Welcome to the found my fitness podcast. I'm your host Rhonda Patrick. Today's episode features. Dr. Peter Atia. Dr. Peter. A TIA is a highly respected expert in preventive medicine with the special focus on applied science of longevity his deep engagement with the topic of longevity is the Cornerstone of his New York Times best-selling book outlive the science and art of longevity. Dr. Arati also extends his expertise into his clinical practice early medical and shares his knowledge through his popular podcast many of you are already aware.
Of the drive in this episode, you will learn why a poby is a superior predictor of cardiovascular disease over LDL particle number and managing the four main factors that elevate a probie why apob exist in humans when it doesn't in most species whether or not low LDL is a risk factor for Cancer and a variety of other surprising facts about LDL biology. You really can't find anywhere else Peter's opinion on April be reference ranges.
Whether there is an ape will be level low enough that it is impossible to die from atherosclerosis, which dietary factors increase apob how statins and other lipid lowering pharmacotherapies work including their side effects and costs and what the alternatives are the pros and cons of different statin alternatives how increased muscle mass helps achieve lower blood sugar levels, which may play a pivotal role in reducing overall mortality.
And the potential for glycemic control to be suboptimal. Well before doctors identify, it Peter's 80% Zone to 20% vo2max training protocol the dangers of visceral fat and why it correlates with increased cancer risk Peter outlines the benefits and risks of aggressive cancer screening and offers insights on optimal screening timing. He also clears up misconceptions about the radiation used in mammograms the hormonal changes of
menopause and their significant impact on women's health along with how hormone replacement therapy influences the risk of dementia cancer and heart disease in women vitamin D sunlight versus supplementing and optimal levels why symptoms of low testosterone are often more important than actual levels when deciding whether or not to go on testosterone replacement therapy why Peters recommended testosterone replacement therapy dosing schedule differs from
The standard Peters protocol for treating low testosterone and why testosterone replacement therapy isn't always the right answer methods for lowering blood pressure exercise nitrates hot tub and cocoa flavanols Peters exercise sleep nutrition and alcohol routines for optimizing longevity and so much more before we dive into our discussion with dr. Peter or Tia. I'd like to highlight a valuable resource available for you. It's a comprehensive report. I've compiled
on evidence-based strategies to optimize cognition and slow down brain aging this report delves deep into the best exercise practices for boosting brain derived neurotrophic factor a key neurotropic factor integral to learning memory mood regulation and combating brain aging additionally. It encompasses a range of Lifestyle approaches including specific protocols for heat exposure through sauna or hot baths along with
Guidance on omega-3 and polyphenol intake all targeted at elevating brain-derived neurotrophic Factor levels. You can find that detailed protocols report at bdnf protocols.com. Once again, that's bdnf protocols.com. And now on to the podcast with dr. Peter a TIA. Hi everyone. I'm sitting here with the amazing. Dr. Peter a TIA
any of you don't need an intro to him. He has changed our understanding of the scientific literature preventive medicine with respect to longevity. Improving Health span. He's a number one New York Times bestselling author of the book outlive amazing book. Also he has a very popular podcast on health and medicine one of the podcast few podcasts that I listened to called the drive.
And he's also a 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 having this conversation. You were on the podcast many years ago about eight years
ago. I was in early 2016, right? I think it maybe yeah, you might have been like 2015 you
might have been one of the like the first I don't know six or seven guess. I mean you were like one of the first guests that I had on body so
A long time ago you were still at new see ya.
So it was a while ago. Thank you for having me
back. I so let's let's dive into like maybe 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 I think the critical spark was the birth of my daughter and I are right about this a little bit in the book, but you know, I think
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 and I do 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 mean, I just adored her more than I could have imagined during my wife's pregnancy.
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 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 died of some other thing or what is it, you know eventually what is 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 about the birth of my son and my I mean, I remember times like, you know,
Within the first couple of years of my son being born going for my long runs and and stopping in the middle of my run and literally bawling 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. And so a you know, like what everything that 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 and so like all of those things have sort of cross my mind at the same time with respect to the cardiovascular disease that you mentioned and you talked about this in the book as well. 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,
People hear the word cardiovascular disease. I mean at least even me when I was a cardiovascular disease. What is that? What does it mean? Where is atherosclerosis come into play where it is coronary heart disease what is cardiovascular
disease? I mean, you could Define it very broadly and include valvular disease and cardiomyopathy is and all of those things but when we talk about a scpd atherosclerosis 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.
What we're referring to is the disease of coronary arteries that leads to ischemia 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 will get into today Cancer near to jump diseases Etc things that you and I have spoken about a lot including when you're on my podcast. It's important understand that 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
Understanding on the cardiovascular front are our understanding of this on the nerd gym decide is also quite small. There are still many things. We don't understand so, you know everything we're about to talk about on the cardiovascular side and 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 cardiomyopathy.
He's there are people that are dying from valvular cardiovascular disease and things of that nature. 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 like a protein burden and inflammation, but this leads to a reduction in blood flow to key parts of the heart muscle and when that happens the heart
Goes in ischemic event. Now sometimes I can be chronic and sometimes that can be acute and if an acute event occurs in 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.
A little up it 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'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 cardio vascular pathology class in the pathologist said, what's the single most common presenting feature for someone having cardiovascular disease?
First time and everyone was like chest pain shortness of breath, you know, rattling off all these rules as he goes. No sudden death again today. It's not quite 50 percent, but that's a very sobering statistic.
Absolutely. I do want to dive into some of the the, you know, major causes of the atherosclerosis and the author's kwatak cardiovascular disease that you're talking about. So lipoproteins you mentioned and you know their most people know,
No, they hear about lipoproteins as your about LDL or htl but it will be why should people know about April be
well, you know, 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 valence when they think about it's like cholesterols a bad thing. So it's worth explaining that that's not really true right cholesterol is an
Schultz thing right? So without cholesterol we wouldn't be alive 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 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 fluidity and it's the precursor to some of the most important 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's Share of it is probably done by the liver and the striatal 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 and water and they
Round 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 ape. Oh lipoprotein and there are broadly speaking two classes of a polite bow proteins. There are the a class and the b-class so
Some of the lipoproteins are wrapped in an ape A lipoprotein called apob 100 and we just abbreviate that to a poby but I'll just say it this one time and we'll never talk about it. Again. There's also an APO b48 that wraps another type of lipoprotein called the chylomicron. We won't talk about that again because it doesn't really factor into cardiovascular disease. So a poby is short for a polite the protein be 100, which is the structural A protein that sits on load.
And City lipoproteins abbreviated ldls. I intermediate density lipoproteins abbreviated ideals, very low density lipoproteins. Abbreviated vldls the ape OAS and this is big a never to be confused with a pole little a which we may talk about those wrap the family of high-density lipoproteins. They're much more complicated than a Toby's believe it or not. And there are many of them but nevertheless broadly speaking. That's what's going on. So
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 can 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 V ldls 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 took people whose total cholesterol was in the top five percent 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 as the cluster all contained within the low density lipoproteins. 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 80 be 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 can you talk about how that see you mentioned LDL total total LDL cholesterol. That number is like some equates like determined by some equation. Right and
we can be but it can also be measured directly. Yes. So there's
click that be particle number of his called
know and 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 freeter Wild equation. So total
Scrolls relatively easy to measure you so you draw the plasma you spin it down and you basically lice all of the lipoproteins, then you can measure total cholesterol. So if you if you just basically apply something to lice all of the proteins, you'll say all the lipoproteins you'll say total cholesterol is 200 milligrams per deciliter, then they directly also measure to other things. They can directly measure total triglyceride concentration and using a separate a say they can measure
Measure the total concentration of cholesterol within the HDL particles. So now you've measured total cholesterol HDL cholesterol and triglyceride the Free World equation stems from an observation that kind of sort of on average sometimes V LDL cholesterol is approximately one-fifth the triglyceride concentration. So the freezer old 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 ldl-c. It'll give a number and unless it says direct you can assume they've done the Free World equation, which is I've seen that wrong more often than I'm seeing it right a good lab will do a direct a say they will actually measure.
DL concentration and they will give you in milligrams per deciliter. The total concentration of ldl-c
that is still an
inferior predictor of risk relative to a poby.
Yes. Okay. So that's the reason I wanted to mention that ldl-c is because as you mentioned many Labs do measure it in directly 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
Regenexx sizes of LDL such as the smaller dense particles and you know, like like how you view that like this the different particle sizes and the particle number and then of course a probie so like the whole
I mean, there's been a big evolution in a way we've practiced medicine in our practice with respect to this. So ten years ago. We were looking at LDL particle number which the both the Mesa population.
So the multi-ethnic study of atherosclerosis and the Framingham Offspring the 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 do this in sort of a like a cumulative insulin incidents graph. So on the x-axis you have time on the y-axis.
You have incidence of cardiovascular disease and you clot out everybody as a function of whether ldl-c was higher or lower than as a percentile then L DL P LD L P stands for the part number of particles. Ldl-c is the 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 so nuclear magnetic resonance is like how an MRI work. So it's applying a magnetic field. It's basically doing I mean this is being a little cheeky 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
From NMR to IM motility for LDL P because it was more accurate. But ultimately this is now about five years ago. We actually switch to a poby 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 LabCorp, for example and Boston Heart have different magnets and different algorithms for how they run their LDL P. So if you run an LDL pee 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
I get at one lab is the same as the apob I get another lab and it's standardized across all fronts, but there's a more important reason why I favor a poby over L DLP, and that is it encompasses the total atherogenic burden and you can get burned and fooled by patients who have very high vldl meaning they have a high burden of very low density lipoproteins. Even if their LDL burden is low, 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 ask for genic risk and you will miss that if you're looking at L DL P or ldl-c you will not miss that if you're looking at a
poby.
What about the fact that if you know small dense LDL, which has been shown to be more atherogenic. So April be does become so you mentioned that 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 the plasma, right but it becomes a 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.
The small dense LDL particles. It will be somewhat obscured as the LDL particle gets smaller in size and more dense. Therefore. It's not 200 a clear heart of a clear exactly. So what about in the case? And the reason I'm asking is because as you mentioned apob is on vldl ideal LDL, right, but there's different sizes of these LDL and and the larger more buoyant LDL is Bennett better than having a higher proportion of the smaller dense LDL,
right?
That's why they've been beat but apob captures that risk, right? So in other words, this is why is another reason why I think that a puppey is the great equalizer because once you have the apob concentration your accounting for the fact that clearance is going down. I mean the one way to think about this is any time you see an elevated apob it always comes back to something on the clearance side is not working. Now, there are really broadly speaking when I talk about this with patients I go through the four sword.
Pillars of what elevates a poby so it's it can be driven by cholesterol synthesis and 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 lifecycle of cholesterol is. But again, it's 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
e factors in to how a poby 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 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? So anyway, a long-winded way of saying the and this is another advantage of a poby 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 I go if you're just using LDL p as your risk, you might miss some of the
the elevated vldls if you're looking at ldl-c you'll clearly Miss some of the size issues that should be captured in LDL P. But again, I guess maybe what you're asking is if you have a low a poby but they're all small. Is that worse than having a low apob where they're all big and the answer is probably 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 level
Get the degree to which the ldls are cholesterol depleted 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 residence time of the LDL, which is driven by the clearance
rate. So let's talk about like the number so the LDL I started the apob number because like if most people go to a standard lab and
They measure their apob. There's a reference range and it says, you know, okay, if you're less than 80 milligrams per deciliter are excellent, then you're okay. Yeah, where does that number come from? And you know what?
Like is it has anyone measured apob levels across the lifespan do we know like is there a correlation with apob levels and the beginnings of atherosclerosis is somewhat done those studies, you know that
sort of thing. Yeah. So the reference ranges are purely population based distribution questions. So every lab will have a different way of doing this but a general, you know, sort of philosophy for labs is, you know, let you know.
48 and the lab we use and by the way, we completely ignore these reference ranges there 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 will say 80 be below 80 is wonderful. Well 80 just happens to be the 20th percentile of the population. It will say 80 to 100 is intermediate or 80 to 120. It says is intermediate risk and above 120 is very high risk. So in for the lab we use we know that 80 is the 20th percentile 120 is the
80th percentile or the 60th percentile? I can't remember so 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 as you may recall I write 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
Which is that once you understand the causality of a poby meaning once you understand that apob is not just associated with cardiovascular disease, but it's cause Ali linked to it meaning it causes a SUV D to get into this discussion about managing 10-year 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 analogy 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 to lung cancer smoked. So you hot 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 smoked and if you do smoke stop immediately.
