FoundMyFitness - #085 Dr. Peter Attia on Mastering Longevity – Insights on Cancer Prevention, Heart Disease, and Aging

Episode Date: December 27, 2023

Download the 9-Page "Cognitive Enhancement Blueprint" Discover my premium podcast The Aliquot Show notes are available by clicking here Peter Attia, MD is a highly respected expert in preventive medicine, focused on the crucial subject of longevity and cardiovascular health. He's also the author of the NY Times best selling book Outlive - which I highly recommend if you have not read it already. Peter's philosophy transcends the conventional goal of merely extending lifespan; it's about enriching the quality of every year, ensuring that each stage of life is lived with optimal health and vitality. In this episode, we discuss: (00:00) Introduction (07:36) Defining cardiovascular disease (09:43) Coronary plaque and fatality risk (13:34) How ApoB predicts heart disease (21:34) Factors elevating ApoB (27:23) Does high ApoB cause cardiovascular disease (37:01) ApoB thresholds for ASCVD prevention (40:27) Dietary factors raising ApoB (49:33) Genetics of ApoB and LDL (53:24) Does low LDL increase cancer? (56:19) Cholesterol-lowering drugs (59:59) Statins, uses, and side effects (1:03:12) Are statins toxic to mitochondria? (1:09:56) Ubiquinol for statin-induced muscle soreness (1:11:09) How to train in zone 2 (1:17:09) Statins and neurodegenerative disease risk (1:21:54) Cholesterol synthesis in the brain (desmosterol role) (1:25:58) Statin alternatives (1:36:49) Berberine for CVD Risk Reduction? (1:39:36) Muscle as a glucose sink (1:51:38) Hemoglobin A1C Levels and Mortality Data (1:55:35) 80/20 Zone 2/VO2 Max Training Protocol (2:02:12) Insights from VO2 max testing data (2:12:17) How obesity increases cancer risk (2:15:03) Cancer screening (2:40:32) Menopause – hormonal shifts and health effects (2:45:13) Hormone replacement therapy (HRT) (2:58:57) Perimenopause diagnosis with hormone levels (3:02:04) HRT's impact on dementia, cancer, and heart disease risk (3:07:42) Vitamin D (3:16:24) Testosterone replacement for women's sexual function (3:18:47) HRT safety 10 years post-menopause (3:23:05) Testosterone & TRT (3:32:33) Blood pressure (3:45:30) Peter's longevity optimization routines Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/premium

Welcome to the Found My Fitness podcast. I'm your host, Rhonda Patrick. Today's episode features Dr. Peter Atea. Dr. Peter Atea is a highly respected expert in preventative medicine with a special focus on applied science of longevity. His deep engagement with the topic of longevity is the cornerstone of his New York Times bestselling book, Outlive, the Science and Art of Longevity. Dr. Atea 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 APOB is a superior predictor of cardiovascular disease over LDL particle number and managing the four main factors that elevate APOB. Why APOB exists 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 APOB reference ranges, whether there is an apobie level low enough that it is impossible to die from atherosclerosis, which dietary factors increase apobie, 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 2, 20% V-O-2 Max 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 miscar 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 in 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. Peter's 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. Peter's exercise, sleep, nutrition, and alcohol routines for optimizing longevity and so much more. Before we dive into our discussion with Dr. Peter Artia, I'd like to highlight a very valuable resource available for you. It's a comprehensive report I've compiled focusing 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 neurotrophic 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 detailed 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, that's bdnf protocols.com. And now on to the podcast with Dr. Peter Attia. Hi, everyone.

I'm sitting here with the amazing Dr. Peter Attia. Many of you don't need an intro to him. He has changed our understanding of the scientific literature, preventative medicine, with respect to longevity, improving health span. He's a number one New York time bestselling author of the book Outlive. amazing book. Also, he has a very popular podcast on health and medicine, one of the 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. Yeah, I was going to say, Probably 2016, right? I think it, yeah. You might have been like, no, 2015. You might have been one of the, like the first, I don't know, six or seven guests. I mean, you were like one of the first guests that I had on the podcast.

It was a long time ago. You were still at New Sea. Yeah. Yeah. So it was a while ago. Well, thank you for having me back. So 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, but I think the, the critical spark was the birth of my daughter. And I know, I write about this a little bit in the book, but, you know, I think, you know, I'm in my mid-30s, she's born. And all of a sudden, that became a manner in which I contemplated my own mortality. And 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 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 does it benefit you if you figure out how to not die of heart disease, but you die of some other thing? Or what is it,

you know, eventually what does 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 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, you know, like, 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 crossed my mind at the same time with respect to the cardiovascular disease that you, you, you know, mentioned and you talk 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 when people hear the word cardiovascular disease, I mean, at least even me, when I,

the cardiovascular disease, what is that? What does it mean? Where is atherosclerosis coming to play? Where is coronary heart disease? is cardiovascular disease? I mean, you could define it very broadly and include valvular disease and cardiomyopathies and all of those things. But when we talk about ASCBD, atherosclerotic cardiovascular disease, which is the leading cause of death in the United States and globally. It's leading cause of death for men and women. 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 we'll get into today, cancer, neurodegenerative diseases, etc. Things that you and I have spoken about a lot, including when you were on my podcast. It's important to 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 very small compared to our understanding on the cardiovascular front. Our understanding of this on the neurodegenergermic side 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 should be at least thought of in the context of

how wonderful is it that we understand these things because we have the most tools for prevention here. So with that said, what we're really talking about that does the lion's share of killing, and again, I'll bracket for a moment that there are other things. There are people that are dying from, you know, cardiomyopathies. There are people that are dying from 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 deeper, as shallow as you want into that, and why that happens, and how that's a function of endothelial injury, lipoprotein, and inflammation. But this leads to a reduction in blood flow to key parts of the heart muscle.

And when that happens, the heart undergoes an ischemic event. Now, sometimes that can be chronic, and sometimes that can be acute. And if an acute event occurs in a region where enough muscle of the hardest compromise, that's going to result in sudden death. That's a heart attack. And it's important to understand that a little, when I was in medical school, it was more than 50%, it's now a little less than 50%, but it's still a very high number. A little less than 50% of people's first brush with a symptom of coronary artery disease is sudden death. That's worth repeating because we couldn't, I remember, I still remember being asked this question in medical school. You know, you're sitting there as a first year medical student in

cardiovascular pathology class and the pathologist said, what's the single most common presenting feature for someone having cardiovascular disease the first time? And everyone was like chest pain, shortness and breath, you know, rattling off all the usual stuff. 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, you know, major causes of the atherosclerosis and the atheroscotic cardiovascular disease that you're talking about. So lipoproteins, you mentioned. And, you know, most people know, they hear about lipoprotein, they hear about LDL or HTL. But APOB, why should people know about APOB? Well, again, I think it's worth maybe just getting everybody

on the same page with cholesterol. Let's start with that, right? So everybody's heard of cholesterol, and I think most people would probably even have kind of a negative valence when they think about it's like cholesterol is a bad thing. So it's worth explaining that that's not really true, right? Cholesterol is an essential 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 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 stroidal tissues. And we, we, have to figure out a way to move this stuff around the body. And the highway system of the body is the blood. And the blood, of course, is water. So if we want to move things that are water soluble throughout the body, like proteins and ions, it's easy because they dissolve freely in water and they move around. But when you want to move something around water that is not water soluble,

such as cholesterol as a lipid, you have to wrap it in something that is water soluble. And that something is the lipoprotein. And the big protein on the surface of that sphere is called an apolypolypo protein. And there are broadly speaking two classes of apolypolypo proteins. There are the A class and the B class. So some of the lipoproteins are wrapped in an apo lipoprotein called APOB 100. And we just abbreviate that to APOB. But I'll just say it this one time and we'll never talked about it again. There's also an APOB-48 that wraps another type of lipoprotein called a chylomicron. We won't talk about that again because it doesn't really factor into cardiovascular disease. So APOB is short for APO-LIPA protein B-100, which is the structural APA protein that sits

on low-density lipoproteins, abbreviated LDLs, intermediate density lipoproteins, abbreviated IDLs, very low-density lipoproteins, abbreviated B.D.Ls. Very low-density lipoproteins, abbreviated, deal deals. The APO A's, and this is Big A, never to be confused with APO little A, which we may talk about, those wrap the family of high-density lipoproteins. They're much more complicated than APO B's, believe it or not, and there are many of them. But nevertheless, broadly speaking, that's what's going on. So why do we care about all this stuff? Well, in the 1950s, when it became clear that cholesterol was playing a role in cardiovascular disease. The first observation was people with very, very, very high total cholesterol,

because at the time that was all that could be measured was total cholesterol. By the way, what that meant was the total amount of cholesterol in all of your lipoproteins, in your HDLs, in your LDLs, and in your VLDLs. Those three lipoproteins constitute the amount of total cholesterol you have in the lipoproteins. We can come back to this idea, because it's important. That represents about 10% of the total cholesterol in your body. The total cholesterol concentration was loosely correlated with cardiovascular outcomes, but only at extremes, meaning if you took people whose total cholesterol was in the top 5%,

and compared them to people whose total cholesterol was in the bottom 5%, there was a clear association with cardiovascular disease. March forward many, many decades, we came to realize that actually this low-density lipoprotein, which is a subset of your total, cholesterol, but it's the cholesterol 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 APO-B particles. So that number, APOB, measured in milligrams per decilure, 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 the APOB number, can you talk about how that, so you mentioned LDL total LDL cholesterol, that number is like some, it's like determined by some equation, right? It can be, but it can also be measured directly. Yeah, so there's, would that be particle number though if it's called? No. So there's, there's two ways to go about doing this. So in the old, days, and unfortunately, many labs still do this, they rely on an equation called the Friederwald

equation. So total cholesterol is relatively easy to measure. So you draw the plasma, you spin it down, and you basically lice all of the lipoproteins, and you can measure total cholesterol. So if you just basically apply something to lice all of the proteins, you'll say, all of the lipoproteins, you'll say total cholesterol is 200 milligrams per deciliter. Then they directly also measure. two other things. They can directly measure total triglyceride concentration, and using a separate assay, they can measure the total concentration of cholesterol within the HDL particles. So now you've measured total cholesterol, HDL cholesterol, and triglyceride. The Friederwald equation stems from an observation that kind of sort of, on average, sometimes, VLDL cholesterol is approximately

one-fifth the triglyceride concentration. So the friderald 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 five, if you're doing everything in milligrams per deciliter. And unfortunately, most labs still do that. So when you look at your cholesterol report, it'll say LDLC, it'll give a number. And unless it says direct, you can assume they've done the free-to-walled equation, which is, I've seen that wrong more often than I'm seeing it right. A good lab will do a direct assay. They will actually measure LDL concentration and they will give you in milligrams per decilator the total concentration of LDLC.

That is still an inferior predictor of risk relative to APOB. Yes. Okay. So let's, the reason I wanted to mention that LDLC is because, as you mentioned, many labs do measure it indirectly. And there are many times. types of LDL, right? So there are different densities and sizes. So I'm curious about what your thoughts are on the different sizes of, like more atherogenic sizes of LDL, such as the smaller dense particles. And, you know, like how you view that, like the different particle sizes and the particle number and then, of course, APOB. So like the whole. I mean, there's been a big evolution in the way we've practiced medicine in our practice with respect to this.

So 10 years ago, we were looking at LDL particle number, which both the Mesa population, so the multi-ethnic study of atherosclerosis and the Framingham offspring population have both demonstrated unequivocally that when you compared LDL particle number to LDL cholesterol, LDL particle number always predicted risk better than LDL cholesterol. So how would you do this? you would follow people longitudinally for cardiovascular events, and you would do this in sort of a like a cumulative incidence graph. So on the x-axis, you have time on the y-axis. You have incidents of cardiovascular disease, and you plot out everybody as a function of whether LDLC was higher or lower than as a percentile than LDLP.

So LDLP stands for the number of particles. LDLC 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 works. 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 the way it's most commonly done in clinical practice. It can also be done with ion motility. we switched from NMR to IOM motility for LDLP because it was more accurate. But ultimately, and this is now about five years ago, we actually switched to APOB, which was superior on all fronts. And here's the reason why. First of all, there are different ways in labs to do this. So LabCore, for example, and Boston Heart have different magnets and different algorithms

for how they run their LDLP. So if you run an LDLP on each of those labs, you'll get a different number. That's a bit disturbing to me. I want to know that the APOB that I get at one lab is the same as the APOB I get at another lab, and it's standardized across all fronts. But there's a more important reason why I favor APOB over LDLP, and that is it encompasses the total arthrogenic 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 asphrogenic risk. And you will miss that if you're looking at LDLP or LDLC. You will not miss that if you're looking at APOB. What about the fact that if small dense LDL, which has been shown to be more athergenic? So APOB does become, so you mentioned 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 plays a role also in recycling. So it interacts with the LDL receptor and can be taken back up in the liver. The small dense LDL particles, APOB is somewhat obscured as the LDL particle gets smaller in size and more dense. therefore it's not harder to clear harder to clear exactly um so what about in the case and the reason i'm asking is because as you mentioned apobie is on v l dl idl ldl right but there's different sizes of these ldl and and the the larger more buoyant ldl is better than having a higher proportion of the

smaller dense ld right that's why apo b captures that risk right so in other words this is why this is another reason why i think that apo b is the great equal i just because once you have the APOB concentration, you're accounting for the fact that clearance is going down. I mean, the one way to think about this is anytime you see an elevated APOB, it always comes back to something on the clearance side is not working. Now, there are really broadly speaking when I talk about this with patients. I go through the four sort of pillars of what elevates APOB. So it can be driven by cholesterol synthesis. And we can talk about that because it's going to factor into, you know, dietary choices, for example. So how certain dietary patterns will lead to higher LDL than others.

