The Most Important Lipid Marker for Longevity

Alright, let me level with you. I have higher cholesterol than most doctors see in their entire careers, sometimes above 700. So according to the prevailing models of heart disease, I probably should be dead. But not only am I evidently not dead, I'm thriving and my heart and blood vessels are actually pristine. So to most doctors, I'm a walking, talking paradox. In fact, it's curiosities like me that inspired me to go into science and medicine, get my PhD, then my MD. But I don't want to just talk about myself as a paradox. I want to talk today about a broader, global, human species-wide paradox. And here it is. Heart disease is one of the leading causes of death worldwide. So chances are you or someone close to you will be affected by it at some point in your life. And many of us have been taught lower cholesterol, especially LDL "bad" cholesterol is better because of course LDL causes heart disease and lowering it should lead to longer life, right? It just fits, 1 1 2. But the fact is it doesn't. That's weird. Is there a biological trade-off? What's going on here? Well, buried in the data, is a detail, a key variable you can measure and you can change that most people, most doctors miss entirely. One that actually matters for healthspan and even lifespan. So in this video, I'm not just going to give you information, I'm going to give you tools. Tools you can use to start modifying your cholesterol metabolism in ways that might just not protect your heart, but could quite literally add years to your life. And life to your years. I know it's a big promise, but I'm ready to deliver. Let's go. It's time we rethink the story we've been telling about lipids and cholesterol. Maybe modern cardiology is focusing the spotlight in the wrong place. And in medicine, that's a paradoxing. The trend goes the opposite direction. ApoC-III is a small protein, but it plays a big role in your whole body health. That is modifiable. That is actionable. I'm actually getting goosebumps just talking to you. Alright, as a quick roadmap to today's video, we're going to tackle: 1. The "lower is better" fallacy. Then 2. We're going to introduce something called ApoC-III, our star player. It's a cholesterol-related molecule that you should have heard of, but I bet haven't. In fact, I bet your doctor hasn't even heard of it. Then in Chapter 3, I'm going to show you how lower ApoC-III associates with longevity and, importantly, How this differs from other lipid and cholesterol genes in the human genome in a critical way. And then finally, 4, we're going to discuss evidence-based strategies to lower your ApoC-III, lifestyle tools to improve your cholesterol metabolism and heart health today. And as always, if you want all the references, extra information, and details, nuances you can't find anywhere else, check out the associated newsletter linked below. But with that, let's get into Chapter 1: The Lower is Better Fallacy. Now, for decades, the guiding principle in cardiology has been simple: lower is better. Lower LDL cholesterol, lower ApoB, lowers these and you lower your risk of heart disease. But the fact is, just having lower LDL and ApoB doesn't actually increase your healthspan or lifespan per se. So let's take an example. Mutations in a gene called PCSK9—this is a target of many drugs called PCSK9 inhibitor—and it leads to much lower LDL cholesterol and ApoB levels, but it doesn't increase lifespan at all. And in medicine, that's a paradox. How can heart disease be a leading killer, but genetics that should and often do reduce LDL and heart disease risk don't provide any lifespan benefit? Now, it's easy to hand wave and say, "Well, the studies just aren't powered enough." But were that the case, we might expect to see at least a trend, a leaning towards a mortality benefit. But when we look at the data, If anything, the trend goes the opposite direction. So, for example, PCSK9 loss of function trends, if anything, to earlier death, more mortality. And more important, if this was just a matter of underpowered studies, we might expect not to see any signal in other cholesterol and lipid genetics in humans, but we do. And this is where the story gets richer. "What's this? What's this?" So, if lowering LDL isn't the whole story, the obvious question becomes, What are we missing? And the answer that we need to talk about is this lesser-known player in lipid and cholesterol metabolism called ApoC-III. So let's introduce ApoC-III in Chapter 2. But before we get into ApoC-III, you need a little bit more background on something broadly known as apolipoproteins, these apos. Apolipoproteins are proteins that bind to fats to form lipoproteins—lipids and proteins. These are the particles that transport lipids throughout your bloodstream. So apolipoproteins, they serve They serve as like a structural scaffold, they're enzyme regulators, they regulate protein activity, and they're address labels that guide these particles that float around in your blood to the right destinations in the body. There are many different apolipoproteins. They