Do we look at people who smoke and say well once your 10-year risk of lung cancer reaches this threshold we're going to tell you to stop smoking or once your pack your 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 a s CBD in the case of a poby.
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 after sclerosis begins at Birth when you do autopsies on people who are very young, in fact in the book include a photo of a guy who you know, a man, I forgot I think maybe 26 years old.
Who was a victim of a homicide or something so it completely unrelated death, but you look at the autopsy sections of his coronary arteries. I mean, he already had very Advanced atherosclerosis 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 a poby so to be able
Take that off the table sooner rather than later is going to has certainly has the potential to take a throw sclerosis off its pedestal at the top of the list of
killing. And so what do you mean take you obviously can't take it off the table completely right? We need it will be but
what well so so so so let's think about it. Yeah. So let's start with what we know apob rise.
Izes with age right? We don't really know there are probably a lot of little reasons. So there are you know, endocrine changes insulin resistance senescence that you know, might involve the decreased life of LDL receptors. There's no clear reason
actually what about so you're talking about Clarence versus synthesis and I remember our mutual friend Ron Krauss like I've had
How many conversations with him? I did my postdoc down the hall from his lab right? And I remember him telling me that you know apob your basically your liver is constantly producing it. You're making vldl just just churning it out. Right? No, but it's just going
going and we also make LDL de novo. By the way, right? Yeah. There's a de novo pathway plus the vldl tell the all
probably know but that you know, the thing is is that you know, he was saying well from an evolutionary perspective.
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 trade with triglycerides fatty acids. It's also transporting and this is where I was so intrigued inflammatory proteins. So cytokines C-reactive protein also are being transported through vldl. Now that was important pre-antibiotic spree everything that we do now to combat, you know, infectious disease and viruses and bacteria parasites.
Whatever, but before that time that vldl did serve that purpose to 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 takes time to make it and so the I was you know, I was thinking will like inflammation also does make it go up even further at the level of
Said I don't know exactly the clearance. You know how it's regulating clearance. But do you think the aging process is mostly affecting the clearance of it or
my intuition is yes. My intuition is that it's primarily impacted on the clearance level which is going to be again some facet of ldlr ldlr beating LDL receptor. So is it we are making less of them they are surviving less the proteins that you know, and that can basically done there are many ways to
Regulate that process but that that's my intuition is it's less a conformational change in the ldlr and more a number of them and or 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 Kay stolen on my podcast a few months ago and he proposed a really interesting idea which completely makes sense evolutionarily which you could argue sort of like we don't really need a bow be like, this is the other thing like most species don't have a bobe.
They don't require
LDL.
But how I mean
they have cholesterol, but they don't they don't they don't
require putting all these, you know, you can do it with HDL. You can transport everything they aged.
Yeah. Okay, they don't need the
LDL HDL was always going in reverse like it was bringing everything back to
know it's actually much more complicated. I mean and US LDL is doing the majority of what's called reverse cholesterol transport. So our CT which is kind of like the good movement of cholesterol you sort of think of the bad movement is taking cholesterol into the arteries the
Good movement is taking it back to the liver and US 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. But John made an interesting point, right which is that, you know, in sort of following up on what you said The evolutionary cost of making cholesterol is enormous. I mean, it's a very labor-intensive step right? I can't remember the number of atp's that are required to make them.
I killed cholesterol, but it's in the tens. Right? Like it 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 because again, this was an energy conserving system. Now this serves this 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 that, you know hundreds of thousands of years ago.
And so this is a bit of an unfortunate Vestige of our past it much in the way that a lot of the things that lead to insulin resistance are a Vestige two things that were once very valuable. I mean the things that allowed us to LEAP up out of the Swan with our swamp with big brains was are primarily our capacity to store excess energy in a way that even primates can't get it served us really well until 150 years ago, and I think the same is probably true of a cholesterol in a Toby so
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 explosion of steroidal.
Shoo, all of these things are done with lipoprotein levels that are incredibly low again what we call physiologic levels of LDL cholesterol in a poby are in 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 would 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 then some need for additional.
All LDL, we don't have it. The majority of what we need is actually, you know before the age of 20,
do you think 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 about the sclerosis if you have if you if you maintain a level
below. Yeah, so Peter Libby from the Brigham who's one of the authorities on this topic has argued and I reference him in my book that if you had an ape OB level below about 30 milligrams per deciliter 20 to 30 milligrams per deciliter. It wouldn't be possible to develop
atherosclerosis.
What about not dying from a source? Like what about like if it's the it's the major cause of death globally. Yep, 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 without a pharmacologic intervention. Yeah. Do you
think that you would would die of atherosclerosis 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 120 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-axis is a poby & you have a curve and you want to figure out what the area under that curve is and we want to minimize the area under that curve. So if you took six
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, ten years 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 individuals 60 milligrams per deciliter is about the fifth percentile at the
Alt population
level. So then that comes back to my question.
Sorry, one of the major attack
across the lifespan when like yeah. Wait, when do you start measuring this? Like people aren't measuring their apob in there, you know teenagers
one. Yeah. I mean I would argue we should be but I want to go back and say one other thing about your question, 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 cause Ali
April be is one insulin resistance is 1 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 a s CB D. So again, it's it's a difficult situation to imagine but it's certainly at least theoretically plausible. You have somebody who's a poby is at 60, but they have uncontrolled hypertension type 2.
beanies and they smoke
I mean you could certainly arrived at that situation pharmacological. You're probably not going to arrive at that situation naturally would I say that that person is free and clear? No, I wouldn't so we you know at the outside I mentioned how the you know, the downside of talking about a scpd. Is this the number one killer? I mean, it's in fact when you talk about it globally the gap between ascd 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.
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 a person is relatively healthy, you know their Community exerciser. They're not insulin as it. I do want to talk about hypertension insulin resistance. Yes, but okay healthy General is quote unquote healthy person right once to lower their apob.
And they want to try everything through diet through lifestyle and you mentioned there are some major lifestyle dietary factors that can increase a Polly. 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 mostly through the vldl triglyceride pathway. So we talked earlier about it how they're really two ways. We make LDL we make LDL directly. We been most of the LDL is made through vldl. So if you're exporting a lot
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 are stating in the first place. The LDL is can't 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 a poby 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, but one has very high triglycerides in one has very low triglycerides. The former is going to have a much higher a poby.
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 ship's 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 is is a
a key to keeping a poby in check and of course, there are other issues as well. So insulin and glucose by themselves, when elevated also create problems at the end of Celia level, which becomes another mechanism by which this is problematic. 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 for it's not fast. Yeah, we're fine and starchy carbohydrates.
Yep, so but that actually feeds really nicely into the next observation, which is what's the next dietary pattern that impacts a poby & that 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.
These relative to others for example a c16 might be potentially more so than a see a teen or c-19. But again What
feelings would you find a see
1600 I can see 16 would be more in I believe like a coconut oil or a palm oil or something like that. But also by the way, that way you would also see that Morrissey 16 like a palmitate would be more of a synthesis would be more of a saturated fat you see in response to insulin resistance. So it actually be a de novo saturated fat synthesis, so
um
Perhaps so I think that's a big part of it. I think cholesterol synthesis big part of it. I think I'm bigger part of it might be that excess saturated fat inhibits the sterile binding the sterol regulatory binding protein in the liver that results in fewer LDL receptors being made. So saturated fat, therefore has two things that it's doing that are driving up a poby and the susceptibility of this varies from different individuals.
So I was on a ketogenic diet for three years. I was not one of the people who seem 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 ldl-c or any of these metrics. Similarly. We have some patients who were on 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 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 ldl-c go through the roof. It's not problematic. 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 you're a pro be 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 with your you know, your ketogenic diet. 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 affect the quantity and composition of fat and the dietary choices that address insulin
sensitivity. So on the people that lets say the they're
Eating a higher saturated fat diet if they swap that out with monounsaturated fat or even polyunsaturated fat which some camps also like to demonize the kind of polyunsaturated. Right? But if you swap that out there, it will be
levels in our in our experience about half of the people who have this hyper response to saturated fat if you aiso calorically 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 know, you have to remember what problem you're solving. So 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 I like they sort of you know, they're like, okay while 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, and so for those people you just got to say dude likes.
Doing hat just like use olive oil on your salad and like let's be reasonable and then it fixes everything but for other people, you know, it's it just can't be addressed and 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 my view clinically is that
It makes very little sense 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 actually become insulin resistant a lot of them because they're really over consuming a lot of poor quality carbs and their suffering other consequences of really low fat intake now again, this doesn't mean that a low-fat 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 tried to make two 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 antibiotics 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.
Rick tools most of medicine doesn't really have great pharmacology. If you stop to think about it, like we don't have great. There's nothing pharmacologically that's adding Brilliance to our Alzheimer's prevention strategy for our cancer prevention strategy. I mean you 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 right diet that's going to work for you in terms of your ability to be compliant with it your ability to be with an 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 low-fat 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 that we 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 have genetically low apob and if so, what's their cardiovascular mortality? They're all cause mortality.
Yeah, so there are there are people so it turns out a poby & ldl-c are highly genetic which is what has allowed us to do the mendelian 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 a cvd 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 it becomes quite helpful. You have all the clinical trial data, which I would divided into primary and secondary prevention data, and then you have the mendelian randomization data, which again for listeners is basically any time 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 randomize that across people and you can look at outcomes of Interest. So in the case of ldl-c 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 life long exposure to a poby or LDL produces lower abs cvd risk over a lifetime. So
Um using this we can say there are people at really low and high extremes with the High Extreme. You have the people who have what's called familial hypercholesterolemia, which is 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 milligrams per deciliter, and there's a couple of other criteria, but just to give you
You a sense of How High the LDL needs to be to meet that criteria at the other end of the spectrum. We have these people with very very low ldl-c or a poby & the most interesting group of these are the people who are folks that have a hypo functioning Gene for pcsk9. So Helen Hobbs made this discovery in probably the early 2000s my vague recollection. I remember reading this paper when it came out.
Was a really mind-boggling paper call it like somewhere 2004 2005 2006 somewhere in that neighborhood which is hey there are these people walking around with?
Ldl-c 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 and these people were found to have a mutation in their pcsk9 Gene that rendered a hypo functioning protein and pcsk9 is a protein that degrades LDL receptors. Now another subset of these people their mirror opposites were
Over several years earlier which had a hyper functioning pcsk9 gene or hyper Funk Gene that produces hyper functioning protein and these people had sky high LDL cholesterol. They were a subset of the familial hypercholesterolemia syndromes and these people weren't and what was interesting to note and is that they didn't develop cardiovascular disease, so I can't tell you what their life expectancy is because I haven't I haven't looked at those data but
But what I did confirm is they have no increase in the incidents of any other disease. So in other words, they're absent a SCV D but they don't make up for it with more cancer and more neurodegenerative disease or more diabetes.
That's that's interesting for a couple of reasons one you see on Twitter a lot. You know, the very very, you know, just the hyper-focused very low carb Community. That's like, you know, they share studies about oh local
All 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. Well,
yeah, the problem with those studies is there I'll only address this one's because I've done so much addressing this that I realized you can only way so much time preaching to an audience that actually has no interest in understanding the truth. 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 your sample.
In 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 a s cvd 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 kind of the problem with that stuff. I'll give you an example. There is a clear Association in the epidemiology. It doesn't come up off.
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 mendelian 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. The other interesting point was with the actual Gene that you were mentioning the pcsk9. Right? So when you were talking about we have pharmacological interventions that do very nicely lower. It will be one of
Is pcsk9 Inhibitors exactly came right out of Helen Hobbs observation.
So I wanted lets you know, let's touch on the the the pharmacological treatments but also the PCS kind of canine Inhibitors, they're not necessarily available to everyone at the start right out the gate and 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 at it, you know, and you're changing you know it.
The nucleotide to essentially make a PCS. Can I do for the people that you're talking about walking around right with no a SCV? Yeah, so,
okay. So let's maybe just talk broadly about what the different pharmacologic strategies are. Right. So the very first drug that was ever used to lower lipids was a was a drug called God. I can I'm always blank on the name of this like try pairing all so this was done in the 1930s.
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 in 96. 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 the step that we use to make cholesterol. So we make cholesterol using two Pathways, but one of the pathways results
in a molecule called does master all 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 to time because monster all levels went sky-high and it lowered cholesterol. So on the basis of that this drug was approved and back at the time. That was only thing you were monitoring was total cholesterol, but it was found that the patients on this drug, even though they had lower cholesterol had a higher incidence of heart attacks.