It's impacted by cholesterol reabsorption. So we can talk about what the life cycle 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 triglystoride burden. So this is where insulin resistance really factors in to how APOB can go up. 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 PCSK-9 inhibitor directly does that. targeting a protein that breaks down LDL receptors. So anyway, a long-winded way of saying, and this is another advantage of APOB is it allows you to, in one measurement, capture all of that risk. Because if you have small, if you have, you know, two individuals,

like if you're just using LDLP as your risk, you might miss some of the elevated VLDLs. If you're looking at LDLC, you'll clearly miss some of the size. issues. That should be captured in LDLP. But again, I guess maybe what you're asking is, if you have a low APOB, but they're all small, is that worse than having a low APOB where they're all big? And the answer is probably, but you'll also see that in the, like there are other metrics that are kind of coming on board now, which are looking at LDL triglyceride levels. So you can look at the degree to which the LDLs are cholesterol depleted. And that can also,

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 sorry, 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 decilator, you're excellent. Then you're, okay.

Yeah. Where does that number come from? And, you know, what, like, has anyone measured APOB levels across the lifespan? Do we know, like, is there a correlation with APOB levels and the beginnings of atherosclerosis? Has someone done those studies, you know, that sort of thing? Yeah. So the reference ranges are purely populated. 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, so for the lab we use, and by the way, we completely ignore these reference ranges, but they're there. We can't avoid them. They're there. And we explain to our patients that we're going to editorialize on top of them. But, you know, the reference lab we use, we'll say APOB 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 it's literally just putting you up against a population distribution and that's that's it. Now our philosophy on APOB is completely different and um, as you may recall, I devote actually quite a bit of real estate to this in the book because I think it is such an important concept. And it is, in my opinion, certainly top three failures of Medicine 2.0 is in failing to appreciate the point I'm about to make, which is that once you understand the causality of APOB, meaning once you understand that APOB is not just associated with cardiovascular disease, but it's cause. causally linked to it, meaning it causes ASCVD. 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 with lung cancer smoked. So you don't need to be necessary and sufficient, necessary or sufficient to still be causal. But our approach to

patients who smoke is very clear, which is never smoke. And if you do smoke, stop immediately. do we look at people who smoke and say, well, once your 10-year risk of lung cancer reaches this threshold, we're going to tell you to stop smoking. Or once your pack-year smoking is above the 50th percentile or the 80th percentile, we're going to tell you to stop. Absolutely not. You immediately eliminate smoking. And so similarly, it makes no sense that we would look at a causal driver of ASCBD in the case of APOB. and kind of take an approach of, well, being at the 20th percentile or the 30th percentile, the 40th percentile is acceptable. None of those things really makes sense. You have something

that is causing the disease. You should eliminate it as soon as possible because it is an area under the curve problem. So atherosclerosis begins at birth. 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 forget, I think maybe 26 years old who was a victim of a homicide or something. So a 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 APOB. So to be able to take that off the table sooner rather than later is going to certainly has the potential to take atherosclerosis off its pedestal at the top of the list of killing. And so what do you, I mean, you obviously can't take it off the table completely, right? We need APO B. But what can you do? So let's think about it. Yeah. So let's start with what we know. Apobie rises with age. Right. We don't really know. There are probably a lot of little reasons. So there are endocrine changes, insulin resistance, senescence that might involve the decreased life of LDL receptors. There's no clear reason, actually. What about, so you were talking about clearance versus synthesis. And I remember our mutual friend Ron Krause. Like I've had,

you know, 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, you're basically, your liver is constantly producing it. You're making VLDL, just churning it out, right? It's just going, going. And we also make LDL-D-Novo, by the way. Right. Yeah, there's a de novo pathway plus the VLDL to LDL-Pathom, yeah. But that, you know, the thing is, is that, you know, he was saying, well, from an evolutionary perspective, you're making this VLDL because, as you mentioned, you know, it's transporting things throughout the body to other organs, right? cholesterol, triglycerides, radii acids. It's also transporting, and this is where I was so intrigued, inflammatory protein.

So cytokines, Cerecta protein also are being transported through VLDL. Now, that was important, pre-A, antibiotics, pre-E, 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 too. And that's why he thinks, you know, it's kind of a relic left over where the reason why we're constantly making is because it's a very large protein in size. It's like tens of millions of like the unit versus like 50,000 or something. It's very big. And so it takes time to make it. And so I was thinking, well, like, inflammation also does make it go up even further at the level of synthesis. I don't know exactly the clearance, you know, how it's regulating clearance.

But do you think the aging process is mostly affecting the clearance of it? 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, meaning 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'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 Kastelin 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 APOB. Like, this is the other thing. Like, most species don't have APOB. They don't require LDL. But how, I mean, they have cholesterol, but they don't, they don't, they don't require. Transporting all these, you know. You can do it with HDL. You can transport everything with HD.

Yeah. Yeah, they don't need the LDL. But I thought HGL was always going in reverse. Like, it was bringing everything back to, you know, No, it's actually much more complicated. I mean, in us, LDL is doing the majority of what's called reverse cholesterol transport. So RCT, which is kind of like the good movement of cholesterol. You sort of think of the bad movement as taking cholesterol into the arteries. The good movement is taking it back to the liver. In 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, 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 ATPs that are required to make a molecule of 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 us no benefit today because today we can make plenty of it. And we are in an energy abundant environment, which we were not in hundreds of thousands of years ago. And so this is a bit of an unfortunate vestige of our past. Much in the way that a lot of the things that lead to insulin resistance are a vestige to 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 primarily our capacity to store excess energy in a way that even primates can't. Again, it served us really well until 150 years ago. And I think the same is probably true of cholesterol and APOB.

So going back to your question, how much APOB is enough? Well, it turns out you don't really need any of it to be perfectly fine. So if you look at a child, they're born with an LDL cholesterol or APOB level. typically below 20 milligrams per deciliter. So a kid, if you think about it, has the greatest need for growth, right? So you think about the cholesterol demand of myelinating the entire central nervous system, all of the enormous explosion of stroidal tissue, all of these things are done with lipoprotein levels that are incredibly low.

Again, what we call physiologic levels of LDL cholesterol and APOB are in the order of 10 to 30 milligrams per decilier. And yet there are no negative consequences to such low levels of that lipoprotein burden. And it's only when we get, you know, would become teenagers and in our 20s, then we start to see those numbers go up. And again, that's really just reflected by a reduction in clearance than some need for additional LDL. We don't have it. 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 oscarosis 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 has argued and I reference him in my book that if you had an APOB 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 anthroxor? Like, what about, like, if 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 a pharmacologic intervention. Yeah.

Yeah. Do you think that you 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 apob, and 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... Exactly. So again, very similar to smoking, right? We talk about risk in pack years of smoking. So if a person smokes a pack a day for 20 years or two packs a day for, you know, 10 years, you have a way of kind of comparing apples to apples on those things. So to have a lifetime ceiling of 60 would also be a very, very low-risk individual.

60 milligrams per deciliter is about the fifth percentile at the adult population level. So then that comes back to my question. Sorry, one other thing I would add. I'm measuring across the lifespan. When do you start measuring this? Like, people aren't measuring their APOB in their, you know, teenage or 20. Yeah, I mean, I would argue we should be. But I want to go back and say one other thing about your question, which I should have mentioned earlier, which is it also depends on other risk factors.

So there are really four big things that are driving risk causally. APOB is one. Insulin resistance is one. Hypertension is one. And smoking is one. Those are the big four. So you have to take everything we're saying on the APOB front and acknowledge that those other things are also causally linked to ASC, vd. So, again, it's a difficult situation to imagine, but it's certainly, at least theoretically plausible.

You have somebody whose APOB is at 60, but they have uncontrolled hypertension, type 2 diabetes, and they smoke. I mean, you could certainly arrive at that situation pharmacologically. 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, you know, at the outset I mentioned how the, you know, the downside of talking about ASCBD, is the number one killer. I mean, it's, you know, in fact, when you talk about it globally, the gap between ASCBD 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. But the good news is our understanding mechanistically of what drives this is so clear. And our tools for prevention are some of the best

and most benign. Okay. So let's say that a person is relatively healthy, you know, they're committed exerciser, they're not insulin. I do want to talk about hypertension and insulin resistance, but okay, healthy, generalized quote-unquote healthy person, right? Once to lower their APOB, they want to try everything through diet, through lifestyle. And you mentioned there are some major lifestyle dietary factors that can increase APOB. 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 there are really two ways we make LDL, we make LDL directly,

but most of the LDL is made through VLDL. So if you're exporting a lot of VLDL, what you're doing is both making a lot of that lipoprotein, but you also have a lot of triglyceride in it. Now, something I didn't mention a moment ago that's worth restating, or stating in the first place. the LDL is carrying around both cholesterol and triglyceride. And the more cholesterol there is, all things equal, the more LDL you need. But the same is true with triglyceride. So the first mechanism in which we see a very clear relationship between diet and APOB is the higher the burden of triglycerides, the higher the burden of APOB.

to state this another way, if you take two people who have the exact same level of LDL cholesterol and the same total cholesterol, but one has very high triglycerides and one has very low triglycerides, the former is going to have a much higher APOB and therefore be at a much higher risk of atherosclerosis because they have more cargo and therefore require more ships in the analogy of cargo being cholesterol and triglycerides and the ships being the lipoproteins. So step number one is lower the triglyceride as much as possible. And the triglyceride being low is an enormous proxy for insulin sensitivity. So this is one of the important ways in which managing insulin resistance is a key to keeping APOB in check.

And of course, there are other issues as well. So insulin and glucose by themselves, when elevated, also create problems at the endothelial level, which becomes another mechanism by which this is problematic. It's pretty clearly observed from a dietary pattern perspective that carbohydrate restriction is the most effective tool, a triglyceride reduction. All carbohydrates? I mean, like vegetables, fruits,

and fash. Yeah, refined and starchy carbohydrates. Yeah. So, but that actually feeds really nicely into the next observation, which is what's the next dietary pattern that impacts apo-gene? be, and that's saturated fat consumption. And the reasons for that are twofold. So the first is that saturated fat directly impacts cholesterol synthesis. Now, this is not true equally of all saturated fats, but we don't really have great data on if certain saturated fats have a greater impact

on cholesterol synthesis relative to others. For example, a C-16 might be potentially more so than a C-18 or a C-19. But again... What foods would you find a C-16 version? Oh, like a C-16 would be more in, I believe, like a coconut oil or a palm oil or something like that. Also, by the way, you would also see that more, a C-16, like a palmitate, would be more of a saturated fat you see in response to insulin resistance. So it would actually be a de novo saturated fat synthesis. So perhaps, so I think that's a big part of it. I think cholesterol synthesis is a big part of it. I think a bigger part of it might be that excess saturated fat inhibits the sterile binding, the sterile regulatory binding protein in the liver that results in

fewer LDL receptors being made. So saturated fat therefore has two things that it's doing that are driving up APOB. And the susceptibility of this varies from different individuals. So I was on a ketogenic diet for three years. I was not one of the people who seemed to suffer from this. So even on a ketogenic diet where I was getting 80% of my calories from fat and probably half of that was saturated fat, I did not have any sort of obnoxious increase in my APOB or LDLC or any of these metrics. Similarly, we have some patients who are on, you know, very low carb, very high fat diets. Some of them have completely normal levels of lipids and some of them have lipids that go absolutely haywire. So it's not entirely clear what the difference is, but clearly there are different genes.

that will allow certain people to metabolize that saturated fat safely while others do not. So I'm not in the camp that believes that, and there is an entire camp of people who believe this, that if you're on a low-carb, high-fat diet and your APO-B and LDLC 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 your APO-B 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 your lipids get out of whack. So those are basically your big manipulations dietary-wise. It's the composition of fat, the quantity and composition of fat and the dietary choices that address insulin sensitivity. So on the people that, let's say, they're eating a higher saturated fat diet, if they swap that out with mono-unsaturated fat or even polyunsaturated fat, which some camps also like to demonize the kind of polyunsaturative fat. But if you swap that out, their EPOB levels. In our experience, about half of the people who have this hyper response to saturated fat, if you isocolorically shift them to high mono unsaturated 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. Like they sort of, you know, they're like, okay, well, I'm doing this, you know, ketogenic diet and I'm just going to basically eat coconut oil and palm oil. Like, it's my job. Yeah, yeah, yeah. And so for those people, you just got to say, dude, like, stop doing that. Just like use olive oil on your salad and like, let's be reasonable. And then it fixes everything.

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 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, they actually become insulin resistant, a lot of them, because they're really over-consuming a lot of poor quality carbs. And they're 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 devil's in the details on what constitutes a reasonable versus an unreasonable low-carb diet. But the point I try to make to people is,

I believe that using nutrition to solve the lipid problem is not a good solution. I think use nutrition to solve the nutrition problem. Use nutrition to address energy balance, protein needs, anabolic structure, energy, all of these other things, and let your lipids fall where they may because this is one of the few areas in medicine

where we have amazing pharmacologic tools. most of medicine doesn't really have great pharmacology if you stop to think about it. Like, we don't have great. There's nothing pharmacologically that's adding brilliance to our Alzheimer's prevention strategy or our cancer prevention strategy. I mean, we have some stuff, but it's nothing compared to what we can do with blood pressure and lipid management. So I always say it's hard enough to find the 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. No, just acknowledge it's not a good thing, but we can fix it with, again, myriad tools that didn't exist 20 years ago. Are there people that are genetically, have genetically low APOB? And if so,

So what's their cardiovascular mortality, their all cause mortality? Yeah. So there are people. So it turns out APOB and LDLC 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 ASCVD. So you have all of the epidemiologic data, which again, epidemiology is rife with problems.

But, you know, when the data. is pretty much all in the same direction and you have the dose effect and all these other things becomes quite helpful. You have all the clinical trial data, which I would divide into primary and secondary prevention data. And then you have the 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 randomized it across people, and you can look at outcomes of interest.

