Stop Counting Calories! Diet Myths Exposed (And What to Do Instead) | Dr. Nick Norwitz : 1245

The calories in, calories out hypothesis. I feel like it's just a way to shame fat people because it doesn't usually work.

It's technically accurate and practically useless. The thing about calories in, calories out is it's not a model of obesity in the first place. It is just describing what has happened.

There are a group of people who say that all you have to do to lose weight is exercise more and eat less. And I did this for 18 months straight in my early 20s. I never lost a pound.

Most people are not overweight because they have a slow metabolism. They have a slow metabolism because they're overweight.

What are the top three blood markers that you think are most important for people metabolically? You're listening to the Human Upgrade with Dave Asprey. This episode is going to be a lot of fun because you're going to get some new information on papers that just came out. And our guest today is Dr. Nick Norwitz, who's a PhD researcher, educator, and just an absolute OG when it comes to metabolic health. Valedictorian at Dartmouth and PhD in metabolism from Oxford. Little things like that. Getting his MD at Harvard. And I'd say we share that mission of making metabolic health something that we all think about, because metabolism powers energy, which powers longevity, which powers willpower, and which powers just being kind to other people. Nick, welcome to the show.

Thanks for having me on, Dave.

So many things. I want to get the latest updates on stuff you're excited about. We're going to get there in a second, including some stuff about hair loss and some stuff about Alzheimer's. But first, if you could only have one pharmaceutical to extend your life or give you superpowers, what would it be.

Like an existing pharmaceutical? Can I just get Stormbreaker from the MCU or something?

I like the MCU answer. However, I'm looking for a real pharmaceutical today. You're like, wow, that thing has some benefits.

I think it's. I don't know if I'm sorry to cop out, but I don't know if I can answer that question because it's so context dependent. It's like, what does an individual need? Is there's something for me, I don't think I need any pharmaceuticals.

I didn't say need. You're talking about to be better than you would have been without it that.

I don't have access to.

Well, no, you have access to whatever pharmaceutical you want. I mean, you have friends, you're in medical school. No cognitive enhancers, no longevity drugs, nothing. You're you're like that.

Not drugs, per se.

Testosterone. Nothing.

No, actually, my testosterone's weirdly high. For the last year, it's been running around 1100. I have no idea why. What's your idea? Why?

But what's your free testosterone look like?

It's all. I don't remember what the number was, but it's also high. I mean, my SHBG runs high, too. That tends to happen when you're lean and low. Far. But my free MI total is pretty high.

Beautiful. And how old are you?

20. I turn 29.

Well, that's why it's high, because, you know, you've. You still have your DHEA and. And pregnant alone.

And jumped. Actually, after I finished, I was on a really stressful rotation on, like, night shifts. Oh, that'll be around like 400. And then I went off of that. I started a new relationship. So a couple variables there. And it jumped from like, 4 to 1100. It's been sitting there since.

Yeah. Having some female pheromones in the environment around you is actually well correlated with increases in testosterone.

It's interesting because it's like that question I was asking a urologist around about this actually, the other day on Instagram. Why I was like, could sexual activity increase testosterone levels? And on the one hand, there's not anything on pubmed. I know how to do a literature search, but then again, you have to think about the methodology and things like sexual sex quality might matter. And how do you actually do that study? You know what I mean?

The best in the world at that is John Gray from the Mars and Venus books, and he's got really good research around the testosterone drop in the 24 hours after ejaculation, along with a big increase in prolactin. And there are ways to mitigate that, of course, but what does happen is that just the presence of women who are ovulating does increase testosterone. In fact, years ago, when I was like, this would be really good from a longevity perspective. You can buy pheromones called copulins, and you just sprinkle them around your house. And then your body knows that there might be fertile women in the environment, and it raises testosterone. And if you're in an environment with no pheromones, after a while your body's like, what's the point? It stops making testosterone because you got nothing to do with it.

Noted. I'll thank my girlfriend.

There you go.

My metabolic boost.

Now, for listeners who are unfamiliar with your work and you've built a name for yourself in the keto world and the metabolism world. Why did you get into it? I know you had a health problem. Just kind of walk us through your basic journey there so people understand why you are so passionate.

Well, I grew up always wanting to do medicine and science. I come from a medical background or medical family, so both my parents are physician scientists and what I wanted to do my whole life. So I studied cell biology and biochemistry in college and then went off to do my PhD at Oxford Metabolism with a plan to come back, do medical school. It's a very standard academic physician path, MD, PhD residency fellowship, all that.

Oh yeah.

Along the way I started dealing with my own health issues. In my case it was inflammatory bowel disease. I hit pretty hard at the end of college and then during grad school to the point that I was like in out of ICU level care. And it was really jarring for me because it went, you know, within a couple of years I went from being a high performing athlete like I was sub 3 marathoner, winning push up competitions, top of my class in school, to being like, you know, physically fragile, laying in a bed, mind not there, social life just corroded. And it makes you think like, you know, how fast you've been following it was definitely very humbling. And I think I reached a point that a lot of people reach, which is desperation. And when you're desperate you'll try anything. So you know, even at that point in time, I had a lot of faith in conventional medicine. I use a word I don't use lightly, faith, because I think a faith is like kind of like a blind belief, but that's in effect what it was because it needs to be right. Like no individual can have a full picture and a full understanding of why we do what we do in conventional medicine. Growing up the son of two doctors and having access to the best medical systems in the world and having some sense of what the training is like and how much there is to learn and what the art of medicine is. I have a lot of respect and I still do for conventional medicine. So it almost seemed arrogant to be like, I can fix this myself. Like, what do I know? I'm in my early 20s, like I haven't done, I haven't paid my dues that all my brilliant physician, you know, caretakers have. So it almost seemed arrogant to try to take control of my own metabolic health journey. But I got to this place of desperation and then you're like, I'll try anything, I just need this to stop. So, you know, after conventional Treatments hadn't worked effectively, I started trying metabolic health interventions. I didn't call them that at that point. I just called them things like diet. And I just started tweaking my diet. So I went through every diet you can imagine. The standard ones for ibd, inflammatory bowel disease and IBS as well are things like low fodmaps, bispocarbohydrate. Tried those, did the whole plant based thing.

Ouch. That didn't help.

Did, didn't. No. I do get a Thor whack.

I went on a similar path. Okay.

It was in my scope of awareness as something I thought of at the time as healthy. And for some people it might work. I'm not saying for some people it wouldn't, but that did not.

Hey, breatharian might work for some people too. We can always hope.

Yeah. I saw someone post the other day about how he lost 60 pounds on a sunlight diet. I'm like, dude, that's fasting. But anyway, that aside, I tried a bunch of different diets and eventually got to a ketogenic diet. And I want to be clear, I tried it not out of expectation, but out of desperation.

Me too.

Why not, right? You have nothing to lose. It's like, all right, I cut out some carbs for a little while, whoop dee doo. I'm already feeling like death. And a light bulb went off in me in every way, shape and form. Yes, I energy got better, my inflammatory markers dropped to the lowest they'd been and I just came back to life. And then actually when I got my ex colonoscopy, I was in biopsy proven remission. So this was feelings biomarkers and biopsy on colonoscopy remission. And you know, it was really striking for me. And at that time I thought I was just what one calls a medical zebra. So there's a saying in medicine when you hear hoof beats saying course is not zebras. And the zebras are the outliers, the weird ones. And so even now I'm like, I'm happy, I'm healthy. But this is weird because there's no like controlled trials on this. This isn't a quote, evidence based therapy. But it did pique my interest enough to start to one, delve into the literature deeper on metabolic health and then two, delve into the community. And what I found, and this is what I like to say most often about my journey is the most amazing thing about my journey is it's not at all unique.

No, it's so common.

So yeah, this motif where People struggle with some metabolic health problem. It could be obesity, it could be diabetes, an autoimmune or inflammatory condition. You know, the standard approaches don't work. So they try something that is considered by society to be out there, to be extreme, say a ketogenic diet or fasting, and they have remarkable success. And so that's really what shaped my journey going into medical school and my perspective, because I started to think about incentive structures and how we do medicine. And there's a lot I've realized. But one thing I want to point out to people is this idea that absence of evidence is an evidence of absence. What I mean by that is I can't tell you that it's proven in a human randomized controlled trial that a ketogenic or carnivore diet will help in inflammatory fallacy. So there's no study, rigorous studies showing that as there are for some pharmaceuticals. However, it doesn't mean that it might not work or might not be the most potent approach for some people. It's just we've never asked the question. And why haven't we asked the question? Well, because the business model for doing these studies isn't very clear. So who's going to fund it? And if we're not going to fund the trials, we're not going to get done, we're not going to have it as quote, evidence based medicine. So this idea that we have now in the western world of conventional evidence based medicine, on the one hand it's good because we do want an evidence based, on the other hand, it's lacking because the research infrastructure is not built to examine metabolic health interventions that we need for the metabolic diseases that are plaguing us, which is so obvious when you see it. But it took a personal experience for me to see that.