include ApoA, the infamous ApoB, ApoC-III, the topic of this video, ApoE, involved in Alzheimer's, and more. ApoB is the most well-known. You've probably heard of it. It's the primary structural protein involved in LDL particles, and it's essentially become the the boogeyman of modern cardiology because each LDL particle carries one ApoB, so it's kind of like a proxy for LDL particle count. But today we're shifting one letter later in the alphabet from ApoB to ApoC-3. Now ApoC-3 is a small protein, but it plays a big role in how your body handles fat, specifically triglycerides, fat fuel that circulates in your blood. ApoC-3 is made in the liver and it circulates in your bloodstream. It functions to slow the clearance of fat triglycerides. So it's like a metabolic brake. When it's active, when ApoC-III is active, it prevents an enzyme called lipoprotein lipase from breaking down these fats, these triglycerides, and the result is higher circulating triglycerides hanging around in your blood for longer than they should. Now here is the twist. People with genetic mutations that reduce or turn off ApoC-III have more efficient metabolisms, better metabolic health, lower cardiovascular risk, and longer lifespan. So let's get to Chapter 3: Lower ApoC-III associates with longevity. As a case in point, look at this study examining genetic variations in the lipoprotein cholesterol metabolism linked to longevity. A variation in the ApoC-III gene led to reduced ApoC-III protein activity levels, and this was enriched in centenarians, people who lived beyond 100 years old. In fact, centenarians, these individuals that lived to 100 or more, were 2.5 5 times as likely to harbor this specific genetic variant in ApoC-III in their genomes as compared to their shorter-lived counterparts. So, in other words, people who lived past 100 years were significantly more likely to carry this mutation that lowered ApoC-III levels. But here's what's fascinating: LDL cholesterol and ApoB levels were virtually identical between those with the ApoC-III longevity genetic variant and comparators. In fact, if anything, ApoB levels were trending towards slightly higher levels, in at least males, with the longevity ApoC-III genetic variant. So if LDL and ApoB weren't the differentiators, what was changing in their lipid panel? Well, the longevity ApoC-III mutation group had higher HDL and a lower triglyceride-to-HDL ratio. These are markers of metabolic health and more efficient lipid turnover and metabolic function. You can actually see the survival benefit visually here in this survival curve. This survival curve covers 381 people, 64 of whom carried the favorable APOC3 genotype. Their survival curve, which is the solid, the dark line, declined much more slowly. Basically, they lived longer. And even when you leave longevity aside for a moment and zoom in specifically on cardiovascular disease outcomes, the advantage still does not trace back to LDL cholesterol or ApoB. So for example, in a meta-analysis, a separate study of 137,895 individuals, they found that ApoC-III loss of function genetic variants led to significantly lower risk of vascular disease, but not because of lower LDL. In fact, LDL basically didn't change, it dropped by 4% on average, while remnant cholesterol, a marker of fat-rich triglyceride-rich lipoproteins, dropped by 43%. The authors themselves conclude that the vascular benefits, the heart health benefits, were not, not mediated by LDL cholesterol. So let me repeat that: a lower risk of heart disease, but without lowering LDL or ApoB. These data provide a conspicuous pattern overall. Across genetic variants, genetic mutations that alter cholesterol and lipid metabolism in humans, most provide no benefits for longevity. Remember the PCSK9 loss of function? It dramatically lowers LDL, And while there are cardiovascular benefits, there's no lifespan benefit. If anything, the trend is towards more mortality, if anything, although it's a non-significant trend. But by contrast, the APOC3 loss of function leads to more efficient lipid metabolism and improved insulin sensitivity with minimal impact on LDL. But in addition to cardiovascular benefits, there's longevity benefits. Anyway, at a high level, the lesson here is maybe modern cardiology is focusing the spotlight in the wrong place. We've We've been chasing LDL as the primary enemy, in part because we have drugs to smash it down, but the biology of aging metabolism, long-term health, and even longevity is pointing us in a different direction. Now, I hope I've convinced you ApoC-III might be one of the most underrated players in lipid metabolism, and lowering it could potentially improve not only your cardiovascular risk, but potentially your healthspan and even lifespan. So if you're still with me, this is the part where we turn insight into action. I'm actually getting goosebumps just talking to you. Anyway, let's break down evidence-based ways, lifestyle strategies for reducing ApoC-III today. And that brings us to Chapter 4: Evidence-Based Strategies to Lower ApoC-III. First, low-carb diets powerfully reduce