a little less than 50% of people's first brush with a symptom of coronary artery disease is sudden death that that's worth repeating because it we couldn't I remember I still remember being asked this question in medical school you know you're sitting there as a first year medical student in cardiovascular pathology class and the pathologist said what's the single most common presenting feature for someone having uh cardiovascular disease the first time and everyone was like chest pain shortness of breath you know rattling off all the usual stuff he goes no sudden death today it's not quite 50% but that's a very sobering uh statistic right now I'm mostly optimized around energy balance which you know stay in energy balance um and protein intake and so most of my conscious effort around my diet goes into making sure I'm getting 40 to 50 grams of protein four times a day hi everyone I'm sitting here with the amazing Dr Peter ratia uh many of you don't need an intro to him he has changed our understanding of uh the scientific literature preventative medicine uh with respect to longevity um improving Health span he's a number one New York time best-selling author of the book outlive amazing book also he has a very popular podcast on health and Medicine um one of the podc few podcasts that I listen to called the drive and he's also a uh renowned speaker so public speaking he does a lot of that as well and you can find a lot of lectures he's given on YouTube so I'm very excited to be sitting here with you today Peter and uh having this conversation you were on the podcast many years ago about eight years ago yeah I was going to say like probably 2016 right I think it maybe earlier you might have been 2015 you might have been one of the like the first I don't know six or seven guests I mean you were like one of the the first guests that I had on the podcast it was a long time ago you were still at uh new SE y y y so it was it was a while ago well thank you for having me back I so let's let's dive into to to like maybe a a a general question that I kind of have for you which is what ignited your interest in the field of longevity I mean I think it's a it was kind of an intersection of two things but but I think the the critical spark was the birth of my daughter um and and I write about this a little bit in the book but you know I think you know I'm in my mid-30s she's born and all of a sudden that became a manner in which I contemplated my own mortality um and I I it's not like I hadn't been aware or had been blind to my family history but I have a very bad family history for cardiovascular disease and so now the idea that I had this daughter and boy she was like I I mean I I just adored her more than I could have imagined um during my wife's pregnancy uh it was so real and I also kind of realized like you know if I don't figure out what's going on here I'm going to potentially um leave this planet sooner than I would like and therefore leave her and potentially other kids to come along so so it was really those two things that really catapulted me into at the time just trying to understand everything I could with respect to cardiovascular disease that became my initial Obsession so it was really less about longevity and more about that but of course once you dive into that you realize well you know what what what does it benefit you if you figure out how to not die of heart disease but you die of some other thing or what do it you know eventually what do it what does it benefit you to delay your death but have a lousy quality of life so then you know all of these things just came as an evolution out of that it's funny because I actually have a very similar story uh about the birth of my son and my I mean I I remember times like you know within the first couple of years of my son being born going for my long runs um and and stopping in the middle of my run and literally balling my eyes out because I knew there was a time that I was going to be gone and he was going to be without me and it was so hard to think about that um and so you know like the what everything that you you just said completely resonates with me where it's like I want to be around when my grandkids are you know getting older I want to be not only around but I want to be jumping rope with them I want to teach them to jump rope uh and so like all of those things have sort of crossed my mind at the same time um with respect to uh the cardiovascular disease that you you mentioned and and you talk about this in the book as well um there's a statistic that I've read from the national health statistics website which is that every 33 seconds someone dies from cardiovascular disease in the United States so when people hear the word cardiovascular disease I mean at least even me when I the cardiovascular disease what is that what does it mean where is aosr come into play where is coronary heart disease what is cardiovascular disease I mean you can Define it very broadly and include valvular disease and cardiomyopathies and all of those things but when we talk about um asbd atherosclerotic cardiovascular disease which is the leading cause of death in the United States and globally it's leading cause of death for men and women um what we're referring to is the disease of coronary arteries that leads to esema and you know just to take a step back for a moment when you think about all of these chronic diseases which I'm sure we'll get into today cancer neurogen diseases Etc things that you and I have spoken about a lot including when you were on my podcast um it it's important to understand this is the disease for which we have the clearest understanding so you know our understanding of what initiates and propagates cancer is is very small compared to our understanding on the cardiovascular front our our understanding of this on the neur side is also quite small there are still many things we don't understand so so you know everything we're about to talk about on the cardiovascular side should be at least thought of in the context of how wonderful is it that we understand these things because we have the most tools for prevention here so with that said what we're really talking about that does the Lion's Share of killing and again I'll bracket for a moment that there are other things there are people that are dying from you know cardiomyopathies there are people that are dying from Val cardiovascular disease and things of that nature um but the majority of what's happening is a disease that leads to plaque formation inside of coronary arteries and we can go as deep or as shallow as you want into that and why that happens and how that's a function of endothelial injury lipoprotein burden and inflammation but this leads to a reduction in blood flow to uh key parts of the heart muscle and when that happens the heart undergos an es schic event now sometimes that can be chronic and sometimes that can be acute and if an acute event occurs in a a region where enough muscle of the heart is compromised that's going to result in sudden death that's a heart attack and it's important to understand that um u a little when I was in medical school it was more than 50% it's now a little less than 50% but it's still a very high number a little less than 50% of people's first brush with a symptom of coronary artery disease is sudden death that that's worth repeating because it we couldn't I remember I still remember being asked this question in medical school you know you're sitting there as a first year Medical student in cardiovascular pathology class and the pathologist said what's the single most common presenting feature for someone having a cardiovascular disease the first time and everyone was like chest pain shortness of breath you know rattling off all the usual stuff he goes no sudden death um again today it's not quite 50% but that's a very sobering uh statistic absolutely um I do want to dive into some of the the you know major causes of the atherosclerosis and the a rtic cardiovascular disease that you're talking about so lipoproteins you mentioned and you know there the most people know they hear about lipoprotein they hear about LDL or htl um but apob B why should people know about apop well again I think it's worth maybe just getting everybody on the same page with cholesterol let's start with that right so everybody's heard of cholesterol and and I think most people would probably even have kind of a negative veilance when they think about it's like cholesterol is a bad thing so it's worth explaining that that's not really true right cholesterol is is is is an essential thing right so without cholesterol we wouldn't be alive and and you know there are really rare fortunately genetic conditions in which cholesterol synthesis is compromised and those tend to be fatal in utero so if if if if an organism can't make enough cholesterol it ceases to exist because cholesterol is the thing that gives every cell fluidity the membrane of every cell cell fluidity and it's the precursor to some of the most important hormones we make so in the case of us as humans right testosterone estrogen progesterone cortisol these essential hormones are all made from cholesterol so every cell in the body with the exception of red blood cells makes plenty of cholesterol The Lion Share of it is probably done by the liver and the steroidal tissues and we have to figure out a way to move this stuff around the body and the the highway system of the body is the blood and the blood of course is water so if we want to move things that are water soluble throughout the body like proteins and ions it's easy because they dissolve freely in water and they move around but when you want to move something around water that is not water soluble such as cholesterol as a lipid you have to wrap it in something that is water soluble and that something is the lipoprotein and the big protein on the surface of that sphere is called an APO lipoprotein and there are broadly speaking two classes of APO lipoproteins there are the a class and the b class so some of the lipoproteins are wrapped in an APO lipoprotein called apob 100 and we just abbreviate that to apob but I'll just say it this one time and we'll never talk about it again there's also an apob48 that wraps another type of lipoprotein called a kyam micron we won't talk about that again because it doesn't really factor into cardiovascular disease so apob is short for APO lipoprotein b00 which is the structural apoprotein that sits on low density lipoproteins abbreviated ldls I intermediate density lipoproteins abbreviated idls uh very low density lipoproteins abbreviated vldls the APO a and this is big a never to be confused with APO little a which we may talk about those wrap the family of highdensity lipoproteins they're much more complicated than apobs believe it or not and there are many of them um but nevertheless broadly speaking that's what's going on so why do we care about all this stuff well in the 1950s when it became clear that cholesterol was playing a role in cardiovascular disease the first observation was people with very very very high total cholesterol because at the time that was all that could be measured was total cholesterol by the way what that meant was the total amount of cholesterol in all of your lipoproteins in your hdls in your ldls and in your vldls those three lipoproteins constitute the amount of total cholesterol you have in the lipoproteins we can come back to this idea because it's important that represents about 10% of the total cholesterol in your body the total cholesterol concentration was Loosely correlated with cardiovascular outcomes but only at extremes meaning if you you took people whose total cholesterol was in the top 5% and compared them to people whose total cholesterol was in the bottom 5% there was a clear association with cardiovascular disease March forward many many decades we came to realize that actually this low density lipoprotein which is a subset of your total cholesterol that's the cholesterol contained within the low density Lio proteins that's much more strongly Associated and what we now know is the case is there's an even better way to predict risk than just saying how much cholesterol is contained within the low density lipoproteins a better way to predict risk is to add up the concentration of all the apob particles so that number apob measured in milligrams per deciliter is the concentration of the entire burden of particles that are capable of undergoing something that I'm sure we'll talk about which is the initiation and progression of atherosclerosis so how how the apob number um can you talk about how that so you mentioned LDL total total LDL cholesterol that number is like some equ it's like determined by some equation right and well it can be but it can also be measured directly yeah so there's would that be particle number though if it's no so so there's there's two ways to go about doing this so in the olden days and unfortunately many Labs still do this they rely on an equation called the freeder wal equation so total cholesterol is relatively easy to measure um you so you draw the plasma you spin it down and you basically lice all of the lipoproteins and you can measure total cholesterol so if you if you just basically apply something to lice all of the proteins uh you'll you'll say all the lipoproteins you'll say total cholesterol is 200 milligrams per deciliter then they directly also measure two other things they can directly measure total triglyceride concentration and using a separate assay they can measure the total concentration of cholesterol within the HDL particles so now you've measured total cholesterol HDL cholesterol and triglyceride the freeder wal equation stems from an observation that kind of sort of on average sometimes vldl cholesterol is approximately 1 the triglyceride concentration so the federal equation is quite literally used to estimate LDL as follows LDL cholesterol is estimated as total cholesterol less HDL cholesterol less triglyceride concentration divided by 5 if you're doing everything in milligrams per deciliter and unfortunately most Labs still do that so when you look at your cholesterol report it'll say ldlc it'll give a number and unless it says direct you can assume they've done the freed to Wal equation which is I've seen that wrong more often than I'm seen it right a good lab will do a direct assay they will actually measure LDL concentration and they will give you in milligrams per deciliter the total concentration of ldlc that is still an inferior predictor of risk relative to apob yes okay so let's the reason I wanted to mention that ldlc is because as you mentioned many Labs do measure it indirectly and there are many types of LDL right so there are different densities and sizes so I'm curious about what your thoughts are on the different sizes of like more atherogenic sizes of LDL such as the smaller dense particles and um you know like like how you view that like this the the different particle sizes and the particle number and then of course apob B so like the whole I mean there's been a big evolution in the way we've practiced medicine in our practice with respect to this so 10 years ago we were looking uh at LDL particle number which the um both the Mesa population so the multi-ethnic study of atherosclerosis and the Framingham uh Offspring population have both demonstrated unequivocally that when you compared LDL particle number to LDL cholesterol LDL particle number always predicted risk better than LDL cholesterol so how would you do this you would follow people longitudinally for cardiovascular events and you would um do this in sort of a like a ACC cumulative in incidence graph so on the x- axxis you have time on the y- axis you have incidence of cardiovascular disease and you plot out everybody as a function of whether LDL c um was higher or lower than as a percentile than ldlp so ldlp stands for the part number of particles ldlc is the um concentration of cholesterol and this was again unequivocally the case particle number always predicted better so how do you count the number of particles well it turns out there are different ways to do this you can do this using NMR um so nuclear magnetic resonance is like how an MRI works so it's applying a magnetic field it's basically doing I mean this is being a little cheap Chey but it's sort of like doing an MRI on the blood and you can count the number of particles that way that's not actually the gold standard but that's that's the way it's most commonly done in clinical practice it can also be done with ion motility we switched from NMR to ion motility for ldlp because it was more accurate um but ultimately this is now about five years ago we actually switched to apob which was Superior on all fronts and here's the reason why first of all there are different ways in labs to do this so lab core for example in Boston Hart have different magnets and different algorithms for how they run their ldlp so if you run an ldlp on each of those labs you'll get a different number that's a bit disturbing to me I want to know that the apob that I get at one lab is the same as the apob I get at another lab and it's standardize across all fronts but there's a more important reason why I favor apob over ldlp and that is it encompasses the total atherogenic burden and you can get burned and fooled by patients who have very high High vldl meaning they have a high burden of very low density lipoproteins even if their LDL burden is low uh so I won't go into it because it's so nerdy it's not worth getting this deep in the weeds but there are certain genetic conditions where people have completely normal LDL but very elevated vldl and they have a very high astrogenic risk and you will miss that if you're looking at ldlp or ldlc you will not miss that if you're looking at apob what about the the fact that if you know small dense LDL which has been shown to be more atherogenic so apob does become so you mentioned the the structural role of apob in the lipoproteins it's very important it also plays a role as you mentioned in allowing the lipids to be soluble in in in the plasma right um but it becomes it plays a role also in recycling so it gets you know it interacts with the LDL receptor and can be taken back up into the liver y the small dense LDL part particles AP is somewhat obscured as the LDL particle gets smaller in size and more dense therefore it's not Tak harder to clear harder to clear exactly um so what about in the case and the reason I'm asking is because as you mentioned apob is on vldl IDL LDL right but there's different sizes of these LDL and and the the larger more buoyant LDL is better better than having a higher proportion of the smaller dense LDL right that's why AP but AP captures that risk right so in other words this is why this is another reason why I think that apob is the great equalizer because once you have the apob concentration you're accounting for the fact that clearance is going down I mean the one way to think about this is anytime you see an elevated apob it always comes back to something on the clear inside is not working now there are really broadly speaking when I talk about this with patients I go through the four sort of pillars of what ele Ates apob so it's it can be driven by cholesterol synthesis and we can talk about that because it's going to factor into you know dietary choices for example so how certain dietary patterns will lead to higher LDL than others it's impacted by cholesterol reabsorption so the we can talk about what the life cycle of cholesterol is but again it's um you know we make it and we reabsorb it and it gets circulated it can have to do with triglyceride burden so this is where insulin resistance really factors in to how apob can go up and ultimately it comes down to clearance and clearance has everything to do with the presentation of the LDL receptor on the liver the confirmation of it the number of them and how long they survive on the liver and all of these things have an enormous effect some of which we can manipulate with drugs so for example all drugs that are used to treat uh LDL in some way or another indirectly or directly impact the LDL receptor some do it really directly like a pcsk9 inhibitor directly does that by targeting A protein that breaks down LDL receptors um so um anyway a long-winded way of saying the this is another advantage of apob is it allows you to in one measurement capture all of that risk because if you have small if you have you know two individuals like going if you're just using ldlp um as your risk you might miss some of the elevated vdl if you're looking at ldlc you'll clearly Miss some of the size issues um that should be captured in ldlp um but again I guess maybe what you're asking is if you have a low apob but they're all small is that worse than having a low apob where they're all big and the answer is probably um but you'll also see that in the like there are other metrics that are kind of coming on board now which are looking at LDL triglyceride levels so you can look at the degree to which the ldls or cholesterol depleted um and that can also give you a sense of risk the question is is that a first or second order term and I think the first order term is still going to be the number of particles that's the biggest driver of risk and everything else factors into it in other words that's not an independent risk because it's driven by the the residence time of the LDL which is driven by the clearance rate so let's talk about like the number so the LDL sorry the apob number because like if most people go to a standard lab and they measure their apob mhm there's a reference range and it says you know okay if you're less than 80 milligrams per deciliter they excellent then you're okay yeah um where does that number come from and you know what like is has anyone measured apob levels across the lifespan do we know like is there a correlation with apob levels and the beginnings of aosc crosis has someone done those studies you know that sort of thing yeah so the reference ranges are purely uh populationbased um distribution questions so every lab will have a different way of doing this but a general uh you know sort of philosophy for labs is you know let you know so for a the lab we use and by the way we completely ignore these reference ranges they're but they're there we can't avoid them they're there and we explain to our patients that we're going to editorialize on top of them but you know the Reference Lab we use we'll say APO below 80 is wonderful well 80 just happens to be the 20th percentile of the popul it will say 80 to 100 is inter or 80 to 120 it says as intermediate risk and above 120 is very high risk so in for the lab we use we know that 80 is the 20th percentile uh 120 is the 80th percentile or the 60th percentile I can't remember um so it's it's literally just putting you up against a population distribution and that's that's it now our philosophy on apob is completely different and um as you may recall I WR I devote actually quite a bit of real estate to this in the book because I think it is such an important concept and it is in my opinion certainly top three failures of medicine 2.0 is in failing to appreciate the point I'm about to make um which is that once you understand the causality of apob meaning once you understand that apob is not just associated with cardiovascular disease but it's causally linked to it meaning it causes ascvd to get into this discussion about managing 10year risk thinking about being in this percent versus this percent makes no sense when you have causal things that cause disease you eliminate them and the analy I use is cigarettes with lung cancer so nobody disputes that cigarettes are causally linked to lung cancer they are it's as clear as you know Tuesday follows Monday but people forget that you know causality doesn't mean everybody who smokes will get lung cancer and it doesn't mean that every person with lung cancer um smoked so you you don't need to be necessary and sufficient necessary or sufficient to still be causal but our approach to patients who smoke is very clear which is Never Smoke and if you do smoke stop immediately do we look at people who smoke and say well once your 10year risk of lung cancer reaches this threshold we're going to tell you to stop smoking or once your pack year smoking is above the 50th percentile or the 80th percentile we're going to tell you to stop absolutely not you immediately eliminate smoking and so similarly it makes no sense that we would look at a causal driver of asbd in the case of apob and kind of take an approach of well being at the 20th percentile or the 30th percentile the 40th percentile is acceptable none of those things really make sense you have something that is causing the disease you should eliminate it as soon as possible because it is an area under the curve problem so atherosclerosis begins at Birth um when you do autopsies on people who are very young in fact I in the book include a photo of a guy who you know a man I forget I think maybe 26 years old who was a victim of a homicide or something so an completely unrelated death um but you look at the autopsy sections of his coronary arteries I mean he already had very Advanced artherosclerosis now it wasn't clinically relevant it wasn't going to kill him anytime soon but the point is this is a disease that takes decades to progress and one of the biggest drivers of it in addition to things like high blood pressure and smoking and insulin resistance is apop so to be able to take that off the table sooner rather than later is going to has has C certain has the potential to take um atherosclerosis off its pedestal at the top of the uh list of killing and so what do you um I mean take you obviously can't take it off the table completely right we need a b but what well so so so so let's think about it yeah so so let's start with what we know APO B Rises with age right um we don't really know there are probably a lot of little reasons um so there are you know endocrine changes insulin resistance um syence that you know might involve the uh decreased uh life of LDL receptors there there's no clear reason actually what about so you talking about clearance versus synthesis and I remember our mutual friend Ron Krauss like I've had you know many conversations with him I did my postc down the hall from his lab right um and I remember him telling me that you know apob you're you're basically your liver is constantly producing it you're making vldl just just churning it out right no just going going and we also make LDL denovo by the way right yeah there's a denovo pathway plus the vldl to LDL P but that you know the the the thing is is that you know he was saying well from an evolutionary perspective um you're you're making this vldl because as you mentioned you know it's transporting things throughout the body to other organs right cholesterol Tri triglycerides fatty acids it's also transporting and this is where I was so intrigued inflammatory protein so cyto kindes cative protein also are being transported through vldl now that was important pre antibiotics pre everything that we do now to combat you know infectious disease and viruses and bacteria parasites whatever um but before that time that vldl did serve that purpose too too and that's why he thinks you know it's kind of a relic left over where the reason why we're constantly making is because it's a very large protein in size it's like tens of millions of like the the unit versus like 50,000 or something it's very big and so it takes time to make it um and so I was the you know I was thinking well like