I went through a period early on where I was actually angry because no one had told me about the keto diet. And when I was about 25, 26, I found out about Robert Atkins. His first book was published the year I was born and I lost £50 in three months. And a lot of my gut issues went away. The other £50 took me 10 plus years. That's why I wrote the bulletproof diet. The first, like keto clean keto cyclical intermittent fasting diet. Because I'm like, here are the things that we're missing. In order to get my metabolism all the way working. It's more than just go keto all the time and don't eat any carbs ever, because that, that usually doesn't end well for people if they're not paying attention to all the other variables. But along that way, I'm like, why did no one tell me it would have been so easy, right? Did you go through a period of that? Like, I've had IBS all the time. If someone had just freaking told me to eat the butter instead of the rice, it would have been better, or did you skip that phase?

I don't think I was ever angry because there was nobody to be angry at.

It's like, yeah, I wasn't angry at anyone. I was just angry in general. Like, why? It's not fair. Why wasn't the information out there, like. Like, everyone needs to know. This is a tool at least, right?

So I've gotten angry at the reality of things, especially as I've gone through medical school and seen patients be mistreated because I'm someone with an incredible amount of resources, not only having parents that can support me in medicine, having access to best healthcare systems in the world, and. But the skill set to actually delve into the literature, develop protocols most people don't have. That. That is profound privilege. And even with that, it took me multiple years to get to a point where I had a solution. So we are not serving the public with respect to metabolic disease. That is very clear. And to me now it's kind of obvious some basic things that we could do, and yet we're stuck in this dysfunctional system doing things that just make absolutely no sense when you can see them. And to shift, that will take, like, a large societal shift. And I'm eager for that to happen. This is what I say. I'm eager for it to happen, but I acknowledge the realities of where we're at. So I'm working for it to happen. And there are moments when I see people being, you know, I think given advice that is not helpful, and then they spin their wheels and put a ton of effort, energy, dreams, trying to recover. It's a futile effort. And I feel like we could serve people better. It's just, you know, the reality is it'll take a little while, but to. To. To get there, it's gonna take a shift in social psyche, which I think we are seeing, but it's just gonna take time.

If you were working on fixing your metabolism and you could either exercise for an hour a day or more, or eat an appropriate diet and get good sleep the way biohackers do, which would you choose?

Oh, the latter without with question. I mean, I think the potty needs some sort of activity. Input. But like. Yeah, no, I think diet and sleep are paramount, especially if you're someone who's trying to say like, lose weight, reverse diabetes, obesity, then it's diet first. It doesn't mean it shouldn't be either or.

Obviously it's not either or.

An hour at the gym is not going to save you.

No, I believe that really strongly. I did 90 minutes a day, six days a week for 18 months in my early 20s trying to lose the weight and fix my metabolism and it didn't work. And man, you can get tired and over train that way and it leads to all kinds of problems. So I just want people to understand it's food first, it's lifestyle second, and the appropriate amount of exercise third. You got to do all three.

Yeah. And realize that it might be a long journey. I don't know if you saw that epigenetic memory of obesity paper that came out.

Is this the multi generational one?

No, no, no. So there was a paper that came out where they were looking basically at fat cells, and this included, included animal models, but it included human studies where they wanted to see, you know, if someone has had obesity but then lost weight, do their fat cells have some sort of memory of the obesity as compared to a lean person. And so this was new 2024 data. They took biopsies from people before and after bariatric surgery before they lost least a quarter of their body weight, and compared the before and after biopsies to always lean people. And what they found is that even two years after the surgery, the fat cells from the people who had obesity had this epigenetic memory. So they tended to have downregulation of pathways related to metabolism and upregulation of pathways related to inflammation. Now, I did a video on this and at the end I said, do you find this pessimistic? Because it kind of sounds like, oh, no, I've like had obesity, but I've recovered. But I'm always going to be behind the eight ball. I don't see it like that.

Me either.

This is how I see it, and this is the reason I brought it up, is the body takes time to adjust. Now, this paper was two years after surgery. It's only two years. And also the weight loss was presumably progressive after surgery. So it's not like they were lean at as soon as they got surgery, it took two years. I believe this is a speculation, but what I would believe is that over time, what you could call the metabolic scar of obesity would fade. But the reason I bring it up. And the reason it was forefront of mind is you said, you know, the first £50 for you came off in a few months, and then it took a long time for the rest to recover. And what I would say to people on this journey is like, you know, the investment, the motivation at the beginning, it's really meaningful. But I think things get easier as you go along the journey. And it is a chronic grass is greener on the other side scenario, which I see is very uplifting, not pessimistic.

And if you look at how often fat cells get Replaced, only about 10% of fat cells get replaced each year. So if you change the epigenetic environment, in other words, all the stuff in your body, when those 10% of cells get turned over and they're in a healthy metabolism, they're likely to do it. And what that means if an individual fat cell lives for eight to 10 years, it's going to take a while to fully recover. I've been relatively lean, as in under 12, 14 body fat, for 20 years now, even though I weighed 300 pounds and I am at 4.8% body fat right now. And I'm not trying to be lean, I'm actually trying to put fat back on. And it's difficult because my body's just used to this.

It's funny how that works.

Yeah, I know, right? And there's people going, dave, you know, shut up. But I'm serious, this is something that's relatively new to me. Or I'm going, God, I'd love to have like 3 pounds of fat added to my frame just so I could use it for longevity purposes. And I'll get there. The idea, though, is you can train the body to do these things. So what do you think about cycling keto versus just continuous keto? There's some debate about that.

Yeah. I would say, all things being equal, to me, it makes sense. There are different levels at which you can dissect. This one is just the. Some people like to take the evolutionary perspective, like, we weren't adapted as a species to be in ketosis all the time. So there's that. I think, you know, maybe the more evolved way to think about it is in general, like biology and nature in general works in cycles, catabolic anabolic cycles, going at the same time, you want to break down, renewal, and then you want to build up. So actually, if you look at some of the data, like, say, the neuroscience data, and this is some of the work of Mark Matson out of Johns Hopkins, what you find is you know, there's like signs of enhanced learning, long term potentiation in fasting feeding cycles during the refeed, because during the refeed you're, you know, getting a boost of growth hormones that help with things that are beneficial. So you really do want a balance of anabolism building up and catabolism building down. So I think keto cycles make sense again, all things being equal. But I caveat that with, I also don't think chronic ketosis is per se harmful. So if you have a metabolic condition, like I do, say inflammatory bowel disease, where this is therapeutic for me, then by all means stay in ketosis all the time. I don't think we have any data to suggest it's truly harmful. There's one paper on cellular senescence and called zombie cells that I've gone over, but I think for the most part the data would say it's largely safe if you have a metabolic condition. But I'm, I'm, I'm pro keto cycling if it works for someone. But again, if it's this kind of thing, adding that car that makes you fall off the band bag and damn back weight, then don't do it. It's very individualized in that way.

Yeah, if it doesn't work, don't do it would be really good advice for everyone.

Do it. If you're like, I know I'm going to gain weight back and you know my diabetes and obesity are going to come back if I add back the carbs, but I really want a keto cycle just because then, no, you don't need to.

My advice, after interacting with tens of thousands of people personally and my own thing is be in ketosis and then Saturday morning have the pancakes, but without the gluten made out of things that don't give you a disease like IBD and don't trigger you. So it could just be a piece of fruit, it could be scarves, just dip out. And the reason for this has to do with akkermansia, because akkermansia, as you know, I'm just educating listeners. It's a generally beneficial probiotic that lives in your gut. But if you don't have enough carbs to make mucus lining for the gut, it will actually poke holes in your gut and it is then associated with Parkinson's. So it's one of those things where you got to get some kind of ability to make mucus. You could also take soluble fiber that keeps you in ketosis. I made one years ago that quadrupled my number of species in the gut. So it's possible to have a healthy microbiome and be in ketosis. But different prebiotics work differently for different people. And since you had ibs, it might be different. What do you think of that perspective? Stay in ketosis but take some soluble fiber that goes to butyrate and just don't worry about it.

