind of alluded to it isn't there a scenario under which too much NAD could be harmful if you had an exist if you took I don't know if this study's been done but if you took

cancer patients or patients who had tumors that were undiagnosed and gave them if you boost if you doubled their NAD levels wouldn't you actually favor the tumor's metabolism well in five have done that pilot study with mice um so the whole thing is like looking at in my area of researching cancer is cancer metabolism right yeah and we know that glycolysis is key for for cancer uh and and NAD is absolutely indispensable to feed that glycolysis as I me as we have me eluded a few times right so the question is like as you say

would would NAD increase that glycolytic rate or glyc IC flux therefore would be favoring more a cancer phenotype uh um so what we did we haven't published that it's a pilot study which just we're curious about it and we had hum mice we have Ann of eight mice four and four so what we did we transfected um uh tumors we have triple negative breast cancer it's very aggressive and it grows very very fast and uh um uh so one group uh we gave them PL just water and the other group we gave them ni nicotin

namid ribosy which is the Ned precursor because n obviously as you know you cannot take it you need to take the precursor and we observe the tumor growth over 23 days um after that the IRB at the University um because you cannot have animals uh with with with high tumors right so it was a flank tumor and you need to um Harvest them so uh after and we were measuring you know every 5 days the tumor growth and we saw in these animals uh um that there was about 15% increase in tumor growth in the

Ned group so uh again I and and you you saw that difference with only four mice in each group yes it's four and four but but but all consistent you know we had statistical significancy we been with a small four I mean there was no cross results all the four mice they grew GRE cancer at a higher rate than in the NAD than the control group again that's where like obviously this is not like publishable uh because we need a more is is that a study you you you'll you'll repeat at at a sufficiently powered

uh size I would love to and this this is why we just did this pilot study we had because we have many mind and say hey let's let's let's give it a shot and let see because this a lot of hype of NAD and and and we saw this so we would love to to to do it at a much higher level because my question which might be a a disruptive question is like you know what if you have a a small tumor that you're aware of like in the pancreas or in the colon or

in the lung could Ned over time day after day after day could favor that glycolytic flux to that tumor and increase a growth in the literature I I've never looked because it just kind of occurred to me when you had that slide up earlier earlier when you showed the mitochondrial slide um it occurred to me that you have that lactate Escape of the tumor hey this would feed it but has anybody in the literature examined this question it seems like a very common it seems like a a a reasonable question to ask yeah I there

are a couple studies um I think once a review uh is more at the conceptual level right and this is what got me thinking like yeah this is this is something that for us working in cancer metabolis we look into this right uh um looking like you know like obviously one of the things that we have shown is that lactate is onom metabolite lactate it uh uh we have shown uh we have a first paper and we have like a like a good six seven papers more to come uh we' working hard for three years

looking into this but we saw that lact regulates the um um the genetic expression of the most important genes in breast cancer we're seeing the same thing now with lung cancer uh uh and lactate as we keep talking about this is the is the mandatory byproduct of glycolysis and and as warber saw in 1923 uh the characteristic of cancer cells or most cancer cells is a high glycolytic flux but what struck warborg was not the glucose itself was the lacit production um so anyways we we are showing that it's an uncom metabolite so if you

if you have a high itic rate in a Cell you're going to produce a lot of lactate right if you cannot clear that lactate it's going to drive self growth and proliferation as we're seeing and in fact we're now um uh blocking lactate production all through genetic engineer as well as DCA for example and we're seeing that uh cancer uh growth and proliferation completely stops within hours so uh now that poses an interesting dilemma right which is ex ex size would increase your capacity for clearing lactate in the long term but in the short term

raises lactate so it begs the question in a cancer patient specifically what's the net impact of exercise yes so uh this is what we're working on that the hypothesis you know with my colleague George Brooks um so he shown that acute response to lactate uh it increases uh over Expressions um about 600 and something genes I forgot right now right all these genes are involved in cellular homeostasis in the benefits of exercise right so we know very very well through his work that lactate is a signaling molecule now the question is like we we know