inflammation also does make it go up even further at the level of synthesis I don't know exactly the the clearance you know how it it's regulating clearance but do think the aging process is mostly affecting the clearance of it or my intuition is yes my intuition is that it's it's it's primarily impacted on the clearance level which is going to be again some facet of ldlr ldlr meaning LDL receptor so is it we are making less of them they are surviving less uh the proteins that you know and and that can basically done there there are many ways to regulate that process but that that's my intuition is it's less a confirmational change in the ldlr and more or a number of them and or uh A reduced amount of time that they stay present one thing I'll add on The evolutionary front you know I had a guy named John kelin on my podcast uh a few months ago and he he proposed a really interesting idea which completely makes sense evolutionarily which you you could argue sort of like we don't really need apob like this is the other thing like most species don't have apob they don't require LDL but how I mean they have cholesterol but they don't they don't they don't require transporting all these you know you can do it with HDL you can transport everything with HDL yeah okay yeah they don't need the LDL but I thought HDL was always going in reverse like it was bringing everything back to no it's actually much more complicated I mean in US LDL is doing the majority of what's called reverse cholesterol transport so RCT which is kind of like the good movement of cholesterol you sort of think of the bad movement as taking cholesterol into the arteries the good movement is taking it back to the liver in LDL is doing the majority of that so hdls are typically transferring their cholesterol to ldls and ldls are bringing them back to the liver um but John made an interesting point right which is that you know in in sort of following up on what you said The evolutionary cost of making cholesterol is enormous uh I mean it's a very labor intensive step right I I can't remember the number of atps that are required to make a molecule of cholesterol but it's in the 10 right like it could could be 40 or something to that effect and so we evolved to have a system that prioritized having a lot of cholesterol being able to keep a lot of it around um because again this was an energy conserving system now this serves us no benefit today because today we can make plenty of it and we are we are in an energy abundant environment which we were not in you know hundreds of thousands of years ago and so this this is a bit of an unfortunate vestage of our past much in the way that a lot of the things that lead to insulin resistance are a vestage to things that were once very valuable uh I mean the things that allowed us to LEAP up out of the Swan with our swamp with big brains was our primarily our capacity to store excess energy in a way that even primates can't um again served us really well until 150 years ago and I think the same is probably true of of cholesterol and apob so going back to your question how much apob is enough well it turns out you don't really need any of it to be perfectly fine so if you look at a child they're born with an LDL cholesterol or apob level typically below 20 milligrams per deciliter so a kid if you think about it has the greatest need for growth right like so you think about the cholesterol demand of myelinating the entire central nervous system all of the enormous uh explosion of steroidal tissue all of these things are done with lipoprotein levels that are incredibly low again what we call physiologic levels of LDL cholesterol and APO are on the order of 10 to 30 milligrams per deciliter and yet there are no negative consequences to such low levels of that lipoprotein burden and it's only when we get we know when become teenagers and in our 20s that we start to see those numbers go up and again that's really just reflected by a reduction in clearance than some need for additional LDL we don't have it majority of what we need is actually you know before the age of 20 do you think uh so like if you were to then estimate or speculate a level of apob that you can say safely well I guess there's two things one you're not going to die of atherosclerosis if you have if you if you maintain a level below yeah so Peter Libby um from the Brigham who's one of the authorities on this topic has has argued uh and I reference him in my book that if you had an apob level below about 30 Mig per deciliter 20 to 30 milligrams per deciliter it wouldn't be possible to develop atherosclerosis what about not dying from AOS like what about like if it's the if it's the major cause of death globally Y and let's say like what it takes to get down to 30 probably is pretty aggressive yeah most people cannot get down to 30 without a pharmacologic intervention yeah y do you think that you would would die of atheroslerosis if you had you know if you're at 60 60 well it comes down to a couple of other things so the first thing is how long are you at 60 so if you say I've never exceeded 60 that's very different from saying hey I showed up and I was at 12 and you now lowered me to 60 so again I think of you know I imagine like everybody walks around and you've got a graph that on the x axis is time and on the Y AIS is apob B and you have a curve and you want to figure out what the area under that curve is and that we want to minimize the area under that curve so if if if you took exactly so if you took so again very similar to smoking right we talk about risk in pack years of smoking so if a person smokes a pack a day for 20 years or two packs a day for you know 10 years you know you have a way of kind of comparing Apples to Apples on those things so to have a lifetime ceiling of 60 would also be a very very low-risk individual 60 milligrams per deciliter is about the fifth percentile at the adult population level so then that comes back to my question sorry one thing across the lifespan when like when do you start measuring this like people aren't measuring their apob in their you know teenage or 20 yeah I mean I would argue we should be but I want to go back and say one other thing about your question um which I should have mentioned earlier which is it also depends on other risk factors so there are really four big things that are driving risk causally apob is one insulin resistance is one hypertension is one and smoking is one those are the big four so you have to take everything we're saying on the apob front and acknowledge that those other things are also causally linked to asbd so again it's it's a difficult situation to imagine but it's certainly at least theoretically plausible you have somebody whose apob is at 60 but they have uncontrolled hypertension type two diabetes and they smoke I mean you could certainly arrive at that situation pharmacologically you're probably not going to arrive with that situation naturally um would I say that that person is free and clear no I wouldn't so we you know at the outset I mentioned how the you know the downside of talking about asbd is it's the number one killer I mean it's you know in fact when you talk about it globally the gap between asbd and cancer is even bigger it's like 19 million people annually to 12 or 13 million for cancer I mean it's an enormous difference um but the good news is our understanding mechanistically of what drives this is so clear and our tools for prevention are some of the best and most benign okay so let's say that um a person is relative healthy you know they're committed exerciser they're not insulin resist I do want to talk about hypertension insulin resistance but okay healthy generalized quote unquote healthy person right um wants to lower their apob they want to try everything through diet through lifestyle and you mentioned there are some major Lifest dietary factors that can increase AP so let's talk about those what are the major so the big two are anything that contributes to insulin resistance so we'll start with that and that does so um mostly through the vldl triglyceride pathway so we talked earlier about it how there are really two ways we make LDL we make LDL directly we but most of the LDL is made through vldl so if you're exporting a lot of vldl what you're doing is both making a lot of that lipoprotein but you also have a lot of triglyceride in it now something I didn't mention a moment ago that's worth restating or stating in the first place the LDL is C carrying around both cholesterol and triglyceride and the more cholesterol there is all things equal the more LDL you need but the same is true with triglyceride so the first mechanism in which we see a very clear relationship between diet and apob is the higher the burden of triglycerides the higher the burden of apob to State this another way if you take two people who have the exact same level of LDL cholesterol and the same total cholesterol ol but one has very high triglycerides and one has very low triglycerides the former is going to have a much higher apob and therefore be at a much higher risk of atherosclerosis because they have more cargo and therefore require more ships in the analogy of cargo being cholesterol and triglycerides and the ships being the lipoproteins so step number one is lower the triglyceride as much as possible and the triglyceride being low is an enormous proxy for insulin sensitivity so this is one of the important ways in which managing insulin resistance uh is is a key to keeping apob in check and of course there are other issues as well so insulin and glucose by themselves when elevated also create problems at the endothelial level which becomes another mechanism by which this is problematic um it's pretty clearly observed from a dietary pattern perspective that carbohydrate restriction is the most effective tool a triglyceride reduction all carbohydrates I mean like vegetables fruits yeah refined and starchy carbohydrates yeah so but that actually feeds really nicely into the next observation which is what's the next dietary pattern that impacts apob and that's saturated fat consumption and the reasons for that are twofold so the first is that saturated fat directly impacts cholesterol synthesis now this is not true equally of all saturated fats but we don't really have great data on if certain saturated fats have a greater impact on cholesterol synthesis uh relative to others for example a c16 might be potentially more so than a c18 or a c19 but again what foods would you find a c16 version oh like a c16 would be more in I believe like a coconut oil or a palm oil or something like that ver also by the way that you would also see that more a c16 like a palmitate would be more of a synthes would be more of a saturated fat you see in response to insulin resistance so it actually be a denovo saturated fat synthesis so um perhaps so so I think that's a big part of it I think cholesterol synthesis is a big part of it I think a bigger part of it might be that excess saturated fat inhibits the sterile binding the sterile regulatory binding protein in the liver that results in fewer LDL uh receptors being made so saturated fat therefore has two things that it's doing that are driving up apob and the susceptibility of this varies from different individuals so um I was on a ketogenic diet for three years I was not one of the people who seemed to suffer from this so even on a ketogenic diet where I was getting 80% of my calories from fat and probably half of that was saturated fat I did not have any sort of obnoxious increase in my apob or ldlc or any of these these metrics similarly we have some patients who are on you know very low carb very high fat diets some of them have completely normal levels of lipids and some of them have lipids that go absolutely Haywire so it's not entirely clear what the difference is but clearly there are different genes that will allow certain people to metabolize that saturated fat safely While others do not so I'm not in the camp that believes that um and there is an entire Camp of people who believe this that if you're on a low carb high fat diet and your apob and ldlc go through the roof it's it's not problematic I I don't believe that at all I think that that's a very bold claim and I would not be willing to play that game I think if your apob goes Haywire even if you're very insulin sensitive and even if you're in energy balance and all the other wonderful things that might come with your uh with your you know your ketogenic diet I I think you have to pay very close attention to if you're if your lipids get out of whack so those are basically your big manipulations dietary wise it's the composition of fat the quantity and composition of fat and the dietary choices that that address insulin sensitivity so on the people that let's say that they're eating a higher saturated fat diet um if they swap that out with mono unsaturated fat or even polyunsaturated fat which some camps also like to demonize the kind of polyat but if you swap that out um their apob levels in our in our experience about half of the people who have this hyper response to saturated fat if you isocalorically shift them to high monounsaturated fat you fix the problem yeah okay it starts to get into a little bit of an issue right which is and this is where you you know you have to remember what problem you're solving so um for some people that's an easy switch you know because they were kind of some people tend to go out of their way to try to eat as much saturated fat as possible I'm not sure why like they sort of you know they're like okay well I'm doing this you know ketogenic diet and I'm just going to basically eat coconut oil and palm oil like it's my job yeah yeah yeah yeah and and so for those people you just got to say dude like stop doing that just like use olive oil on your salad and like let's be reasonable and then it fixes everything um but for other people you know it's it it just can't be addressed and um and I've heard other people say oh you know this is crazy like we know that you know excessive fat restriction in the diet will lower cholesterol and that's true I mean if you go on a really Draconian fat lowering diet you will lower your cholesterol um my view clinically is that makes very little sense um because that usually comes with a whole bunch of other issues so a lot of times when I see people on these excessively restrictive fat lowering diets um they actually become insulin resistant a lot of them because they're really over consuming a lot of poor quality carbs um and they're suffering other consequences of really low fat intake now again this doesn't mean that a lowfat diet is necessarily problematic the devil's in the details here just like you know the devils in the details on what constitutes a reasonable versus an unreasonable low carb diet but the point I try to make to people is I believe that using nutrition to solve the lipid problem is not a good solution I think use nutrition to solve the nutrition problem use nutrition to address energy balance protein needs anabolic structure energy all of these other things and let your lipids fall where they may because this is one of the few areas in medicine where we have amazing pharmacologic tools most of medicine doesn't really have great pharmacology if you stop to think about it like we don't have great there there's nothing pharmacologically that's adding Brilliance to our Alzheimer's prevention strategy or our cancer prevention strategy I mean we have some stuff but it's nothing compared to what we can do with blood pressure and lipid management so I always say it's hard enough to find the the right diet that's going to work for you in terms of your ability to be compliant with it your ability to be within energy balance which is the single most important thing your ability to be insulin sensitive your ability to get adequate amounts of protein if you solve that with a lowfat diet that also happens to keep your lipids low great but if you solve that with a higher fat diet that does everything perfect for you except your lipids go Haywire don't put your head in the sand and act like having lipids that have gone Haywire is a good thing no just acknowledge it's not a good thing but we can fix it with again Myriad tools that didn't exist 20 years ago are there are there people that are genetically um H have genetically low apob and if so what's their cardiovascular mortality their all cause mortality yeah so there are there are people so so it turns out apob and ldlc are highly genetic which is what has allowed us to do the mandelian randomization studies that act as one of the you know there are basically three cornerstones of data that make it unambiguously clear of the relationship between LDL or apob and ascvd so you have all of the epidemiologic data which again epidemiology is Rife with problems but you know when the data is pretty much all in the same direction and you have the dose effect and all these other things uh it becomes quite helpful you have all the clinical trial data which I would divide into primary and secondary prevention data and then you have the mandelian randomization data which again for listeners is basically anytime there is a biologic variable of interest that is under a high degree of genetic control and produces a high degree of variability in the population you can look at how Nature has basically randomized it across people and you can look at outcomes um of Interest so in the case of ldlc because we know it is highly genetic right this is clear in that and I don't just mean in extreme cases but just across a population you can see that lower lifelong exposure to apob or LDL produces lower ascvd risk over a lifetime so um using this we can say there are people at really low and high extreme so at the High Extreme you have the people who have what's called familial hyper cholesterolemia which is um a genetically heterogeneous disease meaning there are literally thousands of mutations that result in a similar phenotype the phenotype is defined as having an LDL cholesterol off medication of more than 190 milligram per deciliter and there's a couple of other criteria but just to give you a sense of How High the LDL needs to be to meet that criteria um at the other end of the spectrum we have these people with very very low uh ldlc or apob and the most interesting group of these are the people who are folks that have a hypofunctioning gene for pcsk9 so Helen Hobbs um made this discovery in uh probably the early 2000s my my vague recollection I remember reading this paper when it came out it was a really mindboggling paper call it like somewhere 2004 2005 2006 somewhere in that neighborhood which is hey there are these people walking around with uh ldlc of like 10 to 20 milligrams per deciliter and and these are adults right so you normally we just never see that in adults and they weren't doing anything different right they just like they weren't on some crazy diet or clearly weren't taking any medication um and these people were found to have um a mutation in their pcsk9 Gene that rendered a hypofunctioning protein and pcs9 is a protein that degrades LDL receptors now another subset of these people their mirror opposites were discovered several years earlier which had a hyperfunctioning pcsk9 gene or hyper fun a gene that produced a hyper functioning protein and these people had sky high LDL cholesterol they were a subset of the uh familial hyper cholesterolemia syndromes and these people weren't and what was interesting to note uh is that they just didn't develop cardiovascular disease so um I I can't tell you what their life expectancy is cuz I haven't I haven't looked at those data but what I did confirm is um they have no increase in the incidence of any other disease so in other words they're absent ascvd but they don't make up for it with more cancer or more neurod degenerative disease or more diabetes that's that's interesting for a couple of reasons one uh you you see on Twitter a lot you know the the very very um you know just the hyperfocused very low carb Community that's like you know they they share studies about oh low cholesterol people with low cholesterol have a higher all cause mortality they're more likely to die from you know all these different causes of death which yeah the problem with those studies is um I mean there I'll only address this once because I've done so much addressing this that I realize you you you can only waste so much time preaching to an audience that actually has no interest in understanding the truth um but just to give you an example of the type of biases that creep into those studies when you look at people who have very low LDL cholesterol you're sampling a subset of people who are at very high risk for a disease typically two diseases right when you have very high LDL you are at risk of ascvd cerebrovascular disease and Alzheimer's disease and all causes of dementia so therefore the people who are at high risk for those are typically the people at a population level who have the lowest level because they're being treated the most aggressively so this is kind of the problem with that stuff I'll give you an example there's a clear Association in the epidemiology it doesn't come up often but it's come up from time to time that the lower the LDL cholesterol the higher the risk of cancer this is a great example of when mandelian randomization becomes very valuable because you can actually go back and look at the genes that are controlling LDL you can look at how those are spread out and you can ask the question once you just look at the random assignment of those genes that control LDL cholesterol does that have any bearing on cancer outcome and the answer is unequivocally no it does not so when you do the Mr you get the answer that the Epi is clearly confounding with something else which is in other words low LDL at the population level is a proxy for other illness this is the issue here yes thank you um the other interesting point was with the the actual Gene that you were mentioning the pcsk9 right so when you were talking about we have pharmacological interventions that do uh very nicely lower apob um one of them is PCS can9 Inhibitors exactly came right out of Helen Hobs observation so um I wanted let let's you know let's touch on the the the pharmacological treatments but also um the PCS K can9 Inhibitors they're not necessarily available to everyone at the start right out the gate and um then I want to get your thoughts on some of the the base editing trials that have started looking at literally like you're doing a gene edit you know and you're you're changing you know a nuclear tide to essentially make a PCS or the people that you're talking about walking around right with no ascv yeah so um okay so let's maybe just talk broadly about what the different pharmacologic strategies are right so the very first uh drug that was ever used to lower lipids uh was a was a drug called uh oh God I I'm always blanking on the name of this like uh Tri triparanol so this was done in the 1950s yeah well there's a reason you never heard of it right so it turned out to be a really bad drug so there was there was a there used to be a day when again in the 1950s and 1960s we just didn't know what the hell was going on so the idea was if you came up with any drug that lowered cholesterol it must be a good thing well it turned out this drug lowered cholesterol by inhibiting an enzyme that was the final enzyme in this step that we use to make cholesterol so we make cholesterol using two Pathways but one of the pathways uh results in a molecule called desol which gets converted into cholesterol so there's an enzyme that facilitates that and this drug blocked that enzyme and as the result cholesterol levels went down and although no one was really paying attention at the time desol levels went Skyhigh and it lowered cholesterol so on the basis of that this drug was approved and back at the time that was the only thing you were monitoring was total cholesterol uh but it was found that the patients on this drug even though they had lower cholesterol had a higher incidence of heart attacks so the drug was ultimately pulled in the 1960s we now know today that it was almost assuredly the case that the desol was even more atherogenic than the cholesterol or at least as atherogenic so fast forward to the 1980s the next class of drugs is developed called bile acid sequestrant we didn't really get into the life cycle of cholesterol so it might be worth doing that now because it'll make sense in the context of the drug so every cell in the body is making cholesterol um so just think path one synthesis of cholesterol if you synthesize less cholesterol that's one way to lower it as you noted all that cholesterol is making its way back to the liver when the liver gets a hold of all that cholesterol it's putting a lot of it into bile and we're using bile acids to digest food so as bile via the bile duct is entering the small intestine it is full of cholesterol the body reabsorbs much of that cholesterol so each of the entc sites which are the gut cells that line uh your intestine um they have couple of Transporters on them so one of the Transporters on them it's called a Neiman pixie one like one transporter it absorbs all of the steriles and this is I use the word sterile very carefully to distinguish it here from just cholesterol this is Zeus sterol and plant sterile which is or animal stero which is called cholesterol it absorbs that all there are um basically regulatory steps inside the cell that determine how much of that should be kept and how much should be excreted and a fraction of that then gets excreted through an ATP binding cassette so point being that's a second point of Regulation at the absorption site but again this is not the cholesterol we eat this is unesterified cholesterol that's easy to get in and out of the body aerified cholesterol can't be absorbed and most of the cholesterol we eat is aerified that's why we just poop it out um so bile acid sequestrants which were the first version of drugs the second version I guess of drugs to lower cholesterol which are not used today blocked that process in a very crude mechanical way they sequestered the bile acids and dragged all the cholesterol out the GI tract they were not a very successful class of drugs uh and not the least of which because the side effects were pretty bad so it really wasn't until the mid to late ' 80s probably I think 1987 if my memory serves me correctly that the first Statin came to be developed and that was the real turning point in um basically the uh you know pharmacologic tool that became valuable against ascvd now the first second and third generation Statin of that era are no longer in use today because their side effect profile was very harsh relative to what we can do today so there are currently seven statins in in existence uh and each of them you know offers some strengths and advantages over others and they're not a benign class of drugs so to be clear they're an effective class of drug they're very effective at lowering uh LDL cholesterol they work by inhibiting the first committed step of cholesterol synthesis they do that everywhere but primarily in the liver and the response of the liver when cholesterol synthesis is being shut down the liver says I got to get more cholesterol in here and what does it do it puts a a whole bunch more LDL receptors all over the liver and that's what's primarily driving down LDL in the presence of a Statin but the side effects are what well about 7% of people develop muscle aches on Statin so that's a if you think about how many