Paul Saladino Talks About The Real Differences Between LDL & HDL Cholesterol

This is something that I want to discuss too. Cardiovascular disease and heart attacks, the difference between the rate of cardiovascular disease and heart attacks today versus like the early 1900s. There's a giant spike, a big change. Same as those other graphs. We could, it would be essentially the same reflection on the graph. It would be an up angle that you would not want to skate, you know? And again, it's the question of what is driving this? What is driving this? We were eating more saturated fat in 1900. We were eating way more saturated fat in 1800 or 1840. And the only oils we used were animal fats, which are not entirely saturated. They're about half mono and half saturated, half mono unsaturated, half saturated with a very small amount of polyunsaturated. So to say that it's saturated fat driving this doesn't make a whole lot of sense. Again, this is just correlation, but there's not even a correlation there. The correlation is with vegetable oil. And if you get into this research, it's complex, but it's pretty darn striking. If you look at linoleic acid, so, and you look at the molecule, it's polyunsaturated. So it's a long chain carbon and polyunsaturation means it has double bonds between the carbons. And those double bonds can be oxidized. Remember we talked about oxidation earlier and this formation of a lipid peroxides? Well, those molecules, polyunsaturated fats and even monounsaturated fat, any unsaturation point in a carbon skeleton molecule, like a chain, long chain fatty acid is going to make it susceptible to oxidation. And then lipid peroxides, which are lipids that have had an electron stolen from that double bond. Then those are more susceptible to those are more reactive with other lipids and they create these lipid peroxide reactions. Then you're getting oxidative stress from the lipids. And if you look at, so we should back up for a moment. This goes back to what we were talking about earlier. The reason, one of the reasons saturated fat has been thought of as bad for so long is because it raises LDL. But if LDL is not de novo causing atherosclerosis, then we have a whole different equation. Well, let's, let's get into that because this is one of the big questions that I got when I told people I was going to eat an animal only diet for a month. Like, what about your cholesterol? What are you going to do about your, and I'm be like, Oh, and then I try to tell them that dietary cholesterol does not raise cholesterol in your blood lipids and they just glaze over and they're like, well, here, you're taking in a lot of cholesterol. And it's just, most people don't have the time to research this or to get into the weeds and to try to shift their perception about what cholesterol is about the, the benefits of cholesterol, the necessity of cholesterol for the human diet for production of hormones. So let's get into that LDL and HDL. That is the difference. So LDL is low density lipoprotein and it's formed from VLDL after it becomes IDL, which is intermediate density lipoprotein. So when you eat fat in your diet, it is generally in triglycerides form, which is packaged into molecules called chylomicrons, which move from the intestines to the liver in the liver. Cholesterol, which is actually a steroid backbone molecule is packaged with triglycerides into a VLDL, a very low density lipoprotein particle. It's like a bus. It moves triglycerides and cholesterol around the body because they're nutrients, because they're essential for human life. Because like you said, hormones are made from a cholesterol backbone. And if you did not have cholesterol, you would be very sick and die. There's a genetic condition called Smith-Lemley-Oppett syndrome, which is a mutation in one of the enzymes that makes cholesterol. It's pretty far down in the pathway, but a lot of these kids die in utero. Children that are born have severe retardation, both mental and physical. They're extremely resistant. They're extremely susceptible to infections, and they have a lot of problems with sleep and diabetes and other issues because they don't make cholesterol. They have extremely low LDL because they can't make cholesterol in the liver, probably in peripheral tissues either. And so the way we treat these kids is with egg yolks. We just give them tons and tons of dietary cholesterol in hopes that that will be some sort of a supplement that they can use to make LDL. As their LDL goes up, they do better. They're never going to have a normal life, but there are so many studies that point to the value of low density lipoprotein. And if we just think about it evolutionarily, why would nature, why would evolution have designed a particle that kills us within our body, that at the same time defends us from infection? There are good studies in animal models that show that if you knock out the LDL receptor in mice and rats, the levels of LDL in the blood drop a lot. And those mice and rats are protected against infections. So they can infuse bacteria, gram-negative bacteria into those rats, and the higher levels of LDL are protective in those studies. And the same thing has been true in humans. You can look for this correlation. This is epidemiology. At some point, we should definitely talk about why epidemiology can be so misleading. But higher levels of cholesterol are correlated with lower admission to the hospital for infectious complications. And we definitely see in animal models and essentially with humans with the Smith-Lemley Oppitt's genetic model that lower levels of cholesterol predisposed to infection because LDL, lower levels of serum cholesterol, meaning low density lip protein, predisposed to infection because that low density lip protein particle is