this at an acute exposure which is exercise you do exercise boom boom boom you're out but cancer uh uh uh doesn't do that cancer accumulates lactate and it keeps accumulating and this this is the main responsible for the um tumor micro environment which is acidic and the more acidic the tumor micro environment the more metastatic the cancer is and the more aggressive like the more glycolytic the tumor is and this is very well documented the more glycolytic the tumor is the more aggressive is and the more lactogenic that is more lactate uh the tumor produces

the more aggressive is now why is that lactate accumul ating right that's what we need to try to find out but we know that that that that that that is not acute anymore it's chronic exposure to lactate um so can exercise counteract that right um when we see that exercise might be beneficial for many patients but again going back to the right intensity uh we know the um the particles which are exosomes right they are microvesicles in the body they're main responsible for metastasis we have seen that uh and this is another publication we're going

to have in in in breast cancer cells and lung cancer cells uh we are looking at the protein content and the micro irones of those exosomes released by these cancer cells and it's incredible the information that they have there if you were to genetically engineer uh um a molecule that can be um um uh you know injected into a tissue and transform into cancer you would replicate an exosome it has all the components needed on the on the other side muscles also release exosomes and this is could be one of the why the benefits of

exercise as an organ you know in the cross talk between skeletal muscle and M many organs uh we know that if you have um um a very good um muscle Health right your health overall the metabolic health is going to be good could you be releasing great EX exosomes they're very uh prooxidative which counter the glycol phenotype of cancer and could those exosomes travel directly to the cancer cells and uh and counteract that and penetrate inside the cancer cells and transform the glycolytic phenotype of the cancer cells into more oxidative phenotype and keep cancer at

Bay we don't know yet but we're we're suspecting that we're scratching the surface of something that potentially could be a very interesting thing to understand better the effects of exercise as well as Neal Therapeutics yeah I just I mean the more the deeper I go in the rabbit hole into all things that relate to longevity the more convinced I am that if you're going to rank order things if you were forced to rank order things you can't there's nothing that ranks above exercise as the single most potent tool or agent we have to impact longevity

and yet paradoxically in the acute setting exercise seems to do everything incorrectly right in the very short acute setting if you look at it in that narrow context exercise does not appear to be geroprotective but of course when you look at the chronic impacts of exercise and what's taking place after the bouts of exercise uh the data seem undeniable I want to kind of pivot from exercise a bit into a subset of that which is something you published this year in Long covid patients M so um you know we'll we'll link to the study so

people can see it but you demonstrated that in people with long covid uh even previously healthy people they basically from a mitochondrial standpoint end up looking like people with type 2 diabetes when they're done in terms of fat oxidation lactate production yeah so first question for you is what fraction of patients recovering from covid do you believe are susceptible to that phenotype that's that's a great question in the trying to understand that so um everything is started by um you know National Jewish hospital is is is probably it's been always with May Clinic competing for

the top one pulmonology Hospital in the country so um you have this people with long covid who are are struggling you know um they they go up the stairs they can't breathe so the first thing they do is they go to different doctors and they end up going to this top hospital so they do U um um you know pulmonary function test and it's completely normal the then they okay the next species is because covid also affects um U the cardiac muscles right so let's let's do let's look at the cardio function it's completely normal

and uh uh they're very good at this hospital where they do um metabolic testing they do a cpad testing that's how I called medically right uh the physiological testing and they even do lactate we've been I've been interacting with them few times so they do la as well so they contacted me and and say in look we're seeing these patients we have 50 25 of them they had previously you know underlying conditions right the other 25 uh they were normal people and in fact most of them they were morally active some of them they were

doing Marathon athlin you know and uh the average is 50 so they're not you know very old either so but there plary function is completely normal and card function is completely normal so we suspected there's some metabolic issue here so they send me all the information the raw information and I apply the methodology that that we've been discussing right looking at fat oxidation and lactate um uh production as a surrogate for metabolic function and or or metabolic flexibility and mitochondrial function and I was shocked because they were significantly worse than people with type 2 diabetes

in metabolic syndrome which could explain why these people cannot go up the stairs and where before they were doing marathons now what are the mechanisms we know that um viruses multiple viruses are are known to hijack mitochondria for their own benefit to for reproduction uh could Co do the same thing so I'm we are suspecting it and we're trying to understand that at a more at a cellular level now unfortunately the majority of this long Co because as you know there are people with long Co syndromes that within weeks months they improve they go back