people are on those drugs or how many people are prescribed those drugs that's a huge number of people the good news is that's a completely reversible side effect so you put a person on a Statin they experience muscle soreness you take them off it's gone within a week or two um the other big side effect the one that I probably think about the most is insulin resistance so um a very small set of subset of people about 4% of people put on a Statin might go on to develop type 2 diabetes as a result of it now I I think any doctor who lets a patient get to the point where they get type 2 diabetes because of their stat and isn't been paying attention we want to know the minute you're becoming insulin resistant in response to the Statin and those data are less clear you don't know exactly how many people are getting insulin and resistant but this is a reason to be paying attention to bigger markers and more important markers than just hemoglobin A1c trips over the threshold of 6.5% you have type 2 diabetes here you want to be able to say is the hemoglobin A1c moving what's happening to the fasting insulin and glucose and these other markers does a patient wear a CGM one of the reasons we like cgms on patients when we put them on statins is we we have a historical level of what their glucose control looks like and if all of a sudden their Baseline average glucose goes up by 10 milligrams per Des Sol which I've seen in patients on a Statin I know it's you know that's not just a quick dietary trigger especially when you take them off the Statin and it comes right back down to normal so even though they haven't become you know they haven't gone to the level of being diabetic they're clearly becoming insulin resistant and the third thing we see with statins is a change in or an increase in the transaminases or the liver function tests liver function test is a bit of a misnomer because the transaminases really tell us more about inflammation than function so all that said statins are still kind kind of you know they're doing the Lion's Share of the work in this area but by no means should we say that that's the only thing that we have at our disposal about 20 years ago another drug called Edomite can I interrupt for a second and ask you about Statin yeah course um because I have a lot I have some questions about them so um I and and I I'll never forget this conversation that again I had with our mutual friend Ron Krauss because he worked down the hall I worked down the hall from him and I collaborated with some of his post dos and um you know they would come and show me data and we would talk uh because you know I had a lot of experience in assing mitochondrial function and mitochondrial biology uh during graduate school and um I remember saying this to Ron I'm like you know so statins are affecting the HMG co co pathway that you mentioned the cholesterol synthesis with which also is important for the synthesis of uh ubiquinol right this is an important or coq1 as I should probably call it um this is important for mitochondrial function I mean it's necessary for mitochondrial function for transferring electron electrons across the electron transport chain which is essentially coupling the oxygen we breathe with the food that we eat to make energy um and I remember saying oh so statens have a side effect of targeting mitochondria and he said to me no it's a direct effect so what are your thoughts on how statins are affecting mitochondria and through this pathway and obviously you might mention supplementation with a you know uh rinol right um measuring mitochondrial function in terms of BO2 Max something yeah so so it's a great question actually and something I have thought a lot about um so the the literature has nothing to offer here unfortunately so so I wish I could say you know Rhonda the answer is this because here's what the literature says here's what I can tell you um and this is not going to be a satisfying answer if there is an impact on mitochondrial function with Statin use it's very small based on what I consider to be the single best measurement we have to measure mitochondrial function which is Zone 2 testing with lactate production so I know you know what this is because we talk about this stuff all day long but just for folks listening uh this requires a little bit of explanation but it's very important and I I think it's I'm glad you brought this up so everybody understands what the mitochondria do if they're if they're you know listeners of your podcast we don't need to explain the mitochondria but it's important to understand that a functional test is a very important test in medicine we don't have many functional tests right most of the things we talk about are biomarkers um and by themselves they don't tell you a huge amount of information they tend to be quite static and not Dynamic but we understand that the healthier individual is the more they can rely on their mitochondria for ATP generation under increasing demands of the cell this is one of the Hallmarks of health and by extension one of the Hallmarks of aging and one of the Hallmarks of disease is an inability to do that meaning as the ATP Demand on a cell goes up there is an earlier and earlier shift to glycolysis as opposed to oxidative phosphorilation so how do we how could we measure that clinically well we can put a person in because we can't you know rather than test a cell Let's test the whole organism right so we put a person in sort of an ergometer right so on a treadmill or on a bike or under some sort of demand where we can control the work that they have to do and we can drive up the amount of work they do while sampling lactate and why does that what does that tell us well just to remind everybody you know glucose enters a cell and it basically has two Fates right so glucose will be converted into pyruvate regardless it has the Fate at which oxygen is plentiful and the body has the time to make a lot of ATP where it goes into the mitochondria and it has the less efficient uh but quicker way to get ATP which is converting lactate uh pardon me Pate into lactate so this is the uh glycolytic pathway versus the oxidative phosphorolytic pathway the longer a cell can stay in that mitochondrial space the better it is it makes way more uh ATP and it accumulates less lactate and hydrogen ion and the more lactate and hydrogen ion you accumulate eventually the cell becomes effectively poisoned by that hydrogen ion and it becomes very difficult for a muscular cell to contract so we use this test with patients this is one of the most important metrics we care about literally it would be in the top 10 things we care about for our patients which is how many watts can you produce on a bike or how many Mets can you exercise at on a treadmill or whatever vehicle you're using while keeping lactate below about 2 Millo 2 m is about the threshold Beyond which you are now shifting away from the maximum capacity of the mitochondria to to um undergo this process okay all of this is to say I have clearly seen the effect of a drug like metformin at impacting that metformin which is a mitochondrial toxin right metformin impairs complex one of the mitochondria we immediately see a change in the lactate performance curve of an individual on Metformin we see a complete reduction in their Zone 2 output they hit that lacta of 2 much sooner we also see an increase not big but significant meaning clinically significant in their fasting resting lactate level so all things equal their lactate is just getting higher to me by the way I don't know if that's necessarily harmful I don't think it's a good idea which is why I don't believe in metformin as a geroprotective agent I think metformin is a good drug for someone who's diabetic if they can't exercise enough and they can't get into energy balance um but I don't think metformin is a great drug for someone like you or someone like me we don't see this with Statin so if it's happening dose dependent or no just don't see it yeah just don't just don't see it so it could be happening but we don't have the resolution to measure it so that that's why I'm saying like I think one always has to have the humility which I hope I have to say look I don't know but what I do know is if there's an effect there it's it's really small now you mentioned ubian or CoQ10 um and there are two states of it ubiquinol and ubiquinone but ubiquinol would be the state we would want to consider here there have been a number of clinical trials looked looking at using or supplementing ubiquinol with patients taking statins they have mostly done this to assess uh the muscle soreness issue so they've mostly done this as a way to ask the question can you reduce the insulin the the incidence rather of muscle soreness with statins I haven't looked at those literature in a couple of years the last I looked at them there was still no difference um that said we have patients that really feel strongly about taking ubiquinol when they're on a Statin and I don't have any issue with that I I I don't think there's any harm in taking it I really don't think there is um and if there's a chance of benefit then I would say let's take it but again I I unless something has happened in the last couple of years that I'm unaware of I don't think we have great data that ubiquinol offsets that and more importantly to your point it's not clear to me that that effect translates to a functional deficit in the mitochondria when you're measuring so uh the the using the zone to you know lactate threshold training to kind of measure mitochondrial function um how so buying the lactate meter Nova diag NOA biom medical or something like that it's like a yellow purple one I got it per year like a but uh for people listening uh if they want to to get one but also knowing like how you know because there's when you when you go to like any sort of if you were to go talk to an exercise physiologist and you say lactate threshold like they kind of know and they're going to push you up they're lactate threshold is a different number right so this is like lower level this is below your lactate press yeah this is lower so um how do people know let's like let's say they have a pelaton at home okay and they get on their pelaton and they want to do a Zone 2 test okay do can you somehow use a you know percent max rate a heart rate sorry max heart rate uh like proxy to kind of know like yeah there are lots of different ways to estimate this and to be clear like I'm one of the very few people that is checking his lactate every you know every day that he's on his bike which is four days a week for me and by the way I'm also doing it while using all the other metrics that I'll explain in a moment mostly just in an ever neverend quest to just have as much data as possible to understand when is lactate the best predictor when was RP the best predictor when was heart rate the best predictor when was absolute wattage the best predictor like there there's a lot of stuff going on here so first thing I always say to people namely my patients when they say I don't want to get that lactate meter I don't want to be poking myself in the finger I'm like great don't you don't have to there are like other ways that you can pretty much approximate your Zone 2 output and the only reason I brought up the whole lactate testing is it is the gold standard and it is the most objective way to do this and therefore if I'm trying to really understand the impact of say metformin or EST Statin that's what I want to do but let's put that aside for a moment and answer the the relevant question which is hey how does someone exercise in this Zone I think the most important you know tool for for virtually anybody is is rate of perceived exertion I think that will almost never let you down um in fact I would argue that for a really really out of shape individual rate of perceived exertion is even better than lactate and the reason for that is you take somebody who's got for example type 2 diabetes their resting lactate may already be at two so in those patients we actually never use lactate until you get somebody to a certain level of Fitness we only use rate of perceived exertion and we will provide heart rate guidance so here's two ways to think about it um RP rate of perceived exertion we give people the test which is the tox test so when you're in zone 2 you should be able to speak to somebody but it should be uncomfortable and not something you want to do if you can't speak you're out of Zone 2 if it's really if you can't speak in a full sentence you're not in zone two anymore you're you're you're north of zone two if you can speak the way you and I are speaking now you're you're not working hard enough you're too far below it so there is that sweet spot where if you're on that pet on and the phone rings and you answer it the person knows you're exercising and you're going to let them do most of the talking but if they ask you a question and you have to answer it you'll you'll answer it and you can speak in a full sentence but you're not that comfortable that's the single most important thing people need to understand about it as far as what heart rate guidance comes with it Phil maone uses a test that I think is a pretty good starting place which is 180 minus your age now the fitter you are the less relevant that becomes so I'm 50 one so that would put me at 130 but I can tell you my zone 2 is above 130 so if you're fitter you may add five to 10 to that I uh my my I use another app that checks my HRV every single morning and it predicts my zone 2 as a result of my HRV and so every day what I'm doing is I'm looking at the heart rate predicted by the app which can vary by as much as 10 beats per minute based on how much I slept the quality of my sleep how sore I am a subjective measurement of how much I want to train that day and my HRV so it it's a what is it's called Morpheus Morpheus yeah um so I have no affiliation with or anything like that so so basically so this morning I got up my HRV was I don't even remember 78 milliseconds slept 7 hours 15 minutes good quality sleep not sore felt good so I actually had a pretty high Target today my Target today was 141 was the heart rate on a day that's about as high as it will predict me to be on a on a day when everything sucks it might tell me as low as 129 usually it's about 136 137 138 is where it's predicting and that's generally aligning with where my lactate is where what that'll generally put me at a lactate about 1.9 um and then on top of that I'm paying attention to the water so I kind of know where to be but again for somebody just starting out RP is all you need to know 180 minus your age is good and then the if a person is fit enough that they truly know their maximum heart rate we tell them to start at somewhere between 75 and 80% of that number great uh recommendations if so if a person is specifically trying to do this functional mondal uh test how long should they be in that zone two before they can measure their lactate we we' like to see people there for 30 to 45 minutes before we do it yeah so a true true steady state awesome um so I kind of want to the the other going back circling back to the statens and um here's here's my question to you okay what questions do you think I should be asking and looking in the literature to convince myself that let's say a lipophilic Statin that could uh you know cross the bloodb brain barrier get into the brain inhibit you know hm COA in the brain um particularly at higher doses uh but generally speaking what can what question should I be asking myself to convince myself that it's not going to put me at a higher risk for both of the neurod degenerative disease that I'm terrified about uh one Alzheimer's disease I have a genetic it's family history genetic risk factor and Parkinson's disease family history um both of those diseases have been associated with Staten use they've also been it the the literature as you know is you know you can find what you want right so do you have any you know advice yeah I did I did a recent AMA on this um although it might not be out yet I lose track of when I record them and when they come out so I apologize if it hasn't come out yet um but I did an entire AMA on this topic because it is so uh important and I think it's as you said it's so confusing um so I was actually surprised to learn this um I was surprised to learn that there has never I shouldn't have been surprised but for regardless here's what it is there has never been a study done that has looked at the use of Statin and the incidence of Alzheimer's disease or dementia as a primary outcome why is that important it's important because in clinical research the primary outcome is the only thing you can really take to the bank because that's what the study is powered to detect there are more than a dozen probably less than 25 so a big number of studies call it 15 16 that have used Statin have had a primary outcome of ascvd but a secondary outcome of Dementia or Alzheimer's disease and I looked at every single one of those and I can tell you that every single one of those found neutral to benefit of Statin use on the incidents of dementia and and the incidents of um Alzheimer's disease so that includes vascular demension I mean I that sort of makes more sense Parkinson's disease have you seen have you looked at the literature on that so Parkinson is a little bit more confusing because the literature is way more sparse um but I do want to go back and talk about Alzheimer's disease because I think there's an important caveat to everything I just said what I basically oh the other point I want to make Rhonda this actually surprised me there was no difference between uh hydrophobic and hydrophilic statins with respect to the to these outomes no difference whatsoever so counterintuitive um but no difference whatsoever um so even though again you might think well gosh you know a Statin that gets in the brain should have more of an impact but it didn't it didn't seem to have is there a difference in those two types of statins with respect to the diabetes uh increased uh diabetes risk that you're talking about or that that's a really good question I I didn't look at that in and that wasn't looked at in this yeah I here's what I can tell you the highest incidence of diabetes is probably with a torva Statin um but that might also be because a torvis Statin is the most widely used like I don't we we basically first of all there's only four statins that I think are even worth prescribing these days maybe only three and I treat them all equally in terms of risk in other words I would assume anytime you put somebody on a stat and you should be looking for any of the side effects and I don't particularly because again at the you might say at the population level it's different but at the individual level who cares you it's it's either one or zero you're going to get it or you're not what's what statins are those with the ones that we would prescribe would be rzua Statin or crester Crestor atorvastatin or Lipitor uh pitavastatin Lio and sometimes we use pravastatin or prol but pretty rarely uh but so usually those be a big four now here's what um I would say and um this is something that we spend a an awful lot of time looking at in our practice and and actually just last week Tom dpring um did gave us an internal presentation that was so incredible um it was months in the making uh looking at the relationship between Staten use and desol levels and dementia risk so you may recall a moment ago I mentioned desol so desol is well let's back up remember how I said there were two cholesterol synthesis Pathways well in the CNS really only you have one pathway and it's the pathway that goes through desol to cholesterol so desol levels are actually a decent proxy for brain cholesterol synthesis lathosterol which is the penultimate molecule in the other pathway is more of a proxy for peripheral cholesterol synthesis are these measure you can measure these on a like they're very difficult to measure in most Labs we use a lab that measures them so we measure dmol and and lathosterol in every patient with every blood draw unfortunately this is not standard of care most Labs can't measure this Boston Hart does this so we that's why we use Boston Heart there are enough data suggesting that if desol levels are very low the risk of AD does indeed go up and the risk of dementia Beyond ad goes up so this is you know kind of what I would describe as personalized medicine medicine 3.0 at its finest which is you have to treat every patient individually and we are doubly careful in patients with an apoe4 Gene Andor a family history and in those patients based on the literature and I'd be happy to send you Tom's presentation he would not have a hard time with me sharing that even though it was kind of an internal presentation in fact I could share with you the recording Tom made because we recorded the internal uh meeting uh because it was so valuable um but basically the cut off we use is 08 so if do monol Falls below .8 mg per deiler uh we think the risk of dementia is sufficiently high enough that we would abort the use of the Statin very good information and and you think uh there is a correlation with apoe status on that no one has done that study yet in your in your clinical but in our clinical practice we just decided like why would we take the risk okay but but yes no one has done the study to show our desol levels lower in apoe4 individuals that's actually a very testable hypothesis and makes a lot of sense cuz we know apoe is heavily involved in cholesterol activity in the brain yeah and so it wouldn't be surprising to me if you know if you put people into three buckets zero Al one Al or two Al E4 alals and then just looked at desol levels like that would be a very easy mindless study to do just a survey like just a quick is there a correlation yes or no um so that's one thing I'd love to know the answer um but even absent that knowledge our view is um there's there's simply no reason to take the risk you know earlier I said it makes no sense to to go on some crazy obscure diet that has a whole bunch of unintended consequences just to control your lipids well I would make the exact same statement here it makes no sense to get all to take unnecessary risks with Statin in a in a higher risk individual when we have these other tools we have as I we talked about or we will talk about aetam pcsk9 Inhibitors bidic acid these are unbelievable tools that have no bearing on brain cholesterol synthesis but Peter aren't people that have an apoe4 Lil more likely to be prescribed Statin based on their their LDL particle number by their physician because a physician doesn't look at their none of this this isn't personalized it's not medicine 3.0 right so Y no it's very frustrating um and it's also frustrating that of those three drugs that are the that are an alternative to statins two of them are still very expensive okay so the three drugs I know the PCS K9 inhibitor y um and highly effective in insanely safe zero side effects um cheaper than when they came out uh so they were approved in 2015 um and we have long-term data with the mat people walking around with a natural mutation right just just amazing yeah exactly we have the natural experiment we have all of the data from the drugs um and these these drugs have been tested in really good trials and they've gone head-to-head with every drug and they always win and there's no side effects um but they're expensive right they're it's a $500 a month drug in the in the United States it's cheaper outside of this country so everything's better out of the US when it comes to drug pricing but in the US you're talking about 500 bucks a month for that drug if it's not a if it's not covered by your insurance company right um and if you can get a doctor to say I'm going to prescribe it to you I mean like I mean at this point a doctor doctor who doesn't who's not willing to prescribe a pcsk9 inhibitor just is a fool um so it's just a question of the the cost because unfortunately most insurance companies will not cover it unless you meet certain criteria such as having familial hyper cholesterolemia or having already had a cardiac event like a heart attack and not being able to tolerate a Statin or what about myopathy like if you have muscle yes significant myopathy on multiple statins but you'd also have to be at high enough risk to justify it so insurance companies are going to go out of their way to not pay for this okay then you have Zam now Zam is relatively inexpensive um it's just not as potent so aedm also effectively serves to increase the LDL receptors on the liver but it does so by impairing cholesterol reabsorption so it blocks one of those two Transporters I was talking about in the gut the first one and by blocking that the body is absorbing way less of its own cholesterol and the liver Sensi says that and the liver says hey I got to get more cholesterol puts more LDL receptors on pulls it out of circulation um it's not as potent and as a monotherapy the only times we see really Head Over Heels responses are in patients who have defective ATP binding cassettes in their gut and we measure that by looking at phytosterol levels so we measure two things one is called cytol one is called compol those are phytosterols so these are cholesterol we don't make it's zerol uh pardon me it's it's it's phytosterol not zerol and so when we measure those levels we know that it speaks to how much plant stero is being absorbed and not being excreted and so when patients have really really high levels of phytosterols you know they have a defective ATP binding cassette and those patients respond really well to aomi it's it's like a Blockbuster in those people wow is is that a common um you know single nucleotide polymorphism that have or you know it's it depends how how extreme it is so um it's not uncommon to see people who are above the 90th percentile but I've only seen like probably three people that have a level that is so high you'd actually be concerned with it just in and of itself meaning like the actual level cuz phytosterols are actually more atherogenic than cholesterol um and that's so like Boston Hart would measured all these ferol okay um they're more atherogenic than cholesterol yeah they're more prone to oxidation more inflammatory are they being carried in lipoproteins they're uh so so are they oxidized they're more oxidized they're more oxidizable and this is by the way is a reason that we don't favor the practice of using phytosterols to lower cholesterol so there are a lot of sort of over-the-counter treatments where people use phoster ol to lower their cholesterol and they it does so if you ingest a ton of phytosterols you will outcompete cholesterol at that osy and your body will regulate and you'll end up N Net reabsorbing less total cholesterol um the problem with that is if you have a defective ATP binding cassette which again it's not that uncommon that you do you will end up really absorbing a lot of those phytosterols and again they can so this is an it's sort of an example of that desol point earlier where you can lower cholesterol but if you're really raising desol too much it can be more atherogenic than cholesterol in the first place so desol has shown up twice today it showed up in a good sense and in a bad sense so too much of it if you're using a drug that blocks the enzyme that comes after it that was the thing that was producing too much atherosclerosis in the 60s too little of it could be a marker of two uh too little cholesterol synthesis in the brain and that can be a whole problem on in of itself the final drug so we