The drug was ultimately pulled in the 1960s. We now know today that was almost assuredly the case that the Des moscar all 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 sequestrants. 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. So just think path 1 synthesis of cholesterol.
If you let synthesized 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 ahold 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 enterocytes which are the gut cells that line your
They have a couple of Transporters on them. So one of the Transporters on them, it's called a niemann-pick see one like one transporter. It absorbs all of the sterols and this is I use the word sterile very carefully to distinguish it here from just cholesterol. This is Zoo sterile and plant sterols, which is or an animal sterile, which is called cholesterol. It absorbs that all there are basically regulatory steps inside the cell the determine how much of that should be kept and how much should be
Greeted 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 uh nasarah fide cholesterol. It's easy to get in and out of the body esterified cholesterol can't be absorbed and most of the cholesterol we eat is esterified. That's why we just poop it out. So bile acid sequestrants which were the first version of drugs the second version I guess.
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 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.
Aunt in basically the you know pharmacologic tool that became valuable against as CBD now the first second and third generation statins 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 and each of them, you know offers some strengths and advantages over others and they're not a benign class of drug. So to be clear they're ineffective class of drug. They're very,
Effective at lowering 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 delivers it I got to get more cholesterol in here. And what does it do? It puts 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
Oh well about seven percent of people develop muscle aches on Statin. So it's 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 the other big side effect. The one that I probably think about the most is insulin resistance. So a very small set of subsets of people about 2.4 percent of people put on a
Might go on to develop type 2 diabetes as a result of it now, I think.
Any doctor who lets it patient get to the point where they get type 2 diabetes because of their status hasn'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 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 in these other markers does a patient where a CGM one of the reasons. We like see GM's on patients when we put them on statins is 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 deciliter, 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 change in our 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 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 is a term
I interrupt for a second ask you about statins. Yeah course because I have a lot I have some questions about them.
And I will never forget this conversation that again I had with our mutual friend Ron Krauss because you work down the hall. I work down the hall from him and I collaborate with some of his postdocs and you know, they would come over and show me data and we were talk because you know, I had a lot of experience in assessing mitochondrial function and mitochondrial biology during graduate school. And I remember saying this to Ron I'm like, you know, so
so statins are affecting the HM G Co a pathway that you mentioned the cholesterol synthesis with which also is important for the synthesis of ubiquinol, right? This is an important or you co Q 10 has should probably call it. This is important for mitochondrial function mean it's necessary for mitochondrial function for transferring electron electrons across the electron transport chain, which is essentially a coupling the oxygen we breathe with the food that we eat to make energy and I remember saying oh so statins have a
Defect 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, reduced form the big one. All right measuring mitochondrial function in terms of VO2 max something. Yeah, so
it's a great question actually and some
Thing I have thought a lot about so the the literature has nothing to offer here, unfortunately, 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 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
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 this requires a little bit of explanation, but it's very important and it I think it's I'm glad you brought this up. So everybody understands that the mitochondria do if they're if they're you know listeners have 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 our biomarkers 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 an 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 phosphorylation. So, how do we how can 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
Mm and 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
Mitochondria, and it has the less efficient but quicker way to get ATP which is converting lactate a pardon me pyruvate into lactate. So this is the glycolytic pathway versus the oxidative phosphorylation pathway. The longer a cell can stay in that mitochondrial space the better it is it makes way more ATP and it accumulates less lactate and hydrogen ion and the more lactate and hydrogen ion you
Emulate 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 add on a treadmill or whatever vehicle you're using while keeping lactate below about to mmol?
To mmol is about the threshold Beyond which you are now shifting away from the maximum capacity of the mitochondria to 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 a complex one of the mitochondria we
Idiot Lee 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 lactate of too 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 gyro protective 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, but I don't think metformin is a great drug for someone like you or someone like me.
We don't see this with statins.
So if it's happening, it's
dose-dependent
or not. 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. Yeah, so 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 really small. Now, you mentioned ubiquinol or co Q 10 and there are two states of it, ubiquinone 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 the muscle soreness issue. So they mostly done this as a way to ask the question. Can you reduce the insolence the the incidents 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 that said
Ed 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 don't think there's any harm in taking it. I really don't think there is and if there's a chance of benefit than I would say, let's take it. But again, 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 the the using the zone to you know, lactate threshold training to kind of measure mitochondrial function. So buying the lactate M. Nova diagnostic noted by a medical or something like that. Like a yellow purple
one. I got it.
/ you're like recommendation, but for people listening if they want to get one, but also knowing like how you know, because there's when you when you go to like any sort,
If you were go talk to an exercise physiologist and you say lactate threshold like they kind of
know the and they're going to push you up there good lactate threshold is a different
number, right? So this is like lower level.
This is below your like this is
yeah, this is lower. So how do people know like like, let's say they have a Peloton at home. Okay, and they get on their Peloton and they want to do a Zone to test. Okay, do you can you somehow use a you know percent max rate heart rate. Sorry max heart rate like proxy.
To kind of know
lik 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 a never never ending quest to just have as much data as possible to understand. When is lactate the best predictor. When was our PE the best predictor when was
Rate the best predictor when was absolute wattage the best predictor like 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 M. 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 saying that
Foreman or a Statin that's what I want to do, but let's put that aside for a moment and answer 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 rate of perceived exertion. I think that will almost never let you down. 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
Biddies, they're resting lactate may already be at to 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.
Rpe rate of perceived exertion. We give people the test which is the talk test. So when you are 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 two, if it's real if you can't speak in a full sentence, you're not in zone 2 anymore. You're you're north of Zone to 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 Peloton 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 answer 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 film a Fatone uses a test that I think is a pretty good starting place, which is 1
B minus your age now the fitter you are the less relevant that becomes so I'm 51. So that would put me at 1:30, but I can tell you my zone 2 is above 130. So if your fitter you may add 5 to 10 to that, I might I use another app that checks my HRV every single morning and it predicts my zone to as a result of my HRV and so every day
Say 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's a what happens? It's called Morpheus. Yeah, so I have no affiliation with or anything like that. So so basically every so this morning I got up my HRV was
I don't even remember 78 Ms. Slept seven 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 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 Lactaid is.
What that will generally put me to lactate about 1.9 and then on top of that I'm paying attention to the wattage. So I kind of know where to be but again for somebody just starting out rpe 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 percent of that
number.
Great recommendations. If so, if a person is specifically trying to do this functional mitochondrial test, how long should they be in that zone to before they can measure their lactate? We
like to see people there for 30 to 45 minutes. Okay, where we do it? Yeah, so we're true true steady state
awesome. So I kind of want to the other going back circling back to the statins. And 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 you know cross the blood-brain barrier get into the brain inhibit, you know ATM Co and the Brain particularly at higher doses, but generally speaking.
What can what questions should I be asking myself to convince myself that it's not going to put me at a higher risk for both of the neurodegenerative disease that I'm terrified about one Alzheimer's disease. I have a genetic it's family history genetic risk factor and Parkinson's disease family history. Both of those diseases have been associated with Statin use they've also been in the literature as you know, is you know, you can find what you want. Right? So do you have any you know,
Yeah, I did. I did a recent AMA on this 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, but I did an entire am a on this topic because it is so important and I think it's as you said it's so confusing. So I was actually surprised to learn this. I'm surprised to learn that there has never should have been surprised but forgot was here's what it is. There is never been a study.
He done that has looked at the use of statins 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 1516 that have used statins have had a primary outcome of a s cvd 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 incidence of dementia and and the incidence of Alzheimer's disease. So that includes vascular
dementia keep running. Yeah. I mean, I that sort of makes more sense. Yeah Parkinson's disease. Have you seen have you looked at the literature on that?
So Parkinson's is a little bit more confusing because the literature is way more sparse, but I do want to go back.
Talk about Alzheimer's disease because I think there's an important caveat to everything. I just said what I basically do the other point. I want to make around this actually surprised me there was no difference between hydrophobic and hydrophilic statins
with respect to the to these outcomes.
No difference whatsoever. So counterintuitive but no difference whatsoever. So even though again you might think we'll gosh, you know a Statin that gets in the brain should
I'd 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 increased diabetes risk that you're talking about
or absolutely good question. 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 atorvastatin but that might also be because a tourist and is the most widely used like I don't we we basically first of all there's only four statins that
Anchor even worth prescribing these days maybe only three and I treat them all equally in terms of risk. In other words. I would assume any time you put somebody on a Statin you should be looking for any of the side effects and I don't particularly like because again at the you might say the population level it's different but at the individual level who cares you it's either one or zero, you're going to get it or you're not what stands are those with the ones that we would prescribe would be reserved a Statin or Crestor Crestor atorvastatin or Lipitor. Pattabhi Statin level 0 and sometimes we use pravastatin or private.
Call but pretty rarely but so usually those are big for now. Here's what I would say and this is something that we spend an awful lot of time looking at in our practice and actually just last week Tom Dayspring gave us an internal presentation. That was so incredible. It was months in the making looking at the
Russian ship between Statin use and does master all levels and dementia risk. So you may recall a moment ago. I mentioned as master all so Des master all is well. Let's back up. Remember 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 does master all to cholesterol. So Des master all levels are actually a decent proxy.
percent brain cholesterol synthesis
Lilith Oster all which is the penultimate molecule in the other pathway is more of a proxy for peripheral cholesterol synthesis
at 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 does master all and clay and with Oscar all in every patient with every blood draw. Unfortunately. This is not standard of care. Most Labs can't measure this. Boston Heart. Does this we that's why we use Boston Heart.
There are enough data suggesting that if Des master all 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 in apoe4 Gene and or 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 that was kind of an internal presentation fact, I could share with you the recording Tom made because we recorded the internal meeting because it was so valuable. But basically the cutoff we use is point eight. So if does master all falls below point eight milligrams per deciliter, we think the risk of dementia
Shh is sufficiently high enough that we would abort the use of the
Statin very good information. And and you think there is a correlation with apoe status on that.
No one has done that study yet
in your in your
clinical put in our clinical practice. We just decided like why would we take the risk? But yes, no one has done the study to show.
Our does master all levels lower in apoe4 individuals that's actually a very testable hypothesis and it makes a lot of sense because we know apoe is heavily involved in cholesterol activity in the brain. And so it wouldn't be surprising to me. If you know, if you put people into three buckets zero alleles one allele or to Lili four alleles and then just look at does master all levels. Like that would be a very easy mindless study.
Just a survey like just a quick. Is there a correlation yes or no? So that's one thing I'd love to know the answer to but even absent that knowledge our view is there's there's simply no reason to take the risk, you know earlier I said it makes no sense to about to go on some crazy obscured 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.
sense to get all to take unnecessary risks with statins in a higher risk individual when we have these other tools we have as a we talked about our we will talk about is that a my pcsk9 Inhibitors been pandemic acid. These are unbelievable tools that have no bearing on brain cholesterol synthesis,
but Peter aren't people that have an APB for a lil more likely to be prescribed statins based on their their LDL particle number by their physician because of physician doesn't look at their sure none of
This isn't personalized. It's not medicine three points, right?
So, yep. No, it's very frustrating and it's also frustrating that of those three drugs that all the are that are an alternative to statins two of them are still very expensive.
Okay. So the three drugs I know the pcsk9 inhibitor. Yep,
and highly effective in insanely safe zero side effects cheaper than when they came out so they were approved in 2015. We
have long-term data with the match.
People walking around with a natural mutation right? Like
just amazing. Yeah. Exactly. We have the natural experiment. We have all of the data from these drugs and 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, but they're expensive right there. It's a 500 dollar a month drug in the United States. It's cheaper outside of this country. So everything's better out of the u.s. When it comes to drug pricing, but in the u.s. you're talking about 500 bucks a month for that drug if it's not a cut if it's not covered by your insurance company.
Right 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 who doesn't who's not willing to prescribe a pcsk9 inhibitor just is a fool. So it's just a question of the cost because unfortunately most insurance companies will not cover it unless you meet certain criteria such as having familial hypercholesterolemia or having already had a cardiac event like a heart attack and not being able to tolerate a Statin
What about myopathy? Like if you have
muscle? Yes significant myopathy on multiple statins, but you'd also have to be at high enough a risk to justify it. So insurance companies are going to go out of their way to not pay for this then you have is Adam I've now is that it might be relatively inexpensive. It's just not as potent. So is that a my 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
And by blocking that the body is absorbing way less of its own cholesterol and the liver senses that in the liver says, hey, I gotta get more cholesterol puts more LDL receptors on pulls out of circulation. It's not as potent. And as a mono therapy, the only times we see really head-over-heels responses are in patients who have defective atp-binding cassette speak in their gut and we measure that by looking at phytosterols levels.