So in the case of LDLC, because we know it is highly genetic, right, this is clear in that, and I don't just mean in extreme cases, but just across a population, you can see that lower lifelong exposure to APOB or LDL produces lower ASCBD risk over a lifetime. So using this, we can say there are people at really low and high extreme. So with a high extreme, you have the people who have what's called familial hypercholestrolemia, 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 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 LDLC or APOB. And the most interesting group of these are the people who are folks

that have a hypofunctioning gene for PCSK9. So Helen Hobbs made this discovery in probably the early 2000s. my vague recollection. I remember reading this paper when it came out. It 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 LDLC of like 10 to 20 milligrams per deciliter. And these are adults, right? So 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 hypofunctioning protein. And PCSK9 is a protein that degrades LDL receptors. Now, another subset of these people, their mirror opposites, were discovered several years earlier, which had a hyperfunctioning PCSK9 gene, or a gene that produced a hyperfunctioning protein, and these people had sky-high LDL cholesterol. They were a subset of the familial hypercholestrolemia syndromes.

And these people weren't. And what was interesting to note, is that they just didn't develop cardiovascular disease. So I can't tell you what their life expectancy is because I haven't looked at those data, but what I did confirm is they have no increase in the incidence of any other disease. So in other words, they're absent ASCVD, but they don't make up for it with more cancer or more neurodegenerative disease or more diabetes. 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, low cholesterol. People with low cholesterol have a higher-all cause mortality. They're more likely to die from, you know, all these different causes of death. Yeah, the problem with those studies is, I mean, I'll only address this once because I've done so much addressing this that I realize you can only. only waste 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, you're sampling a subset of people who

are at very high risk for a disease, typically two diseases, right? When you have very high LDL, you are at risk of ASCVD, cerebral vascular disease, and Alzheimer's disease and all causes of dementia. So therefore, the people who are at high risk for those are typically. the people at a population level who have the lowest level because they're being treated the most aggressively. So this is kind of the problem with that stuff. I'll give you an example.

There's a clear association in the epidemiology. It doesn't come up often, but it's come up from time to time that the lower the LDL cholesterol, the higher the risk of cancer. This is a great example of when 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 PCS K9, right? So when you were talking about we have pharmacological interventions that do very nicely lower APOB. One of them is... PCSK9 inhibitors. Exactly. Came right out of Helen Hobbs' observation. So I wanted, let's, you know, let's touch on 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 edit, you know, and you're changing, you know, a nucleotide to essentially make a PC. Or the people that you're talking about walking around, right, with no ASCV. 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 drug called, oh God, I'm always blanked on the name of this like tripanol. So this was done in the 1950s. Yeah, well, there's a reason you never heard of it, right? So it turned out to be a really bad drug. So there was a, there used to be a day when, again, in the 1950s and 1996,

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. it turned out this drug lowered cholesterol by inhibiting an enzyme that was the final enzyme in this step that we used to make cholesterol. So we make cholesterol using two pathways, but one of the pathways results in a molecule called desmosterol, which gets converted into cholesterol. So there's an enzyme that facilitates that and this drug blocked that enzyme. And as the result, cholesterol levels went down. And although no one was really paying attention at the time, desmostral went sky high. And it lowered cholesterol. So on the basis of that, this drug was approved.

And back at the time, that was the only thing you were monitoring was total cholesterol. But it was found that the patients on this drug, even though they had lower cholesterol, had a higher incidence of heart attacks. So the drug was ultimately pulled in the 1960s. We now know today that it was almost assuredly the case that the desmosterol was even more atherogenic than the cholesterol, or at least as arthrogenic. So fast forward to the 1980s, the next time. So fast forward to the 1980s, the 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 one

synthesis of cholesterol. If you synthesize less cholesterol, that's one way to lower it. As you noted, all that cholesterol is making its way back to the liver. When the liver gets a hold of all that cholesterol, it's putting a lot of it into bile, and we're using bile acids to digest food. So as bile via the bile duct is entering the small intestine, it is full of cholesterol. The body reabsorbsorbs much of that cholesterol. So each of the enterocytes, which are the gut cells that line your intestine, they have a couple of transporters on them. So one of the transporters on them, it's called a Neiman Pixie, one like one transporter. It absorbed. all of the sterols.

And this is, I use the word sterile very carefully to distinguish it here from just cholesterol. This is zoosterol and plant sterile, which is, or an animal sterile, which is called cholesterol. It absorbs that all. There are basically regulatory steps inside the cell that determine how much of that should be kept and how much should be excreted. And a fraction of that then gets excreted through an ATP binding cassette. So point being, that's a second point of regulation at the absorption site. But again, this is not the cholesterol we eat. This is un-aesterified cholesterol.

It's easy to get in and out of the body. Asterified 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, of drugs to lower cholesterol, which are not used today, blocked that process in a very crude mechanical way. They sequestered the bile acids and dragged all the cholesterol out.

the GI tract. They were not a very successful class of drugs, and not the least of which because the side effects were pretty bad. So it really wasn't until the mid to late 80s, probably I think 1987, if my memory serves me correctly, that the first statin came to be developed. And that was the real turning point in basically the pharmacologic tool that became valuable against ASCVD. 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 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 an effective 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, the liver says, 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? Well, about 7% of people develop muscle aches on statins. So 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 subset of people, about 0.4% of people put on a statutes. might go on to develop type 2 diabetes as a result of it. Now, I think any doctor who lets a patient get to the point where they get type 2 diabetes because of their statin 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 wear a CGM? One of the reasons we like CGMs 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 or an increase in the transaminases or the liver function tests. Liver function test is a bit of a misnomer because the transaminases really tell us more about inflammation than function. So all that said, statins are still kind 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 isetamide.

Can I interrupt for a second and ask you about statins? Yeah, yeah, of course. Because I have some questions about them. So I'll never forget this conversation that, again, I had with our mutual friend Ron Krauss. Because I worked down the hall. I worked down the hall from him. And I collaborated with some of his postdocs. And, you know, they would come over and show me data and we would talk because, you know,

I had a lot of experience in assing mitochondrial function and mitochondrial biology. during graduate school. And I remember saying this to Ron, I'm like, you know, so statins are affecting the HMG co-papaa that you mentioned, the cholesterol synthesis, which also is important for the synthesis of ubiquinol, right? This is an important, or co-cutan, as I should probably call it. This is important for mitochondrial function. I mean, it's necessary for mitochondrial function for transferring electrons across the electron

transport chain, which is essentially coupling the oxygen we breathe with the food that we eat to make energy. And I remember saying, oh, so statins have a side effect of targeting mitochondria. And he said to me, no, it's a direct effect. So what are your thoughts on how statins are affecting mitochondria and through this pathway? And obviously you might mention supplementation with a, you know, reduced form. Eibiquinol. measuring mitochondrial function in terms of B.O.2 max, something. Yeah. So it's a great question, actually, and something I have thought a lot about. So 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 mitochondrial function, which is zone two 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 I think it's, I'm glad you brought this up. So everybody understands what the mitochondria do. If they're, you know, listeners of your podcast, we don't need to explain the mitochondria. But it's important to understand that a functional test is a very important test in medicine. We don't have many functional tests, right? Most of the things we talk about are biomarkers. 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 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 demand where we can control the work that they have to do. And we can drive up the amount of work they do while sampling lactate. And what does that tell us? Well, just to remind everybody, you know, glucose enters a cell and it basically has two fates, right? So glucose will be converted into pyruvate regardless. It has the fate at which oxygen is plentiful and the body has the time to make a lot of ATP where it goes into the mitochondria.

And it has the less efficient but quicker way to get ATP, which is converting lactate, pardon me, parruvate into lactate. So this is the glycolytic pathway versus the oxidative phosphoryletic 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 accumulate, eventually the cell becomes effectively poisoned by that hydrogen ion and it becomes very difficult for a muscular cell to contract. So we use this test with patients. is one of the most important metrics we care about. Literally, it would be in the top 10 things we

care about for our patients, which is how many watts can you produce on a bike or how many Mets can you exercise at on a treadmill or whatever vehicle you're using while keeping lactate below about two millimol. Two milamol is about the threshold, beyond which you are now shifting away from the maximum capacity of the mitochondria to 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 impairs complex one of the mitochondria.

We immediately see a change in the lactate performance curve of an individual on metformin. We see a complete reduction in their zone two output. They hit that lactate of two 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 gyroprotective 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... Just don't see it. Yeah.

Just don't see it. So it could be happening, but we don't have the resolution to measure it. 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-Q10, and there are two states of it, ubiquinol and ubiquinone, but ubiquinol would be the state we would want to consider here. There have been a number of clinical trials looking at using or supplementing ubiquinol with

patients taking statins. They have mostly done this to assess the muscle soreness issue. So they've mostly done this as a way to ask the question, can you reduce the incidence, the incidence rather, of muscle soreness with statins? I haven't looked at those literature in a couple of years. The last I looked at them, there was still no difference. That said, we have patients that really feel strongly about taking ubiquinal 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, then 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 using the zone to, you know, lactate threshold training to kind of measure mitochondrial function. So buying the lactate meter, Nova Diagnonaut, no, Nova biomedical or something like that. Yeah, yeah, yeah. It's like a yellow purple one. I got it per your, like, recommendation, but for people listening if they want to get one.

But also knowing, like, how, you know, because there's, when you go to like any sort of, if you were to go talk to exercise physiologist and you see lactate threshold like they kind of know. And they're going to push you up. Lactate threshold is a different number. Right. So this is like lower level. This is below your lactate threshold. Yeah, this is lower.

So how do people know, like let's say they have a peloton at home, okay? And they get on their peloton and they want to do a zone two test. Okay. Can you somehow use a, you know, percent max rate, a heart rate, sorry, max heart rate, like proxy to kind of know. No, like, yeah, there are lots of different ways to estimate this. And to be clear, like, I'm one of the very few people that is checking his lactate every, you know, every day that he's on his bike, which is four days a week for me. And by the way, I'm also doing it while using all the other metrics that I'll explain in a moment, mostly just in an ever, never ending quest to just have as much data as possible to understand when is lactate the best predictor? When was RPE the best predictor? When was heart 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 meter. I don't want to be poking myself in the finger. I'm like, great, don't. You don't have to. There are like other ways that you can pretty much approximate your zone two 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 metformin 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 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 diabetes, their resting lactate may already be at two.

So in those patients, we actually never use lactate. Until you get somebody to a certain level of fitness, we only use rate of perceived exertion. And we will provide heart rate guidance. So here's two ways to think about it. RPE, rate of perceived exertion, we give people the test, which is the talk test. So when you are in zone two,

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 you can't speak in a full sentence, you're not in zone two anymore. You're north of zone two. If you can speak the way you and I are speaking now, 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 it and you can speak in a full sentence, but you're not that comfortable. That's the single most important thing people need to understand about it. As far as what heart rate guidance comes with it, Phil Maffetone uses a test that I think is a pretty good starting place, which is 180 minus your age. Now, the fitter you are, the less relevant that becomes. So I'm 50. So that would put me at 130, but I can tell you my zone two is.

above 130. So if you're fitter, you may add five to 10 to that. I use another app that checks my HRV every single morning and it predicts my zone two as a result of my HRV. And so every day, what I'm doing is I'm looking at the heart rate predicted by the app, which can vary by as much as 10 beats per minute based on how much I slept, the quality of my sleep, how sore I am. a subjective measurement of how much I want to train that day and my HRV. So it's a, what app is it? It's called Morpheus. Morphus.

Yeah. So I have no affiliation with it or anything like that. So, so basically, so this morning I got up. My HRV was, I don't even remember, 78 milliseconds, 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 lactate is. That'll generally put me in a lactate of 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 do. know 180 minus your age is good. And then if a person is fit enough that they truly know their

maximum heart rate, we tell them to start at somewhere between 75 and 80% of that number. Great recommendations. If so if a person is specifically trying to do this functional mitochondrial test, how long should they be in that zone two before they can measure their lactate? We'd like to see people there for 30 to 45 minutes. before we do it. Yeah. So a 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, HEM COA in the brain, particularly at higher doses. But generally speaking, what question should I be asking myself to convince myself that it's not going to put me at a higher risk for both of the 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, the literature, as you know, is, you know, you can find what you want, right? So do you have any, you know, advice for me? I did a recent AMA on this, although it might not be out yet. I lose track of when I record them and when they come out. So I apologize if it hasn't come out yet.

But I did an entire AMA 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 was surprised to learn that there has never, oh, I shouldn't have been surprised, but forget this. Here's what it is. There has never been a study 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 determine. 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 ASCVD, but a secondary outcome of dementia or Alzheimer's disease. And I looked at every single one of those. And I can tell you that every single one of those found neutral to benefit of statin use on the incidence of dementia and the incidence of Alzheimer's disease. So that includes vascular dementia. Vascular health is, I mean,

that sort of makes more sense. 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 and talk about Alzheimer's disease because I think there's an important caveat to everything I just said. What I basically, oh, the other point I want to make, Rhonda, this actually surprised me. There was no difference between 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, well, gosh, you know, a statin that gets in the brain should have more of an impact. It didn't seem to have one. Is there a difference in those two types of statins with respect to the diabetes increased diabetes risk that you're talking about? That's a really good question.

I didn't look at that and that wasn't looked at in this. Yeah. Here's what I can tell you. The highest incidence of diabetes is probably with a torvastatin. But that might also be because a torvastatin is the most widely used. Like I don't. We basically, first of all, there's only four statins that I think are even worth prescribing these days, maybe only three.

And I treat them all equally in terms of risk. In other words, I would assume anytime you put somebody on a statin, you should be looking for any of the side effects. And I don't particularly, because again, at the, you might say at the population level, it's different, but at the individual level, who cares? It's either one or zero. You're going to get it or you're not. What statins are those?

The ones that we would prescribe would be resuvastatin or crested or cressor, chtar, chtor, atorvastatin or lipator, pitavastatin, livealo. And sometimes we use prevastatin or prevacol. but pretty rarely. So usually those would be a big four. 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 Day Spring gave us an internal presentation that was so incredible.

It was months in the making looking at the relationship. at the relationship between statin use and desmostrol levels and dementia risk. So you may recall a moment ago I mentioned desmosterol. So desmastrol is, well, let's back up. Remember how I said there were two cholesterol synthesis pathways? Well, in the CNS, really only you have one pathway. And it's the pathway that goes through desmosterol to cholesterol. So desmosterol levels,

are actually a decent proxy for brain cholesterol synthesis. Lothosterol, which is the penultimate molecule in the other pathway, is more of a proxy for peripheral cholesterol synthesis. Are these measured? 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 desmosterol and lithosterol in every patient with every blood draw.