to normal but there are a handful of people um that I am assuming they're going to be growing right that after one year they haven't improved a bit this is the concern like can we do can we use exercis as a therapeutic way to stimulate mandal function if in fact there's a mandal dysfunction which is severe because if that's the the situation it's going to expose these patients to multiple diseases right um so this is an area of concern and and this isn't talked about as much as what I think people initially spoke about here

which is you know cardio uh like basically you know myocarditis is is what you know and now of course we know that the risk of myocarditis is actually much higher in young males through the madna vaccine than it's ever going to be with covid but the rate with Co is not zero it's I believe it's 2.3 uh cases per gosh it's it's going to be a big difference I think it's 2.3 cases per 100,000 of people with covid are getting myocarditis most of those are transient they recover not all of them are so to a

subset or not but this mechanism would be distinct from just myocarditis myocarditis of course speaks to the inflammation of the cardiac muscle that would explain depressed ejection fraction but what you're describing is a far more diffuse problem which is is a global insult on the mitochondria in the skeletal muscle correct yes that's what we suspect from this data which again is indirect right from the indirect color imetry in the lactate that it points out towards mitochondrial dysfunction uh so that's what we need to do now biopsies to to understand this at a better detail what

what the heck is going on right could be at the micro profusion level too it might not be at the muscle per se it might be at the micro profusion right in in in in the blood um uh in the capillaries meaning something like micro thrombosis that are preventing profusion and raising lactate that way could be could be you know uh uh that that's where we to find out but we know from other viruses right that uh they hijack mitochondria and and they interfere especially with fishion and fusion um uh processes right uh some causes

increase uh fishion uh some other causes increase Fusion uh some other causes increase elongation so we know uh there's a wealth of of of studies out there from virology showing that uh yeah many viruses and bacteria they also they hijack mitochondria and and they they disrupt it significantly now um but most of the times you know it like myocarditis it it it subsides right it's restored um shortly after you know the symptoms are gone now why this virus is different that that's what we are trying to understand uh why people after one year uh they're

and and and and by the way you know most of the people they had just normal mild course of covid they were not hospitalized they were not in the ICU any any evidence or inkling that if people go back to exercising too intensely following recovery it could exacerbate this problem and and do you also yeah do you have a sense of which strains this was this your your work would have been predominantly Alpha and not Delta and obviously not Omron correct yeah yeah yeah yeah yeah exactly this is this was done with patients over you

know yeah yeah way yeah even a mixture between the the the original variant uh and the and Delta so no not Omicron um yeah so in this population which again is presumably mostly Alpha maybe some Delta what was the distribution of male and female so it was about uh yeah we have 35 females in 15 males so was more female predominant 7030 okay uh what you again maybe it's too small a sample to know that could be more an indication of who's seeking out and and again we don't really know the denominator right we don't

know um we don't know what this represents is this one in 100,000 is it exactly you know we we we it could be one in a million if this was everybody that's reporting it at the time yeah our guess is is like it's it's a rare event right they can L that can last that long right uh but you know if you know we're talking about millions of people infected right if it's one in a million right we're talking about a you know some population that is going to need help yeah um I want to

kind of go back to just a few other questions that we didn't get to so not necessarily in any thematic order um what's the relationship between uh or how predictable I should say is the relationship between Zone 2 as defined by maximum fat oxidation and V2 Max so if you run somebody through a CET and you figure out that their V2 Max is at 4 lers how how um predictably can you say at x% of that you will be at maximum fat oxidation that's a very good question and there's another study that we're pre preparing

the manuscript with 225 subjects uh where we look at fat oxidation um V2 and their relationships going back to the same thing we we tend and historically the the the research studies with exercise have been done based on V2 Max that that that's been the the parameter to to to a prescribe exercise you know how many times we read x amount of subjects you know they were exercising for six months at 60% of you to Max or whatever right now that's another thing that I've been thinking of years and by the way when they say

that do they mean the 60% of the heart rate that produced V2 Max or 60% of the power that was produc that that is their max power at V2 max they're they're yeah I mean there's so many different ways you can do this that I've always found it you have to get into the methodology very closely I agree I agree 100% And this is where I think we need to dialing things in better right because yeah 60% of the power output I mean 60 I mean the intensity might be translated into Power output 60% of