ApoC-III, low-carb and keto. This is in part because glucose is a potent stimulator of ApoC-III production. And this makes total physiologic sense when you think about it. If ApoC-3 suppresses lipid metabolism, then when you consume glucose, your body wants to prioritize burning carbs over fats, so it downregulates fat-burning pathways by increasing the brake on fat burning, ApoC-3. This means more glucose, more ApoC-3. How about that? Metabolic logic! By contrast, cutting back on carbs lowers ApoC-3. In fact, in one study, a ki— I don't know why I'm using my hands so much, I'm just excited. In one study, a ketogenic diet led to a 50% reduction in ApoC-3 levels in people with obesity in just 2 weeks. A huge drop in 2 weeks. That is modifiable. That is actionable. Also, digging in a little bit deeper, if glucose is bad, fructose is worse. Fructose appears to be an even stronger stimulus for production of ApoC-3 than glucose. So yes, cutting down on sugar-sweetened beverages and maybe even tropical fruits I said what I said, I'm sorry about mangoes, may be the low-hanging fruit, pun intended, for reducing ApoC-3. And of course, just to double down and double-click on the point, restricting overall carbs is going to be the biggest bang for your buck because you're reducing glucose, fructose, and things that break down into glucose and fructose. And on a related note, insulin signaling suppresses ApoC-3. Now, you might be thinking I'm contradicting myself because carbs raise insulin and insulin suppresses ApoC-3, right? It's not really how it works. When it comes to actual insulin signaling, it's not just about circulating levels but how sensitized certain pathways are. So what I'm really saying is that in states of insulin resistance like obesity and type 2 diabetes, ApoC-3 levels tend to increase. So what this really means is that anything that improves your insulin sensitivity like low-carb diets, ketogenic diets, weight loss, exercise, fasting, just getting good sleep, all of these things improve insulin signaling and in turn help bring down your ApoC-3. Furthermore, now shifting gears a little bit, fatty acid balance matters too. Certain fats help bring down ApoC-3 and improve your metabolic health. For example, omega-3 fatty acids, especially EPA and DHA from fatty fish, have been shown to reduce ApoC-3 levels. Now, if you do want a measurable target, you can get something measured called an omega-3 index from a service, OmegaQuant, that I use. If you want the discount code, it's Nick Norwitz. That'll get you 10% off. That's not a paid promotion, that's just a discount code for you. Anyway, What you want to do is aim for an omega-3 index in your red blood cells of 8%, but for context, the average American falls short, around 5%. I personally, to flex a little bit, sit around 16% because I'm just that cool. Also on fatty acids, it's a little bit controversial, but saturated fat, all things being equal, might increase ApoC-III levels. As a big caveat, I think the rules change in the context of low-carbon keto diets, your metabolism shifts, but if you're eating a mixed macronutrient diet, with still quite a bit of carbs, swapping out saturated fats for mono and polyunsaturated fats, especially omega-3s, could bring down your ApoC-3 levels. I want to best represent the literature that I can. So in summary, interventions that would lower ApoC-3 include fructose and sugar restriction, low-carb or especially ketogenic diets, improving insulin sensitivity any way you can, and increasing your omega-3 fatty acids, and potentially swapping saturated for mono and polyunsaturated fats if you're eating a diet rich in carbs. Now, while the primary focus of this video in this chapter is on lifestyle interventions that can lower ApoC-III, improve triglycerides, and improve healthspan and maybe lifespan, I'd be remiss if I didn't mention that ApoC-III has become a new target of interest by the pharmaceutical industry. Specifically, an antisense oligonucleotide medication called Olazarsen is being explored for the treatment of high triglycerides, hypertriglyceridemia. You can find out more in the letter linked below, Because I'm keeping this video focused on lifestyle, but I just wanted to keep you informed that this is becoming a pharmacological target, and we will see what the actual healthspan and longevity benefits will be, if any. The data aren't there yet. But for real, wrapping up, it's time we rethink the story we've been telling about lipids and cholesterol. For far too long, we've had a myopic, keyhole focus on LDL cholesterol and ApoB. They have dominated the narrative in cardiovascular prevention, overshadowing other perhaps more important markers in health more broadly. So, ApoC-III, what I've introduced to you today, it's not just a footnote in cholesterol metabolism. It's a key player in your whole body health, the biology of aging, fat processing, and potentially longevity itself. And the best part is it's easily modifiable. Stay curious. Let me know what you liked, didn't like about this video, what you learned, and what you want to learn next. Peace.