can just wrap this up because I'm sure the listeners are tired of hearing about this stuff uh is a is a drug called bidic acid that is a prodrug so it's a very elegant drug uh it's taken as a pill uh but it's ineffective until it's metabolized by the liver and in the liver it then inhibits um cholesterol synthesis what makes this drug special is unlike statins this drug only works in the liver so statins work throughout the body they do most of their work in the liver but technically every cell is impacted by a Statin only hepatocytes are impacted by bondic acid and it lowers apob same way lowers cholesterol synthesis liver says I need more cholesterol puts more LDL receptors up pulls more LDL in LDL and cholesterol go down but no side effects no type to diabetes risk nothing nothing it's just it's only acting in the liver well that sounds uh same problem as pcs9 inhibitor it's a $500 a month drug okay yep so again we' we' we'd have every look honestly at this point like if money were were no issue you'd probably just be on pcs9 Inhibitors aetam and um and bempedoic acid I mean eventually we'll get there right yeah yeah they just have to come down in price for people that want a like more clear picture of the plaque accumulation in their in their arteries and their in their vascular system um the best way to do it I think I've heard about CT angiogram CT angiogram okay and is that something you know like you think people should start at a certain age or certainly if they have measured their you know apob and yeah I mean you know I think there's there's different ways to think about this um you know I I think there's a principle in medicine that most doctors try to adhere to which is don't order a test unless there's a chance the test will change your management um and it's it's easy to deviate from that I certainly know I do at times but but as a general rule I try to ask myself the question before I order this test how will the outcome change what I do with this patient so through that lens you could make a case that the only time you should be ordering a CT angiogram is with if you go through the following experiment which is if it comes back normal how will it change what I do if it comes back abnormal how will it change what I do so if if you were sitting in my office and I said well look Ronda you're 35 years old your apob is really high your family history is such that people get cardiovascular disease in your family meaning you know it's not like you've got a bunch of relatives who were in their 90s who have never had a cardiac event so you don't have some genetic protection of cardiovascular disease um do I need a CT angiogram in you to convince me to do anything because the truth of it is at 35 your CT andram is going to be normal I mean it might not be mine wasn't at 35 but it probably will be for most people and if it's normal will I then say we don't need to do anything about this no because that's sort of like saying you're a smoker who has a normal CT scan you don't yet have lung cancer therefore we should let you keep smoking no we should stop you from smoking so in other words I just wouldn't have a huge appetite for doing that test in you there are other patients at the other end of the spectrum where you know they come to me they're 75 years old their APO is through the roof but I noticed like all their relatives lived to be a hundred and they never had heart disease and I look at them and I think do I really want to put this person on lipid lowering medicine at the age of 75 why don't we do a CTA if the CTA is normal which by some miracle it could be I I don't think we need to do something there's clearly something this person has going on that is beyond our understanding of the science so far so in that sense I wouldn't do anything about it the way I think about it is there's a two 2 by two which is age versus finding positive or negative I think CT angiograms are mostly helpful when they have a positive finding in a young person or a negative finding in an old person that's where it can really cause you to act differently outside of those findings I.E positive findings in old people are to be expected negative findings in young people are to be expected I think you should just track the biomarkers of interest and go off that risk okay um I mean like is a 45-year-old considered I would still put that in the young category especially for a woman you think that CT andam would still kind of look uh maybe good it should and again I would only think about it through the lens of if the patient is hesitant um like so so we we we had a new patient you know that started a couple of weeks ago he'd never had one of these tests before um but he had a lot of risk factors right elevated apob elevated LP little a I mean two big risk factors and and um but but insanely healthy individual like very very healthy individual so so on the surface like nobody thought anything of this this person um we decided we were going to treat him regardless and he was completely on board with that but the question was how aggressively would we treat and we said let's let the CTA decide that if the CTA comes back clean as a whistle we're going to treat you to like an apob of 60 which is still aggressive by most people's standards by our standards at sort of middle of the road aggression if the CTA comes back and there's a problem meaning you have calcification and soft plaque we're going to treat you to 30 or 40 so there the CTA helped us make a difference a real treatment difference and this is a person who's you know middle-aged so not too old not too young that makes a lot of sense um before we I you know kind of shift gears and L some other things I want to ask you about um have you looked like I know I know you've mentioned it's been a many years since I've heard you talk about buring but I you know every once in a while I'll get a question and I decide I want to dive into literature and see if there's anything new right so that happened recently my team and I did a deep dive into berberine and its effects on you know clearing away existing plaque on lowering you know LDL particle number um possibly total LDL cholesterol level but um I was surprised yeah what did you find so there was a systematic review and it was 2022 I believe um and these are all like we need this is this sparse data right a systematic review of what the existing literature was which isn't a huge body of evidence but um so there was a bunch of studies that looked at berberine and you know varying Doses and then looking at it in conjunction with statins or comparing it to statins or comparing it to a placebo and in it pretty much to me was convincing that it was beneficial in every in every single scenario so buring Al Bering alone was um lowering the LDL cholesterol and can't remember if it was particle number but it was and it's interesting berberine is also a mitochondrial toxin really yeah berberine is an analog of met foran so so it's a complex one inhibitor is it really wow I didn't know that it it was like it was to me looking really beneficial where it was like I'm not saying that wouldn't be I I'm just sort of pointing out like it's interesting is there literature showing that or is it like a inv vitro kind of thing where it's like I don't remember it's been so long since I've looked at berberine but um but you know berberine is kind of a poor man's met Foreman okay well it was and that's the way I thought about it I think I'd heard you talk about it years ago maybe on Tim's podcast I don't remember it was a long time ago and that's kind of where I even first heard of berberine with you and um I remember cuz I was like going for a run it was when I lived in Oakland and then I was like bbin what's that and I remember you talking about in the context of I think metabolic Health y y and should um this data on the lipids was very interesting and I link yeah what was the magnitude of effect I don't like you the doc it's in that document it's linked the studies the meta analysis so you can look at it cuz I don't remember everything and but what I do know is it also lowered the side effects of Statin myopathy Al was one in particular um it lowered the dose effective dose of statins that was needed to you know lower the LDL cholesterol very interesting right and um I was like you know I actually ordered some some berberine I'm like maybe I should test this uh and see you know and it's there are companies like Thorn that I ordered Thorn yeah yeah which I have no affiliation with I just trust their their brand yeah so anyways I wanted to bring that up because um you know I know that again I'd heard a buring from you like years ago um but speaking of metabolic health and we you kind of talked about this you know earlier with with continuous glucose monitoring and you know measuring um you know measuring your your fasting glucose and also you know your response to foods and so like what you know glucose disposal is something that you've talked about people always hear about you know fasting glucose HB A1C like what what should those numbers be but also what is glucose disposal and why should people be paying attention to that and can cgms can they use cgms to sort of measure that yeah yeah um you know glucose disposal is is is is or take a step back glucose regulation is just it's such a miracle of our physiology I mean there's every time I think about biology I'm really grateful that I've you know came to this field in in one way or another cuz it's it leaves you endlessly uh at awe of what's happening so the the interplay between our endocrine system our liver our muscles in terms of how glucose is regulated is so complicated and exists on such a fine fine line that uh it is it is humbling so let's just put some of these num numbers in perspective so most people who have had a blood test would recognize that a fasting blood glucose of 100 Mig per deiler is sort of right on the cusp of being just just starting to get to be too high so what does that mean right what is 100 milligrams per deciliter well it means that in you know someone my size in all of my plasma floating around all of my body all of my blood I have five grams of glucose so do I have more than 5 grams of glucose in my body of course I do I have way more than that but the majority of the glucose in my body is either in my liver or in my muscles there's only five poultry Gams 20 calories worth of glucose in my entire circulation at this moment in time now if you assume for a moment that I'm just sitting here at rest and nothing in my body is demanding glucose meaning my muscles aren't requiring it the only organ that should be really demanding it at the moment is my brain now of course my red blood cells demand it because they don't have mitochondria so they're going to have to use glucose um and of course the kidney uses it and all sorts of other things but basically the majority of the glucose in my bloodstream at this moment in time is being uh is there for the purpose of my brain and you know you can do the math on this anybody can do the math on this within a number of minutes I will go through that five grams so where does the next drop of glucose come from comes from my liver so my liver is constantly titrating just a little bit of glucose into my circulation to make sure that number never goes from say 100 where it is now down to 50 because that would be way too low but it's never putting so much in that that number would be 150 or 200 at that point I would be full-fledged type 2 diabetes so the difference between you and me if I have type 2 diabetes is literally a teaspoon of glucose in our circulation at any point in time think about how tiny a difference that is and that speaks to this enormous capacitor and buffer sub system of our liver and our muscles so if the liver is the thing that is responsible for the the doing out of glucose into circulation the muscle is primarily responsible for where we put glucose when it gets flooded into our system and that happens every time you eat so you eat and again let's just do some easy math on this like you eat a bowl of pasta like not a Peter Bowl which is like the size of my head but just a normal size Bowl you're easily getting 60 gram of glucose so you eat 60 70 80 g of glucose well remember what I just said a moment ago like if you're blood level goes from 5 to 10 G you're hosed like that's a really big problem now acutely it's not the end of the world right but a healthy person would probably never go from five to eight more than eight grams so how do you get that other 60 gram of glucose away you have to put that into the muscles and so the muscle is the sink for glucose disposal and there are two ways that that happens but the major it of it is an insulin dependent way so insulin is released by the pancreas when glucose levels are sensed so the pancreas sits very high in the um uh GI tract so very early in the absorption of uh glucose as it exits the stomach into the the dadum uh does the endocrine system Vis of the beta cells sense this increase in U in glucose the beta cells release insulin the insulin results in um a signal it goes to the muscle so the insulin hits an insulin receptor the insulin receptor triggers a kinas in a cell and that brings a glucose transporter to the surface of a muscle cell so that passively right without a gradient glucose can flow from outside the cell to inside the cell so that's called insulin dependent glucose disposal in a person who's particularly fit there's also an insulin independent system where just the contractile aspect of the muscle itself is enough to get glucose Transporters up to the surface of the muscle so people who do a lot of cardio training have this capacity to you know and I've seen this in patients with type 1 diabetes who do a lot of training because that's a pure experiment where you have no insulin you can actually see them lower their glucose without insulin just by exercising so the act of exercising itself can produce glucose transport across uh across the muscle without insulin so how does all this figure into Health well as we alluded to glucose is toxic when you have too much of it now I'm not going to talk about acute toxicity so if you ever walked around with like 40 teaspoons of blood 40 teaspoons of glucose in your bloodstream you you would go into a coma so there's an acute toxicity but luckily that's very very rare and only really would occur in somebody um with keto acidosis um but the chronic toxicity of elevated levels of glucose is significant and that's where the difference between having four five 6 7 8 grams of glucose as The Benchmark concentration is a difference in 10 years of life expectancy and again like it seems hard to Fathom that that makes such a difference but it does and it does for several reasons but one of them is that glucose uh is involved in in the um the process by which proteins become sticky and so as the proteins in our blood get glycosilated and get stickier um one their function is lower but two they also tend to obscure the narrowest part of our vascular system so our the tiniest tiniest tiniest capillaries become uh more uded and therefore it's harder to deliver oxygen to those tissues so the the canary and the coal mine believe it or not of microvascular damage is within the eyes so a good opthalmologist is generally the first doctor to tell when a person is on the road to type two diabetes because by looking at the retina and by looking at the capillaries in the back of the eye they're actually able to do something that no one else gets to do in the body right like we don't look directly at the vascular system elsewhere in the body and they get to do that they get to shine a light directly onto those capillary beds so as a general rule glucose elevated levels of glucose are damaging to small vessels elevated levels of insulin are damaging to large blood vessels so the eyes the kidneys the microvasculature of the heart and the brain are very susceptible to high levels of glucose the larger blood vessels of the heart the aorta the iliac vessels card cored arteries more susceptible to the elevated uh levels of insulin and both of these things go hand in hand because of course as is obvious I guess to people now when those glucose levels are chronically elevated the body wants to fix it they it wants to crank up more insulin as the solution to the resistance so the resistance is at the cell where the insulin signal isn't being heard so the pancreas just yells louder and it makes more and more insulin and so before you see that elevated level of glucose you will actually see an elevated level of insulin so postprandial hyperinsulinemia is the metabolic harbinger of all this stuff and so the major obviously it seems like lifestyle factor that is regulating you know glucose disposal insulin sensitivity I mean it seems like both of these things are affected by the contractions of muscle and increasing those glucose Transporters right so that exercise is probably the single most important thing we have at our disposal to increase insulin sensitivity and and then there are other things that are very important right so energy balance really matters sleep really matters so uh both acute and chronic disruptions of sleep will impair that system it's not entirely clear Why by the way the experimental evidence is undeniable and these are experiments that are so easy to do well that they're unambiguous Right Where You disrupt people's sleep you know you take if you just took a normal group of people and you did like what's called a ug glycemic insulin clamp which is a an experiment um where you you run IV glucose and IV insulin into people and and you basically run a fixed amount of insulin into somebody and then determine how much glucose you need to put in to keep their glucose level fixed that's called a ug glycemic keep glucose fixed um that's a that's the gold standard for measuring insulin sensitivity so you do that test on somebody and then for a week sleep deprive them for you know down to five or six 4 hours a night call it four four would be very dramatic uh within days you'll see like a 50% reduction in their ability to dispose of glucose with no other difference no dietary difference no exercise difference so we don't know exactly why that's happening but it's a very repeatable observation so sleep disruptions impair this um energy imbalance uh impaires this hormonal changes impair this right so as we age uh both the reduction in estrogen and testosterone impair this hypercortisolemia impairs this uh and then of course inactivity is the is the is the greatest thing that drives this I definitely uh didn't do the exact experiment you're describing but I've mentioned it to you before I had my my CGM and when I was a new mother it was you know clearly my sleep was being disrupted I was getting up and breastfeeding and you know I mean it was it was like night and day difference in My My My fasting blood glucose my glucose disposal my postprandial levels I mean it was like clear we would have asked you to take that CGM off not that would be an awful time to wear a CGM but I did find that my going to my hit class yeah even though I was like just Dogg ad tired like the last thing I wanted to do yeah really did normalize it so um is there a postprandial level that like you know let's say someone's not trying to do a low carb diet like they're not trying to like because that's a whole other area right but like they just you know they're they're eating maybe a more um omnivore diet more paleo-ish or Mediterranean is right is there a level that you think postprandial you know glucose levels like a threshold they that would signal like oh you shouldn't really be going or it's hard to say I mean um here's what we here's what I think we know more clearly um we we we certainly know with more conviction that the average blood glucose the lower it is the better you are and I say that even outside of diabetic range now I don't have level one data to tell you that because the study's never been done but I can tell you that by proxy based on hemoglobin A1c dat so the hemoglobin A1c data make it very clear that lower is better even outside of the range of diabetes so diabetes is defined as a hemoglobin A1c above 6.5% that translates 6.5% is an estimate of an average blood glucose of 140 milligrams per deciliter so assume for a moment that if you have a CGM that says 6.5% meaning you just trigger the threshold for type 2 diabetes your hemoglobin your your CG g m would say your average blood glucose is 140 Mig per deciliter nobody disputes that that's harmful the question is is it better to be at 130 120 110 100 like at what point does is is it too low and what the hemoglobin A1c data would suggest is being at 5% which is about an average of 100 is better than being at 5.5% which is an average in the 11 both of those are normal by our current definitions neither of those would be pre-diabetic even so five and 5.5 are both considered completely normal levels but the all cause mortality data or the the data on all cause mortality suggest a better outcome if you're at five rather than 5.5 okay that suggests to me by proxy at least that an average blood glucose of 100 on a CGM would be better than that of an average blood glucose of 115 so that's the single most important metric we care about we use other metrics to think about that so that since we can't measure insulin in real time looking at postprandial spikes and variability so looking at the standard deviation which you can get off the CGM and just the number of times you exceed a threshold that threshold you could say maybe make it 150 or 140 Mig per deciliter and you can just say how many times in a week do you exceed that threshold that might give you some indirect proxy of how much insulin are you secreting in response to that because for example if you took two people who had an average blood glucose of 110 milligrams per deciliter by CGM but one arrived at it with you know levels like that and one arrived at it with levels like that the former would be a better way to achieve that than the latter but you know there are lots of things that raise glucose that are not harmful for example that hit class that you were doing probably in the short term really spikes your glucose because your liver is really trying to meet the demands of all that exercise so it's putting a ton of glucose into your circulation and it's going to do the right thing which is always air on the side of too much because in the short term it's better to have too much than too little so if I'm wearing a CGM doing a really hard workout I mean I'll see that glucose get to 160 Which is higher than it'll get with a meal that goes right back down though because um so what do you think about uh by the way this is all great info what do you think about so metabolic flexibility being being the capability to shift between using glucose as a substrate and using fatty acids I mean this is something this is the zone 2 thing right this is exactly why we train that zone 2 system and that's why you know we have our patients spend 80% of their cardio training time in zone 2 that's really pushing that metabolic flexibility you this is a this is the training system for making sure you expand the capacity of your mitochondria to under ever increasing demands have the ability to utilize fatty acids for oxidative phosphorilation and glucose for that matter but if you were to do let's say you're doing more high-intensity interval training which I do a lot of um that increases the capacity because it's such a potent stimulator mitochondrial biogenesis so maybe and I and I hesitate to say like I think a lot of times when I'm doing my hit I am I'm still really using my mitochondria like you know I'm not like doing an allout Sprint but like you know I do shift into to using glucose of course we just think that only 20% of the cardio training volume should be there and the reason for that is actually kind of an empirical observation if you ask the question who are the most metabolically flexible healthiest specimens we have on this planet they are highlevel endurance athletes namely CrossCountry skiers distance Runners and cyclists so what do we know about this group we know that they have the highest V2 Maxes of any humans on the planet and we know that they are the most metabolically flexible of any humans on this planet now my experience is far more with cyclists and so I usually just talk about this through the lens of a cyclist um and the other thing I like about cycling compared to SK skiing or running is we can use wattage because we can put people on power meters and we can get the numbers a worldclass cyclist is able to put out four watts per kilogram of power while keeping lactate below 2 Millo in fact the best cyclist in the world are probably at about 4.2 4.3 watts per kilo so let's just do the math on that if someone's listening to this and they've ever been near a power meter so if you're 80 kilos you're 175 PBS that means you're able to put out 330 to 340 watts which by the way most people who weigh 80 kilos can't do that for one minute literally they can't do that for one minute these people can do it for hours and keep their lactate below 2 m it's the single greatest demonstration of metabolic flexibility that you will ever see how do these people train is this is you know this is one of the questions my patients ask me is Peter where is this 020 coming from where is the study that demonstrated this and I said well the studies are all based on what do you have to do to achieve that level of performance so these athletes and their coaches have all figured out that to produce the highest V2 Max and to produce the greatest degree of metabolic flexibility you think of it as a pyramid where the base of the pyramid is your Zone 2 efficiency and the peak of the pyramid is your V2 Max and the area total area of the pyramid is your cardiorespiratory engine so you want not a narrow base with a high peak not a wide base with a short Peak you want a big base big Peak and the way to get that is about 8020 if you try to do too much high intensity you simply don't have the arobic base on which to build it so yeah you might have more mitochondria but they're not as efficient if you only do the low intensity stuff they're efficient but you might not have enough this is a bit of an oversimplification but you want the Best of Both Worlds right you want you want both the the breadth and the the peak effectively so um what what we basically do with our patients is we we start from a standpoint of time how much time are you willing to exercise a week I'm not going to tell you what you need to do let's start with you telling me what you're willing to do and then the simplest approach is we'll put half of that into strength and stability half of that into card of the cardio it's 8020 80% of that will be Zone 2 20% of that will be V2 Max and V2 Max by the way training is pretty hard because it's slightly longer intervals than what people think of as traditional hit so traditional hit works I'm just saying you know it's it's not the best way to get there um it's a it's a good way to get there and and we know like even just looking at the Tabata studies right Tabata is neither one or the other right like a 20 on 10 off times eight rounds is neither a pure Zone 2 nor it's it's it's way too hard even for v2 Max actually cuz V2 Max sweet spot is 3 to 8 minutes with one to one rest to recovery so three on three off three on three off um that's a lower intensity than most people are doing in a hit class most people in a hit class are doing shorter intervals and pushing much harder