Yeah, I mean the thing with the microbiome research in general is a lot of it is really black box. We can speculate and generate protocols and, and, and you know, we could be right, we could be wrong. I think there's a lot we don't know about the microbiome and this is in large part because it's so dynamic. There's so much inter and intra individual variability. That's a really hard thing to measure. Right now I see things moving towards a more metabolomics focused approach. So rather than saying, you know what gut bugs do, we have, we look at what is being produced by the gut bugs because different bugs can serve different functions in different people. So a lot of the, the pre existing data we call good bugs, good or bad, are based on large scale studies of population who are on mixed diets. So it's really hard to generalize to people on very low carbohydrate diets because then things change. Your compositions are gonna change, the rules different bugs take are gonna change and you're gonna have other molecules serving different functions like beta hydroxybutyrate, which obviously can fuel, you know, intestinal cells as opposed to butyrate, which might be made by the fermentation of certain fibers. So it's not easy. I would say in general best practice for most people and I'd actually put myself in the exclusion group about that in a minute. But yeah, I think eating generally a more diverse diet, including fermented foods, things like sauerkraut, kimchi, kefir is, is going to do well for your gut. I put myself out as an exception because like with all things it's very individual. So there's data that came out of Stanford, I think it was the Sonograph paper showing that for example fibers and about one third of people were pro inflammatory.

Yes, especially inulin. People say that, oh, inulin so healthy for you. It's almost as inflammatory as gluten for a large number of people.

People.

So I tend to steer away from it.

Well, the point being in this study like, you know, there was a portion of people had an anti inflammatory response to fiber and a portion had a pro inflammatory response to. Now I will also caveat that that the pro inflammatory response subgroup tended to have less diversity, which begs the question could you build them up to the point where then they had the positive response? But then we come back to what I'm saying before. Whereas like we don't have good protocols on this, there's so many cool things we could do. Like fecal matter transplants are a whole nother like topic which could be very cool and therapeutic. But we haven't developed clinical protocol so it's very difficult to say. But if you tolerate things like, you know, ferment, low carb, like fresh fermented foods, I can only see a potential upside to including them rather than downsides. But if you don't tolerate them, then don't have them.

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I went through a long phase as I was fixing my metabolism where I would eat fermented foods, some of them, but not all of them, and I would just get the worst response. I would just get profoundly tired and like sugar cravings and just felt awful. It turns out a lot of them make histamine. And histamine is a neurotransmitter and it has effects throughout the body. So if you're sensitive to histamine, you're going to eat these things and feel like crap and you're going to think you're crazy because sometimes you feel good, sometimes you don't. And the bottom line is that batch of kimchi is different than that batch of kimchi, right? So it's okay to just say you got to do what works. And to your point, there's pretty good evidence that you'll figure out something. The best data set that I know of is viome has a million samples now that include RNA to figure out what your gut bacteria is doing and correlating it with with spit and blood. So I think sometimes I'm like, you know what? Our data set shows you might try this food and this one's probably not going to work. That's a good starting point to see how you feel. There are probably other tests as well.

And I think the whole idea of starting point is really key because what we're talking about now is mechanism. And you can speculate all day, but at the end of the day, it's about trying what works for you, having the hypothesis, implementing that on yourself and seeing how you feel. And you can correlate those feelings to any mechanism and you could be right or you could be wrong, but at the end of the day, you probably just care about how you feel and how you're functioning. So as long as an individual is willing to go on this journey, test their hypotheses on themselves and iterate, they generally can get to a good place. Whether or not they're right or wrong about the mechanism of what's going on in their body is kind of irrelevant at the individual level. Well, much as I love mechanism I'm.

So happy you said that. I'm with you. Mechanisms are great stories that help us understand how to solve problems. One of my favorite stories about that is from Candace Pert, the discoverer of the opioid receptor. And in her memoir, she talks about traveling down and meeting shamans in South America. And she got all excited, and she explained how all these receptors work and neurotransmitters. And the shamans started laughing. And she goes, why are you laughing? You think those things exist?

Right.

And it's not that the shamans didn't have a working model for solving problems. It's just an entirely different one. And neither story is accurate, because underneath all that is some kind of quantum stuff we barely understand. And if we aren't looking at it, it probably doesn't even work that way. It doesn't even work in our brains. So understanding both stories are valid. I'm also a mechanistic guy. I love your perspective. But end of the day, like you said, it either works or it doesn't. And if your story's wrong, who cares?

You got the win at the individual level. Yeah.

Yep. Let's talk about some news. You and I are both fans of intermittent fasting. The Bulletproof Diet's a major intermittent fasting book that's been around for a long time. So one of the warnings that I've had about fasting, enough of a warning that I wrote a second book on fasting to talk about this, is that you can increase cortisol if you fast too much. And if you fast too much, that increase in cortisol hits women before it hits men. And the order of operations is, number one, your sleep quality goes down. So you wake up more at night, you don't get as much deep sleep. Something's not right. Number two is you start waking up without a morning kickstand, or if you're a woman, your cycle starts to become irregular. If you have a cycle. And then the third thing that happens is hair thinning in both men and women. And that was driven by cortisol. But there may be other effects. There's a new study, though. Tell me about the new study on fasting and hair loss.

Right. This just came out a couple days ago. I was actually reading it this morning, and it describes the mechanism whereby fasting, intermittent fasting, actually does lead to hair loss. So basically, the mechanism is that when you fast, leptin goes down. Leptin is released from fat tissue. And while it goes like. While it's a chronic hormone, it also can Drop acutely. So during a fast, it can drop quite acutely and that activates the brain, the hypothalamus, to activate the hypoth, hypothalamic, pituitary, adrenal axis. The adrenals kick out cortisol and epinephrine. Now what cortisol and epinephrine are good at doing is stimulating fat burning. And this is what's really interesting. So if your body is actually builds up all, all these little like metabolic pockets, they're called niches. And in the dermis area of the skin, you have these hair follicle stem cells. And the stem cells are surrounded by fat cells, they're called dermal adipocytes. And the epinephrine and the cortisol stimulate the dermal adipocytes to release free fatty acids. In fact, the, the burning of fat in the dermis skyrockets the free fatty acid levels above what it is in the blood. So in this metabolic niche around the stem cells in the dermis that give rise to air follicles, there's this drop in free fatty acids. What happens is it causes the stem cells to burn them. Fatty acid oxidation and at such a high rate that actually there's an increase in oxidative stress, reactive oxygen species that overwhelms the antioxidant capacity, leading to basically like poisoning and apoptosis, programmed cell death of these stem cells. And so hair growth slow. So they showed in this new study, the longer fasts had a more potent effect. And that actually the effect, you know, if it was applied chronically, at least in the animal models, led to basically deaths of the hair follicle. It wasn't something that got adapted to the hair follicle died. And they did these experiments, viewed the paper. It's really cool because they did like shave the mice naked and they saw how long the hair will go back. So you see these like little rows of like naked mice slowly growing hair back. And it's really interesting because it's even dose dependent, where it's like the mice that ate on a 1212 schedule, they grew the hair back the quickest. 16, 8 slower, 18, 6 slower and slower and slower and slower. So it does appear that fasting impairs hair follicle growth. And this is also correlated with a human randomized trial. They pulled data. It was something like 49 young healthy adults and she have a little patch of hair, had some undergo intermittent fasting and the hair grew back about 18 slower. So it's really interesting, what I will say is this was not like a fasting is bad paper. It's so much cooler than that because a lot of other metabolic benefits were identified in the mice. Better glucose control, other markers of better metabolic health, actually lower oxidative stress systemically. So the, the dermis oxidative stress does not correlate with the systemic oxidative stress. But this is just an example of how beautiful the body is at, like, partitioning resources. In fact, other stem cells, including in the epidermis, which is important for the barrier function, were totally fine. And muscle stem cells and gust stem cells, all these might have had positive effects. But you can think of it as like the dermis is martyring itself, the dermal stem cells, and you don't grow hair. So it's actually very adaptive. It makes a lot of sense. And one thing they did in the study on the mice, which is they said, okay, if this is the mechanism, the free fatty acid overload is causing oxidative stress and overwhelming antioxidant capacity. What if we just put some topical antioxidants on? So they put some vitamin E on and it helped. One of the things they said in the paper is like, next step is like, does topical vitamin E protect against hair loss in humans doing intermittent fasting? For who that's concerned? If you look at my eyebrows, evidently it's not a concern for me. But very cool paper. Very, very cool, mechanistic paper with some potential action items.

