Transcription
All right, 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 specieswide 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 plus 1 equals 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 health span 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. Apple C3 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.
All right, as a quick road mapap to today's video, we're going to tackle one, the lower is better fallacy. Then two, we're going to introduce something called ApoC3, our star player. It's a cholesterol-lated 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 three, I want to show you how lower ApoC3 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 four, we're going to discuss evidence-based strategies to lower your apple C3 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 link below.
But with that, let's get into chapter one, the lower is better fallacy. Now, for decades, the guiding principle in cardiology has been simple. Lower is better. Lower LDL cholesterol, lower Apple B, lowers these, and you lower your risk of heart disease. But the fact is just having lower LL and apple B doesn't actually increase your health span 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 apple B levels. But it doesn't increase lifespan at all. And in medicine that's a paradox. How could 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 handwave 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. Watch this. Watch 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 lessernown player in lipid and cholesterol metabolism called ApoC3. So let's introduce Apoc in chapter 2.
But before we get into ApoC3, you need a little bit more background on something broadly known as apo lipoproteins. These appos lipoproteins are proteins that bind to fats to form lipoproteins lipids and proteins. These are the particles that transport lipids throughout your bloodstream. So apple lipoproteins, 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 apple proteins. that include Appleo A, the infamous Apple B, Apple C3, the topic of this video, Apple E involved in Alzheimer's, and more. Appleo B 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 boogeyman of modern cardiology because each LDL particle carries one appleo. So, it's kind of like a proxy for LDL particle count. But today we're shifting one letter later in the alphabet from apple B to apple C3.
Now apple C3 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. Apple C3 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 break when it's active. when apple C3 is active and 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 ApoC3 have more efficient metabolisms, better metabolic health, lower cardiovascular risk, and longer lifespan.
So, let's get to chapter three. Lower ApoC3 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 Apoc3 gene led to reduced APOC3 protein and activity levels and this was enriched in centinarians, people who live beyond 100 years old. In fact, centinarians, these individuals that lived to 100 or more were 2.5 times as likely to harbor the specific genetic variant in Apocc3 in their genomes as compared to their shorter lived counterparts. So, in other words, people who live past 100 years were significantly more likely to carry this mutation that lowered APOC levels. But here's what's fascinating. LDL cholesterol and apple B levels were virtually identical between those with the ApoC3 longevity genetic variant and comparators. In fact, if anything, Apo B levels were trending towards slightly higher levels in at least males with the longevity ApoC3 genetic variant.
So, if LDL and apple B weren't the differentiators, what was changing in their lipid panel? Well, the longevity apocc 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 AOC3 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 apple B. So for example, in a meta analysis, a separate study of 137,895 individuals, they found that APOC3 loss of function, genetic variance 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 fatrich triglyceride rich lipoproteins, dropped by 43%. The authors themselves conclude that 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 apple B.
These data provide a conspicuous pattern overall across genetic variance, 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 apple C3 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 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 apple C3 might be one of the most underrated players in liid metabolism and lowering it could potentially improve not only your cardiovascular risk, but potentially your health span 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 a C3 today. A and that brings us to chapter four, evidence-based strategies to lower ApoC3.
First, low carb diets powerfully reduce ApoC3, low carb and keto. This is in part because glucose is a potent stimulator of ApoC3 production. And this makes total physiologic sense when you think about it. If a C3 suppresses lipid metabolism, then when you consume glucose, your body wants to prioritize burning carbs, glucose over fats. So it downregulates fat burning pathways by increasing the break on fat burning apoc. This means more glucose, more apoc. How about that? Metabolic logic. By contrast, cutting back on carbs, glucose lowers C3. In fact, in one study, a 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 apple C3 levels in people with obesity in just 2 weeks. a huge drop in two 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 apple C3 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. Maybe the low hanging fruit, pun intended, for reducing apple C3. 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 a C3. Now, you might be thinking, I'm contradicting myself because carbs raise insulin and insulin suppresses a C3, 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. What I'm really saying is that in states of insulin resistance like obesity and type diabetes, apple C3 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 apple C3.
Furthermore, now shifting gears a little bit, fatty acid balance matters too. Certain fats help bring down ApoC3 and improve your metabolic health. For example, omega-3 fatty acids, especially EPA and DHA from fatty fish, have been shown to reduce ApoC3 levels. Now, if you do want a measurable target, you can get something measured called an omega-3 index from a service Omega Quant 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. It'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 a C3 levels. As a big caveat, I think the rules change in the context of low carb and 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 apple C3 levels. I want to best represent the literature that I can.
So in summary, interventions that would lower ApoC3 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 a C3, improve triglycerides, and improve health span and maybe lifespan, I'd be remiss if I didn't mention that ApoC3 has become a new target of interest by the pharmaceutical industry. Specifically, an anti-sense oligan nucleotide medication called olarsen is being explored for the treatment of high triglycerides, hypergmia. 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 health span 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 apple B. They have dominated the narrative in cardiovascular prevention, overshadowing other perhaps more important markers in health more broadly. So, apple C3, 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.