I I just had a a a talk with um with Marty cabala and I asked him that question you know and he was like Ronda you got to do more three because I wanted I was like I want to do V2 Max training like this is what I do I do a lot of the you know I do I do 16 rounds and I'll do 20 seconds on 10 seconds off right but my seconds off are I mean my my heart rate's still pretty high like I don't so um he's like you you got to do like 3 minutes at least one you know and so I've shifted my my training now to doing and it's absolutely true I am not going as hard you can't yeah it's you just can't go as hard um and so and it's an art form you'll you'll figure it out because you'll realize and you'll you'll have to you you'll be like I went too hard and I was dead at a minute and a half and I was like loafing the last last minute and a half or I held back too much and by the end of the 3 minutes it was like oh I actually could have gone harder and that's okay like you you you you'll sort of figure out what that sweet spot is um but that that 3 to eight minutes is the is the optimal zone for for generating V2 max power right yeah that's so um so metabolic flexibility obviously hugely important V2 Max hugely important but uh with respect to I would say like eating diet-wise like you hear a lot of people like low carb Community ketogenic you know metabolic flexibility if they're doing does that like affect metabolic flexibility like if you're doing more yeah it's tough to say there there I think there may be a bit of a confounder there so um I I used to think so um I'm not sure anymore truthfully um so so the obvious confounder there is if you're on a completely carbohydrate restricted uh diet your respiratory quotient so on a from a functional standpoint one of the ways we how do we measure what you're oxidizing so when a person does a cpet test a functional test like a V2 Max test we're we're measuring O2 consumed and CO2 produced so if any have you done a V2 Max test yet I haven't okay so you can you just go to any doctor or do typically doctors don't do it no you typically go to um well when I did when I lived in San Diego I used to do them with my coach so he would do them um in in Austin we send people to UT like we just send people to the university and get them done so very inexpensive test like like a hundred bucks or something like that right so they're going to have you do it in one of two ways which is a bike or a treadmill and I always tell patients do it in the way you train because there's a you know there's a you don't want to take a cyclist and make them do the running test or vice versa so it sounds like you're doing most of your work on a pelaton so you would do it on a bike because you're going to sit on a bike and they're going to put a mask on you and it's super uncomfortable The Mask has to be incredibly tight it can't have any interference from the outside world in terms of air that you're breathing can't escape and no air from the outside can get to you there are two gas sensors on the outside of the mask one for O2 one for CO2 this is the bread and butter of this whole device if those sensors aren't calibrated correctly or they don't work the test is meaningless and like one out of 10 times they fail so you got to make sure whenever you're doing this test the per the tech who does it has calibrated this thing and knows what to look for if the calibration fails during the test uh we just had a patient do one recently the test failed so um you're going to be put on a bike and it's going to be an urg which means unlike the pelaton where you set the resistance and how like let's say you have the resistance at 50 well that doesn't determine the wattage by itself how fast you pedal also determines the wattage that's different here here the computer is telling the bike how many watts to put out so the hard the faster you pedal the less the resistance will be okay okay but it's fixed wattage so they might say look Ronda we're going to start you out at 50 Watts nice little warmup we're going to have you spend you know 5 minutes here and then like three every 3 minutes we're going to go up you know 25 watts or something like that and they're you know within about 15 minutes you're going to be in crunch time and at that point they're probably going to increase the wattage every minute and you're going to you're in the The Pain Train has left the station like this is unpleasant and you have to keep your RPMs High the test is usually aborted if you can't keep your RPM above about 50 or 60 so as you're training keep that in mind these are all the things you don't want to fail the test because you didn't know the test you know what I mean um let the physiology be the place you fail um so make sure when you're riding that pelaton you're in that you're really comfortable in that 80 to 100 Zone um of RPM and um and so what is the tech tech looking for so the tech is looking at a bunch of data so what they're looking for is V2 and vco2 those are the things that are being measured so they're they know your heart rate at every moment in time they know how many watts you're pet you're generating because they're you're they're you're generating by definition everything they're sending you and then they're measuring V2 so ventilation rate of oxygen and vco2 ventilation rate of CO2 they also at every moment in time see the ratio of vco2 to V2 that's called respiratory quotient or RQ it's also known as r r that ratio in any moment in time tells you how much fat you're oxidizing versus how much glucose when that ratio [Music] is7 you are 100% fat oxidizing when that ratio is 85 it's about 50/50 when that ratio is one and above your all carbohydrate so what you'll want to see when you do the test is you won't want the report the summary you will also want the raw data which is pages and pages of a spreadsheet and you'll kind of go through and you can see how these things change so when I used to do my tests I used to plot my own data I would just get the spreadsheet and I would make the fuel partitioning curve so what I would draw would be a cur what I would have Excel plot for me is on the x-axis I would have wattage CU I cared more by wattage than by heart rate so you have either wattage or heart rate on the x-axis and on the Y AIS I'd have a Double Y AIS and the Y AIS would be either calories or preferably grams per minute and I would have carbohydrate oxidation and fat oxidation so fat oxidation goes down from as the test starts so it usually has an early Peak and then comes down as intensity goes up and carbohydrate oxidation just Rises monotonically and there's where those two cross some people call that your Anor robic threshold um but that's where your respiratory quotient is equal if you if you've done this in calories if you do it in grams per minute it won't be because obviously there's way more calories in fat than oxygen so one of the other metrics we care very deeply about in our patients is what is your Peak fat oxidation and where does it occur and we plot that so we we we plot their V2 Max we plot their Zone to and we plot fat oxidation and not surprisingly there there there's a family of curves that we put the patients on so we say this is what someone with type 2 diabetes looks like this is their fat oxidation curve this is what a worldclass tour def France cyclist looks like they couldn't be further apart and this is everything in between and where do you stack up so what you want is the highest amount of fat oxidation and you want to be able to sustain that for as long as possible now if you do this on somebody who is heavily carbohydr restricted you will get an artifact of the test because their resting RQ is very very low okay and so it's not clear what the implications of that are other than we typically will feed people carbohydrates before they do the test um like in the days but their V2 Max won't be doesn't affect their V2 Max no cuz the V2 Max is literally taking the peak V2 that they achieve and dividing it by their weight in kilos what V2 Max do you aim for and if you can recall I know that Jama 2018 paper which was probably one of the most convincing studies at BO2 Max is like one of the best metrics of Health and Longevity and there was an even bigger paper that came out that that Jama paper had 120,000 subjects in it there was a jaac paper that came out a year ago that had almost a million subjects in it and it showed the exact same findings do you so the findings if if I recall was like both of them are in the book I think I have I have figures from both of them in the in the you had the numbers in there okay um and that so that was like the top I just remember it was like the top percentile I mean they had like 80% lower the top yeah if you compared the top the difference in Risk between someone in the bottom 25 percentile of V2 Max to the top 2 and a half% has a hazard ratio of five meaning it's four time 400 times greater all cause mortality if you're in the bottom 25% versus the top 2% okay so if I want that number do you know it or I mean what's what like the top yeah are you are you 30 to 40 I'm for I'll be 45 okay so you're right in the middle of the 40 to 50 um I would guess gu but the table is in my book so I that right now I would guess that it's about it's in the high 40s okay yeah so roughly probably like 46 47 48 milligrams uh um sorry milliliters per minute to do but um this is such great information I have other like I there's I want to get into some cancer um hormones especially because I'm going to be 4 I have a very personal personal interest in this um but you know we're talking about metabolic Health obviously you've talked endlessly about the importance of metabolic health for cancer um certainly you know cancer prevention but um looking at like so the biggest risk factor for cancer is H right uh yes if you yeah unless you include yeah if you don't include modifiable risk so yeah we generally talk about modifiable risk yes age age is the greatest risk for all disease including cardiovascular disease the biggest modifiable risk factor so let's talk about modifiable risk factors like obesity being smoking is number one smoking okay still number one of of course smoking I always it's easy to forget duh you should not be smoking but it is easy to forget it's like oh yeah people do still smoke it's it's it's hard to Fathom that but addiction is addiction so smoking is the number smoking is still the number one um modifiable risk fact's after that obesity obes obesity y so why do you think obesity what if you were to speculate why do you think it I I and I feel pretty strongly about this I mean I I'm I'm happy to speculate on things and I'm happy to acknowledge when I have no idea here I think we have a pretty good idea first of all I don't think it's the excess at aity right like I don't I don't think it's the extra two pounds I have on my waist that I wish I didn't have for vanity purposes um it is the environment of growth factors that comes with obesity namely the hyperinsulinemia but also the chronically elevated igf and things of that nature and it is the inflammatory environment that comes Rife with obesity and again that's not due to the excess energy that's stored within the confines of the subcutaneous storage Depot it's due to the um excess fat that spills over from that into these other areas where fat accumulation is very harmful so fat accumulation is not problematic Believe It or Not despite our aesthetic preferences when it occurs in areas that we are designed to store excess energy it becomes problematic when it escapes those areas and gets around the viscera gets around our organs enters the muscle Itself by the way that's how it directly contributes to insulin resistance uh when it accumulates in the liver accumulates around the heart within the pancreas itself where it serves the double role of not just creating an inflammatory environment but also reducing the amount of insulin that the beta cell can release um and also around the the kidneys so those are the main places where even a small amount of fat I.E if just 10% of your total body fat where in those places you would be at enormous risk for cardiometabolic disease yeah I remember I've seen a few studies where it's like visceral fat so you're talking about the fat that's you know covering surrounding your organs you know that was highly correlated with an increased cancer risk and there was like there was also another correlation with like there was some specific inflammatory cyto kindes that were being generated or you know associated with I guess I would say with the visceral fat and the cancer incidents which again it's like uh the inflammatory environment like you're talking about so so the metabolic Health being important we talked about you know the best like exercise being at the top right I mean that's one of the best ways to exercise energy balance sleep and then of course you know management of of of distress right hypercortisolemia will also contribute to this significantly right which of course even doing things like exercise and getting enough sleep help balance right exactly um when it comes to cancer prevention you know you you talk a lot and outlive about cancer screening aggressive cancer screening yeah so can you talk a little bit about weighing the benefits versus is the risk of that type you know doing more of an aggressive type of cancer screening yeah I mean the reason I think we have to pay attention to cancer screening in such an aggressive way is that unlike cardiovascular disease and even though we didn't really go into the pathogenesis of it today I mean I've covered this on other podcasts I'm sure you have as well it's very well understood doesn't mean we know everything I I'll happily spend 20 minutes telling you all the things I don't understand or that we don't understand as as a community but we have a pretty good sense of what's going on that's not the case in cancer it is still a really really big black box to try to understand all the different ways in which people get cancer and if you just want proof positive on this I bet you there's not a single person listening to this not one who can't tell you of at least one person they know who's been Afflicted with cancer who otherwise did everything right they didn't smoke they weren't obese they didn't have you know huge chemical carc exposures they lived a perfectly healthy life and they still got breast cancer or they still got leukemia or they still got some god- awful cancer so the truth of it is in cardiovascular disease when we sit here and talk about modifiable risk factors like lipids smoking blood pressure all these things that virtually accounts for the entirety of the disease in cancer when we talk about the modal modifiable risk factors it doesn't even account for half of it so it's free money don't leave it on the table don't make unforced errors don't smoke and be metabolically healthy but you don't want to leave it at that there's still way too great a chance that you're going to end up getting cancer um relative to you know if you just take the approach of well I've taken care of those things therefore I've done everything I can so the missing link how we bridge that Gap has to be through aggressive screening because about the only thing you can say about cancer that is capital T true is when you treat a cancer in an early stage you will have a better outcome than if you treat that cancer at a later stage and in the book I talk about a couple of very specific examples of this where we have just overwhelming data I use breast and colon cancer as an example so when a person has a stage three colon cancer that's still a big cancer right right and it's by definition because it's stage three it has spread to the lymph nodes but it has not spread visibly beyond the lymph nod so when you do a CT or an MRI on that patient you'll see that there is no other evidence of cancer uh outside of the region of the reection which is the colon and lymph nodes now you know that there's microscopically cancer elsewhere so there are still Millions to billions of cancer cells throughout that patient's body almost assuredly in their liver um but they're not in you know you can't see them if you give that patient the F Fox regimen which is the standard chemotherapy regimen that's three drugs um 65% of those patients will be alive in 5 years so a third of them will still die but two-thirds of them will live if that exact same patient when you go in and you take their colon out and you take their lymph nodes out also has visible metabolic disease in the liver they're now stage four after surgery they will go on to get the same chemotherapy none of those people will be alive in five years there is a fundamental why why that difference same is true with breast cancer same is true with every Cancer the reason is the more cancer cells you have the more heterogeneity you have around the burden of mutations in that cancer the more capable that cancer is to mutate its way out of treatment evade the immune system a whole bunch of other things so if step number one is don't get cancer which it should be and we want to do everything we can to not get cancer step number two is if you do get cancer you want to be able to catch it as soon as possible so that you have the smallest possible burden of this disease to treat and by the way you know there's an entire argument that says well screening is too expensive it's a lot cheaper than treating late stage cancer with very expensive drugs that do very little so you brought up a lot of good points Peter I mean um I I really like the way like you can do everything you can and you know like my one of my favorite pelaton instructors lean Hanby you know she's out she's like doing physical activity every day I mean she looks amazing I'm sure she's you know not eating a terrible diet and she came down with breast cancer was being treated and was still doing pelaton classes while she was being treated I mean amazing um but the reality is is that there like over a lifetime you know you do like there's random amount of like things that can happen let's say you're metabolically healthy and everything like your cells are dividing you can get a mutation your immune cells will take care of it most of the time as you know we're progressing through life until we start to get you know into our what fifth sixth seventh decade maybe the immune system is not working as well I mean there's things that you just can't control like there's that like you mentioned so um with cancer screening what let's say you don't have any known genetic risk factors and there's no like family history right what age would you say or what decade of life around where would you think that or how do you treat it in your clinical practice with respect to cancer screenings um what are the major ones you know to do you said colon and breast um are there any others yeah so you know a discussion like this always begins with our patients by saying um you know you have to understand your risk appetite as an individual and you have to understand the price you're going to pay for screening um because there's a couple of prices you pay the first is economic everything we're about to talk about is going to be outside of the standard of care not everything I mean if you're at a certain age your breast you know your mamography and your colonoscopy will be covered but your colonoscopy won't be covered at the frequency that we're going to recommend you do it and even if your mography is covered they probably won't cover the MRI or the ultrasound that we're going to recommend because we never recommend mamography and isolation ever um if we're doing a PSA on you and any of our metrics show more care is warranted they're not going to cover the follow-up study like a 4K test or a you know multiparametric MRI unless your PSA is very high so so understand there's a cost that has to go into this but I think there's an even bigger cost that you have to be willing to tolerate if you go down this rabbit hole which is the cost of the false positive the emotional cost of the false positive so we always kind of start by explaining how sensitivity and specificity work and I know a lot of people's eyes kind of glaze over and they're like oh my God like I don't want to hear the stats on this but if you don't understand what sensitivity means and you don't understand what specificity means you can never understand the things that really do matter to anybody who gets a test which is positive and negative predictive value positive predictive value means if this test comes out positive How likely is it that I actually have the thing it says conversely if this test comes out negative How likely is it that I'm truly negative you want very high positive predictive value and very high negative predictive value and that's a function of three things the specificity of a test which is the ability of a test to detect a condition being present if it is indeed present the specificity of a test the ability of a test to conclude that something is absent if it is indeed absent and the prevalence of the condition being tested meaning How likely is it that you have this before I test you so you can call that prevalence if you're screening you can call it pre-test probability but the point is this is all a basian process so I really spend a lot of time going through this with people and let's just you know start with something as simple as mamography right so you know so Peter why why are you saying you're not satisfied just doing mography well here's why mography has a sensitivity of about 90% And A specificity of about 85% which is fine except if I'm going to do a mamography on you at this moment in time your pre-test probability for having breast cancer is pretty low like a couple percent that means the positive and negative predictive value of this test in isolation are very poor like less than 20% um furthermore there are features about you personally that might make you a bad candidate for MRI in isolation one is your you're very young you're not in menopause yet your breast tissue is very glandular now in 40 years on a mamogram your breasts are going to look totally different the mamogram will actually have an easier time seeing what's going on in your breast because there's going to be less dense glandular tissue the mamogram because it's an x-ray is really good at seeing calcified lesions it's really bad at seeing non-calcified lesions conversely an MRI is really has no issue with glandular tissue but can't see calcified Legions very well so you go through this analysis and you realize there's actually no perfect test for screening you have to stack tests on top of each other if you want to increase positive and negative predictive value and if you rely on any one test by itself you're always going to have a blind spot the the one exception to that by the way is a colonoscopy a colonoscopy is a a test that has 100% sensitivity and very high specificity um but with colonoscopy you have a whole different risk which is a physical risk there's actually a risk of harm from a colonoscopy basically three big risks there's the risk of dehydration electrolyte imbalance hypotension that comes from the bow prep there's the risk of the sedation and then there's the risk of a perforation or bleeding actual procedural risks now if you look at the largest study that came out on this which was last summer in the New England Journal of Medicine this was actually a study that was meant to show that colonoscopy wasn't worth it um actually showed something totally different in my mind which showed how safe it was so it was a study of I think over 20,000 people uh and had not a singular not a single incident so it showed that in good hands a colonoscopy is a very safe procedure um but I always want to make sure people understand like we don't take this stuff lightly um and there's a reason you don't do colonoscopy three times a year which if you did colon oxy three times a year you'd never get colon cancer because you'd you know colon cancer always has to come from a pup so if you were checking somebody three times a year like you you'd never they would never be able to develop a poop that you wouldn't catch but at that point the risk would be just too high that something else would go wrong um so you know standard recommendations used to be every 10 years starting at 5050 current recommendations are starting at 45 and there's some cont rsy about whether you would do it every 5 to 10 years we typically say with no family history or risk factors meaning you don't have inflammatory bowel disease or Crohn's disease or things like that um we would typically say 40 and then about every 3 years depending on the findings so sometimes the findings on a given colonoscopy will make you want to actually do a more frequent surveillance if you find a CLE pup for example or if a patient has an incomplete bowel prep you might decide you know actually we need to do this a little more urgently and and do it in a year again as opposed to we three great information and with respect to the um combined you know especially for younger individuals like younger like myself um the mamogram uh starting so so I might say like you know at 40 I would start doing a mammo and an ultrasound every other year uh sorry every six months so you do a MMO every year you would an ultrasound every 6 months uh every year but stagger them by 6 months so if there was if there was high enough risk that's probably an approach I would take now is that because there's a lifetime risk of one and eight just for on average forget about all the okay um and again breast cancer is one of those cancers where if you treat it early like it's it's it's absolutely a disease that that can be treated early if you catch this in a stage one it's a non-fatal disease um a stage four disease is a uniformly fatal disease what's the positive predictive Val value of catching it in stage one with the combination well so okay so so the way to think about it is you think about it as what's the positive predictive value of the combined modalities and and and here it's a little more complicated because it depends on the hormone status so I'll give you an example um another uh thing that we use that we haven't talked about are liquid biopsies yeah so we incorporate liquid biopsies into our testing talk about them yeah yeah yeah so so so have you talked about the podcast do listen there was a question I was going to ask you about with um you know the the Grail by the gallery by Grail yeah yeah okay so what does this test do so the there are basically three things that you can figure out by looking at strands of DNA in the blood that can give you a clue as to whether or not a patient has cancer so let's say you collect a bunch of you connect you know the Grail test uses is 10 CC of blood relatively paltry sum of blood and they look at all of the cell-free DNA so again they separate the DNA that's in cells they don't want that right from the cell-free DNA and determined so so basically there could be known mutations that we know are cancer genes like a Kass mutation or p-53 mutation where you might say oh well if you see that k mutation like there's cancer somewhere in the body the second thing that gives you a clue that there could be cancer in the body is the length of the DNA fragments that you see so there's an you know this is not what Grail does by the way but there are other technologies that are looking at fragment length and using fragment length to impute probability of cancer what gra does is they look at a third thing which is methylation so they say okay well all of this DNA is