Surprisingly Sensible Truths About Metabolism

Here are 7 underappreciated truths about metabolism, medicine, and diet. But first, for framing around this video, this is going to be a pretty high-level abstraction. I'm not going to go in depth on anything. I'm not going to say anything too complex. It should be pretty intuitive, the truths I share, even obvious, some of them. Nevertheless, these are 7 truths that often get overlooked, leading to a degradation in nuanced dialogue. So I thought it was worth taking just a moment to highlight these so that you can have them at the forefront of your mind, keep them in mind for yourself so you can extract the most nuance out of social media you interact with, with respect to metabolism, medicine, and diet. And also so that you can share these truths with other people, bring them to the forefront of their minds, so that we can enhance the nuance and dialogues we have around metabolism, medicine, and diet. So with that, let's get to it. Welcome to my channel. Stay curious. Underappreciated truth 1 is that physiology does not care about cut points. Your human physiology doesn't care about the arbitrary cut points that we humans invent as part of our language and classification. And this comes up all the time with people asking if they meet criteria for a particular phenotype, say the lean mass hyper-responder phenotype, or what precise number of hours of fasting will activate autophagy in the brain, or if they eat fewer than 50 calories, if that won't break a fast. The truth is, we love to categorize. Us humans love to categorize to help us organize our thoughts and to facilitate communication. And that is a good thing, but it doesn't mean your biology cares about the cut points we invent. So for example, an HbA1c is the threshold for diabetes, but nothing magical happens at that cut point. Nothing magical happens as you go from an HbA1c of 6.4 to 6.5. That wasn't happening as you went from 6.3 to 6.4. That said, it is worth taking a moment to highlight why we generate cut points. Generally, we want to balance what's called sensitivity and specificity, which simply put is generating cut points that help us optimize having thresholds that capture populations affected and help them distinguish from populations unaffected. But these aren't perfect cut points. Again, the point here is physiology is a continuous process. The cut points we create generate black and white categories, but underlying biology does not care about the cut points we create. So internalize that because it's a really important message and this comes up all the time. Moving on, underappreciated truth 2 is that a ketogenic diet is not defined by a specific carb intake threshold. No, a ketogenic diet is defined by the nutritional state of ketosis. So it's true that in the literature sometimes cut points for carb intake are generated, again, to help us create buckets, to help us organize the literature and organize groups in, say, studies. But technically speaking, a ketogenic diet is defined by being in the metabolic state of ketosis, having your ketone levels elevated. Now, again, for classification, we create other arbitrary thresholds like beta-hydroxybutyrate levels of 0.5 millimoles which are steady state levels that actually don't even tell us about flux of ketones. So that's a whole nother problem. But the point I really want to make here is that a ketogenic diet is defined by being in a nutritional metabolic state where your ketone levels are elevated, not by a specific threshold of carb intake. And this is really important to emphasize because focusing on the nutritional metabolic state helps us integrate or account for user-specific variables. And what I mean by that is carbs hit people differently depending on their metabolism, depending on their activity, depending on their body size, especially especially their muscle mass size. So me, for example, if I'm eating 50 grams of carbs but I'm being sedentary, I will not be in ketosis. If I'm eating 50 grams of carbs and I'm working out 3 hours a day with, say, lots of cardio or training for an ultramarathon, I will absolutely be in ketosis. So it's important to consider that nutritional ketosis is a function of the carb intake and the user. And that's why it's really not good to define a ketogenic diet by a specific carb threshold, because there's so much variability between people and how carbs affect us.. And what really matters is whether or not your ketones are elevated to define a ketogenic diet. Again, pretty obvious, but I think it's something worth highlighting. Underappreciated truth 3 is that biology isn't about balance, it's about cycles. In our lives, many of us as humans like routine, stability, consistency, and balance, but it isn't how our biology and our metabolic bodies like to operate. Obviously, we don't have balanced state of arousal. For example, we are very active, or at least we should be very active and exercise at certain times., and we spend other times sleeping and recovering. And at the subcellular level, we have processes like glycolysis and gluconeogenesis that break down glucose— glycolysis or gluconeogenesis— that build up glucose. And they don't happen simultaneously in a futile cycle, but there's a push and pull, an ebb and flow to meet the needs of the system at a given time. In hormones, for example, they're often linked to rhythmic release patterns. Sometimes these are circadian, sometimes they're on different frequencies. Anabolism, building up. Catabolism, breaking down. They happen in cycles. Rarely, if ever, are things frozen in balance in biology. Biology likes to cycle. Underappreciated truth 4 is that there is no one best human diet. Now, this one can actually be quite controversial. I don't think it should be, but the reason it's controversial is because people will often come forward with a counterpoint. Well, we're all human, and each species should have a species-appropriate diet. Therefore, there should be a best human diet. And at a superficial level, that kind of holds water. But let's dig a level deeper, and let me reframe this by asking another question, which is: what are you optimizing for? Each of us is often optimizing for something different. Are you optimizing for bodybuilding, longevity? There's