part of the immune system. And so is HDL. So HDL is high density lip protein. It leaves the liver as kind of an empty bus. LDL leaves the liver as VLDL, a full bus, drops off people along the way, becomes a less full bus. VLDL becomes LDL. HDL is an empty bus that goes along the body picking things up and then returning to the liver. But HDL and LDL both have roles in the immune system. So why do we think that a molecule, a lip protein particle that serves an indispensable role in human biochemistry or this human physiology is killing us? That's just the first step. Can I stop you there? What is the standard model? Like, what do people believe? Like if you asked a doctor that doesn't have a lot of nutrition training about HDL and LDL, what would they tell you? At a very high level, they would say HDL is good, LDL is bad. You want less LDL and you want more HDL. Why would they say that? Because there's something called the lipid hypothesis. And the lipid hypothesis is that essentially in a concentration dependent manner, LDL ends up in the arterial wall. Okay. This is the lipid hypothesis. I disagree with this. It's a complete hypothesis. And so they would say if you have more LDL, it's just going to kind of leak into your arterial wall because it naturally gets taken up. And as more LDL ends up in your artery wall, you get more atherosclerosis and more plaque. What's the root of this hypothesis? It's a lot of epidemiology, Mendelian randomizations, and genome-wide association studies. So this is really interesting. We should dig into this. If you look at basic epidemiology, so let's just think about epidemiology. You've talked about this on the show before, but I want to define this for people. Epidemiology is essentially an observational study. There's no experiment done. They're giving people surveys and they're either following them moving forward, prospective, or they're looking back at what they've done in the past, a retrospective study. And so epidemiology can generate correlations, but we cannot draw causative inference from that data. We can have a correlation which we then test with an interventional study. LDL is kind of tough to test with an interventional study, but there's some really cool stuff here that starts to break it down. If you look at overall cohorts of people, so if you look at the Framingham study, for instance, and you look at LDL on the x-axis and incidence of cardiovascular disease on the y-axis, I actually have two graphs of this that I'll show you that'll make it really helpful to break it down. So if you look at those two and you don't do anything to, this is in the lipids and CVD folder, Jamie, you see that CAC LDL only graphic. So if you look at this, this is the basic data from Framingham. This is correlation. This is epidemiology, increasing risk of cardiovascular disease on the y-axis, LDL on the x-axis. So it's things like this that make people say, oh yeah, LDL, it's probably causing atherosclerosis, which is the formation of plaque within the arterial wall. But go to the other one, Jamie, CAC LDL HDL. So this is the exact same data stratified by a third variable. And this is what is never considered with LDL, in my opinion. The lipid hypothesis is flawed because it's incomplete. It misses the third variable or fourth variable. In this stratification, we've looked at HDL. We've looked at the quote, good cholesterol, which we really don't know a whole lot about, probably on immune participant. But HDL levels do correlate with metabolic health, synonymous with insulin resistance. So what can we say about these people? This is the exact same data that I've split into four lines here. Those with the lowest level of HDL are the most metabolically unhealthy. These are the most obese, the most likely to have diabetes, the most likely to have insulin resistance. You can see they have a pretty good risk of, relative risk of cardiovascular disease as LDL increases. But look at the bottom. Look at the people who are most insulin sensitive. There's essentially no correlation, or the correlation is massively different between people with a high HDL, good metabolic health, and LDL increasing. Does that make sense? It's a sort of. It says increasing LDL has very little increase in the cardiovascular disease risk with high HDL. Yeah. So as you increase your LDL. As long as you have high HDL, increasing LDL has very little risk. Very little cardiac risk. Can we see that over and over and over in studies? What if you just have high LDL and low HDL? Then you probably have diabetes, and in that case, you have, then you're in trouble. So the issue is not LDL, it's low HDL. Well, the issue, low HDL is reflective of an underlying pathology, which is metabolic dysfunction and or insulin resistance. The issue is insulin resistance, metabolic dysfunction. So we're using HDL level as a proxy for metabolic health here. What is an optimal ratio? Of LDL to HDL? I actually, it's tricky because there's a whole group of people now, right? So I have a good friend, Dave Feldman, who's doing, he's an engineer, super smart guy. He's doing a lot of really cool work on this. And they're actually about to start a study with lean mass hyper responders within the space, the carnivore ketogenic space. There are people who begin eating this way and they see their LDL go up significantly. So some people don't see LDL rise, but I did. I have a pretty high, quote, LDL. And so within the space, there's a lot of people with high LDLs who look like me pretty fit, active, don't have chest pain. Don't believe I have cardiovascular disease. We can talk about my blood work and what I've done to confirm that. But there's a whole group of people called lean mass hyper responders. And Dave's hypothesis, which I agree with completely is that