yours we're not going to worry about what the mutation are what the fragment lengths are but what we do know is certain methylation patterns are indicative of cancer and tissue of origin that's a very big deal so now you are doing a screen for not just does this patient likely have cancer or not but if they do can you tell me where that's coming from so we can now go and look more closely there now there's something really interesting about how this works because it's different from any other type of screening test see that MRI that we talked about or the ultrasound or the mamogram um or the colonoscopy for that matter are basically morphology tests you're looking visually either directly in the case of colonoscopy or indirectly in the form of a mamogram where you have to look through the tissue you're looking at the morphology of a cancer The Grail test says nothing about that it's simply telling you is this a cancer that is leaving its sight of origin or shedding its DNA in sufficient enough quantities outside its sight of origin so something very interesting emerges when you take a closer look at the Grail data and this is why we use the test again I have no affiliation with Grail so this is you know just my clinical um uh experience and observation at first glance the sensitivity of the Grail test for breast cancer is quite low the specificity is very high for Grail by the way meaning if you don't have cancer it is very likely to tell you you don't have cancer the sensitivity is quite low meaning if you have cancer it could miss it and it's been tuned that way so the algorithm has been tuned for a very high specificity a low sensitivity but if you look at breast cancer overall sensitivity it's about 20% for stage one stage two which seems kind of abysmal meaning if you have a breast cancer that's early stage stage one stage two there's only like a 20% chance it'll show up on the Grail test and many people myself included at one point thought that doesn't justify doing the test I don't need a liquid biopsy to tell me I've got a stage three breast cancer like I'm going to figure that out falling off a log right right uh so I need something to tell me when there's a stage one breast cancer but a closer look at the data showed that if you looked at erpr negative breast cancers stage one stage two sensitivity was 75 to 80% it was only in the triple positive erpr positive herun new positive that the sensitivity specificity are so low and since that's the majority of breast cancers it brings it down what does this mean it means that the more indolent a breast cancer is the less likely the Grail test picks it up at an early stage but the more aggressive it is the more lik it is to pick it up at an early stage the implication might be here that it's catching the cancers that matter and I think that's a very interesting way to combine liquid biopsies with morphologic studies do you ever uh not combine like do you think doing just a liquid biopsy by itself would be a useful thing or do you think really it's better with you know in combination with other morphology types of screening yeah it's a great question I mean we don't do them in isolation because I still think we're in really early days and I I just think a little bit of a belt and suspenders approach makes sense um but I it'll be wonderful if the day comes when all you need to do is the liquid biopsy and only if it comes up positive do you need to go and do a morphologic survey a couple of questions um so you know talking about some of the major screenings the colonoscopy the mamogram uh you mentioned PSA uh are so so with like some of these you know types of morphology screenings like the mamogram for example people are concern like there's a whole group of people that are very concerned about the potential the mutagenic potential of you know these types of screening methods um you know potentially causing cancer right so CT scans the x-rays well CT scans would be a very lousy way to screen for that reason right the CT scan has a lot of radiation with the exception the only time we justify the use of a CT scan is in a former smoker or a current smoker we don't have any current smokers in our practice but we do have former smokers we do still use a lowd do CT for lung screening um remember lung cancer risk is lung cancer is the leading cause of cancer death uh globally and in the US for both men and women um and and 85% of lung cancers occur in former smokers or current smokers so in those people you have to ask the question what kind of cancers do they get and you basically have small cell large cell um and squamous cell are the dominant cancers that occur in smokers and those are best detected on a lowd dose CT scan adenocarcinoma of the lung is is the dominant cause of lung cancer in a non-smoker and we can detect that equally well with an MRI so we don't expose a never smoker to that risk whereas to a smoker we or you know a past smoker or current smoker the risk reward trade-off is worth it and that's been documented really clearly in clinical trials mamography has incredibly low radiation um not as low as like a dexa scan or something like that but it's still really really low um so there's a lot of women that avoid them I'm I'm I'm sure there are I don't know maybe there the radiation has lessened over the years and it always has I me radiation is constantly going down I mean just going back to something we spoke about earlier 20 years ago a SE so just let's explain what the numbers mean so radiation is measured in units called mly CTS and um it's generally established that exposure to more than 50 m CTS a year will increase your risk of mutagenesis um so now let's put that in the context of certain things so living at sea level here in San Diego the just the exposure you get to the environment is about 1 to 2 m SE verts a year so that's 2 to 4% of your annual allotment if you live in Denver you're doubling that so being one mile in the sky doubles your exposure but you're still you know you're at you know 4 to 8% of your annual allotment um a CT angiogram 20 years ago was 20 M CTS 40% of your annual radiation allotment on one test the last patient I sent for a CTA last week because when we get the report it also shows the radiation less than one mevert so mammograms are even point less than that yeah yeah yeah yeah they're a fraction so it really is is makes zero sense for a woman who has a lifetime risk of one and eight and perhaps even higher if she's obese and drinks alcohol right um to avoid to to avoid doing mammograms correct okay um but again I I would never rely on a mamogram exclusively I would combine it with an ultrasound or the MRI but they're not concerned about people aren't really scared of the ultrasounds they're SC they're scar yeah and and MRI of course has no radiation so um but but again everyone has you know you just have to unfortunately there's a lot of fearmongering that goes on um but you just have to look at the numbers I mean it's Crystal Clear that a mamogram has a very very they might be confusing it with there there was another test I'm blanking on what it's called now because it's never done anymore um it's called I think it was called molecular breast Imaging it was another high high intensity mammogram it's again I've never seen one done I don't think they've been done in years but pre-mri like pre utility for other tests it was done it was also about a 20 to 30 MBE this where this is all steming from I'm sure it's I'm sure there's a complete misinformation and misunderstanding where people are confusing mammogram from from what's called an MBI is what the test was called well this is good to clear up um I because I mean I'm I'm not just I'm not kidding like I know people I know women that have this fear so um you know I think stepping sort of stepping back just one more thing I want to ask you about is like blood cancers is there any like what is liquid biopsies are very good on blood cancers actually because you have the highest proportion of those cells like you're going to get a much higher concentration of cell-free DNA so yeah we actually that's actually one of the areas where I'm most excited about the liquid biopsies is on leukemias and um you know other other sort of hematologic issues uh such as Myoma and things like that and for people listening wondering about the cost of it typic it's like 900 like ,000,000 right don't think it's D to see so meaning I think you have to go through your doctor to do it I don't think you can just do the test willy-nilly I don't think you can yeah uh but I don't know for sure yeah I I'd be surprised if you could so on the breast cancer topic you know kind of going um into another area just I know we got to we got we're we're doing okay um but I really want to get your thoughts on this this topic which is you know well broader sense hormones um but also just like if you look at the way a woman ages before menopause I mean she's aging slower than a man right like by several yeah when she hits menopause I mean it's like a you hear this quote unquote Cliff they fall off like a woman in terms of their aging they fall off this Cliff but like it's no longer I mean it's just they go rapidly you know down so what are what are let's just talk about some of the risk factors that women face you know after menopause and why yeah so so obviously what happens in menopause is three hormones that are really important to a woman during her reproductive years go away um and they go away in very short order uh so it's it's it can be quite dramatic um and obviously those hormones are estrogen progesterone and testosterone I always mention testosterone because it's it's easily forgotten but it's important to not forget it because a woman's concentration of testosterone in her uh and by the way testosterone declines slower than estrogen and progesterone estrogen progesterone really go down testosterone kind of gradually goes down but um like right now we're sitting here and you're you know you're 45 presumably uh you know you're you're still in the throws of your reproductive you know you're at the tail end of your reproductive capacity but you haven't hit menopause yet um your testosterone right now is at least 10 times higher than your estrogen level wow in absolute quantities and by the way that's the highest that's if you're ovulating so your Peak estrogen is around ovulation um if I take you in the early follicular cycle or in the ludal cycle your testosterone could be a 100 times higher than your testosterone so it's very important to understand don't get confused by the units on the lab test because they're reporting them in nanograms per deiler versus picograms per milliliter and so the estrogen number looks bigger but in terms of absolute amounts of it testosterone is still the uh by far the most dominant hormone for both men and women so um these things go away and a whole bunch of things happen now in the short run and the things that generally get the most attention of the medical community are these vasomotor symptoms so the hot flashes and the night sweats and these are kind of the first things that women tend to notice I mean they might notice that their period is becoming irregular their cycle is lengthening and things of that nature but in terms of actual symptoms that are disruptive to their quality of life it are these Vasa mutter symptoms so hot flashes and night sweats it's not clear why some women get these horribly and some women actually don't get them at all most women do get them um to varying degrees and uh again there's a there's a spectrum there other women will talk about things like brain fog sleep disturbances and again the Sleep disturbances could be related to what we just said cuz I got to think if you're having hot flashes and night sweats that can't be good for your sleep so you know is that sufficiently uh driving the Sleep disturbances or is there something else that's driving them um as time progresses into menopause other things will occur there will be sexual changes so vaginal atrophy dryness and reduction in libido and again those can be related but they can be independent we know testosterone plays an important role in libido and we know that estrad plays an important role in vaginal uh um in the the absence of estrogen is driving the vaginal symptoms so um and of course if and then of course you have uh pain with intercourse that's a result of all of those things as well which then feeds forward on the decreased libido as you go a little bit further you start to see another major consequence of this which is the destruction of bone uh and I use that word I'm being a little aggressive in my language there but the truth of it is both men and women hit Peak bone density in their early 20s and for men the if you look at their reduction in bone mineral density from their 20s on it's it's a gradual decline for women it's a gradual decline until menopause then a very straight harsh line Decline and when you consider the risk of um falling and the impact of um a broken hip or femur later in life both in terms of mortality and morbidity you realize that that may be the single biggest risk of menopause on women though not appreciated in their 50s and not only showing up another 60s so taken together all of these symptoms in my mind completely justify the use of HRT in any woman who is willing to undergo it and unfortunately uh and I've talked about this a lot on my podcast I think there has been no greater disservice brought by the medical community onto anyone but in particular in this case women than the abject failure of the interpretation of the women's health initiative in 20012 2002 whenever it was first was published uh that's a study that was completely misinterpreted the Press um were I mean out to lunch in the way they interpreted the study and the investigators were in my mind um equally at fault for not clarifying it now at least one member of the team who was a part of that study Joan Manson has has been more vocal lately I had her on my podcast she's been more vocal in acknowledging the um the way which that study was misinterpreted but unfortunately the damage has largely been done uh both in terms of the fact that there is an entire generation of women by my estimate and by the estimate of my analysis uh my analyst's analysis um over 20 million women have been deprived hormones that who would have otherwise received them and um we've even come up with some calculations for how many lives have been unnecessarily lost as a result of that and then there's the ongoing damage which is you know as uh um is it Mark Mark Twain is attributed for saying this right like a lie will travel halfway around the world before the truth is tied up its shoes so um just as you said there are women out there who say I can't get a mamography because oh my god of the radiation they may in fact be thinking of an MBI there's just a misunderstanding well similar there are still women walking around today that thinking HRT increases the risk of dying of breast cancer when it never did and it certainly doesn't today so let's let's talk a little bit about um about that like I know like I've looked into the Women's Health Initiative I've heard you speak about it and you know it's uh some of the major major flaws of that study were one being well so I I want to let's let's talk about what the study did right so the study took um two groups of women women who had a uterus and women who didn't have a uterus and randomized each of those groups into two separate groups treatment versus placebo why was that done well it was well understood by then as it Still Remains that in women with a uterus failure to give progesterone with estrogen increases endometrial hyperplasia so if you take a woman with a uterus and you just give her estrogen but there's no progesterone her endometrial lining will thicken will thicken will thicken and as the endometrial lining gets thicker so too goes the risk of hyperplasia and ultimately what's called dysplasia which can lead to cancer in other words un opposed estrogen will increase the risk of endometrial cancer so to this day we know this and we do this um so if you had a uterus you were put into a group where the treatment group was given conjugated equine estrogen and MPA so that's uh that's estrogen taken from horse urine and a synthetic progestin and the treatment and the placebo group was just given a placebo and then in the other group The no uterus group they were just given conjugated equin estrogen versus placebo they didn't have to be given the mpa the synthetic estrogen um these women were on average considerably older they were I want to say 7 to 10 years out of menopause at this point um and the study was looking at a number of outcomes but it was terminated early at about 5 and 1/2 years when it was noted that the women in the CE plus MPA group versus the placebo had um a 0.1% higher risk of developing breast cancer um interestingly the women in the CE alone group had a lower risk of developing breast cancer so the study was halted and the headline read estrogen incre increases the risk of breast cancer by 25% well this wasn't correct um it is true that in the CE plus MPA group The Root the that group had five cases of breast cancer per thousand women compared to four cases of breast cancer per thousand women in the placebo group and it is true that that's a 25% increase in the relative risk but of course the absolute risk is .1% there was no difference in breast cancer mortality in other words there was an extra one case of breast cancer but there was no difference in uh breast cancer mortality those data by the way have been updated every decade or so and we now have like 19-year followup on that group and that fact Still Remains True to this day there is still no difference in the mortality of breast cancer in the CE plus MPA group but you see it would be impossible to make the case that estrogen is the cause there when in the other group you saw the exact opposite effect you saw that the CE group alone had a lower incidence of breast cancer and eventually even a lower mortality due to breast cancer so I feel like I don't know maybe a 10th grade science student might come up with a different hypothesis than estrogen is the culprit in this group you have a plus b in this group you have a what could be the difference might it be the B so I think most people who think about this problem today acknowledge that it's probably the mpa that was driving the very very small clinically insignificant but statistically significant increase in breast cancer incidents that had no translation to a mortality difference and you might as think the question well is MPA in use today and the answer is pretty much by nobody there's I don't I've never once prescribed MPA I've never seen a patient come to me who's taking MPA there probably are some patients on it but I doubt it and what is MPA again it's a synthetic progestin okay nowadays women take bioidentical micronized oral progesterone or they use a progesterone cated IUD if they don't if they don't um benefit symptom atically from progesterone progesterone is a funny hormone some women really don't respond well to it um it doesn't help their symptoms in any way shape or form and in those women we don't even use it we just use a progesterone coated IUD and that provides the local protection that prevents uh uh endometrial hyperplasia um so in that sense you know you you I could dive deeper and deeper and go through the Weeds on the whole study but the punch line is very clear here right which is estrogen absolutely did not drive either the incidence of breast cancer or mortality associated with breast cancer and again that was not true in 2002 it was not true in 2006 it is not true today that is one piece of the study that I didn't uh catch because you know I when trying to to sort of deconstruct it it was like okay well the synthetic of course versus bioidentical versus the age of initiation so like you said these women were like 10 years I mean like on average like after menopause had hit um was another factor and then um you know some of them were very very unhealthy again like yeah it was a very it was a very it was a very unhealthy population to begin with um the other thing about it by the way is we don't use oral estrogen anymore yeah so that's another question what so um can you talk about a little bit of the differences uh just you know sort of not so much de into the deepness of it but like the difference between you know oral estrogen bioidentical estrogens topical like you know what so the only estrogens that are used today are bioidentical which means um they're estr diol and or estriol but there is no FDA approved estriol product so there are three estrogens E1 E2 E3 uh there's some important Nuance here that maybe justifies explaining so um estra diol can be turned into estone which is E1 and it can be turned into E3 estriol but E3 cannot be turned into E2 or E1 so that's a one-way Arrow E3 can be turned into this is complicated let me start E1 can be turned into a 24 and 16 hydroxyestrone so you got E3 that can go into an e sorry E1 can be turned into a two hydroxy a four hydroxy or a 16 hydroxy E3 can actually be turned into the two hydroxy but not the four hydroxy or the 16 hydroxy virtually all the breast cancer risk probably comes from the four hydroxyestrone so you can get that from estriol pardon me from estradiol but you can't get it from estriol there is no FDA approved product for estriol so if a woman is taking estriol which she's probably taking in a topical fashion in combination with um estral that they usually refer to that as a bi EST you'll hear that abbreviated biest which just means by estrogen so they'll combine in some fraction anywhere from 5050 to 802 estra diol with estriol and a woman will apply that topically but again that's not FDA approved that is something that compounding pharmacies would have to make for a physician in terms of FDA approved products you have oral estral bioidentical we don't use it because frankly there's a small but nonzero increase in the risk of hypercoagulability it just doesn't seem like it's a risk worth taking like the only indication in my mind for oral estradiol is for women whose skin will not permit the absorption of any topical estrad product our Preferred Product is an estradiol patch uh we use a branded version I actually when it comes to hormones I really prefer using branded versions of an FDA approved compound we prefer to use something called the Vel dot so it's an FDA approved estradiol patch a woman applies the patch you apply that you know the patch comes in different Doses and you can trim it if you want more or less estrogen and she changes it like every three or 4 days so you know you'll put it on your lower back or your hip butt something like that on your shoulder you just put it somewhere where it's not sort of intrusive um by the way we do not notice variable absorption with sauna use so if the time ever comes for you to use it we should discuss paying attention to different absorption rates um but nevertheless we we don't have any issues with that um there are osto estrogen pellets that can be inserted in the subq space into the fat really and they're also not FDA approved but you know they're still used pretty liberally uh by physicians who know how to put them in uh I used to do this for my female patients I anymore uh I just tend to prefer the patch truthfully because it gives a more steady state level dose of the estradi and you can fix you can make adjustments easily with the pellets you put it in there you got to wait five or six months before you figure it out again and decide what to do so um those are basically the ways in which you you would take estrogen in and as I said progesterone you would do either oral micronized bioidentical or you would use a progesterone coated IUD they also do make progesterone um suppositories but for most women the compliance with that is low it's just messy and and you know kind of inconvenient um there's also topical estrogen products so you do have some women who say look I just do not want to take estrogen under any shape or form I don't want any you know I don't want any um uh estrogen in my body but these vasomotor pardon me these vaginal symptoms are problematic then you can use vaginal estrogen cream or vaginal suppositories of estrogen again that won't give you any of the bone protection that won't stop the night sweats or anything like that but using vaginal estrogen products alone will at least ameliorate the sexual side effects what about the difference between like multiphasic versus whatever the mono like when you so like giving women estrogen in like more like their cycle versus like the same dose like all the time we we would we would kind of use we we sometimes do multiphasic on progesterone in the transition of per menopause we don't do it once women are fully in menopause when women are fully in menopause we just sort of stay at the dose again the dose that a woman is on is a very low dose relative to her pre um menopausal levels as indicated by the fs do you go so that was another question do you like let's in your how do we yeah well like deter let's say a woman is either premenopausal or per menopausal H like I guess postmenopausal too but determining like measuring your estrogen measuring your progesterone measuring your testosterone um what when in this cycle to do it and what are the love like what to you would say Okay This Woman's transitioning to Perry menopause yeah uh you know is there a Le like a threshold levels yeah we look at day five so if day one is the day the period starts regardless right even if it's just a bit of spotting whatever it is like that's that's the starting point on day five somewhere between day five and day seven we just like to do it on day five um you look at estradi levels and FSH levels that is your Canary in the coal mine as that FSH level on day five starts to climb and that estrad will start to come down but it's mostly the rise in FSH that's how you know you're getting closer and closer to the cliff now there's actually some interesting data that's looking at amh levels um and uh antim malarian hormone em so this is basically telling you how many eggs you have left how many follicles you have left so this is something that fertility docs are constantly looking at in women who are you know struggling with fertil or you know deciding if they can still do you know have kids or go through IVF so um there there may be some also some insight that comes from amh but typically watching the rising FSH on day five is what's telling you this is coming and then of course you marry that to symptoms so I I typically do not treat women until they're symptomatic in per menopause so I you know we'll look at their labs and I'll say you know Rhonda look uh I you're getting closer to something let let just be on guard for it and then you know maybe 6 months later you'll say all right I'm having some hot flashes and night sweats well okay good you're and you by the way you still may be ovulating you you know this can this is what per menopause looks like right so to me that's when you start treating and you can get away with much lower doses um but point I wanted to make is once you're in full-fledged menopause like we're only giving you enough estrogen to get your FSH down to about 25 you now never have an FSH above 25 so remember FSH and estrogen work um in opposition to each other so the lower your FSH the higher your estral you right now with your regular cycle you've probably never seen an FSH above 12 just to give you a sense at your lowest