you to Max and then you translate into Power output or you translate into hard R for example or or is it 60% of the V2 so for example if somebody's 4 L V2 at and then they hit that at 300 watts would 60% be 2.4 L which of course is not a very helpful way outside of a laboratory to prescribe exercise to somebody or would it be uh 180 Watts which is 60% of the 300 watts yeah exactly I think that you know normally the studies they look at okay where where you where do you

hit 60% of V2 Max and then okay what how many watts is this right or what's your heart rate what's the wattage that corresponds to 60% of your max V2 exactly so and and in your study what what we are seeing and this is what what because I've been curious about this you know because we look at the cardiorespiratory adaptations to exercise and we look at the uh cellular adaptations to exercise do they really correspond right uh we know very well that with with with athletes um um um you know you can improve tremendously at

the cellular level but not at all at the cardiorespiratory level at least at least based on V2 Max which is the representative of the cardio respiratory adaptations to exercise right um an example that I always give when I when I give talks uh is like an athlete who used to be an average professional and uh the V2 Max was 72.3 or something like that and then two years later he is a very good professional the V2 Max is the same but uh the lactate levels were incredibly better from like I forgot at five watts per

kilogram he was at five milles and now it's at 1.7 right so um the this is where the magic happened to to this specific athlete right it was at the seller level yeah and and we and we we see this across the board right V2 Max at the elite level does not come close to predicting performance not at all not at all and and and and this is exactly so this is why um uh we're putting together this study uh with with all this population of different from from from people with metabolic syndrome all the

way from to to the France athlet so longitudinally we see that yeah sure V2 marks corresponds with a fitness in the same manner that what's corresp ons with Fitness right um so we can also uh imply that sure instead of doing a V2 Max to look at longevity and fitness we can also do a Power test or a speed test and a treadmill because we're going to see the same thing those ones who are very poorly active I mean they have a very poor Fitness they're going to have a lower V2 marks they're going to

have a lower power output they have a lower speed lower lactic lens capacity right so V2 Max has been forever great surrogate right for for fitness and cardiorespiratory Fitness and Longevity but we wanted to see if in fact it's it's really that specific so in our study we see that people and in different categories right um at the same VI to Max they might be in different metabolic States so some people at the same V2 Max might be oxidizing a lot more fat or a lot more carbohydrates so that means that they that do not

not correspond to the same metabolic St status I would have I would have thought that most people by the time they're at V2 Max are dispop I mean they would be disproportionately carbohydrate so really you're just saying how much fat oxidation Still Remains there is really what you're saying and and and I'm assuming a very untrained person has zero fat oxidation by the time they reach V2 Max whereas a more highly trained person would still have some some amount they might still be at2 or3 gr per minute yeah and and and for example we see

that um like a sedentary individual at um um at 75% of the V2 marks might be around 3 mm whereas a a worldclass athlet at the same uh percentage of V2 Max is about one and a half right so metabolically they're different mhm yet the V2 Max is the same so if we prescribe exercise based on V to Max we might not do things correctly exactly and uh and the same thing with carboh hydroxides at a 75% of a V2 Max like a sedentary individual oxidizes about two grams per minute where an elite athlete U

oxidizes about three grams per minute so that's a significant um um difference um and we also see it at the 50% uh already uh so this is why um longitudinally they correspond quite well and same thing as fat oxidation fat oxidation at a 50% of V2 Max um um is about 0 point no yeah it's at 75% of CO2 Max 0.23 in the secondary um uh and it's 0.6 in the m athlet so and and then we we look at the different um uh intensities for example that um you know an athlete that can have

at one mm of lactate within the same group not not just comparing group but we can see that someone within a a very same group whatever the category they are uh the lactate and the view to Max don't correlate the correlations are sometimes in 0.2 or or 0.1 or 0.3 uh so while long that's the that's the r squ you're saying yes yeah so basically yeah no correlation very poor correlation when when we talk about individual um groups when we look at specific one parameter which is lactate with the V2 Max it doesn't really correspond