I love that you can, you can do so much better than vitamin E. A lot of the researchers are still using synthetic vitamin E. And one of the other strategies for hair loss is you increase mitochondrial function, which means the mitochondria make their own antioxidants more easily. Topical aspirin, topical caffeine. There's a long list of things that seem to help and something that isn't in that paper that I'm aware of, but is important is that when people get that activation of their stress response, and I don't care if it's from too many cold plunges, from fasting for too long and inappropriately, or from, you know, over exercising because you think it's going to make you healthy until you die at a normal age, which is some of the advice that's out there, I, I'm kind of looking to go beyond a normal age, and I'm willing to exercise as much as is necessary and no more. So all these things are about stress response. And you can have cortisol that goes up, you can have adrenaline that goes up, but the unsung partner to adrenaline is noradrenaline or epinephrine or norepinephrine, because epinephrine and adrenaline are the same thing just for listeners. So what are your thoughts on fasting and norepinephrine and can you walk our listeners through that hormonal conversation?

Well, norepinephrine is a precursor to epinephrine. They're all in the same catecholine pathway. What exactly is your question with respects to.

There's a ratio of epinephrine or of epinephrine to norepinephrine that you are looking for in people who are not particularly stressed. So if you're working at a nice calm pace, it's 4 to 1. In my mid-20s, when I was metabolically dysregulated, it was 45 to 1. For me, I was entirely stress hormone dysregulated. And norepinephrine, it actually prolongs the resting phase of hair stem cells, so they wait longer and it inhibits activation of follicle cells. Follicle stem cells. So understanding that your stress response may be different than someone else and that you. It might even be possible to use some hormone blockers that block stress hormones, like a beta blocker topically in your hair. So I'm all over this. It's so interesting.

Yeah, it's interesting.

Yeah. And so what do I do? I do a variety of things that involve antioxidants and mitochondrial stimulation in the hair. And I use a little bit of topical minoxidil, and I'm a little bit sketched out by a finasteride. Because that whole idea of chemically neutering yourself for a decade or so to have better hair. The reason you probably wanted better hair was so that you wouldn't have the effects of being chemically neutered. So that seems like a bad risk to take. But that's just me. Thoughts on that strategy or anything else you'd like to add about hair?

Nothing about hair? There's not really been something I thought about a lot, to be honest. This is like I load the mechanism. So I read the paper also a professor of mine, mentor of mine, ironically, the day this paper came out, he said he was trying his first prolonged fast and he falls. So I'm like, good thing you're bald already.

That's funny. You gotta give those professors some crap. They love it.

It was just coincidental timing.

Another area of interest that we share is Alzheimer's. I wrote a big cognitive function book and that C8MCT oil that I popularized when I was running bulletproof in phase 2 trials. C8MCT has a beneficial effect on Alzheimer's disease. I can never say that. So I'm like, I'll just get everyone to drink coffee and do some mct and it's going to help Alzheimer's. Mct, as I think most listeners know, leads to mildly elevated ketones. But there's a new paper out about Alzheimer's and protein. Talk to me about that.

Yeah, so this came out of the Buck Institute. Matt Haven was the first author. Other people you might know, Brianna Stubbs, who you know was an author on the paper, she actually did her PhD in the same lab I did at Oxford a couple years before me. And so this paper was about protein misfolding. So as people may or may not know, neurodegenerative diseases in general, not just Alzheimer's, but Parkinson's, Als, Huntington's, they're diseases of proteins misfolding pathologically. And you know, Biology 101 is structure determines function. So something misfolds as the wrong structure, it has a wrong or pathological function. So things like amyloid plaques that you might have heard about, tau tangles, the hallmarks of Alzheimer's are basically from protein misfolding. And so, you know, in an ideal world, what you do is get these misfolded proteins out of the brain. And there's a lot of things ketones can do that are beneficial for brain health. But there's no new study shows how they can actually target misfolded proteins, help them transition from a soluble to an insoluble form and get them cleared out of the brain, which is really incredible. So basically when the proteins misfold, the ketones bind to this now exposed pocket on the proteins and then help can make clear exactly how via ecophagy or the proteosome isn't really, isn't really aware, isn't really known yet. Although that'll be the next step in research. But it was really quick, cool and just fascinating to me because I was looking at it and I'm like, wow, isn't nature incredible? Because it's like ketones are this simple molecule and yet not only are they clearing these proteins out, but bear in mind that they're not just clearing proteins willy nilly, they can actually identify this simple molecule, can identify the misfolded proteins based on the binding pockets that are exposed when they misfold and get them cleared out of the brain. So the analogy I used in a video I have coming up on this paper was it's Kind of like if your brain is a really messy apartment and trash is just building up everywhere all over the apartment, what you want to do is get the trash from the trash bin so ketones can somehow go around and clean up all the trash and put it in the trash bin. And not only that, they can then take the trash bin and dump it to the garbage chute, which is amazing. Actually, there's a great quote in the paper by the authors themselves when they say something to the effect of ketones are like the janitor of the brain. It was really brilliant. So I'll have coverage coming out on that. And the first author of the paper was kind enough to give his two cents, so I'll include that as well. Wow.

You always have the best reporting on the latest papers. I appreciate how you explain it for people.

It's fun.

It is fun. It's an unusual skill to be able to do that.

I'm new to it and I think we. It's just there's a lot of opportunity that opens up. I like to teach about it, but I realize, and now I can be a bridge to the author as being like, you know, hearing from the horse's mouth. So in upcoming videos we have a few where after I give my two cents, it's like. And here's what the authors had to say on like, why is this exciting and what is the next stage in the research? And just to kind of plug some initiatives we have going. You know, we're both excited about making metabolic health mainstream. I can talk to the general public, but I'd really like to get my claws into the next generation of doctors. So I'm actually working with a company called Exam Crackers. They're a bunch of companies that help people prep for medical school in the mcat. Exam Crackers is one of the companies and now we are providing MCAT medical school exam entrance exam style passages free with a lot of these paper breakdown videos so students can prepare for the MCAT with free resources. And we're going to be moving towards actually getting some of my videos and content CME accredited. So current physicians, you get continuing medical education credits. Yeah.

Nice job, Nick.

It's going to be fun. I'm working with the Metabolic Health initiative on that. So Dom d', Agostino, Victoria Fields, really great people. So we're going to drop a pilot on that. I'm covering some research on a food addiction virus, which is a whole nother topic. But there's just so much bull stuff coming out in metabolic health space and it's just about awareness because I know there is interest in the topic. We just need to kind of light stimulate this interest, especially in the next generation.

It's so cool when physicians learn how to do the systems biology stuff. The way that it seems like you think suddenly sometimes things just become apparent. Like when I heard about the Alzheimer's and protein folding paper, my mind goes to hdacs or histone deacetylase chemicals. And a lot of the stuff in the bulletproof diet and in Head Strong, the cognitive enhancement book, like there's benefits to ketosis that go beyond just losing weight or having more energy. And it's funny because both coffee and ketosis can change HDACs, and that they are what regulate gene expression around folding and unfolding, or we'll say refolding proteins, and they stack incredibly well with heat shock proteins, which means that if you're intermittent fasting or you have a keto diet and you have a cup of coffee and you hop in your sauna, or you hop in a hot tub that's hot enough, then you're kind of doubling down on your body's ability to potentially remove or at least prevent plaques. Thoughts on that?

I would say that the, the HDACs, the HDAC and or folding, they're. They're distinct, I would say, but parallel. So in terms of folding or unwinding, there's things like the protein misfolding that we talked about and heat shock proteins, which help with protein folding. So you're right. If you go in a sauna, basically you can increase the expression of these proteins that make your protein folding system more robust. And then there are HDACs. So histone deacetylases, as your name suggests, deacetylate histones. Which brings the question, what are histones? Histones are protein complexes around which DNA is wound. So it's not as much folding but winding of genes. So the DNA kind of string folds around these histones and by changing the histone deacetylase function, you can wind or unwind sections of your chromosome, your DNA, to change how genes are read into mRNA, which is read into protein. So that's more about gene expression than protein misfolding per se. So there's a winding and unwinding. I see how those things can get conflated, but the HDACs aren't actually helping in protein folding.

Interesting. So they're, they're helping to define the protein as it comes off. Well, as it's read off mRNA, which.

Holds then develop into a protein, but it's I guess you could say that the histambia acetylases are helping define what proteins your body makes. And then you want to make sure they get folded properly.

The interesting thing is that inhibiting HDAC reactivates heat shock folding protein. And we have a couple papers now that show when you're in a sauna and you have those high temperatures, your body will unfold, fold misfolded proteins, and then refold them. So there's a kind of cool, mechanistic dance. I don't think we understand all of it. And, and thanks for the little lesson on HDACs. It's been a while since I wrote a chapter on that. So do you do heat therapy with your ketosis? Do you do cold therapy?