So we measure two things one is called site Oscar. All one is called competitor. All those are phytosterols. So these are cholesterol we don't make its Zoo sterile are part of me. It's phytosterol Natsu sterile. And so when we measure those levels, we know that it speaks to how much plant sterols 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 is that a my big it's like a Blockbuster in those
people. Wow it is that a common, you know single nucleotide polymorphism.
You know, it's it depends how how extreme it is. So 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 because phytosterols are actually more atherogenic than cholesterol.
And that's also like Boston Heartwood measured all these phytosterols. Okay, they're more atherogenic than
cholesterol. Yeah more prone to oxidation more inflammatory.
Are they being carried in lipoproteins? They're so so profit. Is there more
oxidized or more oxidizable? And this is by the
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 phytosterols to lower their cholesterol and they'd it does so if you ingest a ton of phytosterols, you will out-compete cholesterol at that enter a site and your body will regulate and you'll end up net reabsorbing less total cholesterol 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 insert of an example of that does Monster all Point earlier where you can lower cholesterol, but if you're really raising does master all too much. It can be more atherogenic than collector on the first place. So does master all has shown up twice today at showed up in a good sense in a bad sense. So too much of it if you're using a drug that blocks the enzyme.
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 22 little cholesterol synthesis in the brain and that can be a whole problem in and of itself the final drugs we can just wrap this up because I'm sure the listeners are tired of hearing about this stuff is a drug called Benedict acid. That is a prodrug those very elegant drug. It's taken as a pill but it's ineffective until it's metabolized by the liver and in the liver.
It then inhibits 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 Bevin doke 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 2 diabetes.
Nothing nothing nothing. It's just it's only acting in the liver.
Well, that sounds
same problem is pcsk9 inhibitor. It's a $500 a month drug. Okay. Yeah. So again we
Have every look honestly at this point like if money were on a we're no issue. You'd probably just beyond pcsk9 Inhibitors. Is that a my and and been Potomac
asset? I mean eventually we'll get there,
right? Yeah. I'll just have to come down in price
for people that want to like more clear picture of the plaque accumulation in their in their arteries in their vascular system 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
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. You know, I think there's a principle in medicine than most doctors try to adhere to which is don't order a test unless there's a chance the test will change your management.
Then 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 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 what Grande you're 35 years old, you're a poby 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 are in their 90's who have never had a cardiac event. So you don't have some genetic protection of cardiovascular disease. Do I need a CT angiogram in you to convince me to do anything because the truth of it is at 35 your CT angiogram 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 know 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 apob is through the roof.
But I noticed like all their relatives live to be 100 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 CT a if the CTA is normal which by some miracle it could be. 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 2 by 2, which is age versus finding positive.
- I think CT angiograms are mostly helpful when they have a positive finding in a young person or a negative finding an old person. That's where it can really cause you to act differently outside of those findings IE positive findings in old people are to be expected - findings in young people are to be expected. I think you should just track the biomarkers of interest and go off that
risk. Okay, I mean like is a 45 year old
considered I would still put that in a young category as you still think for a woman.
You think that CT angiogram would still kind of look maybe
good it should and again I would only think about it through the lens of if the patient is hesitant like so we had a new patient, you know that started a couple of weeks ago. He'd never had one of these tests before but he had a lot of risk factors right elevated apob elevated LP little a I mean to big risk factors and but insanely healthy individual like very very healthy.
Also on the surface like nobody thought anything of this this person.
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 ape OB of 60, which is still aggressive by most people's standards by our standards that sort of middle of the road aggression if the CTA comes back and there's a problem meaning you have calcification and soft black. We're going to treat you to 30 or 40. So they're 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 before we you know kind of shift gears.
To some other things I want to ask you about.
Have you looked like I know I know you've mentioned it's been a mini or since I've heard you talk about barbering 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 clearing away existing plaque on lowering, you know, LDL particle number possibly total LDL cholesterol level, but I was surprised what did you find? So there's a systematic review
It was 20 22, I believe and these are all like we need this is the sparse data right systematic review of what the existing literature was which isn't a huge body of evidence. But 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 bring it.
Burbling alone was lowering the LDL cholesterol and I can't remember if it was particle number but it was
elements interesting berberine is also a mitochondrial toxin. Really? Yeah berberine is an analog of
metformin.
So it's a complex one Inhibitors
it yeah.
Wow. I didn't know that it was like it was to me it looking really beneficial where it was.
Like I'm not saying that wouldn't be I'm just saying sort of pointing out. Yeah, it's interesting their
literature showing that it or is it like an in vitro kind of thing where it's like remember it's been so long
since I've looked at berberine but but berberine is kind of a poor man's metformin. Okay? Well it was
and that's the way I thought about 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.
Yeah, and that's kind of where you been first heard a berberine with you. And I remember she was like going for a run. It was when I lived in Oakland and then I was like bourbon. What's that? And I remember you talking about in the context of I think metabolic Health. Yep. Yep, and it should low-income. There's nothing good in here. Yeah, but this data on the lipids was very interesting and I like
and what was the matter? Yeah. What's the magnitude of
effect? I don't like you your document. It's in that document. It's linked. I do the studies the meta-analysis. You can look at it because I don't remember everything and
but what I do know, is it also lowered the side effects of Statin myopathy also was one in particular it lowered the dose effective dose of statins that was needed to, you know, lower the LDL interest. Let's draw very interesting. Right? And so I was like, you know, I actually ordered some berberine like maybe I should test this and see, you
know, it's their companies like Thorn
and I did I ordered Thorne. Yeah. Yeah, which I have no affiliation with I just trust their yeah. So anyways, I wanted to bring that up because you know,
that again I'd heard about bringing from you like years ago, but speaking of metabolic health and we are you kind of talked about this, you know earlier with continuous glucose monitoring and you know measuring measuring 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 hb1 A1C like what should those numbers be but also what is glucose
ezel and why should people be paying attention to that and can see GM's can they use to GM's to coat it sort of measure
that yeah, you know glucose disposal is is 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 one way or another because it's it leaves you endlessly 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 it is. It is humbling. So let's just put some of these numbers in perspective. So most people who have had a blood test would recognize that a fasting blood glucose of 100 milligrams per deciliter is sort of right on the
But 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 5 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 paltry G twenty 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 do.
Ending 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 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 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 5 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 subsystem of our liver and our muscles. So if the liver is the thing that is responsible for the Doling 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 Bol which
Like the size of my head, but just a normal sized Bowl you're easily getting 60 grams of glucose.
So you eat 60 70 80 grams of glucose will remember what I just said a moment ago. Like if your blood level goes from 5 to 10 grams, 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 8 G. So how do you get that other 60 grams 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 majority of it is an insulin dependent way. So insulin is released by the pancreas when glucose levels are sense to the pancreas sits very high in the GI tract. So very early in the absorption of glucose as it exits the stomach into the duodenum does
The endocrine system vis-à-vis the beta cells sense this increase in glucose. The beta cells release insulin the insulin results in a signal that goes to the muscle. So the insulin hits an insulin receptor the insulin receptor triggers a kinase 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.
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
active exercising itself can produce glucose transport across 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 a 40 teaspoons of glucose in your blood stream, 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.
With ketoacidosis, but the chronic toxicity of elevated levels of glucose is significant and that's where the difference between having four five six seven eight 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 is involved in the The process by which proteins become sticky and so as the proteins in our blood get glycosylated and gets stickier one their function is lower. But to they also tend to obscure the narrowest part of our
Our system so are the tiniest tiniest tiniest capillaries become more occluded and therefore it's harder to deliver oxygen to those tissues. So the the canary in the coal mine Believe It or Not of micro vascular damage is within the eyes. So a good ophthalmologist is generally the first doctor to tell when a person is on the road to type 2 diabetes because by looking at the retina and by looking at the capillaries in the back of the eye.
II 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 the 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 micro vasculature 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 cardiac carotid arteries more susceptible to the elevated levels of insulin and both of these things go hand in hand because of course as is obvious, I guess two 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's
It's 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 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
Ambiguous 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 you glycemic insulin clamp, which is a an experiment where you you run IV glucose and IV insulin to people and you basically run a fixed amount of insulin to somebody and then determine how much glucose you need to put in to keep their glucose level fixed. That's called the you glycemic keep glucose Flex. That's a that's the gold standard for measuring.
Insensitivity so you do that test on somebody and then for a week sleep deprived them for you know down to five or six four hours a night call it for would be very dramatic 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 different so we don't know exactly why that's happening but it's a very repeatable observation. So sleep disruptions a this energy imbalance.
A this hormonal changes impair this right. So as we age both the reduction and estrogen and testosterone a this hypercortisolism Mia a this and then of course in activity is the is the is the greatest thing that drives this
I definitely didn't do the exact experiment you're describing what I've mentioned it to you before I had my my CGM and when I was a new mother, it was 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 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 only an awful time to wear a CG,
but I did find that my going to my hit class even though I was like just dog and tired like with the last thing I wanted to do ya really did normalize it. So is there a postprandial level that like, you know, let's say someone is not trying to do a low-carb diet.
You're
not trying to like because that's a whole other area. Right? But like they just you know, they're eating maybe a more omnivore diet and more paleo assure Mediterranean dish, 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 is hard to
say. I mean, here's what we here's what I think we know more clearly. 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 1 data to tell you that because the studies never been done, but I can tell you that by proxy based on hemoglobin A1c data. 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 percent 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 percent meaning you just trigger the threshold for type 2 diabetes your hemoglobin. Your CGM would say your average blood glucose is 140 milligrams per deciliter. Nobody disputes that that's harmful. The question is is it better to be at one-thirty one-twenty? One-ten 100 like at what point does
is it too low and
What the hemoglobin A1c data would suggest is being at five percent which is about an average of 100 is better than being at 5.5 percent, which is an average in the one teens. Both of those are normal by our current definitions. Neither of those would be pre-diabetic even so 5 + 5 .5 are both considered completely normal levels, but the all-cause mortality data.
Or the data on all-cause mortality suggest a better outcome. If you're at five rather than five point five. Okay that suggests to me by proxy at least that an average blood glucose have 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.
Young 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 and the threshold you could say, maybe make it 150 or 140 milligrams 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. Bye.
GM but one arrived at it with you know levels like that and one arrived that it would 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
These are 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 will get
with a meal.
That goes right back down. I'll be good. Yeah, so what do you think about by the way? This is all great info. What do you think about so metabolic flexibility being be the capability to shift between using glucose as a substrate and using fatty acids. I mean, this is
something this is the zone to thing, right? This is exactly why we train that zone to 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 phosphorylation and glucose for that
matter. But if you were to do let's say you're doing more a high-intensity interval training, which I do a lot of that increases the capacity because
It's such a potent stimulator mitochondrial biogenesis. So maybe 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 all-out Sprint but like, you know, I do shift into using
glucose. Well Wars and 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 high-level endurance athletes namely cross-country skiers distance Runners and cyclists. So what do we know about this group? We know that they have the highest VO2 max has 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.
And the other thing I like about cycling compared to skiing or running is we can use wattage because we can put people on power M and we can get the numbers a world-class cyclist is able to put out for watts per kilogram of power while keeping lactate below to mmol.
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 your 175 pounds, that means you're able to put out 332 340 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 to mmol.
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 80/20 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 vo2max and to
Just the greatest degree of metabolic flexibility you think of it as a pyramid where the base of the pyramid is your Zone to efficiency and the peak of the pyramid is your VO2 max and the area total area of the pyramid is your cardio respiratory engine. So you want not a narrow base with a high peak? Not a wide base with a short Peak. You want a big bass big peak and the way to get that is about 80/20 if you try to do too much high end.
Density you simply don't have the aerobic 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 breath and the the peak effectively. So what we basically do with our patients is we start from a standpoint of time. How much time are you willing to exercise?
Days a week. I'm 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 will put half of that into strength and stability half of that into cardio of the cardio. It's 80/20 80% of that will be zoned to 20% of that will be vo2max and VO2 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. It's a it's a good way to get there and and we know like even just looking at the Tabata studies right tomatoes. Neither one or the other right like a 20 on 10 off times eight rounds is neither a pure Zone to know. It's way too hard even for vo2max actually because vo2max sweet spot is 3 to 8 minutes with 121 rest to recovery so three on three off three-on-three off.