elevated LDL alone is too simplistic a metric. Mainstream medicine gets hyper focused on LDL or more specifically, Apo B, which is a proxy again for the number of LDL particles. That's too simplistic because I think there's context here. And the context is that I don't believe there's sufficient evidence to say that high LDL in somebody that's metabolically healthy is the same as high LDL in somebody that's metabolically unhealthy. There's a third variable. We have to think about multiple variables because there's a context and it makes sense, right? There are other things that are like this. Uric acid is a good example too. Incidentally both LDL and uric acid rise when humans fast. So if you stop eating, your LDL is going to go up. And that's been demonstrated multiple times in studies. Fasting raises LDL. They've even shown this in hibernating bears. Hibernating bears see, have a rise in LDL, but they don't develop atherosclerosis over the course of their hibernation period. There's actually a screenshot at the bottom in the lipid CVD folder, Jamie, and I'll pull up. There's another study here with the hibernating bear study. It's pretty fascinating. The bears, a thorough hibernation. So we see this over and over in humans that fasting raises LDL, fasting raises uric acid, but fasting, people who fast, people who do ketogenic diets, they don't get gout. They don't get atherosclerosis in quite the same way, or at least that's the hypothesis. Certainly bears don't. And we have seen- It seems strange that fasting would raise LDL. It does until you think about LDL as a nutrient carrier. So Dave is developing something called the lipid energy model, and I want to give him all credit for this. I've actually got a set of slides that'll probably make it clear when I talk about it. But Dave's hypothesis is that if you are burning mostly fat as energy, and even somebody that eats some carbohydrates can be burning mostly fat as energy, you are going to be moving more LDL in your blood to move that fat around. And we certainly know that interventions can do that. And it makes sense. When you fast, you're depleting liver glycogen, your ketones are going up, and you are burning fat. You're not burning as much glucose. You're burning more fat. Your free fatty acids are going to go up. Your LDL is going to go up. And so you kind of scratch your head there, at least I did, and looked at this and thought, are you telling me that in something that would happen routinely for humans, fasting, like we talked about, intermittent fasting, unsuccessful hunts, that's killing us in a way? That's causing atherosclerosis? That doesn't make any sense. And it certainly doesn't happen in bears and other hibernating mammals. So LDL will rise in response to fasting. LDL seems to rise in response to what we choose to burn as our primary fuel. We're still kind of trying to figure this out. Dave's had, he just texted me this morning. He's like, I've got all this really great data. He's almost ready to share it. It's super interesting stuff. But the whole idea of what LDL is doing in the human body, I think has been misconstrued and misunderstood. Again, the lipid hypothesis would say the more LDL, the more atherosclerosis. Well, if that's the case, and it's kind of tied into that model, is the notion that LDL must cause atherosclerosis de novo, or in and of itself. Because if more LDL equals atherosclerosis, then LDL is causing atherosclerosis. I don't think anyone who subscribes to the lipid energy model is going to debate that. But if LDL causes atherosclerosis de novo, why don't we get atherosclerosis in veins? Why do we only get atherosclerosis in arteries? There's the same amount of LDL throughout our body. Veins and arteries are a contiguous system. And so why are we developing plaque in arteries, but not veins? We never see plaque in veins unless they are transplanted into the arterial system. So there's clearly more things going on. And in the case of arteries versus veins, the prevailing hypothesis is that it's endothelial damage. So the inside of a blood vessel is the endothelium. And something has to damage the endothelium for this to happen, it seems. And higher pressure systems, the arteries seem to damage the endothelium in this network of glycoproteins on the surface of the endothelium called the glycoalyx. And that doesn't happen in veins. They're lower pressure. There's one hypothesis. But for LDL to cause atherosclerosis in and of itself, it just doesn't seem to work. And studies like that with Framingham make me think there's a third variable. So if you look at the general population, sure, you might see a correlation between LDL and cardiovascular disease. But if you look at it a little more precisely or a little more carefully, you start to separate out those who are metabolically healthy, which granted is the minority from those who are metabolically unwell. If the majority of people in our society are metabolically unwell, of course it looks like there's a correlation. But what about this group over here, you and me, who are metabolically healthy? If our LDL goes up, is that going to cause atherosclerosis? I think the evidence for that is paltry at best, and it's not there. And I think that we are eating a diet that we believe to be ancestrally consistent. Why would that kill us, right? Episodes of the Joe Rogan Experience are now free on Spotify. That's right. They're free from September 1st to December 1st. They're going to be available everywhere. But after December 1st, they will only be available on Spotify, but they will be free. That includes the video. The video will also be there. It'll also be free. That's all we're asking. Just go download Spotify. Much love. Bye-bye. Mmm. Mmm. Mmm. Mmm. Mmm. Mmm. Mmm. Mmm. Mmm. Mmm. Mmm. Mmm.