I have been very resistant to cold exposure because I. Of all the things that I don't like, you know, it's like, there's a lot of things you can do for your health. Do you all know we're healthy, but everybody has that one or two thing that it was like, I just hate this so much that it's not worth it. To me, cold therapy has been that I'm pulling the trigger and going to do some experiments on it. But historically, like, you know, I'd. I'd rather run a marathon on a broken foot than get into cold water. I just hate it so much. But I love saunas. Like, I like heat, so I've always enjoyed that. Honestly, for me, my, let's say metabolic health protocol has up and optimized the last little while, largely because of where. Where I am in life. Being an HD researcher and medical students and young person trying to make it in Boston with current real estate prices, while managing social media is not the most conducive to always taking care of yourself in every moment. So I'm aware of that and I try to be transparent about that. But it could further optimize for sure.

Can I share a section of my new book that comes out next year called heavily meditated with you that'll make you like your cold plunge?

Sure. There was a paper I was just reading on. Well, I was looking into reasons why or why not to cold plunge. And what I've come to is like, you don't cold plunge for fat loss or calorie burning. It's just not efficient. There's actually a new study that came out on this.

Not efficient on calorie burning.

It's not. So, for example, this new study came out where they exposed people to cold water in a, like a, a wetsuit. That enough to induce shivering.

Okay.

But the way that they defined like the threshold was actually 50% above, you know, resting energy expenditure. So basically 1.5 MET.

Okay.

Now by comparison walking at 3 miles per hour is like 3 MET. So if you want to burn calories like you can go for a walk. And the amount of time you spend walking is probably going to be more efficient than cold exposure for the most part. And there doesn't appear to be a significant afterburn effect. In fact, after a tent that like.

Flies in the face of, of a lot of papers I've seen. Wow.

No, so and after a 10 day exposure, there was no change in like fat mass in this intervention. I will say. I mean there's some studies showing like increased metabolic rate, but it's also like these people were swimming in freezing water for multiple hours. I'm like, yeah, that's different than like sitting in your cold plunge for 15 minutes. So I don't think it's an efficient way to burn calories. Yes, you need to maintain your body heat. So while you're sitting in the cold water your energy expenditure is going to go up. But the amount it goes up, up, it's not like you're like turning your brown fat on. You're going to get a six pack and cold. So don't do it for that reason.

And also when you're in the water isn't when a lot of the calorie increase that I've read about comes, it's in the next couple hours afterwards as you warm yourself back up. But again, it's not the same as going for a bunch of exercise.

It's not that much. But there's other reasons. So the spike in dopamine that happens, there's about a greater than 250% spike in dopamine that happens after cold water exposure. This was a paper published in 2000 and they looked at least into the one hour recovery period, there's a big jump in dopamine. I will say a caveat with that paper because you might have talked about it. People talk about it is they are measuring plasma dopamine and dopamine does not cross the blood brain barrier. So we don't know what's happening with brain dopamine. I do think it just in intuitively obvious that there is a central nervous system activation and people feel great after cold plunging to the degree to which the serum dopamine is actually like predicting anything going on in the brain is or to what degree it's correlating is Another story. But I think a reason to cold plunge is one the mental health benefits. And then there's things like anti inflammatory benefits. So have you heard of Marison? No, I think there was a paper in 22. Oh my. And basically. So it's made.

They're SPMs.

Uh, yes. So okay, I take that it's actually derived from dha. It's a, is a DHA derivative and if you are exposed to cold, a cold exposure then your fat cells turn the DHA into these marines which signal to your liver and systemically to reduce inflammation. So there's probably anti inflammatory benefits to old quenching via literal hormones that are released from fat tissue. So I think cold plunge is very interesting. I just wouldn't do it for calorie burning purposes. And also just on the anti inflammatory thing, you probably mentioned this to our audience before but like do a cold plunge right after you worked out because you actually want a post workout inflammatory response. So people say like when should you cold plunge? I say when should you not cold plunge? Not after a workout and not right before bed.

Well you want to do it before you work out. And there are some people where the mammalian dive reflex helps them sleep better with a cold plunge and there's that temperature drop that helps you go to sleep, but then your body will become warmer afterwards which may affect deep sleep. So it's kind of a double edged sword if it gets very mixed before. The new concept in heavily meditated is something that I called bicep and it's not this one. It's brief.

I actually just got my first tattoo.

Oh, nice. Sweet. What does it say there? Stay curious, stay curious. Mine is similar. It. Do you recognize it?

Oh, it's a little fuzzy on my screen. Which hormone is it?

It's trimethylxanthine.

Ah, caffeine. It was dangerous to try to guess the molecule is on somebody's tattoo.

It is dangerous, especially when you can't see what what molecules are on it.

Is that a nitrogen? I can't tell.

Yeah, bicep is brief, intentional conscious exposure to pain. And it turns out that doing something painful for a minute every day changes dopamine receptor sensitivity and cold plunge counts. So does whipping yourself the way monks used to or getting a tattoo, which a lot of people do if they're depressed. And it turns out that throughout the rest of the day it takes less stimulus for you to benefit from the dopamine levels that you have. So for people with ADHD or attention issues or just a lot of stress or People just want to be able to expend less willpower to do what they want to do. That one minute of painful stuff, which can include a cold plunge. It benefits you psychologically and from a motivation perspective, entirely different than the endorphins you get. Entirely different than the cold shock proteins, all those other biohacking benefits. This is a new benefit in cold plunge or frankly, getting a spanking, doing something that hurts as long as it doesn't hurt you is totally fine.

Is the book in its final, has it been, is it complete or can you add a reference? Because I have a reference that you are going to love me for.

I might be able to add a reference if it's not already in there. Tell me about it.

So this is, this is a paper published in Cell Metabolism. It was entitled Physical exercise mediates cortical synaptic protein lactilation to improve stress resilience. I can send you the link. It's 2024. September 3, 2024. Cell Metabolism by Yan it up and what they show. All right, high level. I think they probably agree exercise is good for anxiety and they show a mechanism about how this might work. So let's go back to the histamine acetylases. What they're doing is they're removing a functional group called acetyl group from proteins. Now, protein function can be determined by putting tags on and taking tags off. Histone decetellase is removing a tag. A tag that is relatively newly identified is lactate itself. So lactate can attach to proteins and change their function. And what they show in this study is that physical exercise, especially high intensity exercise that is boosting lactate levels, will boost lactate levels in the prefrontal cortex of the brain. The lactate can then act as a tag on different proteins, including one at the synapses between neurons. I think it was called snap 91. And in so doing, the lactate changes the protein function to change the neuron function to actually have anti anxiety effects. Lactate molecule itself is changing brain function to reduce anxiety. I had a video on it. It wasn't very popular, but I can send you that as well.

That's interesting.

How cool is that, right?

Yeah. There are so many things that we don't quite know about yet. Probably the way I would approach that as a biohacker is I would do something from the last book called blood flow restriction. Are you familiar with that?

Yeah, I have BFR bands. I just never have used them.

Yeah, I use them on occasion. I go through phases. So BFR bands. What these do is they increase lactate levels dramatically in the tissues, where some blood flow, but not all blood flow is cut off. And presumably, after you release the bands, you get a wave of lactate that goes through the body and then does good things to the brain. So. So there you go. If. If you're feeling anxious and. Or depressed, maybe you should try some BFR bands. They're very affordable on Amazon. And maybe it'll work, maybe it won't do what works.

Yeah, I know. Super cool.

All right, let's talk about cholesterol. My advice has been for 15 years, if it's harming you, your LP PLA2 levels should go up because that's an enzyme released from damage to the lining of your arteries, or your crp, which is a marker of inflammation risk. Or your homocysteine levels are the things I pay attention to, regardless of cholesterol. But different people have very different opinions. Tell me where you are with cholesterol versus inflammation. Teach me something.

As discussed in public settings is very devoid of nuance. So we're going to talk about some things. LDL apob, insulin resistance. Statements like lower is better. And what I want to be clear on is none of these things are things to take as definitives. So when I talk. Let me start with more the devil's advocate. Conventional viewpoint. Things like apple B and LDL particles, Some people say they're causal and heart disease, and then people bucket that idea. No, they are. They're part of the causal pathway. They are necessary for the cascade of heart disease. So that's a totally appropriate statement.

So is breathing. Yes.