so anyways um um this is what I think that we have learned a lot over these last decades where we can really pinpoint more at the cellular level right uh to to improve metabolism more than at the cardio respiratory function which is very important absolutely absolutely they both are going to improve right but I think that if we want to prescribe exercise it's going to be more uh specific if we look at um cellular surrogates like lactate like fat oxidation for example right then looking at V2 Max or Mets I mean don't get me into

there you know that's a you know very you know prehistoric u in my mod opinion I don't want to offend anybody right but the whole met concept right used for exercise prescription it's it's hard to swallow in in today's Times you know in you go when when we think about some of the the muscle biopsy data again this this term of mitochondrial function I it's it's such an important part of longevity because it is one of the Hallmarks of Aging is declining mitochondrial function I I usually explain to patients that the type of physiologic exercise

that we're prescribing that Zone 2 exercise is the way to measure mitochondrial function it's both the treatment and the test but but I'm guessing on the cellular level there's even more that we can talk about here so the last thing I really want to talk about today because you we've been I know we've been going for a while you've been generous with your time when you when you get into the omix when you start to biopsy the muscles when you start to look at the mitochondria in a way that we can't do it you know

in a regular clinical setting what else are you seeing that's that's differentiating the healthy from the unhealthy mitochondria or the the high functioning from the low functioning mitochondria yeah so there there's this again I keep talking about papers I going to publish it but we've been working for three years quite hard and now we we cannot continue doing this we need to start writing the papers right and over that you need more post dos you you need more more graduate students and post help with the writing yeah but we have completed a pretty cool study

uh and they writing the script now um looking between sedentary and active we know already there are a bunch of research showing at the cellular level the difference between people with type two diabetes or mitochondrial um I mean metabolic syndrome and uh active individuals or or even sedentary we want to see also or or we want to show that people who are sedentary they already have problems and uh we wanted to compare them with morally active people who should be kind of how we should be as humans right so we looked into the mondria into

mondria so we looked that there's significant dis regulation at the mondria level everywhere you look in the mondria in sary individuals uh you see a decreased uh capacity to oxidize to burn glucose uh in terms of pyruvic fatty acids amino acids you see a significantly decrease in electron transport chain as well all the complexes uh and you see also a significantly decreased capacity in the Transporters of different substrates so uh um uh one thing that it really caught our attention and we think that uh this is something that we really want to emphasize and hopefully

others in the future is that we have identified that there's the mitochondrial pyit carrier which is as I discussed earlier that's the transporter of of pyu into the mitochondria which is um disregulated already down significantly down regulated in in seter individuals compared to uh um active individuals then we are matching it with the pyoid flux the oxidation itself so both the transporter and the flux are significantly disregulated what that does this mean potentially so that's shuttling all that's going to shuttle pyruvate to the other way it's going to get in the cell which is through

lactate exactly exactly so uh and and also what what what are the implications of this so we again these people are don't have diabetes or pre-diabetes right they're they're they're they're this could be a healthy person who's not active exactly and this is what unfortunately this been the model in in most research uh papers out there comparing the unhealthy with a sedentary healthy individual right I've been pushing for for for years that the model should not be the the healthy sedentary individual uh because that that is uh the intervention you know as humans we're meant

to walk or to exercise so we need to look at Perfection to understand imperfection the the intervention of of of of human evolution has been becoming sedentary you know and in fact I had you know a hard time to to to to get IRB you know to to to to start the study I have a hard time with the committee to convince them that using active people as the gold standard to understand imperfection that's the way to go but anyways what we see is that these people already they don't have Clinic uh but yet they

have a significant they don't have they don't have clinical signs clinical symptoms sorry they're not they're not clinical symptoms they're the healthy senary individuals but um um so they're they don't they don't have insulin resistance and they don't have done regulation of glute for Transporters even hyper insulinemia do they have even are they hyperinsulinemic when challenged with the glucose tolerance test these people they have no symptoms they haven't reported any glucose toolerance test that is abnormal normal people um and then uh they have a significant disruption in in this mandra per carrier so which might

mean that the the the first door that might be jammed uh is is that entrance of pyro inside mitochondria most of the research in diabetes has done more at the peripheral level if you will glucose levels more at the surface levels of the cell the glute four the insulin resistance the pancreas release of insulin the better cells Etc but what's the fate of glucose once enters the cell right um and this is what we're looked into this so and the Fate is pyate but what's the fate of pyu as you said very well does it

enter the mandra or is shutle to or reduce to lactate so I I I I think that this is important to see because uh it could be a marker down the road uh because again these people don't have clinical symptoms yet they have a significant disregulation in their glucose metabolism so could the this be 10 15 years ahead of clinical symptoms and insulin resistance so this is more reason also to consider sedentary individuals to see hey they have a metabolic disregulation already same thing we're doing at the fat oxidation level the cpt1 and cpt2 the