Unfortunately, this is not standard of care. Most labs can't measure this. Boston Heart does this. That's why we use Boston Heart. There are enough data suggesting that if desmastral levels are very low, the risk of AD does indeed go up. And the risk of dementia beyond AD goes up. So this is kind of what I would describe as personalized medicine slash medicine 3.0 at its finance. which is you have to treat every patient individually,

and we're doubly careful in patients with an APOE4 gene and or a family history. And in those patients, based on the literature, and I'd be happy to send you Tom's presentation. He would not have a hard time with me sharing that, even though it was kind of an internal presentation. In fact, I could share with you the recording Tom made because we recorded the internal meeting because it was so valuable.

But basically the cutoff we use is 0.8. So if desmosterol falls below 0.8 milligrams per deciliter, we think the risk of dementia is sufficiently high enough that we would abort the use of the statin. Very good information. And you think there is a correlation with APOE status on that number going? No one has done that study yet. In your clinical... But in our clinical practice, we just decided like why would we take the risk?

Okay. But yes, no one has done the study to show are desmosterol 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 put people into three buckets, zero alleles, one allele or two allele, E4 alleles, and then just looked at Dismostrol levels. Like that would be a very easy, mindless study to do, just a survey. Like just a quick, is there a correlation, yes or no?

So that's one thing I'd love to know the answer to. But even absent that knowledge, our view is there's simply no reason to take the risk. You know, earlier I said it makes no sense to go on some crazy obscure diet that has a whole bunch of unintensive consequences just to control your lipids? Well, I would make the exact same statement here. It makes no sense to get all, to take unnecessary risks with statins

in a higher risk individual when we have these other tools. We have, as we talked about, or we will talk about, azetamide, PCSK9 inhibitors, bumpadoic acid. These are unbelievable tools that have no bearing on brain cholesterol synthesis. But Peter, aren't people

that have an APOE4 allel more likely to be prescribed statins based on their their LDL particle number by their physician because the physician doesn't look at their None of this. This isn't personalized. It's not medicine 3.0, right? Yeah, yeah. No, it's very frustrating.

And it's also frustrating that of those three drugs that are an alternative to statins, two of them are still very expensive. Okay, so the three drugs, I know the PCSK9 inhibitor. Yeah. Highly effective, insanely safe, zero side effects. cheaper than when they came out.

So they were approved in 2015. And we have long-term data with the natural people walking around with a natural mutation, right? 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? It's a $500 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 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 hypercholestrolemia, 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 risk to justify it. So insurance companies are going to go out of their way to not pay for this.

Okay. Then you have azetamib. Now, Zetamib is relatively inexpensive. It's just not as potent. So azetamib also effectively serves to increase the LDL, receptors on the liver, but it does so by impairing cholesterol reabsorption. So it blocks one of those two transporters I was talking about in the gut, the first one. And by blocking that, the body is absorbing way less of its own cholesterol. And the liver senses that. And the liver says, hey, I got to

get more cholesterol, puts more LDL receptors on, pulls it out of circulation. It's not as potent. And as a monotherapy, the only times we see really head over heels responses are in patients who have defective ATP binding cassettes in their gut. And we measure that by looking at phytosterol levels. So we measure two things. One is called cytosterol. One is called cytoestrol. Those are phytosterol.

So these are cholesterol we don't make. It's zoosterol. Pardon me, it's phytosterol, not zoosterol. And so when we measure those levels, we know that it speaks to how much plant sterol 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 azetamibic. It's like a blockbuster in those people.

Wow. Is that a common, you know, single nucleotide polymorphism that we have? You know, it depends 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 Heart would measure all these phytosterols. Okay.

They're more athergenic than cholesterol. Yeah. They're more prone to oxidation, more inflammatory. Are they being carried in lipoproteins? They're, so oxidized. They're more oxidized. They're more oxidizable. And this is, by the way, is a reason that we don't favor the practice of using phytosterols

to lower cholesterol. So there are a lot of sort of over-the-counter treatments where people use phytosterols to lower their cholesterol. And it does. So if you ingest a ton of phytosterols, you will out-compete cholesterol at that enterocyte, 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 sort of an example of that desmostrol point earlier where you can lower cholesterol, but if you're really raising desmosterol too much, it can be more atherogenic than cholesterol in the first place. So, Desmastrol has shown up twice today. It showed up in a good sense and in a bad sense. So too much of it, if you're using a drug that blocks the enzyme that comes after it, that was the thing that was producing too much arthroscarosis in the 60s. Too little of it could be a marker of too 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 Bampadoic.

acid that is a pro-drug. So it's a 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 betmindoic 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 risk. Nothing, nothing, nothing. It's just, it's only acting in the liver. Well, that sounds

same problem as PCSK9 inhibitor. It's a $500 a month drug. Okay. Yep. So again, we'd have every, look, honestly, at this point, like, if money were on a, were no issue, you'd probably just be on PCSK-9 inhibitors, azatomide, and, and benpidoc acid. I mean, eventually we'll get there, right? Yeah, they just have to come down on price. For people that want to, like, more clear picture of the plaque accumulation in their, in their arteries, in their, 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, know, like you think people should start at a certain age or certainly if they have measured their, you know, A-O-B and... Yeah, I mean, you know, I think there's different ways to think about this. You know, I think there's a principle in medicine that most doctors try to adhere to, which is don't order a test unless there's a chance the test will change your management. And it's easy to deviate from that.

I certainly know I do at times. But as a general rule, I try to ask myself the question. 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 you were sitting in my office and I said, well, look, Rhonda, you're 35 years old, your APOB is really high. Your family history is such that people get cardiovascular disease in your family, meaning, you know,

it's not like you've got a bunch of relatives who are in their 90s 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 is going to be normal. I mean, it might not be. Mine wasn't at 35, but it probably will be for most people. And if it's normal, will I then say we don't. need to do anything about this? No, because that's sort of like saying you're a smoker who has a

normal CT scan. You don't yet have lung cancer, therefore we should let you keep smoking. No, we should stop you from smoking. So in other words, I just wouldn't have a huge appetite for doing that test in you. There are other patients at the other end of the spectrum where, you know, they come to me, they're 75 years old, their 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 CTA? 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 two by two, which is age versus finding, positive or negative. I think CT angiograms are mostly helpful when they have a positive finding in a young person or a negative finding in an old person. That's where it can really cause you to act differently. Outside of those findings, i.e., positive findings in old people are to be expected, negative findings in young people are to be expected.

I think you should just track the biomarkers of interest and go off that risk. Okay. I mean, like, is a 45-year-old considered? I would still put that in a young category. Okay. Especially for a woman. You think that CT androgram 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. So we had a new patient 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-A. I mean, two big risk factors. But insanely healthy individual, like very, very healthy. individual. So on the surface, like nobody thought anything of 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 APOB of 60, which is still aggressive by most people's standards. By our standards, it's sort of middle of the road aggression. if the CTA comes back and there's a problem, meaning you have calcification and soft plaque, we're going to treat you to 30 or 40. So there the CTA helped us make a difference,

a real treatment difference. And this is a person who's, you know, middle age, so not too old, not too young. That makes a lot of sense. Before we, I kind of shift gears in the test, some other things I want to ask you about, have you looked, like, I know you've mentioned, it's been many years since I've heard you talk about burboring,

But 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. Yeah, what did you find? So there was a systematic review and it was 2022, I believe. and these are all like we need this is the sparse data right it's 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 it pretty much to me was convincing that it was beneficial in every single scenario so berbering alone was lowering the LDL cholesterol and I can't remember if it was particle number, but it was L-BELB. And it's interesting. Berberine is also a mitochondrial toxin. Really? Yeah.

Burberine is an analog of metformin. So it's a complex one inhibitor. Is it? Really? Wow. I didn't know that. It was like, it was to me looking really beneficial where it was like it was. I'm not saying that wouldn't be.

I'm just sort of pointing out. Yeah. Is there literature showing that? Or is it like an in vitro kind of thing where it's like mechanistically? It's been so long since I've looked at berberine. But. But, you know, Berberine is kind of a poor man's metformin. Okay.

Well, it was, and that's the way I thought about it. I think I'd heard you talk about it years ago, maybe on Tim's podcast. I don't remember. It was a long time ago. Yeah, yeah. And that's kind of where I even first heard of berberine was you. And I remember because I was like going for a run. It was when I lived in Oakland.

And then I was like, Perberin, what's that? And I remember you talking about it in the context of, I think, metabolic health. Yep, yep. And chinoids or something. Yeah. But this data on the lipids was very interesting. And I linked it in that document. Yeah, what was the magnitude of effect?

I don't like you, the document. It's in that document. It's linked the studies, the meta-analysis. You can look at it because I don't remember everything. But what I do know is it also lowered the side effects of statin myopathy, was one in particular. It lowered the dose, effective dose of statins that was needed to, you know, lower the LDL cholesterol. Very interesting, right? Yeah, I'll check that out.

I was like, you know, I actually ordered some berberine. I'm like, maybe I should test this. and see, you know, how... And there are companies like Thorn that make good... I ordered Thorn, yeah, yeah, which I have no affiliation with. I just trust their brand. Yeah, yeah. So anyways, I wanted to bring that up because, you know, I know that, again, I'd heard of

bringing from you like years ago. But speaking of metabolic health, and you kind of talked about this, you know, earlier with continuous glucose monitoring and, you know, measuring, you know, 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, HBA1C, like, what should those numbers be? But also, what is glucose disposal and why should people be paying attention to that? And can CGMs, can they use CGMs to sort of measure that?

Yeah, yeah. You know, glucose disposal is, or take a step back, glucose regulation is just, it's such a miracle of our physiology. I mean, there's, every time I think about biology, I'm really grateful that I've, you know, came to this field in one way or another because it's, it leaves you endlessly at awe of what's happening. So 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 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 cusp of being just starting to get to be too high. So what does that mean, right? What is 100 milligrams per deciliter? Well, it means that in, you know, someone my size, in all of my plasma floating around all of my body,

all of my blood, I have five grams of glucose. So do I have more than five 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 grams, 20 calories worth of glucose in my entire circulation at this moment in time. Now, if you assume for a moment that I'm just sitting here at rest and nothing in my body is demanding glucose, meaning my muscles aren't requiring it, The only organ that should be really demanding it at the moment is my brain.

Now, of course, my red blood cells demand it because they don't have mitochondria, so they're going to have to use glucose. 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 there for the purpose of my brain. And, you know, you can do the math on this. Anybody can do the math on this. within a number of minutes, I will go through that five grams. So where does the next drop of glucose come from?

It 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 system 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 bowl, which is like the size of, in my head, but just a normal size bowl, you're easily getting 60 grams of glucose. So you eat 60, 70, 80

grams of glucose. Well, remember what I just said a moment ago. Like, if your blood level goes from five 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 eight grams. 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 sensed. So 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-a-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 who's particularly fit, there's also an insulin independent system where just the contractile aspect of the muscle itself is enough to get glucose transporters up to the surface of the muscle. So people who do a lot of cardio training have this capacity to, you know, and I've seen this in patients with type 1 diabetes who do a lot of training, because that's a pure experiment where you have no insulin, you can actually see them lower their glucose without insulin just by

exercising. So the act of exercising itself can produce glucose transport across the muscle without insulin. So how does all this figure into health? Well, as we alluded to, glucose is toxic when you have too much of it. Now, I'm not going to talk about acute toxicity. So if you ever walked around with like 40 teaspoons of blood, 40 teaspoons of glucose in your bloodstream, you 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, 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 process by which proteins become sticky. And so as the proteins in our blood get glycosylated and get sticky, year. One, their function is lower, but two, they also tend to obscure the narrowest part of our vascular system. So the tiniest, tiniest, tiniest capillaries become more occluded, and therefore it's harder to deliver oxygen to those tissues. So the canary in the coal mine, believe it or not, of microvascular 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, they're actually able to do something that no one else gets to do in the body, right? Like we don't look directly at the vascular system elsewhere in the body. And they get to do that. They get to shine a light directly onto those capillary beds. So as a general rule, 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 macroscopy or 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, 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, to people now, when those glucose levels are chronically elevated, the body wants to fix it.

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 post-pranidial hyperinsulinemia, is the metabolic harbinger of all this stuff. And so the major, obviously, it seems like a lifestyle factor that is regulating, you know, glucose disposal, insulin sensitivity. I mean, it seems like both of these things are affected by the contractions of muscle and increasing those glucose transporters, right? Exercise is probably the single most important thing we have at our disposal to increase insulin sensitivity.

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 unambiguous, right, where you disrupt people's sleep. You know, you take, if you just took a normal group of people and you did like what's called a eoglycemic insulin clamp, which is an experiment where you run IV glucose and IV insulin to people and you basically run a fixed amount of insulin into somebody and then determine how much glucose you need to put in

to keep their glucose level fixed. That's called a euglycemic, keep glucose fixed. That's the gold standard for measuring insulin sensitivity. So you do that test on somebody. And then for a week, sleep deprive them for, you know, down to five or six, four hours a night. Call it four, four 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 difference. So we don't know exactly why that's happening, but it's a very repeatable observation. So sleep disruptions impair this. Energy imbalance impairs this. Hormonal changes impair this, right? So as we age, both the reduction in estrogen and testosterone impair this.

Hypercortosolemia impairs this. And then of course, inactivity is the greatest thing that drives I definitely didn't do the exact experiment you're describing, but I've mentioned it to you before. I had my CGM and when I was a new mother, it was, you know, clearly my sleep was being disrupted. I was getting up and breastfeeding and, you know, I mean, it was like night and day difference in my fasting blood glucose, my glucose disposal, my postpranial levels. I mean, it was like clear. Oh, yeah. We would have asked you to take that CGM off. That would be an awful time to wear a CGM. But I did find that my going to my hit class, even though I was like just dog and tired, like the last thing I wanted to do. Yeah, yeah.