Yeah. So. So, however, just because some. I think people get wrapped up in the terminology. So things like causal. When they say causal, they necessarily think important, and then they jump from that to, like, it needs to be pharmacologically treated. These are not the same thing. Something can be part of a causal pathway. And mechanistically, it can make sense to undermine the disease process by knocking out something that's necessary during the disease process. However, at the individual level, it's not quite so simple, because something can be causal, but how much risk is it actually providing? So you can have elevated cholesterol. And at an individual level, you know, the relationship between the exposure and, say, plaque accumulation can be very weak. So if you actually think about it, like, just a simple graph of, like, Y axis is plaque accumulation and also heart risk, and X axis is cholesterol exposure, I'm gonna say LDL particle or apple B milligram per deciliter years. The question is not is it a positive slope? The question is how positive is it? Because if it's like a straight up line, very steep, then yeah, you're accumulating plaque really quickly for an exposure and you should do something about it.

And you can measure that.

Yeah. And if it's really shallow, then it's like, well, is it worth intervening on? If your risk is increased 0.001%, it's still quote increase, but it's very different than it being increased by, you know, 20. So like by goofy analogy, I use this on a thumbnail on video is like the Geico Gecko and Godzilla. They're both lizards, they both constitute a lizard threat, but they're very different in terms of their magnitude. And you might want to drop a nuke on Godzilla, you don't want to drop a nuke on the Geico Gecko to deal with that problem. So, you know, it's in a word or two, context dependent, like your LDL level. Let's just say the risk it presents is highly context dependent on other metabolic factors, your metabolic milieu, your family and genetic background. So it's impossible based on a single marker to say you should do xyz. And, and that is a totally. I think anybody listening can be like, yeah, that's obvious and kind of totally reasonable. And also the art of medicine, a doctor is going to work with their patient hopefully to figure out what works best for them. But in the public sphere, what I see happening is these gross oversimplifications. So you get statements like you might have heard lower is better. You know, conventional is talking about LDL or Apple B. And I'm like, and well, what? The reason they say this, at least the reason I think they say it and they can feel free to correct me, is they're worried about giving an inch and having a mile taken. And they'd prefer to present the most conservative stance. So people don't do things that they perceive as risky with their health. Now the problem I see with that is first lore is better as a garbage statement because it's devoid of nuance. Lower. Better for what? All cause mortality or just cardiovascular disease. And also what are you doing to get the lowering effect? Because you can't just isolate ate one biomarker and snap your fingers like Magic and Lori. You're affecting other things. Are you changing your diet? Are you taking a medication? And what are the acute and chronic effects of those interventions? So it's grossly over simplistic. And the Problem I have as a scientific communicator is I understand the concern about the people potentially getting confused in doing something dangerous. That's a legitimate concern. I hear that. However, people are also very good at knowing when they're being patronized to and condescended to and they hate that, understandably so then they rebel. So in presenting these overly simplistic messages and trying to be dogmatic about it, things like lower is better, you are actually creating the rebellion that you're pretending to fight against. And so the best thing I think we can do is approach these topics with nuance and say, look, yes, LDL particles, apple B particles are part of the causal cascade. Quote, all things being equal, lowering it could lower your cardiovascular risk. But what is your presumed absolute risk and what are we going to do and what other effects might this have? Then let's make a global reasonable determination of what we're actually going to do. And in some people a statin might be appropriate. Therapy. I think these medications have their place. But in other people, even those with very high cholesterol, it might be, you know, maybe we're going to monitor you with coronary CT angiography and see how things progress rather than jumping to a medication. And there's a lot we don't understand right now about in particular people who are very metabolically healthy who have very high cholesterol. That's where our research is on these so called lean mass hyper responders because they're just a new population that hasn't been studied. And medicine 101, you should be very cautious about generalizing from population X to population Y. So if you have this new population that's never been studied, where you have a metabolic response to low carb diets where cholesterol goes up, that's unlike any other population because it's not, as far as we know, a genetic defect like familial hypercholesterolemia and these people are metabolically healthy, then all we can see, say with respect to risk is we don't know. But we need to do more research, which is where we're at now. So in terms of practical quote advice, I would say, you know, functional markers will always be biomarkers. So like for me what I'm doing is I'm monitoring with imaging. So you know, there's corner CT and geography you can look at, which has its value. And then also CT, CTA, coronary, coronary artery, calcium scan, CAC and then also CCTAs, you can have a discussion with your doctor. But like monitoring how Much plaque is actually in your vessel is valuable. So like if you are a, you know, 60 year old woman and this is a case I'm aware of, someone very close to me in my family, I might call her mom, I have permission. But she's had high cholesterol all her life. She's also a LEAS hyper responder. So you know, she's had something on the order of 10,000 milligram per deciliter years. She doesn't want to restore heart health, so she gets an imaging and her arteries are perfectly clean. Now after 60 years on this earth, very high cholesterol exposure and she has no plaque progression. Chances are it's not going to crop up in the next two years. So should she go on a medication? Her doctor talked and it's like, look, based on your imaging, you as an individual may not need medication. Someone else, if she had gotten that scan, she had a ton of plaque, then maybe she would have adopted some sort of therapy. But what we can say is there's a ton we don't know and there's a bunch of individual variability. So don't go to the Internet and try to get your advice there. Compile the picture of what you are as a metabolic organism and then have.

It even from your page. We shouldn't go there. It seems like there are some reliable.

Sources on the Internet, but not, not for generalities though.

Oh yeah, okay.

Like you. One can't say, I can't say. You listeners should do X because I don't know your family history, I don't know your genetics, I don't know your metabolic state, I don't know your personal priorities and preferences. So given all that, I think you can listen to people and say, oh, I took this interesting tidbit away from X, Y and Z person. I'm not saying the Internet isn't reliable. I'm saying you should not take academic information and arguments as gospel for your health. You should integrate it into a consideration, a deep consideration, hopefully with, you know, medical support on what to do and understand that all these options are appropriate. People who say statins are rat poison know they have their place. People who say if you have high cholesterol you need to treat and you need your LDL under 40. I don't agree with that either. It's like these things aren't simple matters and in being dogmatic about it, we all just lose and people get put in dangerous situations.

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I love the nuance there and I don't think that there's a cause for panic for almost any of those results. It's like, oh, here's something that's trending in a direction I don't want. So I'm going to figure out what are the levers I can pull. Poll and for listeners, you can go to Axo Health. Axo Health and you can order a lab test that's very affordable. No insurance company conversations ever have to happen there, which is why it's affordable. And you can get your apob and you can get your cholesterol and your triglycerides and your CRP and your homocysteine and your LPP and all those things and just know where you are. And if you don't like some of those numbers, there's easy stuff to do to manipulate most of those. And that means maybe you should go get a soft plaque scan like a clearly or one of the scans you talked about. But if those numbers are pretty good, you probably don't have to pay attention to that with your energy right now because you may have something else like cognitive function to focus on. So it's like, should you pay more attention? Those seem like good markers. What are the top three blood markers that you think are most important for people metabolically?

Metabolically overall?

Ooh, I can guess one of them.

What are you thinking?

HbA1c?

Yeah, I mean that. That in the context of also like a home IR and an insulin. Like, as you know, HbA1c does not tell all. It's your average blood sugar, so you want that low. But you can also be on the road to developing diabetes where you're. Your body is compensating for hyper for insulin resistance by producing more insulin. So let's say an HBA1C and either a fasting insulin or Homa IR. So a marker of insulin resistance and a marker of blood sugar. And then beyond that let. I mean, it's gonna be very individual. Maybe a triglyceride, a fasting triglyceride. I can't think of anything good that would come from a very high fasting triglyceride. And I think it can be the of kind canary in the coal mine. I'll caveat. It's a noisy marker. So like, you know, say you fast for a very long time. It can go up. You just worked out it can either be up or down. Make the best way to do it is like 12 to 14 hours water only fasted. So not even coffee. But I would say if you have a high Aoma IR, a high or a bad home IR, like a high fasting insulin, high A1C or high triglycerides, Something's probably awry. And those are all very basic. So there's like esoteric tests you can get. But like I would say most people should know those markers.

Yeah, yeah, I like to do those every three to six months in My own journey and just making it easy to do so someone comes to my house and draws it has been life changing. That's why AXO Health does that as well. And by the way, if, if you're curious, guys, it's $80 to have someone come to your house. Or you can just go into a lab and save 80 bucks. But it's not a huge amount of money compared to the time you save. And the idea that you should have to go to your doctor and beg to get these markers is offensive to me. So now you can go to your doctor when you have the markers and have the conversation and just save a ton of time.

Yeah. No. There are more and more companies putting data in people's hands.

It's a human right to know what's going on in your body, I think.