Transporters of fat they're significantly downregulated as well so that means they're not going to be able to transport fat very well which also matches to the fat oxidation itself where we inject uh fatty acids into the mandra they don't oxidize it well so they all match as well so they have a a disregulation already that is significant compared to Mota individuals at the glucose met metabolism and fat metabolism then uh we see that uh many of these people who I mean who have diabetes or metabolic syndrome they have what's called intra intramuscular triglycerides the fat

droplet and it's adjacent right by the mitochondria right and it's it's a type of um that in Elite athletes it's also there that fat droplet but it's very active because about 25 to 30% of the fat oxidation comes from that fat droplet adjust to mitochondria which it could probably is an an evolutionary mechanism to not rely on the adipose tissue which might take time and have something right away there right so when you say it's metabolically active the difference between the intramuscular fat of the athlete and the intramuscular fat of the person with type two

diabetes is it the flux then in the person with type two diabetes it's a static source of fat in the athlete it's constantly turning over and being oxidized and replenished exactly whereas in in this in this population it continues to grow my colleague Brian Bergman from the university is working a lot um into the content of what's inside this these flat droplets but one thing that we know is like they're very high in ceramides and dig glycerites and especially ceramides are key in the atherosclerotic process um atherosclerosis is is it's obviously it's a it's a

Hallmark right of cardiovascular disease and uh ceramides are key for this process uh historically has been thought and it's been shown that ceramides come from the liver they're released but we're seeing that this intramuscular triglyceride is that high in ceramides so could this be a connection between also um um cardiovascular disease and type two diabetes but this is only in the in in the high turnover high flux one you're not accumulating them as much yes like people who are um um again people who end up having uh type two diabetes uh they accumulate this uh

fat droplet right um athletes as well that's the athletes Paradox right but athletes as you said they keep turning around and it's very active whereas in in in uh um people with type two diabetes or obesity it's it's it's stagnant it keeps growing and and it releases pre-inflammatory mediators and it also is high in ceramides which are key in AOS sclerosis so this is where we're trying to establish the connections between type two diabetes and and cardiovascular disease at the mitochondrial level as a Nexus because we know that about 80% of people with type to

diabetes they also have cardiovascular disease and vice versa which is what we call cardiometabolic disease so could the the Nexus of all that a m Kindle impairment um that's where we believe well what I take away from this is we're probably going have to do a third podcast in a couple of years because uh there's going to be a lot of data that's going to be published then that isn't published now there's going to be a lot more questions that we're going to have answered again I I'm still really yearning to understand the effect of

Metformin in terms of pure mitochondrial function and performance in in a trained individual um so as always I I just uh can't thank you enough for for your for your generosity of of insight and uh look forward to talking tomorrow when we have a call about some other nerdy stuff we're going to get into but uh thank you so much Inigo and uh and also congratulations on the remarkable success of your team and uh Pacha uh who you know amazing cyclist to watch He's got everybody very excited about the tour to France again well thank

you very much Peter and uh all the listeners I really appreciate um uh what you do I think that um the first time I I met you uh the first first podcast we were two and a half hours talking about mandria and and I first I thought like this guy's crazy there's nobody out there who's going to be interested in listening to two and a half hours about mandria and metabolic health and uh you showed me that um yeah the that the the Cs are out there uh and I was in a moment where I

was kind ofof not many people are seems interested in this and you were already an inspiration for me to continue doing this and and the remarkable work that you're doing to educate people and and inspire people it's something that uh yeah it's it's uh it's a transformational so I really appreciate um the invitation which is an honor well thanks for being with us today thank you very much thank you for listening to this week's episode of the drive if you're interested in diving deeper into any topics we discuss we've created a membership program that allows

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