Really did normalize it. So is there a post-pranthial level that like, you know, let's say someone's not trying to do a low-carb diet. Like they're not trying to like, because that's a whole other area, right? But like they just, you know, they're eating maybe a more omnivore diet and more paleo-ish or Mediterranean-ish, right? is there a level that you think post-preandial, you know, glucose level, like a threshold that would signal like, oh, you shouldn't really be going? It's hard to say. I mean, 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 one data to tell you that because the study's never been done, but I can tell you that by proxy based on hemoglobin A1C 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%.

That translates 6.5% is an estimate of an average blood glucose of 140 milligrams per deciliter. So assume for a moment that if you have a CGM that says 6.5%, meaning you just trigger the threshold for type 2 diabetes, your hemoglob, 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 130, 120, 110, 100? Like, at what point does, is it too low? And what the hemoglobin A1C data would suggest is being at 5%, which is about an average of 100, is better than being at 5.5%, which is an average in the one teens. Both of those are normal by our current definitions.

Neither of those would be pre-diabetic even. So 5 and 5.5 are both considered completely normal levels. But the all-cause mortality data, or the data on all-cause mortality suggests a better outcome if you're at five rather than 5.5. Okay. That suggests to me, by proxy at least, that an average blood glucose of 100 on a CGM would be better than that of an average blood glucose of 115. So that's the single most important metric we care about.

We use other metrics to think about that. So that, since we can't measure insulin in real time, looking at post-pranthial 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 that 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 desk leader by CGM, but one arrived at it with, you know, levels like that and one arrived at it

with levels like that. The former would be a better way to achieve that than the latter. But, you know, there are lots of things that raise glucose that are not harmful. For example, that hit class that you were doing, probably in the short term, really spikes your glucose because your liver is really trying to meet the demands of all that exercise. So it's putting a ton of glucose into your circulation, and it's going to do the right thing, which is always air on the side of too much. Because in the short term, it's better to have too much than too little. So if I'm wearing a CGM doing a really hard workout, I mean, I'll see that glucose get to 160,

which is higher than it will get with a meal. That goes right back down. Yeah. So what do you think about, by the way, this is all great info. What do you think about, so metabolic flexibility, being the capability to shift between using glucose as a substrate and using fatty acids. I mean, this is something. This is the zone two thing, right? This is exactly why we train that zone two system. And that's why, you know, we have our patients spend 80% of their cardio training time in zone two. That's really pushing that metabolic flexibility.

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 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 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, of course. 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 maxes of any humans on the planet. And we know that they are the most metabolically flexible of any

humans on this planet. Now, my experience is far more with cyclists. And so I usually just talk about this through the lens of a cyclist. 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 meters and we can get the numbers. A world-class cyclist is able to put out four watts per kilogram of power while keeping lactate below two millimol. In fact, the best cyclist in the world are probably at about 4.2, 4.2.4.4.4.4.5. 3 watts per kilo.

So let's just do the math on that if someone's listening to this and they've ever been near a power meter. So if you're 80 kilos, you're 175 pounds, that means you're able to put out 330 to 340 watts, which, by the way, most people who weigh 80 kilos can't do that for one minute. Literally, they can't do that for one minute. These people can do it for hours and keep their lactate below 2 milamol. it's the single greatest demonstration of metabolic flexibility that you will ever see. How do these people train?

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 V-O-2 mag. and to produce the greatest degree of metabolic flexibility, you think of it as a pyramid, where the base of the pyramid is your zone 2 efficiency, and the peak of the pyramid is your VO2 max. And the area, total area of the pyramid, is your cardiorespiratory engine. So you want not a narrow base with a high peak, not a wide base with a short peak.

You want a big base, big peak. And the way to get that is about 80-20. If you try to do too much high intensity, 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 both the breadth and 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 a week? I'm not going to tell you what you need to do. Let's start with you telling me what you're willing to do. And then the simplest approach is we'll put half of that into strength and stability, half of that into cardio. Of the cardio, it's 8020. 80% of that will be zone two. 20% of that will be VO2 max. And V02 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 not the best way to get there. It's a good way to get there. And we know, like even just looking at the Tabata studies, right? Tabata's neither one or the other, right? Like a 20 on, 10 off times eight rounds is neither a pure zone two.

It's way too hard even for VO2 max, actually. Because VO2 max, sweet spot is three to eight minutes. with one-to-one rest to recovery. So three on, three off, three-off, three-off. That's a lower intensity than most people are doing in a hit class. Most people in a hit class are doing shorter intervals and pushing much harder. I just had a talk with Marty Cabala, and I asked him that question. And he was like, Rhonda, you got to do more three. Because I was like, I want to do VO2 Max training.

This is what I do. I do a lot of the, you know, I'll do 16 rounds and I'll do 20 seconds on, 10 seconds off, right? But my 10 seconds off, I mean, my heart rate's still pretty hot. So he's like, you got to do like three minutes, at least one, you know. And so I've shifted my training now to doing. And it's absolutely true. I am not going as hard. You can't.

Yeah. 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 too 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, oh, I actually could have gone harder. And that's okay. Like you'll sort of figure out what that sweet spot is. But that three to eight minutes is the optimal zone for generating VO2 max power. Right. Yeah.

So metabolic flexibility, obviously hugely important. VO2 max 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, you know, metabolic flexibility if they're doing, does that, like, affect metabolic flexibility, like if you're doing more? Yeah, it's tough to say. There, I think there may be a bit of a confounder there. So, um, I used to think so. Um, I'm not sure anymore, truthfully. So the obvious confounder there is if you're on a completely carbohydrate restricted

diet, you're respiratory quotient. So from a functional standpoint, one of the ways we, how do we measure what you're oxidizing? So when a person does a CPET test, a functional test, like a VO2 max test, we're measuring O2 consumed and CO2 produced. So have you done a VO2 max test yet? I haven't. Okay. So you'll, can you just go to any doctor or do it? Typically doctors don't do it. No, you typically go to, well, when I lived 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 100 bucks or something like that, right? So they're going to have you do it in one of two ways, which is a bike or a treadmill. And I always tell patients, do it in the way. you train because there's a, you know, there's a, you don't want to take a cyclist and make them do the running test or vice versa. So it sounds like you're doing most of your work on a Peloton. So you would do it on a

bike. Because you're going to sit on a bike and they're going to put a mask on you and it's super uncomfortable. The mask has to be incredibly tight. It can't have any interference from the outside world in terms of air that you're breathing can't escape and no air from the outside can get to you. There are two gas sensors on the outside of the mask. One for O2, one for CO2. This is the bread butter of this whole device. If those sensors aren't calibrated correctly or they don't work, the test is meaningless. And like one out of ten times they fail. So you've got to make sure whenever you're doing this test, the tech who does it has calibrated this thing and knows what to look for if the calibration fails during the test. We just had a patient do one recently. The test

failed. So you're going to be put on a bike and it's going to be an ergue, which means unlike the Peloton where you set the resistance and how, like let's say you have the resistance at 50, well, that doesn't determine the wattage by itself. How fast you pedal also determines the 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, Rhonda, 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. And they're, you know,

Within about 15 minutes, you're going to be in crunch time. And at that point, they're probably going to increase the wattage every minute. And you're going to, you're in the pain train has left the station. Like, this is unpleasant. And you have to keep your RPM's 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 when you're riding that peloton, you're in that you're really comfortable in that 80 to 100 zone of RPM. 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 they know your heart rate at every moment in time. They know how many watts you're generating because you're generating by definition everything they're sending you. And then they're measuring VO2, so ventilation 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 you're oxidizing versus how much glucose. when that ratio is 0.7, you are 100% fat oxidizing.

When that ratio is 0.85, it's about 50-50. When that ratio is one and above, you're all carbohydrate. So what you'll want to see when you do the test is you won't want the report, the summary. You will also want the raw data, which is pages and pages of a spreadsheet, and you'll kind of go. through and you can see how these things change. So when I used to do my tests, I used to plot my own data. I would just get the spreadsheet and I would make the fuel partitioning curve. So what I would draw would be a curve, 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. And on the Y axes, 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 as the test starts. So it usually has an early peak and then comes down as intensity goes up and carbohydrate oxidation just rises monotonically. And there's where those two cross, some people call that your anaerobic threshold, but that's where your respiratory quotient is equal. If you've done this in calories, if you do it in grams per minute, it won't be because obviously there's way more calories in fat than oxygen.

So one of the other metrics we care very deeply about in our patients is what is your peak fat oxidation and where does it occur? And we plot that. So we plot their VO2 max. We plot their zone two and we plot fat oxidation. 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 this on somebody who is heavily carbohydrate-restricted, you will get an artifact of the test.

because their resting RQ is very, very low. Okay. And so it's not clear what the implications of that are other than we typically will feed people carbohydrates before they do the test. Like in the days leading up. But their VO2 max won't be. It doesn't affect their VO2 max.

No, because the VO2 max is literally taking the peak V-O-2 that they achieve and dividing it by their weight in kilos. What VOTOMX do you aim for? And if you can recall, I know that JAMA 2018 paper, which was probably one of the most convincing studies at V-O-2-Max is like one of the best metrics of health and longevity. And there was an even bigger paper that came out. That J-Mah paper had 120,000 subjects in it.

There was a J-A-C paper that came out a year ago that had, almost a million subjects in it. And it showed the exact same findings. Do you, so the findings, if I recall, was like... Both of them are in the book. I think I have figures from both of them in the exercise. Do you have the numbers in there? Okay.

And that, so that was like the top, I just remember it was like the top percentile. I mean, they had like 80 percent lower. The top, yeah, if you compared the top, the difference in risk between someone in the bottom 25 percentile of VO2 max to the top two and a half percent, has a hazard ratio of five, meaning it's 400 times greater all-cause mortality if you're in the bottom 25% versus the top 2%. Okay, so if I want that number, do you know it?

Or, I mean, what's like the top? Yeah, are you 30 to 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 I can put that right now. I would guess that it's about, it's in the high 40s. Okay.

Yeah. So roughly, probably like 46, 47, 48 milligrams, sorry, milliliters per minute. So I probably have more work 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. I have a very personal, personal interest. in this. I love it.

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 age, right? Yes. Unless you include, yeah, if you don't include modifiable risk. So, yeah, we generally talk about modifiable risk. Okay.

Yes. Age is the greatest risk for all disease, including cardiovascular disease. The biggest modifiable risk factor. So let's talk about modifiable risk factors, like obesity. Smoking is number one. Smoking. Okay. Still number one.

Of course smoking. I always, like, it's easy to forget. Duh, you should not be smoking, but it is easy to forget. It's like, oh, yeah, people do still smoke. It's hard to fathom that, but addiction is addiction. So smoking is the number one. Smoking is still the number one modifiable risk factor. What's after that?

Obesity. Obesity. So why do you think obesity? if you were to speculate, why do you think it? Yeah, and 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 adiposity, right? Like, 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 hyperinsulinia, 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 accumulation is very harmful. So fat accumulation is not problematic. believe it or not, despite our aesthetic preferences when it occurs in areas that we are designed to store excess energy.

It becomes problematic when it escapes those areas and gets around the viscera, gets around our organs, enters the muscle itself. By the way, that's how it directly contributes to insulin resistance. When it accumulates in the liver, accumulates around the heart within the pancreas itself,

where it serves the double role of not just creating an inflammatory environment, but also reducing the amount of insulin that the beta cell can release and also around the kidneys. So those are the main places where even a small amount of fat, i.e. if just 10% of your total body fat

were in those places, you would be at enormous risk for cardiometabolic disease. Yeah, I remember I've seen a few studies where it's like visceral fat, so you're talking about the fat that's covering surrounding your organs. you know, that was highly correlated with an increased cancer risk. And there was like there was also another correlation with like there was some specific

inflammatory cytokines that were being generated or, you know, associated with, I guess, I would say, with the visceral fat and the cancer incidence, which again, it's like the inflammatory environment like you're talking about. So the metabolic health being important, we talked about, you know, the best like exercise being at the top, right? I mean, that's one of the best ways to exercise. energy balance, sleep, and then of course, you know, management of distress, right? Hyperchortosolemia will also contribute to this significantly.

Right, which, of course, even doing things like exercise and getting enough sleep, help balance that. Right, exactly. When it comes to cancer prevention, you know, you talk a lot in Outlive about cancer screening, aggressive cancer screening. So can you talk a little bit about weighing the benefits versus the risk of that type, you know, doing more of an aggressive type of cancer screening. Yeah, I mean, the reason I think we have to pay attention to cancer

screening in such an aggressive way is that unlike cardiovascular disease, and even though we didn't really go into the pathogenesis of it today, I mean, I've covered this on other podcasts. I'm sure you have as well. It's very well understood. Doesn't mean we know everything. I'll happily spend 20 minutes telling you all the things I don't understand or that we don't understand as a community. But we have a pretty good sense of what's going on. That's not the case in cancer. It is still a really, really big black box to try to understand all the different ways in which people get cancer. And if you just want proof positive on this, I bet you there's not a single person listening to this, not one, who can't tell you of at least one person they know who's been

afflicted with cancer who otherwise did everything right. They didn't smoke. They weren't obese. They didn't have, you know, huge chemical 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 modifiable risk factors, it doesn't even account for half of it. So it's free money. Don't leave it on the table. Don't make unforced errors. Don't smoke and be metabolically healthy. But you don't want to leave it at that. There's still way

too great a chance that you're going to end up getting cancer 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's stage

three, 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 patient's body, almost assuredly in their liver. But they're not in, you know, you can't see them. If you give that patient the Folfox Regiment, which is the standard chemotherapy regimen,

that's three drugs, 65% of those patients will be alive in the state. 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. They're now stage four. After surgery, they will go on to get the same chemotherapy. None of those people will be alive in five years. There is a fundamental Why? Why that difference? Same is true with breast cancer. Same is true with every cancer. The reason is the more cancer cells you have, the more heterogeneity you have around the burden of mutations in that cancer, the more capable that cancer is to mutate its way out of treatment, evade the immune system,

a whole bunch of other things. So if step number one is don't get cancer, which it should be, and we want to do everything we can to not get cancer, step number two, 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 one of my favorite Peloton instructors, Leanne Haynesby, 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 you're metabolically healthy and everything, like your cells are dividing, you can get a mutation. Immune cells will take care of it most of the time as we're progressing through life until we start to get into our, what, fifth, sixth, seventh decade, maybe the immune system's 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, you know, 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 PSA on you and any of our metrics show more care is warranted, they're not going to cover the follow-up study, like a 4K test or a multi-parametric MRI, unless your PSA is very high. So understand there's a cost that has to go into this. But I think there's an even bigger cost that you have to be willing to tolerate.

if you go down this rabbit hole, which is the cost of the false positive, the emotional cost of the false positive. So we always kind of start by explaining how sensitivity and specificity work. And I know a lot of people's eyes kind of glaze over and they're like, oh, my God. Like, I don't want to hear the stats on this. But if you don't understand what sensitivity means and you don't understand what specificity means, you can never understand the things that really do matter to anybody who gets a test, which is positive and negative predictive value.