That's a lower intensity than most people are doing in a hit class most people in hit class or doing shorter intervals and pushing much harder.
I just had a talk with them with Marty Kabbalah and I asked him a question, you know, and he was like Rhonda you had to do more three because I wanted to I was like, I want to do VO2 max training like this is what I do. I do a lot of the you know, do you do 16 rounds and I'll do 20 seconds on 10 seconds off, right but my 10 seconds off or I mean I my height my heart rates still pretty hot like Ida so he's like you got to do.
You like three minutes at least one, you know, and so I've shifted my training now to doing and it's absolutely true. I'm not going as hard. I can't yeah, it's you just can't go as hard. And
so and it's an art form. You'll figure it out because you'll realize and you'll have to you know, you'll be like I went to hard and I was dead at a minute and a half and I was like loafing the last minute and a half or I held back too much and by the end of the three minutes it was like actually could have gone.
Her and that's okay. Like you'll sort of figure out what that sweet spot is, but that that 3 to 8 minutes is the is the optimal zone for for generating VO2 max
power, right? Yeah, that's so so metabolic flexibility obviously, hugely important vo2max hugely important, but with respect to I would say like eating diet-wise like you hear a lot of people like low-carb Community ketogenic
Metabolic flexibility if they're doing does that like affect metabolic flexibility like if you're doing yeah,
it's tough to there. I think there may be a bit of a confounder there. So
I used to think so, I'm not sure anymore truthfully. So the obvious confounder there is if you're on a completely carbohydrate restricted diet your respiratory quotient. So on a from a functional standpoint one of the ways, we how do we measure what your oxidizing so when a person does a see Pat test a functional test like a VO2 max test we're measuring 02 consumed and
Go to produced. So if any have you done a VO2 max test yet? I haven't. Okay, so you can you
just go to any doctor or
do doctors don't do it? No, you typically go to well when I did when I live in San Diego I used to do them with my coach. So he would do them in Austin. We send people to UT like we just send people to the university and get them done. So very inexpensive test like it like a hundred bucks or something like that, right? So they're going to have you do it in one of two ways, which
It is a bike or a treadmill and I always tell patients do it in the way you train because there's a there's a you don't take a cyclist and make them do a running tests or vice versa. So it sounds like you're doing most your work on a pallet on so you would do it on a bike because you're gonna 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. 1402 14 CO2. This is
Rotten butter this whole device if those sensors aren't calibrated correctly or they don't work. The test is meaningless and like one out of ten times they fail so you got to make sure whenever you're doing this test the pert the tech who does it has calibrated this thing and knows what to look for if the calibration fails during the test. We had a patient do one recently the test fail so you're going to be put on a bike and it's going to be an ERG which means unlike the Peloton where you set the resistance and how like, let's say you have the resistance
It's at 50. Well that doesn't determine the wattage by itself how fast you pedal also determines the water that's different here here the computer is telling the bike how many watts to put out. So the heart the faster you pedal the less the resistance will be okay. Okay, but it's fixed wattage. So they might say look, we're going to start you out at 50 Watts. Nice little warm-up. We're going to have you spend, you know, five minutes here and then like three every three minutes we're going to go up, you know, 25 watts or something like that it did and there.
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 your in 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 your training keep that in mind, these are all the things that you don't want to fail the test because you didn't know the test, right? You know what I mean? Let the physiology be the place you fail. So make sure
Sure, when you're riding that Peloton you're in that you're really comfortable and that 80 to 100 zone of RPM. And and so what is the tech looking for so the tech is looking at a bunch of data. So what they're looking for is VO2 and vco2. Those are the things that are being measured. So there they know your heart rate at every moment in time. They know how many watts your pet you're generating because there you're there you're generating by definition everything they're sending you and then they're measuring VO2. So
Elation rate of oxygen and vco2 ventilation rate of CO2. They also at every moment in time see the ratio of vco2 to VO2 that's called respiratory quotient or RQ. It's also known as rer that ratio in any moment in time tells you how much fat your oxidizing versus how much glucose
when that ratio is 0.7. You are 100% fat oxidizing when that ratio is .85. It's about 50/50 when that ratio is 1 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 test 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 what I would have Excel plot for me is on the x-axis. I would have wattage because I cared more by wattage than by heart rate. So you have either wattage or heart rate on the x-axis.
This and on the y-axis. I'd have a double y axis and the y axis 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 start. So it usually has an early peek 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 anaerobic threshold, but that's where your respiratory quotient is equal. And 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 and 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 plot their VO2 max. We plot their Zone 2 and we plot fat oxidation.
Shannon and not surprisingly 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 world-class Tour de 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
Do this on somebody who is heavily carbohydrate restricted, you will get an artifact of the test because they're resting our queue 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 tests like in the days later
BO2 Max won't
be
Doesn't affect their VO2 max. No because the VO2 max is literally taking the peak VO2 that they achieve and dividing it by their weight in
kilos. What if you go to Max do you aim for and if you can recall I know that Jama 2018 paper, which was probably the one of the most convincing studies that VO2 max is like one of the best metrics of Health and
Longevity and I wasn't even bigger paper that came out that Jama paper had
120,000 subjects in it. There was a JCC paper that came out a year ago that had almost a million subjects in it and it had the exact same
findings. Do you know so the findings if I recall
was like both of them are in the book? I think I have I have figures from both them in the in the air and
you have the numbers in there. Okay, and that so that was like the top I just remember was like the top percentile. I mean they had like 80%
lower the taught ya if you compared the top the difference in Risk between
In the bottom 25% I love vo2max to the top two and a half percent had a hazard ratio of five meaning it's four time four hundred times greater all-cause mortality. If you're in the bottom 25 percent versus the top two percent.
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 40. I'll be
45. Okay, so you're right in the middle of the 40 to 50, I would guess but the table is in my book. So kind of everywhere that I would guess that it's about. It's in the high 40s.
Okay. Yeah, so roughly probably like 46 47 48 mg plus re ml per minute
per kg to do but
this is such great information. I have other like there's I want to get into some cancer.
Hormones, especially because I'm going to be 45 by the very personal personal interest in this but you know, we're talking about metabolic Health. Obviously, you've talked endlessly about the importance of metabolic health for cancer certainly, you know cancer prevention but looking at like so the biggest risk factor for cancer is H, right?
Yes, if you unless you include my yeah, if you don't invite her on a viable risk, so yeah we
And we talked about modifiable risk. Okay, yes age is the greatest risk for all diseases including cardiovascular disease
the biggest modifiable risk factor. So let's talk about modifiable risk factors of obesity being smoking is number one
smoking. Okay. Don't know that
one. I've cooked of course smoking. I always it's easy to forget. Yeah, you should not be smoking but it is easy to forget. It's like, oh, yeah, people do still smoke. It's hard to Fathom that but addiction is addiction. So smoking is the number
one king is still the number one.
Modified will risk. What's after that would be so
base obesity. So why do you think obesity what if you were to speculate? Why do you think yeah, I think I
feel pretty strongly about this. I mean, 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 out of paucity. 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. 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 excess fat that spills over from that into these other areas, where fat
At 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 run. Our organs enters the muscle Itself, by the way, that's how it directly contributes to insulin resistance when it accumulates in the liver accumulates around the heart within the pancreas itself where it
The double role of not just creating an inflammatory environment but also reducing the amount of insulin that the beta cell can release and also around the kidneys. So those are the main places where even a small amount of fat IE. If just 10% of your total body fat were in those places you would be at enormous risk for cardio metabolic
disease.
Yeah, I remember seeing 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's some specific inflammatory cytokines that were being generated or you know associated with I guess what I would say with the visceral fat and the cancer incidence which again it's like the inflammatory by our environment like you're talking about so so the metabolic
Health being important we talked about you know, the best bike 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 distress, right hypercortisolism, Mia will also contribute to this
significantly right which of course even doing things like exercise and getting enough sleep help help balance it out us right exactly when it comes to cancer prevention, you know, you talk a lot.
Not outlive about cancer screening aggressive cancer screening. Yeah, so can you talk a little bit about weighing the benefits versus the risks of that tight, 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 in other podcasts, I'm sure you have as well. It's very well understood doesn't mean we know everything.
I'll happily spend 20 minutes telling you all the things I don't understand or that we don't understand is 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 carcinogen 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 Monaco 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.
They're still way too great a chance that you're going to end up getting cancer relative to you know, if you just take the approach of while 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 and it's by definition because it stage 3 it has spread to the lymph nodes, but it has not spread visibly beyond the lymph nodes. So when you do a CT or an MRI on that patient, you'll see that there is no other evidence of cancer outside of the region of the resection, 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 patients body almost assuredly in their liver, but they're not in you know, you can't see them. If you give that patient the full Fox regimen which is the standard chemotherapy regimen that's three drugs.
Sixty-five percent of those patients will be alive in five 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 there now stage 4.
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 that 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 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, I really like the way like you can do everything you can and you know, like my one of my favorite Peloton instructors. I Lee Ann Haynes be 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 Peloton classes while she was being treated. I mean amazing, but the reality is is that they're like
Over a lifetime, you know, you do like there's random amount of like things that can happen. Let's say your metabolically healthy and everything like your cells are dividing. You can get a mutation. You mean cells will take care of it most 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 they mean systems not working as well. I mean, there's things that you just can't control like there's that like you mentioned so 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? What are the major ones, you know to do you said colon and breast are there any
others? Yeah, so, you know a discussion like this always begins with our patients by saying
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 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 your mammography 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 mammography is covered, they probably won't cover the MRI or the ultrasound that we're going to recommend because we never recommend mammography and isolation ever if we're doing a piece.
Say on you and any of our metrics show more care is warranted. They're not going to cover the follow-up study like a fork a test or a multi parametric 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,
it was 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 want to hear the stats on this but if you don't understand what sensitivity means 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 - 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.
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 pretest probability. But the point is this is all a Bayesian 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 mammography, right? So so Peter, why are you saying you're not satisfied just doing mammography. Well, here's why mammography has a sensitivity of about 90% And A specificity of about 85 percent, which is fine except if I'm going to do a mammography on you at this moment.
Min time your pretest probability for having breast cancers 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% furthermore. There are features about you personally that might make you a bad candidate for MRI and isolation.
One is you're very young. You're not in menopause yet. Your breast tissue is very glandular now in 40 years on a mammogram. Your breasts are going to look totally different. The mammogram 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 mammogram 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 lesions very well. So we 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 anyone test by itself. You're always going to have a blind spot.
The one exception to that by the way is a colonoscopy a colonoscopy is a test that has 100% says sensitivity and very high specificity. 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 bowel prep. There is 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 England Journal of Medicine. This was actually a study that was meant to show that colonoscopy wasn't worth. It 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 and had not a singular not a single incident. So it showed that in good hands a colonoscopy is a very safe procedure, but I always want to make sure
People understand like we don't take this stuff lightly and there's a reason you don't do a colonoscopy three times a year, which if you did Co not to be three times a year you'd never get colon cancer because you'd all you know colon cancer always has to come from a polyp. So if you were checking somebody three times a year like you you'd never they would never be able to develop a polyp that you wouldn't catch but at that point the risk would be just too high. That's something else would go wrong. So, you know standard recommendations used to be every 10 years starting at 50.
Current recommendations are starting at 45 and there's some controversy about whether you would do it every five to ten 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. We would typically say 40 and then about every three 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 Cecil polyp, for example, or
Patient has an incomplete bowel prep, you might decide, you know, actually we need to do this a little more urgently and do it in a year again as opposed to wait three
great information and with respect to the combined, you know, especially for younger individuals like younger like myself the mammogram starting so
so I might say like, you know at 40, I would start doing a Mamo and an ultrasound every other year. Sorry every six months so every you do a memo every year
You would an ultrasound every six months every year but stagger them by six months. So if there was if there was a high enough risk, that's probably an approach I would take
now is that because there's a lifetime risk of one and ages for on average forget about all that much. Okay. Yeah,
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 can be treated early if you catch this in a stage one. It's a non fatal disease.
A stage 4 disease is a uniformly fatal
disease. What's the positive predictive value of catching it in stage one with the
combination? Well, so ok. 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 another thing that we use that we haven't talked about our liquid biopsies.
So we incorporate liquid biopsies into our testing team. Yeah. Yeah. Yeah. So so have you talked about on the podcast and let them know what
their question I was going to ask you about with, you know, the Grail by the gallery by Grail.