So if you're like, I talk to people like, my doctor won't get a fasting insulin. I'm like, why? They're like, why? Know why? They're like, because it's not, quote, actionable. Like, they're not going to change your medication team. Like, but it's information that the patient wants. Order the freaking tests.

At a certain point, I'm like, doctor, I'm paying you for your prescription pad to get me the data that I want and you set up the system along with the AMA in order to make sure that you're in the loop. And I respect that. So please do what I paid you for this appointment for, which is I wanted my information and you're part of my care team, so like, let's work together.

I understand there are limited resources. I do. So I'm not a fan of just like testing willy nilly, but, like, if it's valuable to the patient and it can inform lifestyle change, then I consider something like, you know the cost of an insulin test pretty well.

I mean, if the patient's bearing the cost. Okay, I agree. If it's going to be paid for by a socialized medicine or, you know, equivalent, which is an insurance company, there's all kinds of bureaucratic stuff. But if you're like, hey, some people want to go out and spend $100 on drinks, I want to spend $100 on getting my lab work done. Okay. More power to you. Right?

Yeah. It's such an inefficient system, it's absolutely grotesque.

Yeah.

And I'm not going to tend to understand all medical economics, but, like, there are just some things you see. I'm like, I don't understand why we're spending Money on this.

Geez, we can go on for, for probably several hours. About that, I want to talk about something interesting. There are a group of people who say that all you have to do to lose weight is exercise more and eat less. And I did this for 18 months straight. In my early 20s. I never lost a pound. I maxed out all but two of the machines at the gym and I never lost a belt size. Yes, I had more muscle and less fat, but I was still fat and I was eating low calories. I was starving all the time. It was hellish. So I consider that advice to be mean spirited from people who never had to deal with obesity. Or if they did deal with obesity, they had a working metabolism and bad habits. But if you have something dysregulating you, no amount of effort is going to work until you unblock some pathways. So I came up with several use cases that disprove the calories in calories out thing, including you can't eat uranium and gain weight. And they say, well, you can't metabolize that. Oh, so metabolism matters. And then you say, oh, there's a drug called zearalenone they give to cows that gets them fat on 30% less calories. If you have that drug, eating less might not work. But there's also a contagious type of obesity. And there's a couple cases I wrote about in the bulletproof diet. A guy gets scratched by a chicken and there's a certain virus that causes rapid obesity that's infectious. And so there's another case, but there's some new stuff about food addiction and a virus. Tell me what you found out about that.

Yes. So this was a paper that came out of a Spanish group a little while ago. And basically what they did is they were looking at this phenomenon of food addiction, which isn't technically in the dsm, which is like a manual of psychiatric diagnoses. However, it can be classified based on just a substance use disorder. So the criteria of a substance use disorder and measured using something the most common is called the Yale Food Addiction Scale or Yale food addiction scale 2.0. So it's a clinical phenomenon. People have basically substance use disorder for food generally, like processed foods and sugar. And then, you know, the thought is, what causes it? Is it just habitual? I would say, you know, anybody who's kind of a biological materials like me. No, it's like there's something biological going on here. And what they did was they were looking for fingerprints of this food addiction phenomenon in the microbiome and in particular the microviron. So your microbiome is the microorganisms in your body. But that's not just bacteria, it's also viruses, which is kind of underappreciated. So they were able to identify a one family of virus in particular called Microviridae and within there there is a particular virus called Bilku show virus. And what they found was it was strongly associated with food addiction in multiple cohorts, including a validation cohort and that the mechanism appeared to be and they used animal models to demonstrate the mechanism, but changes in the metabolism of the serotonin and dopamine precursors, so tryptophan and tyrosine respectively for serotonin and dopamine and basically by binding to or by infecting, they're called bacteriophage viruses, bacteria and then changing the the bacterial metabolism, they changed dopamine and serotonin precursor metabolism to then change brain function, which they could see on functional magnetic resonance imaging in association with changes in food addiction scores. So basically they identified a virus that appears to at least to some degree contribute to, one could even say cause food addiction phenomenology, which is freaking fantastic. Or I mean not for the people who add it, but it's very, very interesting. And just as another layer, it's the idea that even with respect to quote behavior and call food addiction a behavior as opposed to just same metabolism at the level of odipocyte and fuel partitioning with insulin. This idea of obesity is so, so complex. And I'm on the same wavelength with you Dave, as far as calories in calories out being such a gross oversimplification that it offends my sensibilities to even hear eaten, eat less, move more. At our current stage we can delve more into that. But that was literature you're asking about.

Is there an easy way to determine if someone has that virus? I don't think that's a clinically available test, no.

This is brand new research and generally research is well ahead of clinical diagnostics. So no, I can't say here's a task, go get to see if you have Microviridae, yada yada.

So the biohacker approach, if you have food addiction that isn't trauma based and doesn't make any sense and you've tried everything and you think it's a possibility and you can't order the test and you've exhausted everything else, you could try something like a broad spectrum antiviral like cytofovir and you look at the side effects and decide if they're worth it. I have no idea what they are. And go, hmm, maybe it's gonna work. And if you try it for a week and you're like, holy crap, something changed, great, but your doctor's probably not gonna wanna do that. But you still might want to.

I wouldn't recommend going that far yet. I think there's probably other empiric things you can toy with. I know a lot of people with food addiction. If they try cutting out all sugar or even going keto, that could help before eating pharmaceuticals. I'm, you know, I'm not gonna tell you what you should do. I do think they'll probably be. People will be very eager to figure out how you can diagnose and treat this in humans.

But, yeah, lab tests will come. Until then, you should try a gram of animal protein per pound of body weight, intermittent fasting, keto diets. You know, I don't. I have a whole book about all this. You have a whole YouTube channel full of stuff. You can try a lot of things that affect. Affect food cravings. And if you're like, no, I've done everything, and I know people like that. I got to that point where I've done everything that's supposed to work, and I'm gonna have to try the crazy stuff because I'm desperate and I'm still £300. So just the way of thinking about it, if that might be a variable, what are the odds that that's your variable? They're low. Right. And if you've exhausted everything else, hey, now, you know, there might be something. And the idea that it's possible is just yet another hole in the target that is the calories in, calories out hypothesis. I feel like it's just a way to shame fat people because it doesn't usually work. And if it does, more power to you. But you might try fasting, which is different than calorie reduction, and get a totally different result because of ketones.

Yeah, well, on the calories in calories out, I think something to point out is that it's technically accurate and practically useless. And people want me to understand why you can reconcile quote calories in calories out with things like the carbohydrate insulin model. Because the thing about calories in calories out is not all. It's not a wrong model. It's not a model of obesity in the first place, Biologically speaking. It is just describing what has happened when there's been a weight change post hoc and you can even see this how people like describe as like oh, you know, this person ate 6,000 calories and their estimated needs were 3,000 but they didn't gain weight. And people are like well their energy expenditure must have been higher. I'm like great, you're just post topic rationalized your model or you know, you could do the vice versa. This person was restricting but they didn't gain weight and they were predicted to by their Harris Benedict equation. Oh well, their basal metabolic rate went down. It's still calories. I'm like, but yeah, now it's practically useless. So we need to understand the whole idea of calories in, calories out. It applies but it is not the independent variable. It is the dependent variable. It is what is resulting from other interventions, other variables like how you partition fuel in your body. If you have a hormonal lu, say very high insulin level that telling your body I'm going to partition the calories I take in into fat tissue. What happens downstream of that is more hunger which leads to more energy intake and less energy expenditure too. So your body will finagle the calories and calories out to get the outcome it wants. And in the chronic sense, which I would differentiate in the acute sense because yes, you can slam 10,000 calories a day for a few days and acutely gain weight, but that doesn't tell you anything about the actual chronic development of obesity in a real world setting. So calories in, calories out is not even a, a, a model of obesity. And just for kicks and giggles, because I saw this on threads the other day. There was a guy who put out a thread and I usually don't respond to these things, I usually don't, but this one was just so dumb I needed to. He said most people are not overweight because they have a slow metabolism. They have a slow metabolism because they're overweight. And this guy, what lean? Ly fe coach just like you know the standard, like young 20 something flexing his hicks back which is like to your point, I think people who really parrot that the calories in, calories out model, one major reason they do it is because it's a self serving bias. If you're a chronically lean person or you should person who's even currently lean, if your world model is this is a function of basically eat less, move more, then there's a virtue like literally a positive human quality to being able to exert the willpower needed to get that outcome. And so it serves you to have a very, very basic Simplistic understanding of I have high willpower, which means I can eat less and move more, you know, and rather than challenge, what does this actually mean? Does this model actually make sense? And so you get people like these quote, this guy's a coach, or he calls himself a coach, saying most people are not overweight because they have a slow metabolism. They have a slow metabolism because they're overweight, which if you stop and think about it, is so stupid. Now if people want to know what I replied, I said, most influencers don't make up nonsense because they're influencers. They're influencers because they make up nonsense. Now if this individual is trying to suggest that fat tissue burns less energy at rest than muscle tissue, he should have chosen better terminology. As stated, the thread as is is empty calories for the mind. Anyway, I love that one thing that does get under my skin, the calories and calories out. I'm gonna call it nonsense because of what it is, is nonsense.