Positive predictive value means if, you know, this test comes out positive, how likely is it that I actually have the thing it says? Conversely, if this test comes out negative, how likely is it that I'm truly negative? You want very high positive predictive value and very high negative predictive value. And that's a function of three things, the specificity of a test, which is the ability of a test to detect a condition being present if it is indeed present. the specificity of a test, the ability of a test to conclude that something is absent if it is indeed absent, and the prevalence of the condition being tested, meaning how likely is it

that you have this before I test you? So you can call that prevalence if you're screening. You can call it pre-test probability. But the point is this is all a 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, you know, 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%, which is fine, except if I'm going to do a mammography on you, at this moment in time, your pre-test probability for having breast cancer is pretty low, like a couple percent.

That means the positive and negative predictive value of this test in isolation are very poor. Like less than 20 percent. Furthermore, there are features about you personally that might make you a bad candidate for MRI in 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 any one 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% 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's the risk of the sedation. And then there's the risk of a perforation or bleeding, actual procedural. risks. Now, if you look at the largest study that came out on this, which was last summer in the New England Journal of Medicine, this was actually a study that was meant to show that colonoscopy wasn't worth it, 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 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 colonoscopy three times a year, which if you did colonoscopy three times 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'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 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 10 years. We typically say with no family history or risk factors, meaning you don't have inflammatory bowel disease or Crohn's disease or things like that, 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 if a 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 8.3. Great information. And with respect to the combined, you know, especially for younger individuals, like younger, like myself, the mammogram starting.

So I might say, like, you know, at 40, I would start doing a mammo and an ultrasound every other year. Sorry, every six months. So you would do a mammoth every year. You would do an ultrasound every six months every year, but staggered them by six months. So 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 in age just for, on average, forget about all that. Yep, yep, okay. And again, breast cancer is one of those cancers where if you treat it early, like, 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 four disease is a uniformly fatal disease. What's the positive predictive value of catching it in stage one with the combination? Well, so, okay, so the way to think about it is you think about it as what's the positive predictive value of the combined modalities. 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 are liquid biopsies.

So we incorporate liquid biopsies into our testing. Talk about them, yeah. Yeah, yeah. So have you talked about them in the podcast? Do you know what they are? There's a question I was going to ask you about with the gallery by grail. Yeah, yeah. Okay.

So what does this test do? So there are basically three things that you can figure out. out by looking at strands of DNA in the blood that can give you a clue as to whether or not a patient has cancer. So let's say you collect a bunch of, you connect, you know, the grail test uses 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 could be known mutations that we know are cancer genes, like a K-RAS mutation or P-53 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 an, you know, this is not what Grail does, by the way, but there are other technologies that are looking at fragment. length and using fragment length to impute probability of cancer. What 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 test.

See, that MRI that we talked about or the ultrasound or the mammogram or the colonoscopy for that matter are basically morphology tests. You're looking visually, either directly in the case of colonoscopy or indirect. 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 its site of origin or shedding its DNA in sufficient enough quantities outside its site 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 Grail, by the way, meaning if you don't have cancer, it is very likely to tell you you don't have cancer. The sensitivity is quite low, meaning if you have cancer, it could miss it. And it's been tuned that way. So the algorithm has been tuned for a very high specificity, a low sensitivity. But if you look at breast cancer overall sensitivity, it's about 20% for stage one, stage two,

which seems kind of abysmal. Meaning if you have a breast cancer that's early stage, stage one, stage two, there's only like a 20% chance it'll show up on the grail test. And many people, myself included at one point, thought that doesn't justify doing the test. I don't need a liquid biopsy to tell me I've got a stage three breast cancer. Like I'm going to figure that out falling off a log, right? So I need something to tell me when there's a stage one breast cancer. But a closer look at the data showed that if you looked at ERPR negative breast cancers,

stage one, stage two sensitivity was 75 to 80%. It was only in the triple positive ERPR positive, her two 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 cancers that matter. And I think that's a very interesting way to combine liquid body. biopsies with morphologic studies. Do you ever not combine, like do you think doing just a liquid biopsy by itself would be a useful thing? Or do you think really it's better with, you know, in combination with other morphology types of screen?

Yeah, that'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 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, the mammogram, you mentioned PSA, are... So with like some of these types of morphology screenings like the mammogram, for example, people are concerned, 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, the x-rays. Well, CT scans would be a very lousy way to screen for that reason, right? The CT scan has a lot of radiation. With the exception, the only time we justify the use of a CT scan is in a former smoker or a current smoker. We don't have any current smokers in our 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 in the U.S., for both men and women. And 85% of lung cancers occur in former smokers or current smokers. So in those people, you have to ask the question, what kind of cancers do they get? And you basically have small cell, large cell, and squamous cell are the dominant cancers that occur in smokers. And those are best detected on a low-dose CT scan. Adonocarcinoma of the lung is the dominant cause of lung cancer in a non-smoker. And we can detect that equally well with an MRI.

So we don't expose a never-smoker to at risk. Whereas to a smoker, or a past smoker or current smoker, the risk reward tradeoff is worth it. And that's been documented really clearly in clinical trials. Mammography has incredibly low radiation. Not as low as like a dexas scan or something like that, but it's still really, really low. There's a lot of women that avoid them. I'm sure there are. I don't know maybe the radiation has lessened over the years.

It always has. I mean, 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 milly cverts. And it's generally established that exposure to more than 50 mili severts a year will increase your risk of mutagenesis. So now let's put that in the context of certain things.

So living at sea level here in Sandy. Diego, just the exposure you get to the environment is about one to two millicverts a year. So that's 2 to 4% of your annual allotment. If you live in Denver, you're doubling that. So being one mile in the sky doubles your exposure. But you're still, you know, you're at 4 to 8% of your annual allotment. A CT angiogram 20 years ago was 20 million. C-verts, 40% of your annual radiation allotment on one test.

The last patient I sent for a CTA last week, because when we get the report, it also shows the radiation less than one Milleceivert. So mammograms are even point, less than that. Yeah, yeah, yeah, yeah. They're a fraction of that. So it really makes zero sense for a woman who has a lifetime risk of one and eight, and perhaps even higher if she's obese and drinks alcohol. way, to avoid doing mammograms.

Correct. Okay. But again, I would never rely on a mammogram exclusively. Right. I would combine it with an ultrasound or the MRI. But they're not concerned about it. People aren't really scared of the ultrasounds. They're scared of mammograms.

Yeah, and MRI, of course, has irradiation. But again, everyone has to, you know, you just have to, unfortunately, there's 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 millie severed. Maybe this is all stemming from. I'm sure it's I'm sure there's a complete misinformation and misunderstanding where people are confusing mammogram 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? The liquid biopsies are very good on blood cancers, actually, because you have the highest proportion of those cells. You're going to get a much higher concentration of cell-free DNA. So, yeah, we actually, that's actually one of the areas where I'm most excited about the liquid biopsies is on leukemia's 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, it's like 900, like close to a thousand. Yeah, but it's directionally a thousand dollars. And 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. I don't think you can, yeah. But I don't know for sure. Yeah. I'd be surprised if you could.

So on the breast cancer topic, you know, kind of going into another area, I know we got a, we're doing okay. But I really want to get your thoughts on this topic, which is, you know, 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 by several metrics. Yeah. When she hits menopause, I mean, it's like a, you hear this quote unquote cliff they fall out. Like a woman in terms of their aging, they fall off this cliff.

But like it's no longer, I mean, it's just they go rapidly, you know, down. So what are, what are, let's just talk about some of the risk factors that women face, you know, after menopause. And why? Yeah. So, so obviously what happens in menopause is three hormones. that are really important to a woman during her reproductive years go away. And they go away in very short order. So it can be quite dramatic.

And obviously those hormones are estrogen, progesterone, and testosterone. I always 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 and pedestrian, pedestrian, really go down, testosterone kind of gradually goes down. But like right now we're sitting 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 ludial cycle, your testosterone could be

a hundred times higher than your testosterone. So it's very important to understand. Don't get confused by the units on the lab test because they're reporting them in nanograms per 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 hormone 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 community are these vasomotor symptoms. So the hot flashes and the night sweats. And these are kind of the first things that women tend to notice. I mean, they might notice that their period is becoming irregular. Their cycle is lengthening and things of that nature. But in terms of actual symptoms that are disruptive to their quality of life, it are these vaso motor 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 to varying degrees. And again, 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. 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 esteradile 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 their 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 showing them another 60s. So taken together, all of these symptoms in my mind completely justify the use of HRT in any woman who is willing to undergo it. And unfortunately, and I've talked about this a lot on my podcast, I think there has been no greater disservice brought by the medical community onto anyone, but in particular in this case, women, than the abject failure of the interpretation

of the Women's Health Initiative in 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 more vocal lately. I had her on my podcast. She's been more vocal in acknowledging 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 women 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 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 just as you said, there are women out there who say, I can't get a mammography because, oh my God, of the radiation. They may, in fact, be thinking of an MBA. There's just a misunderstanding.

Well, similar, there are still women walking around today that thinking HRT increases the risk of dying of breast cancer when it never did, and it certainly doesn't today. So let's talk a little bit 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 of that 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 too 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 equine estrogen and MPA. So 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 equine 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, seven to ten 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 CEE plus MPA group versus the placebo had a 0.1% higher risk of developing breast cancer. Interestingly, the women in the CE alone group had a lower risk of developing breast cancer.

So the study was halted and the headline read, estrogen increases the risk of breast cancer by 25%. Well, this wasn't. correct. It is true that in the CEE plus MPA group, 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 0.1%. There was no difference in breast cancer mortality. In other words, there was an extra one case of breast cancer, but there was no difference in 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 CEE plus MPA group. But you see, it would be impossible to make the case that estrogen is the cause there when in the other group you saw the exact opposite effect. You saw that the 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

different hypothesis than estrogen is the culprit. In this group you have A plus B. In this group you have A. What could be the difference? Might it be the B? So I think most people who think about this problem today acknowledge that it's probably the MPA that was driving the very, very small, clinically insignificant, but statistically significant increase in breast cancer incidents that had no translation to a mortality difference. And you might ask the question. well is MPA in use today? And the answer is pretty much by nobody. There's I don't, I've never once prescribed MPA. I've never seen a patient come to me who's taking MPA. There probably are some patients on it, but I doubt it. And what is MPA again? It's a synthetic progestin.

Okay. Nowadays, women take bioidentical, micronized oral progesterone or they use a progesterone coated IUD. If they don't, if they don't benefit symptomatically, from progesterone. Progesterone's 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 those women, we don't even use it. We just use a progesterone coated IUD.

And that provides the local protection that prevents endometrial hyperplasia. So in that sense, 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 the study that I didn't catch because, you know, when trying to sort of deconstruct it, it was like, okay, well, the synthetic, of course, versus bioadentical 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. Yeah, 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. So can you talk about a little bit of the differences, just, you know, sort of not so much 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 estriol. But there is no FDA approved estriol products. So there are three estrogens, E1, E2, E3. There's some important nuance here that maybe justifies explaining. So estradialial.

can be turned into estrone, which is E1, and it can be turned into E3 estriol, but E3 cannot be turned into E2 or E1. So that's a one-way arrow. E3 can be turned into, this is complicated. Let me start. E1 can be turned into a two, four, and 16 hydroxyestrone. So you've got E3 that can go into an E, sorry, E1 can be turned into a two hydroxy, a four hydroxy or 16 hydroxy. E3 can actually be turned into the two hydroxy, but not the four hydroxy or the 16 hydroxy.

Virtually all the breast cancer risk probably comes from the four hydroxy estrone. So you can get that from estriol, pardon me, from estradiol, but you can't get it from estriol. There is no FDA approved product for estriol. So if a woman is taking estriol, which she's probably taking in a topical fashion in combination with estradiol, they usually refer to that as a bi-est. You'll hear that abbreviated bi-est, which just means bi-estrogen. So they'll combine in some fraction, anywhere from 50-50 to 80-20, estradial with estriol. And a woman will apply that topically.

But again, that's not FDA-approved. that is something that compounding pharmacies would have to make for a physician. In terms of FDA approved products, you have oral estradiol bioidentical. We don't use it because frankly, there is a small but non-zero increase in the risk of hypercoagulability. It just doesn't seem like it's a risk worth taking. The only indication in my mind for oral estradiol is for women whose skin will not permit the absorption of any topical estradial product. Our preferred product is an estradiol patch. We use the branded version.

Actually, when it comes to hormones, I really prefer using branded versions of an FDA-approved compound. We prefer to use something called the Vavell dot. So it's an FDA-approved estradiol patch. A woman applies the patch. You apply that, you know, the patch comes in different doses and you can trim it if you want more or less estrogen. And she changes it like every three or four days.