Yeah. Okay. So what is 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 connect, you know, the Grail test uses 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
Determine so basically there are could be known mutations that we know are cancer genes like a k-ras mutation or p53 mutation where you might say. Oh, if you see that k-ras 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 a 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 Grail 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 mutations 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 tests see that MRI that we talked about or
the ultrasound with a mammogram 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 mammogram 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 at site of origin or shedding? Its DNA insufficient enough quantities outside inside 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 just my clinical experience and observation at first glance. The sensitivity of the Grail test for breast cancer is quite low. The specificity is very high for
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 1 stage 2, 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
Percent 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 3 breast cancer. Like I'm going to figure that out falling off a log, right? So I need something to tell me when there's a stage 1 breast cancer, but a closer look at the data showed that if you looked at er, PR negative breast cancers stage one stage two sensitivity was 75 to
80% it was only in the triple positive PR PR positive her2 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 likely it is to pick it up at an early stage. The implication might be here that it's catching the
Is that matter?
And I think that's a very interesting way to combine liquid biopsies with morphologic studies.
Do you ever not combine? Like do you think doing just the 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 screen.
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 just think a little bit of a belt and suspenders approach makes sense, 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? So, you know talking about some of the major screenings the colonoscopy of the mammogram you mentioned pasa.
Are so so with like some of these, you know types of morphology screenings like the mammogram, for example, people are consider 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, you know, potentially causing cancer, right? So CT scans
x-rays. Well CT scans would be a very lousy way to screen before 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 on our products, but we do have former smokers. We do still use a low dose CT for lung screening. Remember lung cancer risk is lung cancer is the leading cause of cancer death globally and in the US for both men and women and eighty-five percent of lung.
Cancers occur in former smokers or current smokers. So in those people you have to ask question, what kind of cancer is do they get and you basically have small cell large cell and squamous cell are the dominant cancers that occur in smokers and those are best detected on a low dose CT scan Adeno carcinoma of the lung is the dominant cause of
lung cancer in a nonsmoker and we can detect that equally well with an MRI so we don't expose a never smoked or two at risk whereas to a smoker we or you know wrap a smoker or current smoker the risk-reward trade-off is worth it and that's been documented really clearly and clinical trials mammography has incredibly low radiation not as low as like a dexa scan or something like that, but it's still really really low. So
A lot of women that avoid
them. I'm sure there are
I don't know maybe they're the radiation has lessened over the years
and it always has always radiation is constantly going down. I mean just going back to something. We spoke about earlier 20 years ago a seat. So just let's explain what the numbers mean. So radiation is measured in units called millisieverts and it's generally established that exposure to more than 50 millisieverts a year will increase your risk of mutagenesis.
He's 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 122 millisieverts a year. So that's two to four percent 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 you know, four to eight percent of
annual allotment
a CT angiogram 20 years ago was 20 millisieverts 40 percent 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 1 millisievert.
So mammograms are even point less than that. Yeah, they're a fraction. So it really is makes and zero cents for a woman who has a lifetime risk of one in a and perhaps even hi.
Are if she's obese and right Frank Sal Khan way to avoid to avoid doing mammograms, correct? Okay. Yeah,
but again, I would never rely on a mammogram exclusively, right? I would combine it with an ultrasound or the MRI.
Yeah, but they're not concerned about people aren't really scared of the ultrasounds their skin
their skills, right? Yeah and MRI of course has a radiation so but but again everyone has to you know, you just have to unfortunately as a lot of fear-mongering that goes on but you just have to look at the numbers. I mean, it's Crystal Clear that a
Mammogram has a very very there might be confusing it with there was another test. I'm blanking on what it's called now because it's never done anymore. 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 millisieverts where this is all starting. I'm sure it's I'm sure there's
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 because I mean, I'm not just I'm not kidding. Like I know people I know women that have this fear. So, 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 that like
biopsies are very good on blood cancers actually because you have the highest proportion of those cells like you're
gonna get a much higher concentration of cell free DNA. So yeah, we actually that's one of the areas where I'm most excited about the liquid biopsies is on leukemias and you know other sort of hematologic issues such as myeloma and things like
that and for people listening wondering about the cost of its typical it's like 900 like yeah close to it's actually a
thousand a thousand dollars, right? I don't think it's D to C. 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
Don't think you can yeah, but I don't know for sure.
I'd be surprised if you
could sew on the breast cancer topic, you know kind of going into another area of just I know we got to we got we're doing okay, but I really want to get your thoughts on this this topic which is a broader sense hormones, 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
Bye. Yeah, except electrics. Yeah when she hits menopause. I mean, it's like a you hear those quote unquote Cliff they fall out like a woman in terms of their aging they fell 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. We 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 and they go away in very short order. So it's clear. It can be quite dramatic. And obviously those hormones are estrogen progesterone and testosterone. I was mentioned testosterone because it's easily forgotten but it's important to not forget it because a woman's concentration of testosterone in her and by the way, testosterone declines slower than estrogen and progesterone estrogen progesterone really go down testosterone kind of gradually goes down but like right now we're sitting here.
Here and you're you know, you're 45 presumably, you know, you're still in the throes of your reproductive, you know, you're at the tail end of your reproductive capacity, but you haven't hit menopause yet. Your testosterone right now is at least 10 times higher than your estrogen level in absolute quantities. And by the way, that's the highest that's if you're ovulating so your Peak estrogen is around ovulation if I take you in the early follicular cycle or in the luteal cycle your testosterone.
Could be 100 times higher than your testosterone. So it's very important to understand don't get confused by the units on the lab tests because they're reporting them in nanograms per deciliter versus picograms per milliliter. And so the estrogen number looks bigger, but in terms of absolute amounts of it testosterone is still the by far the most dominant or moment for both men and women. So 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
Immunity are these vasomotor symptoms? So the hot flashes and 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 a regular 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 vasomotor 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, too.
Varying degrees. And again, there's this 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 because 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 driving the Sleep disturbances or is there something else that's driving them as time progresses into menopause other things will occur there will be sexual changes.
Ages 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 estradiol plays an important role in vaginal in the absence of estrogen is driving the vaginal symptoms. So and of course if and then of course you have 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 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 the reduction in bone mineral density from their 20s on 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 falling and the impact of 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 show him another 60s. So taken together all of these symptoms in my mind completely.
Either use of HRT in any woman who is willing to undergo it and unfortunately and I've talked about this a lot on my podcast. I think there has been no greater disservice brought by the medical community on to anyone but in particular in this case women then the abject failure of the interpretation of the women's health initiative in 2001-2002 whenever it was first published. That's a study that was completely misinterpreted the Press.
Were I mean out to lunch in the way? They interpreted the study and the investigators were in my mind equally at fault for not clarifying it now at least one member of the team who was a part of that study. Joanne Manson has been has been more vocal lately. I had her on my podcast. She's been more vocal in acknowledging the the way in which that study was misinterpreted. But unfortunately, the damage has largely been done both in terms of the fact that there is an entire generation of
and by my estimate and by the estimate of my analysis my analysts analysis over 20 million women have been deprived hormones that who would have otherwise received them and 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 as it marked 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
So just as you said, there are women out there who say I can't get them ography because oh my god of the radiation. They may in fact be thinking of an MBI. There's just a misunderstanding will somebody there are still women walking around today that it 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 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 some of the major major flaws
Study were one being
well, so I want to let's let's talk about what the study did right? So the study took 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 2 goes the risk of hyperplasia and ultimately what's called dysplasia, which can lead to cancer in other words unopposed estrogen will increase the risk of endometrial cancer. So to this day,
We know this and we do this. So if you had a uterus you were put into a group where the treatment group was given conjugated Aquinas estrogen and MP a so, that's 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 at coin estrogen versus placebo. They didn't have to be given the mpa the synthetic estrogen.
these women were on average considerably older they were I want to say 7 to 10 years out of menopause at this point and the study was looking at a number of outcomes, but it was terminated early at about five and a half years when it was noted that the women in the c e + MP a group versus the placebo had
a 0.1 percent higher risk of developing breast cancer
interestingly the women in the CTE alone group had a lower risk of developing breast cancer. So the study was halted and the headline read estrogen increases the risk of breast cancer by 25% Well, this wasn't correct. It is true that in the c e + MP a group the route 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 point one percent. 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 breast cancer.
Mortality those data by the way have been updated every decade or so, and we now have like 19 year follow up 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 c e + MP a 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
Cee 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 bee so I think most people who think about this.
Problem today acknowledge that it's probably the MPAA 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 ask the question. Well is MPA and 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.
But I doubt
it and what is MPA again? It's a
synthetic progesterone. Okay, nowadays women take bioidentical micronized oral progesterone or they use a progesterone coded IUD. If they don't if they don't benefit symptomatically from progesterone progesterone is a funny hormone. Some women really don't respond well to it. 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 coded IUD.
And that provides the local protection that prevents an endometrial hyperplasia. So in that sense, you know, you know, I could dive deeper and deeper and go through the Weeds on the whole study, but the punchline 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 this study that I didn't catch because you know, I when trying 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 was another factor and then 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
The other thing about it, by the way is we don't use oral estrogen anymore?
Yeah, so that's another question what so can you talk about that a little bit of the differences just you know, sort of not so much di 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 they're estradiol and or estradiol but there is
FDA approved as tree all products. So there are three estrogens E1 E2 E3. There's some important Nuance here that maybe justifies explaining. So estradiol can be turned into s trone which is e 1 and it can be turned into e3s tree all but III cannot be turned into E2 or E1. So that's a one-way.
Arrow III can be turned into this complicated. Let me sir. E1 can be turned into a 24 and 16 hydroxy Esther own. So you got III that can go into an E2. Sorry one can be turned into a two hydroxy for hydroxy with 16 hydroxy III can actually be turned into the two hydroxy, but not the for hydroxy or the 16 hydroxy virtually all the breast cancer risk.
Probably comes from the for hydroxy s drone so you can get that from S3 all part of me from estradiol, but you can't get it from S3. All there is no FDA-approved product forestry. Also if a woman is taking estradiol which she's probably taking in a topical fashion in combination with estradiol that they usually refer to that as a biased you'll hear that abbreviated biased which just means by estrogen so they'll combine in some
Action anywhere from fifty fifty to eighty twenty estradiol with s tree all 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 estradiol bioidentical we don't use it because frankly there is 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 all.
Roll estradiol is for women whose skin will not permit the absorption of any topical estradiol product. Our Preferred Product is an estradiol patch. We use the 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 devel dot so it's an FDA-approved estradiol patch a woman applies the patch you apply that near 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 four days. So, you know, you'll put it on your lower back or your hip but something like that on your shoulder. Do you just put it somewhere where it's not sort of intrusive by the way, we do 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, but nevertheless we don't have any issues with that. There are Australis.
Virgin pellets that can be inserted in the Sub-Q space are into the fat really and they're also not FDA approved. But you know, they're still used pretty liberally by physicians who know how to put them in I used to do this for my female patients. I don't anymore. I just tend to prefer the patch truthfully because it gives a more steady state level dose of the estradiol 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
To do so those are basically the ways in which you would take estrogen in. And as I said progesterone you would do either oral micronized bioidentical or you would use a progesterone coded IUD. They also do make progesterone suppositories, but for most women the compliance with that is low. It's just messy and you know kind of inconvenient. 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 sin.
I don't want any 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 this sexual side
effects. What about the difference between like multiphasic versus whatever the mono like when you select giving women as
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 sometimes do multiphasic on progesterone in the transition of perimenopause. We don't do it once women are fully in menopause when women are fully amount of pause. 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 menopausal.
Balls as indicated by the
FSH do you go so that was another question do you like let's in your car we titrate. Yeah. Well like determine let's say a woman is either pre menopausal or perimenopausal hat like I guess postmenopausal to but determining like measuring your estrogen measuring your progesterone measuring your testosterone 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 perimenopause. Yeah. You know, what? Is there a lot like a threshold levels?
Yeah.
Yeah, we look at day 5. So if day 1 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 5 and day seven. We just like to do it on day five you look at estradiol levels and FSH levels. That is your Canary in the coal mine as that FSH level on day five starts to climb and that estradiol 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.