a lot of things you can optimize for. Without defining what you're optimizing for, you can't define a best diet. Now, in addition to that, there is huge variability among us as individuals. There is variability in our genes and our predisposition to different diseases. Variations in our lifestyle patterns, our activity levels, and variations in our microbiome. While our human DNA might be pretty similar one person to another, our microbiome DNA is vastly different. And what really matters is not just the human, but the human microbiome metaorganism, because that's what's interacting with your diet. So that's actually the framework we should be taking in there. There is massive variability. And just to give you a single example, there are data showing that if you give humans, or the human microbiome metaorganism, dietary fiber, some humans have an anti-inflammatory response, whereas other humans— human microbiome metaorganisms— have a pro-inflammatory response. So you can have opposite responses to the same input, just showing how big the variability can be. And building on that, I just want to make the point that I don't think we should extrapolate from what works well for us in our personal stories to what we think or what we're certain works well with other people. In other words, I think we should be humble and non-defensive about various eating patterns. I think that seems pretty reasonable. I hope you agree. Anyway, moving on. Underappreciated truth 5 is that metabolic adaptation takes time. So by way of analogy, if my friend Jill decided after never running a day in her life, she wanted to train for a marathon and on her first day went out and ran 10 miles and then the next day found to her dismay, she was not a better runner, but a worse runner. She was tired, she was sore, and she concluded, oh, well, evidently training running does not make you a better runner because I trained for a whole day and the next day I was not any better? Would you conclude that running, training running doesn't make you a better runner? Obviously not. There wasn't enough time for her body to adapt. Now, food diet is a little bit different, but the same point remains. Adaptation takes time, and not appreciating this truth creates confusion and leads people to be deceived about what really drives dietary success in a whole host of outcomes, but especially weight loss. So for a specific example, we, my colleagues and I, led by Professor Adrian Sotomayor, did a reanalysis recently of Metabolic Ward trial. I have a separate video on this specifically, which you can check out. But basically, this was a trial in which there were very short-term dietary arms comparing a low-fat diet to a low-carb diet, and they were stacked back to back. And what ended up happening is that there were negative metabolic adaptations in the low-fat diet that kind of bled into the low-carb diet. So the low-fat diet blamed the low-carb diet, and vice versa. There were positive metabolic adaptations with the low-carb diet that bled over into the low-fat diet. So the low-fat ended up stealing credit from the low-carb, and vice versa. And what what you ended up with was deceptive and misleading outcomes. So you can go check out that video separately, but the important thing to acknowledge and really emphasize here is that metabolic adaptation, especially, especially to macronutrient shifts, take time. So bank that in your brain because it's super, super important. And if you want more details on that, check out the other video. And if you want even more details, you can check out the links to the papers below. Underappreciated truth 6 is that you can rarely target a biomarker in isolation. We like to focus on biomarkers in isolation, like LDL cholesterol or ApoB, and consider their individual contribution to predicting outcomes or impacting physiology. Then we consider how modifying this individual variable could potentially help, say, attenuate disease risk. But the fact of the matter is, almost always, if not always, because I actually can't think of a single counterexample, an intervention will impact something else. Diets and lipids is a good example. If you change your diet, you will rarely affect just one lipid parameter, say LDL or ApoB, and and not change others. Others will change— HDL, your triglycerides, or the profile of your LDL, etc., etc. But even were, say, a dietary intervention to only affect one measurable lipid parameter, there are a myriad of other variables that could be impacted on which the spotlight of attention and measurement might not be focused. Things like insulin, other hormones, the microbiome. And as a point of emphasis, changes and risks might not even be in the scope of awareness. Given limitations on what we can measure and long-term outcome data that we may or may not have. So I think it's just important to remain humble about what we know and what we don't, and above all, acknowledge the fact that every intervention will change more than just the variable we might be talking about. Underappreciated truth 7 is that the host's metabolic context matters. This one is obvious but incredibly important, so I'll say it again: the host's metabolic context matters. For example, a bowl of pasta hits very differently if you're a sedentary middle-aged person with diabetes and very little muscle versus a healthy, active college athlete. That bowl of pasta, it's going to hit very differently in those two scenarios. And the same goes true actually for exercise. Believe it or not, exercise, which exerts a lot of its benefits by changing the expression of your genes, affects people differently based on their insulin sensitivity, whereby some genes can be upregulated or downregulated if somebody's insulin sensitive. And then there's the opposite pattern in somebody who's insulin resistant. So whereby a gene might have been upregulated if somebody was insulin sensitive in exercise, that gene will be downregulated in someone who's insulin resistant. So Again, host metabolic context matters, not just with respect to diet, but also with respect to exercise. Now, as a final and bonus 8th underappreciated truth, science is a process, not an institution. So stay humble about your knowledge, stay curious, and I hope you enjoyed this video. Bye.