estrogen right now your highest FSH is 12 when you're in menopause you're going to be managed to an FSH of about 25 to 35 which means your estradi is going to be lower than it is at any point in your cycle today but that's sufficient to take care of all of your symptoms and preserve your bone density so preserving bone te preserving bone density obviously symptoms but uh preserving bone density also lowering cardiovascular risk yes uh lowering Alzheimer's risk uh Alzheimer's is less clear Rhonda the data right now suggest the following late initiation of HRT may be counterproductive for ad risk may actually increase ad risk um early initiation appears to potentially only be beneficial in E4 women but not E3 women okay so for you I would say doubly beneficial to initiate at the time of menopause because of your E4 got it that's really good to know and also um defining what is early and late like you know so that you know there was a study there's a couple of studies one was the elite study and one was the do so like I don't it was like early intervention for estrad or something um and then there was another one that was the the Danish osteoporosis prevention study and both of those studies in the in the Dos one um the the initiation of the they did uh estral I think they did like triphasic or something but also they did the progesterone so it had proest as well um it was like the the cardiovascular disease risk or mortality went down the B Venus throm thrombo embolism like the things that happen um that can increase with uh menopause went down over the followup which was 16 years or something um but these women only took it for 11 years and they started at age either between the age of 45 and 58 so per menopause was in there and also just you know you know a few yeah this is to me the biggest unknown question Rhonda and I don't we don't know the answer and what's what I find very frustrating is we're not going to know the answer because nobody's going to do the study I I am as comfortable with anything in medicine as I am that initiating HRT at the time of menopause does not increase a woman's risk of heart disease breast cancer or anything else in fact it reduces her risk it clearly reduces her risk of heart disease dementia and bmd and it's either protective or neutral on cancer it was it was neutral on it's protective or neutral on cancer I am very confident of all of those things here's the thing we don't know what do you do 10 years later what do you do when she's 60 right and again if you look at the HRT data from the Women's Health Initiative with all of its flaws the answer would be you should probably stop but again that study is so flawed on so many levels that I'm not sure and here's where I would argue there's one area where you absolutely know things will get worse when you stop the estrogen and that's bone density so the other things are a little less uh clear to me there's there's some there's there's some you know opacity around what will happen to cardiovascular disease risk dementia disease risk and cancer disease risk if you start completely initiated HRT after 10 or 15 years but what is unambiguously clear is her bones are going to get brittle again cuz the moment you take the estrogen away bone density goes down estrogen is the most important hormone in men and women for the regulation of bmd it is the chemical transduction system that turns Force into bone building so so we have you know basically strain gauges in our bones that are sensing forces on the bones and that force is being turned via estrogen into a chemical signal to osteoblast and osteoclast to promote bone building and once estrogen goes down that goes away so if you take the estrogen off a woman 10 years postmenopause she will once again go into a rapid state of decline now she's still better off because she'll still be further ahead than where she is if you put her in Decline 10 years sooner so you know I've had arguments with people on the anti-rt side and they say you should never use estrogen for treating bmd because we have bis phosphinates and I say first of all you only use bisphosphonates for 3 to 5 years two they suck meaning they're not as good as estrogen and third you can use estrogen for longer and and they say well yeah but once you take it off it still goes down and it's like yeah but it's a new Baseline and it's a high it's like waiting to retire like you're going to have more in your retirement fund if you retire at 70 versus 60 but so but this is the big question because because I mean and my and and again I we've done a back of the envelope calculation that would suggest even if the risk of Alzheimer's disease or heart disease or cancer even if you lost any protection from HRT and maybe had a slight increase in Risk given how big the risk of falling is um you you might still end up being neutral risk carrying out HRT indefinitely so this is where you know the lifestyle factors quality of life right but this is probably where lifestyle factors do play somewhat of a role as well because if you have obviously if you've been doing resistance training uh up until that point and continuing it you're building not only bone you you know certainly built up a lot of bone density Reserve earlier in life but muscle mass helps right and then let me throw this at you um because I've you know I've thought a lot about the nuclear hormone nuclear hormones basically like so so vitamin D is the one that I've really focused on and when I was doing a lot of research on it so so nuclear hormones you know we have steroid hormones nuclear steroid hormones I should say sorry so we have estrogen testosterone vitamin D is one so these are these are binding to a receptor that you know in some cases the receptor complexes with other ones it goes into the nucleus of a cell which is where all the DNA is and it goes down to the level of genes and it regul recognizes a little sequence of genes so in the case of estrogen it's called an estrogen response element and ER in the case of vitamin D is called a vdre a vitamin D response element um there's a lot of overlap between vitamin D and the estrogen in terms of the genes they're regulating and so I'm wondering if avoiding vitamin D deficiency also becomes one of those important lifestyle factors because uh you know in some cases obviously vitamin D also plays a own role in bone metabolism right but independent of that also just looking at the cross Talk of the genes that vitamin D and estrogen regulate and they're like they're both and the the the response elements are they're different but there's somewhat I'm looking at that it's like oh I wonder if there's like that seems like you might be able to compensate a little so it's kind of another interesting in addition to being you know Physically Active resistance training one of the most important things right um but also like I did a lot of jump roping I was like Star jump roper as a kid lots and lots of jumping rope which there is evidence that that also builds bone Den so I want to ask you a question about this so what do we know about the relationship between call it naturally acquired vitamin D through sunlight versus supplementation of vitamin D uh exogenously through you know a supplement do we do we have any reason to believe that those are different at the same level of vitamin D in the same like like in terms of like how Vitamin D is acting so the thing is is that when you're in sunlight like there's other things going on right that's my point like if you're outs getting sunlight you're more active and you're nitric oxide like there's like other things that you're getting from the sunlight so there's a confounder there but um I mean like with respect to let's say forget every like let's say you finally you you you convert the vitamin D3 into the 25 hydroxy vitamin D into the 125 you know at that level it's it is the same like you know to some degree I mean that's not when it's when it's binding to the vitamin D receptor the the the actual 125 hydroxy vitamin D which is the active steroid hormone it it's the same yeah um now with respect to like you know your body regulates how much vitamin D3 is converted or is released into bloodstream and converted into 25 hydroxy vitamin D at the level of sun exposure so at a certain level you're not making the vitamin D3 when you've gotten so much of it that's how you avoid toxicity right like you're not you're not going to keep yeah what's the highest level of vitamin D A person can ever get to natur Al meaning if if you just like took a an individual and put them in the sun put you know shorts only no shirt go out there and work in the Sun for all summer like how high like how high were were my vitamin D levels when I was in high school working construction I know I I I know there's like data out there where there where people have looked at like you know um you know people that are that are like out in the they're out they're outside all the time but they're they're honestly often looking at uh people like in the tropics and stuff that have uh more melanin yeah which again so it might depend you also on on that but that would be an interesting at least way to say like the if the body has a built-in mechanism to say I'm not going to let you make more vitamin D than this supplementing above that would be a bad idea it yeah like and so that's why looking at measuring do you think that threshold is um I I think going above 60 nanograms per milliliter is probably still okay like going to 80 you know like there's there's studies looking at 80 and it's still associated with lower all cause mortality um and in fact I mean honestly if you start to look at some of the literature you have to take a really high dose daily for like a decade to start getting like the the high calcium but like the problem is that when you absorb uh when you're vit when you have a lot of vitamin D you absorb more dietary calcium and you also absorb more phosphorus and calcium plus phosphorus can precipitate right and so like there's so many factors involved but I think most people are not supplementing like there's some people that are crazily supplementing and it's like they just think more of everything is good but I don't think most people are doing that like I don't think taking 5,000 7,000 I for most people some people have to take more than that because they have Snips right and you've probably seen it in your patients where it's like they had to take a high level just to get up to 30 or 40 um this by the way is why I think all these vitamin D trials the mega trials are so flawed is they're always doing it on the basis of a they're they're taking too low a dose and they're doing it based on dose not level like to me the dispositive study on this would be take a whole bunch of people whose vitamin D is 30 give half of them a placebo give half of them whatever vitamin D is necessary to get them to 60 or 80 80 yeah get something higher yeah get create separation go 30 to 40 but be like do it the way we do blood pressure trials when we do a blood pressure trial we don't say you're going to take a fixed dose of a med we give you whatever dose of the med is necessary to change the blood pressure so we're comparing two blood pressure levels not Placebo versus 10 milligram of a drug that for one guy is too much and for one guy is too little and yet this isn't done in vitamin D and I find it infuriating that we have no really good reliable RCT data on what seems like a jugular question are you better off with a vitamin D level of 80 than you are of 30 I mean again we think the answer is yes but the you know evidence-based medicine you know crowd will tell you no because this trial that gave people 2,000 IU for 10 minutes found no difference right or they they measured maybe if they if they measured anyone's level they measured like 10% of the population yes exactly like the most recent study we only got a level on 10% of people with with like you know the fact of the matter is so many people do have these Snips too and I remember having an email dialogue with Joan Manson this was years when I was postto and I was and she was I think at the time she was doing the vital study it hadn't been published yet and it was like please please can you get the snip data in there can you get measure the levels like do everything you know like it's it's so important um but I'm with you on that I think I think what is clear is avoiding deficiency and I do say that a lot because and where are you drawing the line is is 30 or 40 where you I say 30 I mean it it does depend on are you looking are you looking at what the endocrine society says uh is more of an adequate level or inadequate are you looking at deficiency where you're like literally like you know like your bones are like your bone health isn't you know good yeah so um but for me I I I want to know the same thing like I'm always kind of like hovering around 50 60 but I'm like should I be at 80 yeah you know and I don't know um so it's always like okay well air on the side of caution you know air on the side of caution certainly avoiding deficiency yeah um but even with respect to like all these genes I'm talking about you know like what if there's some cross talk with that there is cross talk but what if there's some way that um having a level of vitamin D you know 50 50 or 60 NRS per Mill does help alleviate some of the effects of having no estrogen you know like we don't really know interesting it is especially when you look at the mechanism and I like I said I spent a lot of time looking at these response elements and and I you know looking at the fact that estrogen can actually compensate for um vitamin D deficiency in some cases with certain genes too and it goes both ways so I'm like well I feel like that should be an important uh component in the equation right um but I'm with you on the tent like like this even the studies I was talking about where there was protective effects against you know in the cardiovascular health in uh cancer prevention with uh hormone replacement therapy when initiated like you know within a a close range like not greater than six years so was six years or less so if you you're doing it seven years that's not part of the study um they only did it for like 10 or 11 years and they stopped Y and it's like well what happens then when you're 65 and you she started at 55 you know like so we don't we don't know question to that I mean the answer to that either um but I'm happy that you're thinking about it uh so oh you know one thing maybe even before we go to mail uh hormones that I didn't mention on the female side was testosterone um and and this is you know I mentioned earlier of course the the abundance of testosterone in a woman prior to menopause but what's what's far less studied is the impact of testosterone replacement in women uh postmenopause and this is something that is being studied um so so by the time this podcast comes out there'll be a couple of podcasts I've released on the topic of sexual health but through the lens of both male and female so so Sharon parish and mo Cara will be the two folks that I've have discussed with on that and Mo's actually involved he's at Baylor uh in Texas he's involved in a study that is um looking at the use of testosterone replacement in women for sexual function so both Mo and Sharon talk extensively about the importance of testosterone in sexual function specifically around libido and orgasmic function along with arousal so this is like I mean I I I've said this before you know I said it I think to them on the podcast it's rare that I go into a podcast with so little information on a topic usually I like you know like you like you know all the answers to the questions you're asking me because you've prepared for it right but but you know usually when I'm going into a podcast I kind of know what's going on but I was blown away in my discuss discussions with with with Mo and and Sharon on these topics so um the long and short of it is we have become much more liberal in our use of testosterone in women uh for any sort of sexual side effects also keep in mind we've talked about it but the importance of maintaining muscle mass as you age is imperative uh just as imperative for women as it is for men and testosterone is the dominant hormone there so again when people hear this they kind of think what are we talking about like anabolic steroids and it's like well yeah testosterone is an anabolic steroid what we're talking about is replacing women to the levels that they were at in their 30s and 40s these are very very low levels of testosterone uh typically about on10th the dose that men take to also have a physiologic replacement and that's about on10th the level that you know bodybuilders would take so we're not talking about huge amounts of testosterone but just restoring someone to physiologic levels uh can have profound impacts but is that in combination with also so giving these women the the EST EST estrogen progesterone y because you you know what would happen if you just were doing the testosterone and and let's say a woman let's say a woman was 10 years out missed the whole uh interesting yeah missed the the window yeah um and and and this is something that people have asked me um what what do I do like how do I how do I you know get some benefits you know without actually taking you know estrogen progesterone um would you also give that person so there's two questions here there are yeah um great great question um we we handle each of those I hate to say this because it sounds like such an obvious cliche we handle each of those on a case-by Case basis um so I won't you know I won't sugarcoat it like we're not very comfortable doing initiating HRT and women who are 10 years out but at the same time we realize there are a lot of women who are 60 today who went through menopause at the height of the stupid around the Whi and as a result of that like they're worse off today than they would have been had they been on the appropriate hormones 10 years ago and we have to make a very difficult decision about whether it's worth additional risk and I say that because we don't know what the risk is um and so the way we handle that is we basically try to figure out what is your risk of AD a ascvd and cancer specifically breast cancer as it stands now and you know for example if a woman is especially high risk for one of those things particularly ad if she's a 33 um or even or even a 3444 and and or if she's very high risk of breast cancer we might be a little bit more reluctant to do so um or if we do it we do it at an even lower dose than we normally would and we have to increase our surveillance around those things um so not not an easy question to your other question would we be comfortable using testosterone in isolation without opposition um I would say at this point I'm not I'm not I don't think I know the answer to that question yet um and I think that that's something that would need further study before we could sort of make a clear recommendation in in the cases of the uh in your clinical practice you're handling the hormone replacement therapy is is testosterone part of that equation or do you ask is it like a more of a symptom thing like my libido's down even though I'm also on estrogen with it's not a yeah it's not nothing is standard right everything is bespoke and I and I think that that's just really important for anybody listening to this right it's like you don't want to go to somebody who does paint by numbers you know paint Pine numbers is a bad approach everybody's on this everybody's on that no no no it's like you know some women do not absorb testosterone very well pardon me do not absorb estrogen very well from a cream some you know might end up requiring to take get orally some uh much prefer a cream some prefer a patch some can tolerate some only need this dose some need that dose some need a very small amount of oral progesterone you do need at least 100 milligrams to oppose the estrogen at the endometrial level so you know somewhere between 100 and 200 is probably necessary some can't tolerate it at all and you have to use the IUD when it comes to testosterone there's lots of ways to deliver it right so one of the most interesting ways that's being studied now is using um an FDA approved product it's not approved for this use so it's called nesto and it's a it's an intranasal testosterone spray that is FDA approved for male use for testosterone replacement therapy um but it's being used off label it's also being tested in a clinical trial for libido in women uh it has a higher acting so what another point to think about here is where the testosterone where the Androgen receptors are factors into it so the intranasal testosterone probably is more more rapid acting in terms of sex drive and libido whereas the intravaginal testosterone for women increases orgasmic function so even the way in which you use testosterone can impact function and what your indication is I and a question I have is is well one of the questions I had regarding men had to do with the types of testosterone like you're administering but like taking a step back like you hear a lot about um uh low te yeah low te and there's like this controversy around it like what defines low te is it a levels is it a combination of levels and symptoms um so how are like we're looking at menopause and women we're talking about an average age of about 51 or something like that right men let's take the same period of of life for men okay 50s do they start to experience like a decrease in testosterone around yeah but it's more gradual and it starts frankly in your 20s and 30s um so so male testosterone probably peaks in the 20s and it's just a slow steady decline it's not um it's not like in the case of women where they you know they go through puberty they have these hormones that are cyclical and then fall off a cliff with men it sort of you go through puberty you kind of peak and then you're on a slow uh decline down so um you're right low te is really a combination of levels and symptoms and it's really important to remember that symptoms matter because levels are really well how can I put it delicately I mean just not as helpful as we'd like to believe they are um and it's actually comes back to something you talked about a minute ago right which is how do these hormones work these hormones work by binding to Androgen receptors and the testosterone Androgen receptor complex has to make its way into the nucleus where it impacts trans descrition factors now we know that not all men have the same density of Androgen receptors and we know that not all Androgen receptors function in the exact same way so have this problem which is we sit here and we measure testosterone levels in men and maybe we measure bioavailable or free testosterone but those are just estimates they aren't actually telling you free testosterone level um you're measuring total testosterone you're measuring sex hormone binding globulin you're measuring albumin you use those to estimate the free amount of testosterone but that's still an estimate kind of like ldlc calculated by the fredwell formula is an estimate and then you sort of have to guess well maybe their Androgen receptors are saturated maybe they're not but if you're giving a guy testosterone in the presence of mild to low te you're assuming his Androgen receptors are not saturated and therefore giving him more testosterone will lead to an increase saturation of the AR and will lead to more nuclear transcription but we have no way of measuring that and so what I always say to patients is I got to see a certain set of symptoms in combination with a biochemical set of labs that make sense and then we have to test it out but it's not going to be a placebo test so we're going to have a placebo effect and then if the if if the response we see isn't a hell yes I think we should pull it all off and see if we notice a response in the deficit and I'm looking for symptoms as follows right so I'm looking for some signs and some symptoms most of it is symptoms so it's you know reduction in libido reduction in energy mood um and then on the signs we're kind of looking for um insulin resistance uh difficulty putting on muscle mass and difficulty recovering from exercise those are kind of your big ones and some combination of those signs and symptoms coupled with a biochemical story that's plausible so you know your total testosterone might be below the 30th percentile or even 40th percentile um and your free is commensurate with that even though again that's an estimate is probably reason in in my book to initiate and uh is there a level that you decide to go to like so I mean is there like a threshold where it's like this is too much testost yeah it's actually kind of like what we were talking about on the vitamin D front like you don't be too incremental you're not going to get the answer so if if if and again each lab's going to have different scales but in you know in the lab we use um the fifth percentile of total testosterone well let's do free testosterone because we actually even though free is an estimate we kind of look more closely at free so approximately the fifth percentile is 5 nanograms per deciliter and the 95th percentile is about 24 nanograms per deciliter so call it 5 to 25 basically so if a guy is at 8 and we have the the case to make that he's going to we should try trt I'm not going to take him to 12 it's incremental like I'm going to take him from 8 to 20 and see if something M and if he says to me at 20 I don't feel any different and we take it away and he says I don't feel any different unless we were only treating this for insulin resistance and muscle mass those were the only things in which case I would say we still say the and see if those things get better but if he you know if if we were doing this because there was you know some of the other actual symptoms um then I would say that look this guy might have been already saturated at at 8 nanograms per deciliter where he started and all that additional testosterone may have done him no good whereas somebody else might have been woefully undersaturated and when you you know increased him by 150% you actually got benefit from it does the like injection versus like a gel does that matter like we're we're very biased towards injections um I think they're far more consistent um I think you know you have variable absorption and it doesn't just vary by individual it varies by time a day so you know for example like if you're if you just finished a workout and you're sweating and even if you go and have a shower you're still kind of in a less absorptive State than maybe if you're cold um you know what part of your body do you put it on do you have to exfoliate the skin first you have hair on the skin you know you want to put it on an area that doesn't have hair there's just more issues with it um we so we recommend um an injection we also recommend instead of doing it every two weeks which is standard doing it twice a week at obviously a much lower dose so typical dose would be somewhere between 80 and 100 milligrams of testosterone a week so it would be 50 40 to 50 milligrams twice a week and that produces just a much more steady uh level cuz you're you're really trying to get the steadiest level possible and the problem with doing it every two weeks which was usually done in the days when people would go to their doctor to get the injection and you wanted to minimize the inconvenience of that um you're just super physiologic for you know four or five days then you're kind of physiologic and then you're actually back down to being very subphysiologic before