Looking at amh levels and me anti-mullerian hormone Emirate. So this is basically telling you how many eggs you have left. How many follicles you have left? So this is something that fertility docks are constantly looking at and women who are you know, struggling with fertility or you know deciding if they can still do, you know have kids or go through IVF. So there may be some also some insight that comes from am age, 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 symptom so I typically do not treat women until their symptomatic and perimenopause. So, you know, we'll look at their labs and I'll say, you know, Rhonda look like you're getting closer to something. Let's just be on guard for it and then you know, maybe six months later. You'll say alright, I'm having some hot flashes and night sweats. Well, okay good your and you by the way, you still may be ovulating, you know this can this is what perimenopause looks like, right? So to me, that's
You start treating and you can get away with much lower doses. 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 in opposition to each other. So the lower your FSH the higher your estradiol 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 estradiol 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 to preserving bone density obviously symptoms, but preserving bone density. Also lowering cardiovascular risk. Yes lowering
Alzheimer's risk of Alzheimer's is less clear Rhonda the data right now suggests the following late initiation of HRT may be counterproductive for ad risk may actually increase ad risk.
Early initiation appears to potentially only be beneficial in E for women but not III women. Okay. So for you I would say ee beneficial to initiate at the time of menopause because of your E4
got it that's really good to know and also 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 in one was the dops. So it like I don't know was like early intervention for
Estradiol or something and then there was another one that was the the Danish osteoporosis prevention study in both of those studies the in the daps one, the the initiation of the they did estradiol. I think they did like triphasic or something. But also they did the progesterone so it had petition as well. It was like the the cardiovascular disease risk or mortality went down. The bean is thrombin thromboembolism like the things that
Happen that can increase with menopause went down over the follow-up which was 16 years or something. But these women only took it for 11 years and they started at age either between the age of 45 and 58. So perimenopause was in there and also just you know, you know few years. 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 this study. 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 anything else. In fact, it reduces her risk, it clearly reduces the risk of heart disease dementia and bmd and it's either protective or neutral on cancer. It was like it was new
And yeah, it's protective or Neutron cancer. I am very confident of all of those things. Here's the thing. We don't know. What do you do Ten 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 clear to me. There's there's some there's some you know opacity around what will happen to cardiovascular disease risk dementia disease risk and cancer disease risk, if you start appropriately initiated HRT after 10 or 15 years, but what is unambiguously clear is her bones are going to get brittle again because the moment you
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 post menopause she will once again go into a rapid state of decline now, she 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 HRT side and they say you should never use estrogen for treating bmd because we have bisphosphonates and I say first of all you only use bisphosphonates for three to five years to 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
like waiting to retire like you're going to have more in your retirement fund if you retire at 70 percent Sixty by so this
is the big question because because I mean,
And my and again, 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 their risk of falling is you might still end up being neutral risk carrying out HRT
indefinitely. So this is where you know the lifestyle
Actors, which is probably 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 up until that point in continuing it you're building not only bone, 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 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 nuclear hormones, you know, we have to stare at home with nuclear steroid hormones. I should say sorry. So we have estrogen testosterone vitamin D is 1 so these are these are binding to a receptor that you know in some cases the receptor complexes with other ones that 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 regulates recognizes a little sequence of genes. So in the case of estrogen is called an estrogen response element in ER e and
Vitamin D is called a vdr e vitamin D response element. There's a lot of overlap between vitamin D and estrogen 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 you know in some cases obviously vitamin D also plays a role on role in bone metabolism, right but independent of that also just looking at the cross.
Talk of the genes that vitamin D and estrogen to regulate and they're like, they're both and the response elements are there different but there's some what I'm looking at that and say, 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, 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 density.
So I'm gonna 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 exogenously through you know 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 a like in terms of like how Vitamin D is acting. So the thing is that when you're in sunlight like there's other things going on, right?
But that's my point. Like if your outs are getting something like you're more
active and your nitric oxide like there's like other things that you're getting from this
Light so there's a confounder there but I mean like with respect to let's say forget like let's say you find that 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 like the the actual one 25 hydroxy vitamin D, which is the act of steroid hormone. It's the same.
Now with respect to like, you know, your body regulates how much vitamin D3 is converted or is released in the 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 you know, what's the highest level of vitamin D A person can ever get to naturally meaning 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 I remember my vitamin D levels when I was in high school working
construction. I know I know there's like data out there where there were people of looked at like, you know, you know people that are that are like out in the they're out there outside all the time, but they're all there honestly Lofton looking at people like in the tropics and stuff that have more melanin. Yeah. Yeah which again so it might depend also on
that that would be an interesting at least way to say.
Say like the but if the body has a built-in mechanism to say, I'm not going to let you make more vitamin D than this does supplementing above that would be a bad
idea and it is yeah like and so that's why looking at measuring what am I thinking about threshold is 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 Toshi with lower all-cause mortality. And in fact, I mean, honestly if you start to look at some of the literature you have
Take a really high dose daily for like a decade to start getting like the the high calcium. But the problem is that when you absorb when you're invited 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
people are doing that like I don't think taking 5000 7000 I use for most people some people have to take more than that because they had Snips right and you've probably seen in your patients wear this like they had to take a high level just to get up to 30 or 40
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 taking too low a dose and they're doing it based on dos not level like to me the dispositive study on this would be take a whole bunch of people whose vitamin D is
T give half of them a placebo give half of them whatever vitamin D is necessary to get them to 60 or
80. Yeah, get something higher get create separation 30 to 40
but be like do it the way we do blood pressure trials. When we do a blood pressure drop. 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 mg of a drug that for one guy is too much and for one guy is too little and yet this is
Not done in vitamin D and I find it infuriating that we have no really good reliable our CT data on what seems like a jugular question. Are you better off with a vitamin D level of 80 then 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 2000 IU for 10 minutes found no
difference, right or they measured maybe if they if they
Measured anyone's level they measured like 10% of the population.
That's exactly what most recent study. We only got a level on ten percent of people
with with like, you know, the fact of the matter is so many people do have these Snips to yeah, and I remember having an email dialogue with Joanne Manson. This was years ago when I was a postdoc and I was in she was I think at the time she was doing the Bible study. It hadn't been published yet. And it was like, please please. Can you get this snip data in there? Can you get measure the levels like do everything, you know, like it's so important, but I'm with you on that.
That I think I think what is clear is avoiding deficiency. And I do say that a
lot because where you drink wine is is to 30 or 40 where you I
say 30. I mean it does depend on are you looking are you looking at with the endocrine society says is more of an adequate level or inadequate or 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 but for me it 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?
You know, and I don't know so it's always like okay, well, err on the side of caution, you know, err on the side of caution certainly avoiding deficiency. Yeah, but even with respect to like all these jeans I'm talking about, you know, like what if there's some crosstalk with that there is crosstalk but what if there's some way that having a level of vitamin D, you know, 50 50 or 60 nanograms per ml does help alleviate some of the effects of having no estrogen, you know, like we don't really know it is especially when you look at the
In ISM and I like I said, I spent a lot of time looking at these response elements and and I and you know looking at the fact that estrogen can actually compensate for vitamin D deficiency in some cases with certain genes to and it goes both ways. So I'm like, well, I feel like that should be an important component in the equation. Right but I'm with you on the 10th like like this even the studies I was talking about where there was protective effects against, you know in the cardiovascular health in cancer prevention with hormone replacement.
Therapy when initiated like, you know within a close range like not greater than six years. So it's six years or less. So if you're doing it seven years that's not part of the study. They only did it for like 10 or 11 years and they stopped. Yeah, and it's like well what happens then when you're 65, and you see if you started at 55, you know, like so we don't we don't know the question to that. I mean the answer to that either but I'm happy that you're thinking about it.
So, oh, you know one thing maybe even before we go to mail.
Hormones that I didn't mention on the female side with testosterone 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 post menopause and this is something that is being studied. So by the time this podcast comes out, they'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 Sharon parish and mo carrot will be the two folks that I've discussed with on that and Mo's actually involved. He's at Baylor in Texas. He's involved in a study that is looking at the use of testosterone replacement and women for sexual function. So both Mo and Sharon talked 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 mean, 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 podcast I kind of know what's going on, but I was blown away in my discussions with with with Moe and Sharon on these topics. So the long and short of it is we have become much more liberal in our use
Of testosterone in women 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 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 when 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
of testosterone typically about one-tenth the dose that men take to also have a physiologic replacement and that's about one-tenth 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 can have profound
impacts, but is that in combination with also giving these women the
the ostrich does not? Yes, estrogen progesterone
is 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 miss the whole interesting. Yeah, the missed the the structure to window. Yeah, and and this is something that people have asked me. 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. Would you also give that person so there's two questions
here are yeah great. Great question. We handle
Each of those I hate to say this because it sounds like such an obvious cliché. We handle each of those on a case-by-case basis. 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 stupidity 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
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. And so the way we handle that as we basically try to figure out what is your risk of AD acas cvd 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
Or even an organ a 3/4 4/4 and and or if she's very high risk of breast cancer. We might be a little bit more reluctant to do so 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. So not at not an easy question to your other question. Would we be comfortable using testosterone in isolation without opposition? I would say at this point. I'm not
I'm not I don't think I know the answer that question yet. And I think that that's something that would need further study before we could sort of make it clear recommendation
in the cases of the in your clinical practice. You're handling the hormone replacement therapy is testosterone part of the equation or do you ask is it like a more of a symptom thing? Like my libido is down even though I'm also on estrogen with
it's not a state. Yeah. It's not nothing is standard, right? Everything is
Bespoke 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's does paint-by-numbers, you know paint-by-numbers is a bad approach. Everybody's on this everybody's on that. No. No, it's like, you know some women do not absorb testosterone very well a part of me do not absorb estrogen very well from a cream some, you know, might end up requiring to take it orally some much prefer cream some prefer a patch some can tolerate s some only need this do some need that.
So some need a very small amount of oral progesterone. You do need at least 100 mg 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 an FDA-approved product. It's not approved for this use so it's called net esto and it's a it's an intranasal testosterone spray that is FDA approved.
Male use for testosterone replacement therapy, but it's being used off-label. It's also being tested in a clinical trial for libido and women it has a higher acting. So 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 rapid acting in terms of sex drive and libido. Whereas the intravaginal testosterone for women.
Reese's orgasmic function so even the way in which you use testosterone can impact function and what your indication is.
I in a question I have is 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 Low T with low T. And there's like this controversy around it. Like what defines Low T. Is it a levels.
Is it a combination of levels and symptoms? So how are like, we're looking at menopause in women we're talking about an average age about 51 or something like that. Right men. Let's take take the same period of life for men. Okay 50s, do they start to experience like a decrease in testosterone
around but it's more gradual and it starts frankly in your 20s and 30s. So so male testosterone probably peaks in the 20s, and it's just as slow.
Steady decline. It's not 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 decline down. So you're right Low T 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 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 antigen receptors and they testosterone Androgen receptor complex has to make its way into the nucleus where it impacts transcription 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 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 ldl-c calculated by the freed wall formulas.
An estimate and then you sort of have to guess. Well, maybe there Androgen receptors are saturated. Maybe they're not but if you're giving a guy testosterone in the presence of mild to Low T. 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 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 and then on the signs were kind of looking for insulin resistance 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 and your free is
commensurate with that even though again, that's an estimate was probably reason in my book to initiate.
And 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 to
stop. Yeah. It's actually kind of like what we were talking about on the vitamin D front. Like don't be too incremental. You're not going to get the answer. So if and again each lab is going to have different scales but in you know in the lab we use the 5th 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 5th percentile is five nanograms per deciliter and the 95th percentile is about 24 nanograms per deciliter. So call it 5225 basically. So if a guy is at 8:00.
And we have 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 that 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 course and see if those things get better, but if
You know if we were doing this because there was you know, some of the other actual symptoms then I would say that look this guy might have been already saturated at at eight nanograms per deciliter where he started and all that additional testosterone may have done him. No good. Whereas somebody else might have been woefully under saturated and when you you know increase in by 150% you actually got benefit from it.
Does the like injection versus like a gel does that matter?
Like we're very biased towards injections. I think they're far more consistent. I think you know you have variable absorption and it doesn't just vary by individual it varies by time of day. So, you know, for example, like if you're if you just finished a workout and you're sweating and you even if you go and have a shower, you're still kind of in a less absorptive State than maybe if you're cold, you know, what part of your body do you put it on?
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. So we recommend 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 to 40 to 50 milligrams twice a week and that produces just a much more steady level because your
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 want to minimize the inconvenience of that you're just super physiologic for you know, 45 days. Then you're kind of physiologic and then you're actually back to down to being very sub physiologic before the dose. So we'd like to avoid that.
Is there any like what's the relationship between testosterone replacement therapy and like the prostate?