So, you know, you'll put it on your lower back or your hip, but some, like that on your shoulder. 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 osteoestrogen pellets that can be inserted in the subcue space 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 estradial. And you can fix, you can make adjustments easily. With the pellets, you put it in there. You got to wait five or six months before you figure it out again and decide what to do. So 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 coated 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, you know, I don't want any estrogen in my body. but these vasamotor, pardon me, these vaginal symptoms are problematic, then you can use vaginal estrogen cream or vaginal suppositories of estrogen. Again, that won't give you any of the bone protection that won't stop the night sweats or anything like that, but using vaginal estrogen products alone will at least ameliorate the sexual side effects. What about the difference between like multifasic versus whatever the monoc, like when you, so like giving women estrogen in like, more like their cycle versus like, the same dose like all the time.

We would we would kind of use, we sometimes do multifasic on progesterone in the transition of perimenopause. We don't do it once women are fully in menopause. When women are fully in menopause, we just sort of stay at the dose. Again, the dose that a woman is on is a very low dose relative to her pre-menopausal levels

as indicated by the FSA. Do you go, so that was another question. Do you, like, let's, in your... How do we titrate? Yeah, well, like, let's say a woman is either premenopausal or perimenopausal, like, I guess, postmenopausal, too, but determining, like, measuring your estrogen, measuring your progesterone, measuring your testosterone, 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, is there, like, a threshold levels? Yeah, we look at day five, so if day one, is the day the period starts regardless, right? Even if it's just a bit of spotting, whatever it is. Like that's the starting point. On day five, somewhere between day five and day seven,

we just like to do it on day five. You look at estradiol levels and FSAH levels. That is your canary in the coal mine. As that FSAH level on day five starts to climb and that estradial will start to come down, but it's mostly the rise in FSAH. That's how you know you're getting closer and closer to the cliff. Now, there's actually some interesting data

that's looking at AMH levels. and anti-malarian hormone. 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 struggling with fertility or deciding if they can still have kids or go through IVF. So there may be also some insight that comes from AMH,

but typically watching the rising FSH on day five is what's telling you this is coming. And then of course you marry that to symptoms. So I typically do not treat women until they're symptomatic in perimenopause. So I'll, you know, we'll look at their labs and I'll say, you know, Rhonda, look, 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, all right, I'm having some hot flashes and night sweats. Well, okay, good.

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 when 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 FSAH down to about 25. You now never have an FSAH above 25. So remember FSAH and estrogen work in opposition to each other.

So the lower your FSA, the higher your estradial, you right now with your regular cycle, you've probably never seen an FSAH above 12. Just to give you a sense. At your lowest estrogen right now, your highest FSA is 12. When you're in menopause, you're going to be managed to an FSAH

of about 25 to 35, which means your estrodial 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 density, obviously symptoms, but preserving bone density, also lowering cardiovascular risk, lowering Alzheimer's risk. 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 E4 women, but not E3 women. Okay.

So for you, I would say doubly beneficial to initiate at the time of menopause because of your E4. Got it. That's really good to know. And also defining what is early and late. Like, you know, so that, you know, there was a study, there's a couple of studies. One was the elite study and one was the DOPS. So, like, I don't know, it was like early intervention for estradiol or something.

And then there was another one that was the, the, the, you know, it was. the Danish osteoporosis prevention study. In both of those studies, in the DOPS one, the initiation of the, they did estradiol, I think they did like trifasic or something, but also they did the progesterone, so it had progesterone as well. It was like the cardiovascular disease risk

or mortality went down, the venous thromboambulism, like the things that happen that can increase with menopause went down over the fall. 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 is in there and also just, you know, a few years after. This is to me the biggest unknown question, Rhonda. And I don't, we don't know the answer. And what's, what I find very frustrating is we're not going to know

the answer because nobody's going to do the study. I am. as comfortable with anything in medicine as I am that initiating HRT at the time of menopause does not increase a woman's risk of heart disease, breast cancer, or anything else. In fact, it reduces her risk. It clearly reduces her risk of heart disease, dementia, and BMD, and it's either protective or neutral on cancer. It was neutral on cancer. Yeah, yeah, it's protective or neutral on cancer.

I am very confident of all of those things. Here's the thing we don't know. What do you do 10 years later? What do you do when she's 60? Right. And again, if you look at the HRT data from the Women's Health Initiative with all of its flaws, the answer would be you should probably stop. But again, that study is so flawed on so many levels that I'm not sure. And here's where I would argue.

There's one area where you absolutely know. things will get worse when you stop the estrogen and that's bone density. So the other things are a little less clear to me. There's there's there's some you know opacity around what will happen to cardiovascular disease risk, dementia disease risk and cancer disease risk if you start 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 take the estrogen away, bone density goes down. Estrogen is the most important hormone in men and women for the regulation of BMD. It is the chemical transduction system that turns force into bone building.

So we have 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 and osteoclast to promote bone building. And once estrogen goes down, that goes away. So if you take the estrogen off a woman 10 years postmenopause, she will once again go into a rapid state of decline. Now, she's still better off because she'll still be further ahead than where she is if you put her in decline 10 years sooner. So, you know, I've had arguments with people on the anti-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. Two, they suck, meaning they're not as good as estrogen.

and third, you can use estrogen for longer. 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 like waiting to retire. Like you're going to have more in your retirement fund if you retire at 70 versus 60. But this is the big question. 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 the risk of falling is, you might still end up being neutral risk carrying out HRT indefinitely. So this is where the lifestyle factors probably- Which is quality of life. Right. But this is probably where lifestyle factors do play somewhat of a role. as well because if you have, obviously if you've been doing resistance training up until that point

and 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 hormones, basically. So vitamin D is the one that I've really focused on. And when I was doing a lot of research on it, so, so, nuclear hormones, you know, we have steroid hormones, nuclear steroid hormones, I should say, sorry. So we have estrogen, testosterone, vitamin D is one. So these are binding to a receptor that, you know, in some cases the receptor complexes with other ones. It goes into the nucleus of a cell, which is where all the DNA is, and it goes down to the level of genes and it recognizes a little sequence

of genes. So in the case of estrogen, it's called an estrogen response element, an ERE. In the case of vitamin D is called a VDRE, vitamin D response element. there's a lot of overlap between vitamin D and estrogen in terms of the genes they're regulating. And so I'm wondering if avoiding vitamin D deficiency also becomes one of those important lifestyle factors because, you know, in some cases, obviously vitamin D also plays a role in bone metabolism, right? But independent of that, also just looking at the crosstalk of the genes that vitamin D an estrogen or regulate and they're like

they're both and the response elements are they're different but they're somewhat I'm looking at that and it's like oh I wonder if there's like that seems like

you might be able to compensate a little so it's kind of another interesting in addition to being 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 want to ask you a question about this so what do we know about the relationship between, call it naturally acquired vitamin D through sunlight versus supplementation of vitamin D exogenously through, you know, a supplement. Do we, do we have any reason to believe that those are different at the same level of vitamin D? In the same, like,

like, in terms of like how vitamin D is acting. So the thing is, is that when you're in sunlight, like there's other things going on. That's my point. Like, if you're outsurg, getting sunlight, you're more active. And you're nitric oxide. Like, there's, like, other things that you're getting from the sunlight. So there's a confounder there. But, I mean, like, with respect to, let's say, forget, like, let's say you finally, 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 125 hydranty, you know, you know, it's the, the actual 125 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 into bloodstream and converted into 25 hydroxy vitamin D at the level of sun exposure. So at a certain level, you're not making the vitamin D3 when you've gotten so much of it. That's how you avoid toxicity, right?

Like you're not going to keep it. Yeah, what's the highest level of vitamin D a person can ever get to naturally? Meaning if you just took an individual and put them in the sun, put, you know, shorts only, no shirt, go out there and work in the sun for all summer. Like how high, like how high were my vitamin D levels when I was in high school working construction? I know, I know there's like data out there where people have looked at like, you know, people that are like out in the, they're outside all the time, but they're honestly often looking at people like in the tropics and stuff that have, more melanin.

Yeah. Yeah, which again, so it might depend also on that. But that would be an interesting at least way to say, like, if the body has a built-in mechanism to say, I'm not going to let you make more vitamin D than this. It does. Supplementing above that would be a bad idea. And it is. Yeah.

And so that's why looking at measuring your vitamin D. What do you think that threshold is? I think going above 60 nanograms per milliliter is probably still okay. Like going to 80, you know, like there's studies looking at. 80 and it's still associated with lower all-cause mortality. And in fact, I mean, honestly, if you start to look at some of the literature, you have to take a really high dose daily for like a decade to start getting like the high calcium. But like the problem is that when you absorb, when you have a lot of vitamin D, you absorb more dietary calcium. And you also absorb more phosphorus.

And calcium plus phosphorus can precipitate, right? And so like there's so many factors involved. but I think most people are not supplementing. Like there's some people that are crazily supplementing, and it's like they just think more of everything is good, but I don't think most people are doing that. Like I don't think taking 5,000, 7,000 I use for most people. Some people have to take more than that because they have SNPs, right?

And you've probably seen it in your patients where it's like, they had to take a high level just to get up to 30 or 40. 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 dose, not level. Like to me, the dispositive study on this would be take a whole bunch of people whose vitamin D is 30, give half of them a placebo, give half of them whatever vitamin D is necessary to get them to 60 or 80.

80. Yeah, get something higher. Yeah. Create separation. Don't go 30 to 40. But be, like, do it the way we do blood pressure trials. When we do a blood pressure trial, we don't say you're going to take a fixed dose of a med. We give you whatever dose of the med is necessary to change.

the blood pressure. So we're comparing two blood pressure levels, not placebo versus 10 milligrams of a drug that for one guy is too much and for one guy is too little. And yet this isn't done in vitamin D and I find it infuriating that we have no really good, reliable RCT data on what seems like a jugular question. Are you better off with a vitamin D level of 80 than you are of 30? I mean, again, we think the answer is yes, but the, you know, evidence-based medicine, you know, crowd will tell you no, because this trial that gave people 2,000 IU for 10 minutes found no difference. Right. Or they measured maybe if they measured anyone's level, they measured like 10% of the population. Yes, exactly, like the most recent study. We only got a level on 10% of people. With, like, you know, the fact of the matter is so many people do have these snips to.

And I remember having an email dialogue with Joanne Manson. This was years ago when I was a post-doc. And I was, and she was, I think at the time, she was doing the vital study. It hadn't been published yet. And it was like, please, please can you get the SNIP data in there? Can you measure the levels? Like, do everything, you know, like, it's so important. But I'm with you on that. I think, I think what is clear is avoiding deficiency.

And I do say that a lot. And where are you drawing the line? Is 30 or 40? I say 30. I mean, it does depend on, are you looking at what the Endricon Society says is more of an adequate level or inadequate or are you looking at deficiency where you're like literally like, you know, like your bones or like your bone health isn't, you know, good. Yeah.

So, but for me, I want to know the same thing. Like I'm always kind of like hovering around 50, 60, but I'm like, should I be at 80? Yeah. You know, and I don't know. So it's always like, okay, well, air on the side of caution, you know, air on the side of caution, certainly avoiding deficiency. Yeah. But even with respect to like all these genes I'm talking about, you know, like, what

there's some cross talk with that? There is cross stock, but what if there's some way that having a level of vitamin D, you know, 50, 50 or 60 nanograms per millimeter does help alleviate some of the effects of having no estrogen, you know, like we don't really know. That's interesting. It is, especially when you look at the mechanism. And I, like I said, I spent a lot of time looking at these response elements and, you know, looking at the fact that estrogen can actually compensate for vitamin D deficiency in some cases with certain genes too. And it goes both ways. So I'm like, well, I feel like that should be an important component in the equation, right? But I'm with you on the tent, 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 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. stopped. And it's like, well, what happens then when you're 65? And 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 male hormones that I didn't mention on the female side was testosterone. And this is, you know, I mentioned earlier, of course, the abundance of testosterone and a woman prior to menopause. But 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, there'll be a couple of podcasts I've released on the topic of sexual health, but through the lens of both male and female. So Sharon Parrish and Mo Carra will be the two folks that I have discussed with on that. And Mo is actually involved.

He's at Baylor in Texas. he's involved in a study that is looking at the use of testosterone replacement in women for sexual function. So both Mo and Sharon talk extensively about the importance of testosterone in sexual function, specifically around libido and orgasmic function along with arousal. So this is like, I mean, I'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 top.

Usually I like you know like you know all the answers to the questions you're asking me because you've prepared for it right But but you know usually when I'm going into a podcast I kind of know what's going on But I was blown away in my discussions with with with with mo and and and sharing 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, what do we

talking about like, anabolic steroids? And it's like, well, yeah, testosterone is an anabolic steroid. What we're talking about is replacing women to the levels that they were at in their 30s and 40s. These are very, very low levels of testosterone, typically about 1 tenth the dose that men take to also have a physiologic replacement. And that's about 1,10, 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 estrogen?

Estrogen and progesterone, yeah. Because you, you know, what would happen if you just were doing the testosterone? And let's say a woman, let's say a woman was 10 years out, missed the whole. Yeah, interesting. Yeah, missed the, the woman. The window. Yeah. 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 and progesterone? Would you also give that person? So there's two questions here. There are, yeah. Great, great question. We, we handle each of those. I hate to say this because it sounds like such an obvious cliche.

We handle each of those on a case-by-case basis. 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 WHA. And as a result of that, like they're worse off today than they would have been, had they been on the appropriate hormones 10 years ago.