the dose so we'd like to avoid that is there any uh like what's the relationship between testosterone replacement therapy and like the prostate yeah very well studied um so couple things we know as clear as day right so we know that the lower the testosterone the higher the risk of high-grade prostate cancer um so again contrary to popular belief testosterone replacement therapy does not increase the risk of prostate cancer um but what it does do is potentially increase uh BPH benign prostatic hypertrophy so it does increase the size of the prostate potentially um so so one you know needs to be mindful of that it also there are there are side effects of testosterone right it will drive hair loss in an individual who's susceptible to hair loss through um uh the the sort of Androgen p Pathways there um it can increase acne in a susceptible individual again these things are typically more the type of side effects that people talk about when testosterone is being used in super physiologic levels so I'm just trying to think the last time we saw a patient who had acne um I'll probably see it once a year um so so these are really infrequent side effects um but we do have a lot of patients who you know are concerned about hair loss and um and and so we say look I mean there are strategies around that of course you can take a five Alpha reductase inhibitor uh so those are drugs that block the conversion of testosterone to dihydrotestosterone which is a more potent Androgen and that's the that's the Androgen that's driving Androgen specific hair loss um or they might say you like I've had patients say oh you know what like my My Hair Matters more to me than my testosterone I don't want to take testosterone so so so those are the things that we just kind of want to point out um the only other thing that's worth noting is I do believe that in a susceptible individual in the short run there's there's probably a slight increase in the risk of cardiovascular events with testosterone and it's probably born through an increase in blood pressure so there's um a very large study that looked at kind of high-risk men and they were given testosterone and at one year post initiation of trt there was a slight increase in the risk of major adverse cardiac in the testosterone group compared to the placebo group that vanished at 2 and 3 years uh almost suggesting that the highest risk men probably those that were closest to having an event were actually pushed over the edge a little bit again I I would probably attribute that to an increase in blood pressure as the thing that was potentially driving it so you know we're not keen to put guys on testosterone until we have the house in order with respect to everything else what what sort of blood pressure do you you like levels do you like to see we're very aggressive right I mean if you look at the Sprint trial I think it's very clear that 120 over 80 or better is the place to be and that's better than 130 over 85 which used to be the standard for hypertension right that's right right okay so we're very aggressive um the good news with blood pressure unlike the lip you know we spent a lot of time talking about lipids and a listener may come away from that thinking okay there's some dietary stuff but you guys didn't talk about exercise and you're right exercise doesn't move lipids much like you're going to be you're heading down the path of pharmacology much sooner on the lipid front but blood pressure is just as big a risk factor for cardiovascular disease as lipids and it's way more amenable to I hate the word but lifestyle intervention you know losing weight and exercising will fix a lot of people's blood pressure not everybody we have some very lean fit healthy people in our practice who still have essential hypertension and it has to be lowered pharmacologically but for many people um you know losing 20 lbs and and exercising especially cardio is going to do amazing things on their blood pressure have you looked at um so I have a relative who exercises uh good diet like uh the only thing that lowers her blood pressure is hot tubs interesting in addition to the exercise interesting and it's like very she's also very high stress like so she's which is obviously I wonder if it's funny I wonder if it's the impact of you know whether it be sauna or or uh or hot tub on on hypercortisolemia that might be having the indirect effect on blood pressure because she is absolutely prone to high cortisol she's like it's a very high stress and the other thing is um you know uh so Dan he also I mean he's exercises a lot di like we have the same diet um my blood pressure I mean like I've got phenomenal blood pressure like always always I mean like really low like I'm I'm actually on the side of like I need to be make sure I'm not like too low um but he at times like when measuring it at home by the way people at home should just get an automated cuff right I mean like absolutely it's just yeah and then when you finish this story I I'll walk through to make sure everybody's measuring correctly because it's very important yes please do um he has uh H hemocromatosis okay and um there's some other relatives that had it and noticed that their blood pressure was high like we're talking people that are like very phys like doing lots of these are like you running marathons they're doing you know like they're very super healthy and donating blood seemed to help normalize the blood pressure for whatever reason I don't know I which is important for obviously getting rid of the iron and hemocromatosis right um but the other thing that's really helped so Dan is doing that now but the other thing that seems to really help him I mean he does Sauna hot tubs exercise you know and there'll be times when he's in his office working and he's like 135 systolic and it's like what in the world that's crazy right um green shakes help him so like tons of like nitrates so a bunch of like green vegetables and these are like nasty tasting shakes these aren't like good tasting on it's not AG no um and that will that will help him as well so um yeah exercise is very important but like there's also like has he tried like coca flavonoids things like that you know we I was I give that to so another story no I wasn't doing that we haven't been doing that because we take a lot of our vitamins at night we do take some fish oil in the morning I did mention that to him because another story my mother um who is sedentary she's lost a lot of weight but she's still overweight um she you know she she she's losing the weight was great I mean she's lost like 75 lb like she's lost a lot of weight if you look at the pictures it's like years to her life have been extended just by that alone um but I can't like I can get her in the sauna sometimes um but it's still it's still like a little bit more of an effort um but one thing about her is she will take the vitamins I give her and um she's got she's homozygous for MTHFR if she's not taking a high dose like b supplement along with like methyl fola like her homocysteine will go high and her blood pressure goes up and she had stopped taking all those because she wasn't over my house all the time when I was giving it to her every day and so I I got her you know this like sort of like battery of supplements that I was giving her um including all the the methyl folate and um lowering her the things that were lowering her homosysteine along with magnesium and COC flavanol so I was giving her cocoa uh she was getting four of those pills she gets four she still takes them her blood pressure went from like 155 to like 1225 okay her doctors are like they wanted to get her on anti-hypertensive treatment before she came to me and it's like and this has been like months now it's it's it's it's h you know she measures it at home she takes she does a l I mean so I'm very happy about that uh you know the fact that she's been able to do that um but again it just it shows that there are they definitely are the lifestyle factors I know you hate that word but you know exercise being one of the main ones but there are people also that in addition to being very Physically Active like they still get high blood pressure you know yeah yeah and there and and you know I don't think we have the outcome data to look at the direct impact of um Coca flavonoids or all the suite of B vitamins that are necessary to lower homocysteine and their impact on blood pressure but here's what we do know and again this is mechanistic and it's very strong mechanistic but that doesn't necessarily equate to outcomes but we know that as homocysteine is elevated it impairs the clearance of something called asymmetric and symmetric dimethyl Arginine I don't know if you've talked about adma and sdma and adma and stdma directly and indirectly inhibit nitric oxide synthes so the we know that homocysteine is associated with poor outcomes in cardiovascular disease um and I think that this mechanism of homosysteine impairing the clearance of adma and sdma is the is the mechanistic link because when you directly inhibit nitric oxide synthes in the endothelium you are preventing the creation of nitric oxide and of course that's what coca flaven oils actually do the opposite of that so I think the one two punch of lower Ing homocystine and raising uh nitr oxide synthes activity via coca flavanol could could certainly explain a reduction in blood pressure that's really interesting I I was giving her the Coca Flav now just because I had seen the studies on increased blood flow and I'm like okay that's let's we need that you know like we need that um measuring blood pressure yeah so um this was established really clearly through the Sprint trial and and this has basically been now kind of the gold standard for how we use an automated cuff so that trial was done by um having individuals sit for 5 minutes check a blood pressure no stimulation during that time so not talking not looking at a phone not doing anything and then repeat that two more times so it's a 15 I'm not suggesting this is what Dan does or what anybody does but just so you understand at the level of how the trials are done you're sitting for 15 minutes having a check at 510 and 15 minutes you're sitting like this the cuff is 2 in above uh the elbow and um the cuff is right at the level of the right atrium so you know you're and by the way if anybody wants to do this experiment at home it's really interesting to do put a put an automated cuff on your arm and put your arm here put your arm above your head and put your arm in the right spot and look at how big a difference you get so measurement errors are a huge problem being overstimulated is a huge problem so you really want to make sure you're getting an accurate reading of that blood pressure and we have our patients do that twice a day uh you know an early in the day and a late in the day check and then you know we just have everybody do that for two weeks to start and that's that's what's considered your blood pressure so you know the idea that you're going to walk into the doctor's office and get a blood pressure is not valuable for most people so when when someone says what's your blood pressure it should be what's the average of those two weeks of twice daily checks done where you take the five-minute protocol and test perfectly and I think everybody listening to this should should know that number yeah that's great I'm GNA like I'm G to do it um Peter so this has been amazing I mean so much information actionable information uh a lot of people listening here they want medicine 3.0 they want aggressive prevention um do you have some tool like some some some uh pointers maybe some strategies that people can work within the existing Healthcare System to kind of like help them like how can they you know get some of these tests that we've talked about whether it's through Boston Hart or you know doing doing the the the Grail um working with their Physicians to like being able to order them you know like H how can people try to get as close as they can to Medicine 3.0 I mean we've I I hate to sound like a Shameless plug we've created something to help do this because you know I've talked here about our practice our practice is super small it's it's we it's just never there's no desire to scale this practice and we will never be able to meet the demand of the you know the people that want to come in and and the amount of room that we can make because um it's just not the model doesn't make sense right it's it's too labor intensive the way we're doing it but the good news is like I really don't think you need to be my patient to get the benefits of what we do I really think you can get most of these benefits if first and foremost you are a really thoughtful consumer of your own Healthcare information so to that end we've we've created this product called early um it is um I mean it's going to be fully released next year but it's having a limited release this year so we released it for four days in the spring just to our subscribers um the the the reception to that has been very positive it's going to be released again once more this year just to people on a wait list so anybody who goes to I as shamed to say I don't know the website I think it's early.com but maybe it's early medical.com yeah I don't know Google early medical yeah yeah something like that uh and there's a waight list and those who sign up on the wait list will be offered the next uh window it'll be a very short window in the fall and basically that program does everything right it walks you through everything how to operationalize everything that I've written about in the book or that we're talking about here today it also allows you to directly go to um any lab you want and we've and we have no affiliation with any of these people so we don't want to make any money on how these labs are done but you can you can run our panel at Boston Hart and get all these results and then we sort of you know give you our dashboard on how to walk through these we give you the these are the ranges and what I hope to be able to do because so far a lot of people who are buying this product from us are Physicians what I really hope will eventually happen is we'll have a critical enough mass of both people who are buying this who want this kind of medicine and Physicians who are buying this who want to practice this kind of medicine that there could be sort of a match made here and you know the good news is I think a lot of Physicians really want to practice this way um and the challenge of practicing this way is you just have to get re-educated and that takes a little bit of time and that's why we've put this together right we we sort of taken two and a half years to build this program this curriculum and it's an investment I make no you know it's probably 30 hours of video uh plus tons of downloadable material that are you know lead you through a bunch of exercises you have to do like how to take a correct family history like what to really look for in your family history um stuff like we're talking about the blood pressure Stuff how to check the labs and all those things so you know I think that that's I think that's the way to maybe not at the societal level you know I don't have the policy solution for how to fix medicine but I think at the individual 11 at the individual level just sort of taking control over it and saying okay I'm done with medicine 2.0 it's time to go to Medicine 3.0 and Medicine 3.0 is really about highly preventive super early personalized care there are a couple of personal questions that I'm going to ask you at just at the very end of this um that I know people are also very interested in one being your ideal your ideal diet and exercise routine and other factors that you're doing um for longevity or maybe for the day or for the week whatever whichever way you kind of bunch them in like what's ideal for you for you to um you know improve your longevity I know that's a very general way with respect to nutrition and exercise um nutrition exercise and anything else sleep like you know son whatever whatever is your ideal like program the whole sweet yeah um well I will say this I I I'm sure that everything I'm about to say is going to make me sound really rigid and people are going to be like that guy's a psycho so I'm always little hesitant when in talking about what I do um well they want to people want to know what you do okay so um look probably compared to most people I am considered quite regimented um I'm way less regimented than I used to be um but nevertheless here here's sort of how I think about things so uh let's start with sleep um I really take my sleep seriously and I'm you know someone who believe who functions best with a consistent bedtime and wakeup time so I am in bed usually for 8 hours a night and that's typically 10 to 6 um and that usually results in probably 7 and a half hours of sleep um I'm going to just rattle off the names of things I use because I don't have any affiliation with these things so I use eight sleep as my mattress cover I love what these guys have done um it's a fantastic cooling product and it's made an enormous difference for me I've been using it for the last years most of our patients are using it uh there are other products out there and I've tried them and they're good this one I just happen to Fancy the most agreed um I'm also very particular about what I'm doing before bed and what I'm not doing before bed so I really and I'm not perfect with this I'm not perfect with any of these things Rhonda but I really go out of my way to not look at anything that's going to um activate me so I try not to look at email for a couple hours for bed in fact I have two separate phones I have like my regular phone that has email and social media and junk on it and then I have what I call my bat phone that literally has nothing it's just of it has like the remote to the TV you know and it has like a phone and email but like sorry a phone and text but only like two people know the number my wife and my daughter and um that's about it and the camera so it's basically an excuse to have a camera and a phone if I'm going someplace and I don't want my phone with me um so that's kind of the phone that's with me if I'm watching TV downstairs or something like that but it I can't even be tempted to look at social media or look at email so it's it's all in this Spirit of like turning the system down before bed um even little things like I'll brush and floss my teeth before I go in the sauna because I sauna before bed as well so that once I'm done with that sauna and shower like I'm just going straight into bed um so for me that's also a very productive uh sleep trick uh there's certain supplements that I use to sleep as well also I'm a fan of glycine um ashwagandha um magnesium l38 and um and just straight mag oxide as well I don't use melatonin or phosphaline unless I'm jet lagging if I'm time zone hopping I'll use those as well uh so that's sleep um on the nutrition side I don't follow any particular diet I I guess you could say I eat what's what's what would be called a balanced diet so I'm an omnivore who um will probably always struggle with food in the sense that like if left to my own divices I would eat everything uh and too much of it so I do need to be mindful about what I eat so what do I pay attention to so I just generally pay attention to not eating junk that's that's like the most important Credo of my diet I would say and I say this as someone who's done everything right like I've been vegan I've been keto I've been like the most you know um you know hardcore fasting intermittent fasting Tim restricted eating like I've done there's no diet I don't think I've I've done for long periods of time and I have found benefit in one form or another from various different aspects of these things but um you know right now I'm mostly optimized around energy balance which you know stay in energy balance um and protein intake and so most of my conscious effort around my diet goes into making sure I'm getting 40 to 50 grams of protein four times a day um and a lot of s at least two of those are in meals that are just like just just venison or just you know eggs or something where it's just a protein and you know there's not a lot of other stuff in it um I do make sure I stop eating at least 3 hours before bed it really makes a difference going back to sleep that I go to bed a little hungry um if I ever go to bed with my belly too too full it feels nice but I don't sleep as well so I really try to air on the side of going to bed a little hungry and that's you know I'm really lucky because we have young kids so we eat early so we're eating at 6 so I'm going to bed typically with four hours between when I last ate and and when I um um when I go to sleep we can talk about alcohol I um I'm in the camp that believes there is absolutely no benefit to alcohol at any dose from a purely you know biochemical standpoint um however I acknowledge that there are probably some pro-social benefits to it and I happen to really really like alcohol so I probably have well I don't know it depends I mean anywhere from zero to seven or eight drinks in a week um probably NE I don't think there's a time that I can recall in the last five six years where I've had more than two drinks in a day and I also try to do my drinking early now by that I don't mean to in the afternoon but I mean with dinner so that again um alcohol is completely it it fun functionally the alcohol doesn't factor into my sleep and I know this because I track all these things and I know exactly how alcohol negatively impacts sleep in me and I know that as long as I have that drinking done by six or seven uh it doesn't show up anywhere on any metric that I'm tracking with respect to sleep okay exercise most important uh thing from a physiologic standpoint for me um I exercise every day and it's an you know it's much of what I do revolves around it so even here being in San Diego this week I mean it's like I have a membership at a great gym when every time I'm here and I just know that I'm going to get up first thing in the morning and I'm going to go and I'm going to do my workouts and they're going to be completely you know they're not going to be the exact same workouts I'd be doing at home but I'm still generally doing you know 4 hours of Zone 2 a week with one sort of higher intensity workout that's geared towards V2 Max a week and then four strength training sessions a week um so that's kind of the foundational pill pillar of everything I do and then there's other things that get layered on top of that like rucking and recreational activities that are also physical as well um so and then the the the last thing I guess I would say on that which we didn't talk about but it's an equally important part of this is you know mental health so everything that we've talked about factors into so so the right sleep the right nutrition exercise all of that factors into creating you know what I kind of describe as a wider buffer zone around distress tolerance and then you know therapy which I do at least one session a week sometimes two plus journaling um and and and you know doing something called dialectical behavioral therapy these things have been you know enormously important at increasing kind of the quality of my life in the past five years that's amazing I mean thank you so much Peter so um if people want to I mean people definitely are going to want to hear more from you you've got a podcast the drive I mentioned it's everywhere it's on YouTube Spotify iTunes you've got a book that is a must read I read it it took me about 7 hours I did a FL I mean it was but there were Parts where I was like I know this I know what Peter has his thoughts on this and I was 2x in it you know whatever whatever you want to call it but um yeah it was like I oh you audio readit you mean no no I read it read it and you read it in seven hours I I did but like I said they're a fast reader well I I think the the the more more important factor was I'm very familiar with your your thoughts and lots of things there were things where I was like I know I know and I'm just skimming this part and then there were things that were a little bit more so um phenomenal book I mean lots of important lots of things we talked about today but even more and lots of applications there so it's called outlive um I went to a spa the other day and I saw it right there and I was like awesome um that you've got a website I mean Peter aa.com yeah I think petera md.com is the website that's where you people can sign up for our newsletter which comes out every Sunday and then I think early medical.com is a separate website where where that other thing exists um so question for you when are you going to write a book has this has this ever has this ever is this ever something you thought about I've thought about it I'm not sure that I want to go I mean I can't imagine the work like cuz your book was I mean it it was it's impressive you know and to to write a book in the scientific world like that that people are excited about can understand um I mean it's it's really challenging so um yeah I mean I I I guess um all of those things are true and yet I think as I stand here on this side of it I can say I think there are benefits to it not I don't want to talk you into doing something that's really hard because it is but you know like Andrew huberman is working on a book and you know it's it's it's hard he knows it and and but but books do communicate in in a way that podcasts don't um and they reach different audiences too so um there was a part of me throughout the process that was kind of like because I started the book two years before I started podcasting and then as I'm into the book and podcasting there's a lot of time when I thought why am I doing this like this is such a waste of time like this is taking so much time and I could cover all of this material in 10 podcasts like the book could be summarized into 10 really wellth thought out podcasts um but now that it's all said and done I realize a couple things one writing sharpens your thinking so much um and I'm not saying that your thinking isn't sharp or that my thinking wasn't sharp but there's just no two ways about it like as I sit here talking I'm sort of blabbering but like when you have to write it down you really have to get clear on what you're saying um and and as I said there's you know there's probably somebody out there there more than somebody there's there probably a lot of people out there who would who would get to know who you are and what your message is going to be that wouldn't figure it out from a podcast so you know maybe there's a bunch of listeners who are saying yeah Peter tell her tell her tell her so but I I think there'd be a lot of people who would love it if you wrote a book if you decided to make that commitment well it's it's good to hear that from you for sure um especially being on the other side of it you know because you often wonder was it worth it you know like yeah uh Peter there are other things that we didn't get to discuss believe it or not um so let's please do this again my podcast your podcast I want to do both um because you know there's just there's so much to dive into and we have so much overlap in our interests that it's always a pleasure to talk with you and um so thank you again really really enjoyed this conversation well thank you for having me and thank you for for pouring through the book and and coming up with so many awesome topics to to get through and it's funny that we barely got through half of them as a 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