Yeah, very well studied. So couple things we
As clear as day, right so we know that the lower the testosterone the higher the risk of high-grade prostate cancer. So again contrary to popular belief testosterone replacement therapy does not increase the risk of prostate cancer. But what it does do is potentially increase BPH benign prostatic hypertrophy. So it does increase the size of the prostate potentially so one, you know needs to be mindful of that it also there are out. There are side effects of testosterone, right? It will drive hair loss in an individual who's susceptible to hair loss.
Through the sort of Androgen Pathways there. 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 Supra physiologic levels. So I'm just trying to think the last time we saw a patient who had acne. I'll probably see it once a year. So these are really infrequent side effects, but we do have a lot of
Who you know are concerned about hair loss. And and and so we say look, I mean there are strategies around that of course, you can take a 5 Alpha reductase inhibitor. So those are drugs that block the conversion of testosterone to dihydrotestosterone, which some more potent Androgen and that's the that's the engine that's driving and region-specific hair loss or they might say you like I've had patients say oh, you know, what like my hair matters more to me than my testosterone. I don't want to take testosterone so
So those are the things that we just kind of want to point out. The only other thing that's worth noting is I do believe that in a susceptible individual in the short-run. 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 is 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 events in the testosterone group compared to the placebo group that vanished at two and three years almost suggesting that the highest risk men probably those that were closest to having an event where actually pushed over the edge a little bit again. 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.
It to everything else.
What what sort of blood pressure do you like levels? Do you like
you'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. Okay,
so we're very aggressive the good news with blood pressure unlike the lip, you know, we spend 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 that 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
People, you know losing 20 pounds and exercising especially cardio is going to do amazing things on their blood
pressure have you looked at so I have a relative who exercises good diet, like the only thing that lowers her blood pressure is hot
tubs. Hmm
interesting in addition to the exercise interesting and it's like very she's also a very high-stress like switches, 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 or hot tub on hypercortisolism Mia 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, you know, some Dan he also I mean, he's exercises a lot. Like we have the same diet 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 made
Sure. I'm not like too low. Yeah, 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 it when you finish this story, I'll walk through to make sure everybody's measuring correctly. Okay, that's very
yes, please do he has him at hemochromatosis. Okay, and there's some other relatives that had it and notice that their blood pressure was high up. Like we're talking people that are like very feels like doing lots of super easy.
Like, you know 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'm too
important for obviously getting rid of the iron and hemochromatosis,
right? But the other thing that's really helped to 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 they'll be times when he's in his office working and he's like 135 systolic and it's like in the world. That's crazy, right?
Right 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 my good-tasting wine about AG know and that will that will help him as well. So yeah exercise is very important but like there's also
actually 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 where we haven't been doing that because
We take a lot of vitamins at night. We do take some fish oil in the morning. I did mention that to him because another story my mother who is sedentary. She's lost a lot of weight, but she still overweight. She you know, she's losing the weight was great. I mean, she's lost like 75 pounds like she's lost a lot of weight you look at the pictures. It's like years to her life have been extended just by that it alone, but I can't like I can get her in the sauna sometimes but it's still
Still it's still like a little bit more of an effort. But one thing about her is she will take the vitamins I give her and she's got she's homozygous for MTHFR. If she's not taking a high dose like be supplement along with like methylfolate 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 got her, you know,
It's like sort of like battery of supplements that I was giving her including all the the methylfolate and lowering her things that were lowering her home assisting along with magnesium and cocoa flavanols. I was giving her cocoa via she's getting four of those pills she gets for and she still takes him her blood pressure went from like 155 to like 125. Okay, her doctors are like they wanted to get her on antihypertensive treatment for she came to me and it's like and this has been like months now. It's
It's happening if she measures at home, she takes she does logs. I mean, so I'm very happy about that. You know, the fact that she's been able to do that. But again, it just it shows that there are they definitely are 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 and there and you know, I don't think we have the outcome data to look at the direct impact of
Coco 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 if you've talked about a dma and fdma and a dma and STM a directly and indirectly
Actually inhibit nitric oxide synthase. So the we know that homocysteine is associated with poor outcomes in cardiovascular disease and I think that this mechanism of homocysteine impairing the clearance of a dma and SEMA is the is the mechanistic relink because when you directly inhibit nitric oxide synthase in the endothelium, you are preventing the creation of nitric oxide. And of course, that's what cocoa flavanols actually do the opposite of that.
That so I think the one-two punch of lowering homocysteine and raising nitric oxide synthase activity via cocoa flavanols could certainly explain a reduction in blood pressure.
That's really interesting. I was giving her the cocoa flavanols just because I had seen the studies on increase blood flow and I'm like, okay this that's we need that, you know, you need that measuring blood
pressure. So this was established really clearly through the Sprint Thailand and this has basically been now kind of the gold standard for how we use an automated cuff, so,
That trial was done by 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 5 10 and 15 minutes. You're sitting like this the cuff is
Is two inches above the elbow and the cuff is right at the level of the right atrium. So, you know your 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 over stimulated 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, you know 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 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 5-minute protocol and test perfectly and I think
Is everybody listening to this should know that number?
Yeah, that's great. I'm going to like do it Peter so
This has been amazing. I mean so much information actionable information a lot of people listening here. They want medicine 3.0. They want aggressive prevention. Do you have some tool like some some some pointers maybe some strategies that people can work within the existing Health Care 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 heart or you know doing doing
The The Grail working with their Physicians to like being able to order them, you know, like how can people try to get as close as they can to Medicine 3.0.
I mean, we've hate to sound like a Shameless plug we've created something to help do this because you know, I've talked to you about our practice. Our practice is super small. It's it's 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 the amount of room that we can make because it's just not the model doesn't make sense. Right? It's too labor-intensive the way we're doing it.
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 health care information. So to that end we've created this product called early. It is 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.
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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 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 Heart 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 or 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 and the challenge of practicing this way is you just have to get re-educated.
That takes a little bit of time and that's why we put this together, right? We've 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 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 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 just at the very end of this that I know people are also very interested in one being your ideal your ideal diet and exercise routine and other factors that are doing for longevity or maybe for the day or for the week, whatever whichever way you kind of bunchems in like what's ideal for you for you to you know, improve your longevity. I know that's a very general way.
Respecting nutrition and exercise
nutrition exercise and anything else sleep like, you know, sonnet whatever whatever is your ideal like program
sweet. Yeah. Well, I will say this 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 a little hesitant when in talking about what I do.
Well, they wanted people want to know what you do.
Okay. So look probably compared to most people I am considered quite regimented.
I'm way less regimented than I used to be but nevertheless here is sort of how I think about things. So let's start with sleep. I really take my sleep seriously and I'm you know, someone who believe who functions best with a consistent bedtime and wake-up time. So I am in bed usually 48 hours a night and that's typically 10 to 6 and that usually results in probably seven and a half hour.
Of sleep. I'm going to just rattle off the names of things I use because I don't have any affiliation. So I use eight sleep as my mattress cover. I love what these guys have done. It's a fantastic cooling product and it's made an enormous difference for me. I've been using it for the last three years. Most of our patients are using it. There are other products out there and I've tried them and they're good this one I just happen to Fancy the most great. 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 activate me. So I try not to look at email for a couple hours before 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 it has like the remote to the TV.
You know and it has like a phone and email but like a sort of phone and text but only like two people know the number my wife and my daughter and 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. So that's kind of the phone. That's with me if I'm watching TV downstairs or something like that, but I can't even be tempted to look at social media or look at email. So it's all in the spirit of like turning the system down before bed even little
Like I'll brush and floss my teeth before I go in the sauna because I saw him before bed as well. So that once I'm done with that sauna and shower like I'm just going straight into bed. So for me, that's also a very productive sleep trick there certain supplements that I used to sleep as well. So I'm a fan of glycine ashwagandha magnesium L 3 and 8 and and just straight mag oxide as well. I don't use melatonin.
Or phosphatidylserine unless I'm jet-lagged going if I'm time zone hopping I'll use those as well. So that's sleep on the nutrition side. I don't follow any particular diet. I guess you could say I you what's called. What would be called a balanced diet? So I'm an omnivore who will probably always struggle with food in the sense that like
If left to my own devices, I would eat everything 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 Kido. I've been like the most you know, you know hardcore fasting intermittent fasting time restricted eating I got done. There's no diet. I don't think I've done for long periods of time and I
Found benefit in one form or another from various different aspects of these things. But you know right now I'm mostly optimized around energy balance which you know, stay in energy balance 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 4 times a day and a lot of times at least two of those are in meals that are just like just just venison or just you know,
a eggs or something where it's just a protein and you know, there's not a lot of other stuff in it. I do make sure I stopped eating at least three hours before bed. It really makes a difference going back to sleep that I go to bed a little hungry if I ever go to bed with my belly to too full. It feels nice, but I don't sleep as well. So I really try to err 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 60. I'm going
That typically with four hours between when I last ate and when I when I go to sleep we can talk about alcohol. I I'm in the camp that believes there is absolutely no benefit to alcohol at any dose from a purely, you know, biochemical standpoint. 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 probably net. 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 alcohol is completely it 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 impact sleep in me, and I know that as long as I have that drinking done by
Six or seven it doesn't show up anywhere on any metric that I'm tracking with respect to sleep. Okay exercise most important thing from a physiologic standpoint for me. I exercise every day and it's Anna, you know, it's much of what I do revolves around. 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 work outside be doing at home, but I'm still generally doing, you know, four hours of Zone to a week with one sort of higher intensity workout. That's geared towards vo2max a week and then for strength training sessions a week. So that's kind of the foundational 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. So and then they'll
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 the right sleep the right nutrition exercise all of that factors into creating, you know, what I kind of described 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 and and and, you know doing something called dialectical behavioral therapy.
These things have been you know enormously important that increasing kind of equality of my life in the past 5
years.
That's amazing. I mean, thank you so much Peter. So 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 seven hours. I did a flat. 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 to Xing it, you know, what whatever you want to call it, but
Yeah, I was like I
owe you. Audio Reddit. You mean no no read. I read it read it. Yeah, but it in 7
hours I did but like I said, there are fast reader. Well, I think the the more important factor was I'm very familiar with your thoughts and lots of things there were things where I was like, I know he's I know and I'm just skimming this part and then there were things that were a little bit more so 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
It out live I went to a spa the other day and I saw it right there and I was like awesome but you've got a website. I mean Peter
Atia.com. Yeah, I think Peter TMD.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. So question for you. When are you going to write a book is this has this ever is this ever is a server 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 were like because your book was I mean it was it's impressive, you know, and to write a book in the scientific world like that that people are excited about can understand. I mean, it's it's really challenging. So the
yeah, I mean, I guess 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 that I 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 hard he knows it and but but books do communicate in a way that podcast don't and they reach different audiences to so 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 was a lot of time when I thought why am I doing?
Doing this like it's 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 well-thought-out podcasts, but now that it's all said and done. I realize a couple things one writing sharpens your thinking so much and I'm not saying that you're thinking isn't sharper 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
When you have to write it down, you really have to get clear on what you're saying. And and as I said, there's you know, there's probably somebody out there more than somebody. There's 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 teller teller teller so but 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, it's good to hear that for me for sure.
Especially being on the other side of it, you know because you often wonder was it worth it, you know like yeah Peter there are other things that we didn't get to discuss believe it or not. So let's please do this again my podcast were podcast. I want to do that 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 so thank you again really really enjoyed this conversation.
Well, thank you for having
And thank you for for pouring through the book and coming up with so many awesome topics to to get through and it's funny that we barely got through half of
them.
Thank you so much to dr. Peter Atia for his Relentless pursuit of strategies to extend health span as a companion to today's episode. I've created a free evidence-based blueprint that you can download in this guide, which you can find at bdnf protocols.com. You will find protocols designed to improve cognitive function and delay brain aging this guide explores modifiable lifestyle factors, the tactics strategies and things you can do particularly when it comes to exercise nutrition and even supplementation to improve cognition.
In and enhance neuroprotection many of which are at least partially mediated through increases in brain derived neurotrophic Factor levels. This guide, you will also find a section entitled Rhonda's protocols. These Protocols are either practices. I actively engage in or strategies. I'm currently exploring curated specifically for their promising potential for beneficial cognitive and neuroprotective impact. These Protocols are detailed and specific everything you look for in a blueprint. So if you're looking to dive deeper into these
insights and start applying them head over to bdnf protocols.com to get your free guide It's a valuable tool for anyone committed to optimizing their brain Health and Longevity. Once again, that's bdnf protocols.com.