And we have to make a very difficult decision about whether it's worth additional risk. And I say that because we don't know what the risk is. And so the way we handle that is we basically try to figure out what is your risk of AD, ASCVD, and cancer, specifically breast cancer as it stands now. And, you know, for example, if a woman is especially high risk for one of those things, particularly AD if she's a 3-3 or even a 3-4-4 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 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 don't think I know the answer to that question yet. And I think that that's something that would need further study before we could sort of make a clear recommendation. In the cases of the, in your clinical practice, you're handling the hormone replacement therapy. Is testosterone part of that equation? Or do you ask, is it like more of a symptom thing? Like my libido's down, even though I'm also on estrogen with. It's not a stand. 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 does paint by numbers. you know pain pain numbers is a bad approach everybody's on this everybody's on that no no no it's like you know some women do not absorb testosterone very well uh pardon me do not absorb estrogen very well from a cream some you know might end up requiring to take it orally some uh much prefer a cream some prefer a patch some can tolerate some only need this dose some need that dose some need a very small amount of oral progesterone you do need at least 100 milligrams to oppose the estrogen at the

endometrial level. So, you know, somewhere between 100 and 200 is probably necessary. Some can't tolerate it at all and you have to use the IUD. When it comes to testosterone, there's lots of ways to deliver it, right? So one of the most interesting ways that's being studied now is using an FDA approved product. It's not approved for this use. So it's called netesto. And it's a, it's an intranasal testosterone spray that is FDA approved for male use for testosterone replacement therapy. But it's being used off-label. It's also being tested in a clinical trial for libido in 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 increases orgasmic function. So even the way in which you use testosterone can impact function and what your indication is. And 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. 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 menopauseant women.

We're talking about an average age of about 51 or something like that, right? Men, let's take the same period of life for men, okay, 50s. Do they start to experience, like, a decrease in testosterone? Yeah, but it's more gradual, and it starts, frankly, in your 20s and 30s. So male testosterone probably peaks in the 20s. And it's just a slow, steady decline. 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's 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 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 endrogen receptors

and the 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 antigenesis. and we know that not all androgen receptors function in the exact same way. So you have this problem, which is we sit here when 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 LDLC calculated by the Friedwell formula as an estimate. And then you sort of have to guess, well, maybe their androgen receptors are saturated. Maybe they're not. But if you're giving a guy testosterone in the presence of mild to low T, you're assuming his androgen receptors are not saturated and therefore giving him more testosterone will lead to an increased 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 makes 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. it. 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, we're 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. There's probably reason in my book to initiate. And is there a level that you decide to go to? So, I mean, is there like a threshold where it's like, this is too much testosterone? 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 if, and again, each lab is going to have different scales. But in, you know, in the lab we use the fifth percentile of total testosterone. Well, let's do free testosterone because we actually, even though free is an estimate, we kind of look more closely at free. So approximately the fifth percentile is five nanograms per deciliter and the 95th percentile is about 24 nanograms per deciliter. So call it five to 25, basically. So if a guy is at eight and. 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 he, 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 eight nanograms per decilator where he started. And all that additional testosterone may have done him no good. Whereas somebody else might have been woefully undersaturated. And when you, you know, increased him by 150 percent, you actually got benefit from it. Does the, like, injection versus like a gel, does that matter? 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 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? Do you have to exfoliate the skin first? You have hair on the skin. You know, you want to put it on an area that doesn't have hair.

There's just more issues with it. 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 40 to 50 milligrams twice a week. And that produces just a much more steady level because you're really trying to get the steadiest level possible. and the problem with doing it every two weeks, which was usually done in the days

when people would go to their doctor to get the injection and you wanted to minimize the inconvenience of that. You're just super physiologic for, you know, four or five days. Then you're kind of physiologic and then you're actually backed it 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 a couple things we know as clear as day, right? So we know that the lower the testosterone, the higher the risk of high-grade prostate cancer. 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 prosthetic hypertrophy. So it does increase the size of the prostate potentially. So one needs to be mindful of that. And also, 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 suprophysiologic 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 patients who, you know, are concerned about hair loss. 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 dihydro testosterone,

which is a more potent androgen. And that's the, that's the indigent that's driving androgen-specific hair loss. Or they might say, you know, 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 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 borne through an increase in blood pressure. So there was 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 were 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 to everything else. What sort of blood pressure do you, like levels, do you like to see?

We're very aggressive, right? I mean, if you look at the sprint trial, I think it's very clear that 120 over 80 or better is the place to be. And that's better than 130 over 85, which used to be the standard. For hypertension, right? That's right. Okay. So we're very aggressive. The good news with blood pressure, unlike the lip, you know, we spent a lot of time talking about

lipids and a listener may come away from that thinking, okay, there's some dietary stuff, but you guys didn't talk about exercise and you're right. Exercise doesn't move lipids 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, 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 lower, her blood pressure is hot tubs. Interesting. In addition to the exercise. Interesting. And it's like very, she's also a very high stress. Like so she's, which is obviously.

I wonder if, it's funny. I wonder if it's the impact of, you know, whether it be sauna or, or hot tub on, on hyperchortosillemia 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,

so Dan, he also, I mean, he's, exercises a lot, diet, 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 actually on the side of,

like, I need to be, make 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, do you think, I mean, it's just, yeah. And then when you finish this story, I'll walk through to make sure everybody's measuring correctly.

Okay. He has hemachromatosis. Okay. And there's some other relatives that had it and notice that their blood pressure was high. Like we're talking people that are like very physical, like doing lots of. These are like running marathons. They're doing, you know, like they're very super healthy. And donating blood seem to help normalize the blood pressure for whatever reason.

I don't know. Which is important for obviously getting rid of the iron and hemachromatosis. Right. But the other thing that's really helped. So Dan is doing that now. But the other thing that seems to really help him I mean he does sauna hot tubs exercise you know and there'll be times

when he's in his office working and he's like 135 systolic and it's like what in the world that's crazy right green shakes help him so like tons of like nitrates so a bunch of like green vegetables and these are like nasty tasting shakes

these aren't like a good tasting ones not agey no and that will that will help him as well. So, yeah, exercise is very important, but like there's also like... Has he tried like coca flavonoids, things like that? You know, we, I was, I give that to, so another story. No, I wasn't doing that. We haven't been doing that because we take a lot of our vitamins at night. We do take some fish oil in the

morning. I did mention that to him because another story, my mother, who is sedentary. She's lost a lot of weight, but she's 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. If you look at the pictures, it's like years to her life have been extended just by that alone. But I can't, like I can get her in the sauna sometimes, but 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 B supplement along with like, like, methyl folate, 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 where I was giving it to her every day. And so I got her, you know, this like sort of like battery of supplements that I was giving her, including all the methyl folate and lowering her, things that were lowering her homocysteine along with magnesium and cocoa flavanol. So I was giving her cocoavia. She was getting four of those pills. She gets forward. She still takes them. Her blood pressure went from like 155 to like 125. Okay. Her doctors are like, they wanted to get her on anti-hypertensive treatment

before she came to me. And it's like, and this has been like months now. It's, it's, it's happy. You know, she measures it 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 the lifestyle factors. I know you hate that word, but You know, exercise being one of the main ones, but there are people also that in addition to being very physically active, like they still get high blood pressure, you know? Yeah, and they're, and, you know, I don't think we have the outcome data to look at the direct impact of cocaflavinoids 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 dimethylargining. I don't know if you've talked about ADMA and SDMA. And ADMA and STMA directly and indirectly inhibit nitric oxide synthase.

So we know that homocysteine is associated with poor outcomes in cardiovascular disease. And I think that this mechanism of homocysteine impairing the clearance of ADMA and STMA is the mechanistic link. 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 flavonols actually do the opposite of that. So I think the one-two punch of lowering homocysteine and raising nitric oxide synthase activity via cocaflavinol could could certainly explain a reduction in blood pressure. That's really interesting. I was giving her the cocoainol just because I had seen the studies on increased blood flow.

And I'm like, okay, we need that. You know, like we need that. Measuring blood pressure. Yeah. So this was established really clearly through the sprint trial. 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 five 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 two inches above the elbow.

And the cuff is right at the level of the right atrium. So, you know, you're, and by the way, if anybody wants to do this experiment at home, it's really interesting to do. Put an automated cuff on your arm and put your arm here, put your arm above your head, and put your arm in the right spot, and look at how big a difference you get. So measurement errors are a huge problem. Being overstimulated is a huge problem. So you really want to make sure you're getting an accurate reading of that blood pressure. And we have our patients do that twice a day, you know, an early in the day and a late in the day check. And then, you know, we just have everybody do that for two weeks to start. And that's 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 five minute protocol and test perfectly? And I think everybody listening to this should know that number. Yeah, that's great. I'm going to like, I'm going to 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 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 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 I hate to sound like a shameless plug we've created something to help do this because you know I've talked here about our practice. Our practice is super small. It's, it's, it's, it's, 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, and the amount of room that we can make. Because, um, it's just not,

the model doesn't make sense, right? It's, it's, it's too labor intensive the way we're doing it. But the good news is like, I really don't think you need to be my patient to get the benefits of what we do. I really think you can get most of the, these benefits, if first and foremost, you are a really thoughtful consumer of your own healthcare information. So to that end, we've created this product called Early. It is, I mean, it's going to be fully released next year, but it's having a limited release this year. So we released it for four days in the spring just to our subscribers. The reception to that has been very positive. It's going to be released again once more this year, just to people on

a wait list. So anybody who goes to, I'm ashamed to say, I don't know the website. I think it's early.com, but maybe it's early medical. Yeah, I don't know. Google, early medical. Yeah, yeah, something like that. And there's a wait list. And those who sign up on the wait list will be offered the next window. It'll be a very short window in the fall. And basically that program does everything, right? It walks you through everything, how to operationalize everything that I've written about in the book or that we're talking about here today. It also allows you to directly go to 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 are physicians what i really hope will eventually happen is we'll have a critical enough mass of both people who are buying this who want this kind of medicine and physicians who are buying this, who want to practice this kind of medicine, that there could be sort of a match made here. And, you know, the good news is I think a lot of physicians really want to practice this way. And the challenge of practicing this way is you just have to get reeducated. And that takes a little bit of time. And that's why we've put this together, right? We've,

we've sort of taken two and a half years to build this program, this curriculum. And 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.

I don't have the policy solution for how to fix medicine, but I think at the individual level, just sort of taking control over it and saying, okay, I'm done with Medicine 2.0, it's time to go to Medicine 3.0. And Medicine 3.0 is really about highly preventive, super early personalized care. There are a couple of personal questions that I'm going to ask you at 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 you're doing for longevity or maybe for the day or for the week whatever whichever way you kind of bunch them in like what's ideal for you to you know improve your longevity I know that's a very general way

with respect to nutrition and exercise nutrition exercise and anything else sleep like you know saw on whatever whatever's your ideal like program the whole sweet yeah Well, I will say this. 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, 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's 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 believes, who functions best with a consistent bedtime and wake up time. So I am in bed usually for eight hours a night. And that's typically 10 to 6.

And that usually results in probably seven and a half hours of sleep. I'm going to just rattle off the names of things I use because I don't have any affiliation with things. 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. Agreed. 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, oh, sorry, a 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 things like I'll brush and floss my teeth before I go in the sauna because I sauna before bed as well.

So that once I'm done with that sauna and shower, like I'm just going straight into bed. So for me, that's also a very productive sleep trick. There's certain supplements that I use to sleep as well. So I'm a fan of glycine, aschaganda, magnesium L3 and 8, and just straight magoxide as well. I don't use melatonin or phosphatidyl syrin unless I'm jet lagging. 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 eat what's called what will 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 like the most important credo of my diet, I would say. And I say this as someone who's done everything, right? Like I've been vegan.

I've been keto. I've been like the most, you know, hardcore fasting, intermittent fasting, time restricted eating. Like I've done, there's no diet. I don't think I've done for long periods of time. And I have found benefit in one form, 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 four times a day. And a lot of times at least two of those are in meals that are just like just venison or just 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 stop eating at least three hours. 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 too, 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 six. So I'm going to bed typically with four hours between when I last eight and when I go to sleep. We can talk about alcohol. I'm in the camp that believes there is absolutely no benefit to alcohol at any dose from a purely 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 about that, I don't mean two in the afternoon, but I mean with dinner. So that again, alcohol is completely, functionally, the alcohol doesn't factor into my sleep. And I know this because I track all these things. And I know exactly how alcohol negatively impacts sleep in me. And I know that as long as I have that drinking done by six or seven, 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 much of what I do revolves around it. So even here being in San Diego this week, I mean, it's like I have a membership at a great gym 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 go.

and I'm going to do my workouts and they're going to be completely, you know, they're not going to be the exact same workouts I'd be doing at home, but I'm still generally doing, you know, four hours of zone two a week

with one sort of higher intensity workout that's geared towards VO2 max a week and then four 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. and then 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 describe as a wider buffer zone around distress tolerance. And then, you know, therapy, which I do at least one session a week, sometimes two, plus journaling and doing something called dialectical behavioral therapy, these things have been enormously important at increasing kind of the quality of my life in the past five years.

That's amazing. I mean, thank you so much, Peter. So 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 fly. I mean, it was, but there were parts where I was like, I know what Peter has his thoughts on this. And I was two-xing it, you know, whatever you want to call it. But yeah, it was like I. Oh, you audio read it, you mean? No, no. I read it, Reddit, read it.

And you read it in seven hours. I did. But like I said, there are fast reader. Well, I think 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, because 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 things we talked about today, but even more and lots of applications there. So it's called Outlive. 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, peteratia.com. Yeah, I think peteratia m.d.com is the website. That's where people can sign up for our newsletter, which comes out every Sunday.

And then I think earlymedical.com is a separate website where that other thing exists. So a question for you, when are you going to write a book? Has this ever, is this ever something you've thought about? I've thought about it. I'm not sure that I want to go. I mean, I can't imagine the world. Because your book was, I mean, 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 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. But books do communicate in in a way that, podcasts don't. And they reach different audiences too. 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 this? Like, this is such a waste of time. Like, this is taking so much time. And I could cover all of this material in 10 podcasts. Like, the book could be summarized into 10. really 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 your 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 like, when you have to write it down, you really have to get clear on what you're saying. 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 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, tellers. 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 from you 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 or a podcast. I want to do both because, you know, there's just 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, really enjoyed this conversation. Well, thank you for having me. And thank you for pouring through the book and coming up with so many awesome topics 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 and enhanced neuroprotection, many of which are at least partially mediated through increases in brain-derived neurotrophic factor levels. In this guide, you will also find a section entitled Ronda'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'd look for in a blueprint. So if you're looking at, to dive deeper into these insights and start implying 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.