Thank you. We're in agreement. And I do invite guests on the show who disagree on it because I'm curious, what am I missing here? But between Gary Taubes, you, so many metabolic experts and longevity doctors, it's just become clear that manipulating calories isn't that powerful yet manipulating timing of calories and type of calories and the whole ketosis thing and amount of proteins and specific aminos, those seem to move the needle in a way that just radically restricting calories with Diet Coke that you can cancel out with a Snickers bar, it just doesn't work.

No, it's, it's defted because it might again, the acute doesn't equal chronic. If you fast, which is extreme caloric restriction, although you're also going into ketosis and carbohydrate restricting. So there's complaining variables there. It you'll lose weight, but obviously that's not sustainable. So the, you know, Diet Coke and special K diet that might work for a week, it will inevitably fail. As your metabolism slows, your energy output goes down, your, your hunger goes up and then you'll fail. And the system and common knowledge, the way it is will say you failed rather than this approach was doomed to fail in the first place. So yeah, no, I think the calories in calories out psyche needs to die. Not just because I'm attached to some other academic model, but because it's hurting people. Like you see it in the world around you where people want to treat their obesity and this is what they get told, some version of calories in calories out, eat less, move more. Then they try it. They put a tremendous amount of will in, and they do. And then when it fails, they blame themselves. And that happened to me. Cycle go on enough, and people end up with learned helplessness. And, you know, like a dog, it's been shopped too many times. And then what do you do? And I think as a society, one of the things that's happening, and I might get in trouble for saying this, but this, this is how I think it's manifesting and coming out, is you end up with movements like healthy at any size, where people start to excuse it. And I really feel, because I see the learned helplessness. I'm like, you were pushed here, and I understand why, because you put all this effort in. You genuinely did, but down a misdirected path.

I've been to that point where it doesn't matter what I do. Like, I'm sitting here, I'm eating less than 5 of my friends combined, and I'm working out more than all of them, and I'm still fat. And I'm like, it's a helpless thing, and it is a terrible thing. So they're saying, well, this is just normal. It's my state. It just means that you haven't found what works yet. But if you just deceive yourself and say, no, this is healthy, that's not what your labs say. And I want you to feel good all the time, and I want you to be actually healthy instead of identify as healthy. It's not okay to do that.

I will also caveat that I do think BMI is a crappy metric. And just because you're in the cool overweight category doesn't mean you're unhealthy. But I'm. I'm like, the distinction here is like, look, we can go beyond the mi. We could say there are definitely different body types. And because somebody's heavy set doesn't mean they're unhealthy. But at the same time, it's not appropriate to have somebody whose metabolic markers are screwed up with a BMI of 48, excess visceral adiposity, and say, quote, healthy at any size as an excuse, because that's just hurting that person.

Yeah, it. It's mean.

It's not their fault. Like, they need support health, but it's not helping society. It's not helping that person.

If it makes you feel better listening to this, my BMI is still a little too high. So if I get my avatar on one of those fitness apps, it actually has me as round around the middle. I'm 4.8% body fat, but my bone density is like Wolverine. I have exceptionally dense bones because of my biohacks. So they're saying, well, you must be fat. Like this is just a nonsense variable. What I do look at is total fat mass in the body. And when you come into upgrade labs, we have medical grade gear that measures that. You can also get it with Adexa and that doesn't change even percent body fat. You want to drop your percentage body fat, drink a gallon of water, hopefully with electrolytes and magically now you have more water. So your percentage body fat drops because there was more water in your body. So don't put poop and drink a lot of water and get your percentage body fat and feel good about yourself until you go to the bathroom and pee.

I'm sure the. Yeah. Impacted feces is equivalent to metabolic weight of muscle mass, which I was. Eddie hall, you know Eddie hall, he's one of the world's strongest men.

Yeah.

Well, Carnivore for three months and just came out with his results. He went in three months on carnivore, down from 27 body fats and 19% on DEXA.

Wow.

And his strength, he only. And look, I think like that was almost entire. Well, it was entirely fat mass that he lost. But he's, he's now 19% body fat at something like 350 pounds. And 19% on DEXA. Not like Aler. Like that. That is bananas and that kind of drop. My goodness. So that was banana.

That's a really cool.

He was eating 9 to 10,000 calories per day.

Oh yeah, yeah. It's not about number of calories.

An absurd amount of body fat over three months eating 9 to 10,000 calories per day. So yeah. Thank you. Calories in, calories out. I did a video on his one month progress and I had like a dietary record from him. So I was like, he's eating 10,000 calories. I'm like, let's just put his age sex weight into like Herodus Benedict. And his is based on my bulk. It was like 3,000 calories. And I'm like, so he's somehow losing weight on top of like a maintenance deficit of 7,000. And there were some of you, the comments like, yeah, but he like exercises a lot.

I'm like, not that much.

And that was not that much. Like, no. Like this is just Nick.

I did something similar before I published the Bulletproof diet. The big cyclical clean keto intermittent fasting book that it's almost a million copies sold at this point.

Wow. Congrats.

Thank you. I was like, I want to stress test this. So I decided that for a month I was going to eat at least 4,500 calories a day. I was going to do my recommendation. So this was the equivalent of Carnivore. It was steak and meat and butter. I did have coffee and butter. Some people say that's not Carnivore. Most people are okay with those things. And I would have possibly one serving of broccoli a day and that was it. And 4,500 calories, I said. And to make sure I stack the deck against myself, I will sleep less than five hours a night and I'll stop exercising. And my goal was I'm going to gain three pounds. But all the science says I should have gained 20 pounds and say it's not possible. I lost weight. I ended up doing this for months and I grew a six pack and posted a picture of it. It was insane.

I tried doing similar things over a feeding experiment. At some point it becomes self limiting. I couldn't do it for months, but I've done 5,000 calories for a month. And if people see me, I'm small. I'm like 5, 8. BMIs never tops 22.5. And even that at 5,000 calories for a month on a strict keto, I will not gain a pound. I just won't. I will notice other things happening. My body temperature goes up, my heart rate goes up. I bounce around like a, like a pogo stick. I can't stop it. But my body is just like in this state. It's just like, I don't want you to be fat. Like, go away, nmg. Go away. And it just, you, you don't gain weight. It's kind of bananas. I'm not saying it'll happen with everyone, but it is.

It's also not good for you from a longevity perspective.

No, definitely not. I'm comfortable, Sue. Like, I didn't sleep well. It's like, it's not fun. People think it sounds fun. It's, it's fun for like two days.

And then you're like, I, I wish that I had done it less in retrospect. I just did it for a while because I used the extra energy to stick, start the biohacking movement while I was working full time. And I had a new baby. So, you know, I, I burned the energy one way or another. But I don't think it, it was beneficial for longevity. But for listeners, both of us have eaten stupid amounts of calories and not gotten fat, which is yet another piece of anecdotal evidence that says just cutting calories, being hungry all the time, probably isn't going to make you get your metabolic gains. Okay, Nick, your work is fascinating, and I'm grateful that you're one of our up and coming people talking about metabolism in a meaningful way. You've got great academic credentials and more coming your way. You've become a really good communicator at, frankly, a relatively young age. It takes a while to learn how to communicate the way you do. So whatever you did, you did it right. And so you're making a big difference. And you're setting yourself up to continue carrying the torch of upgrading ourselves just with real science instead of with this dogmatic belief in whatever Kellogg's told us. So thank you.

I appreciate it. It's been a really fun journey. I'm at that stage in my life that listeners, if they're older than me, might remember where you're like, huh? This is what I actually want to do. You know, I grew up thinking what the right thing to do was, and recently I kind of made a leap towards. I'm really passionate about metabolic health teaching. I want to figure out how to do this. We're living in a really exciting time, especially for me, as like an AC young academic, where, like, I have access to communicate directly with people, get creative in how I provoke discussions in ways that prior generations just didn't have access. So, like, when I'm frustrated because people won't talk about research I think is important, I don't have to just like, say, oh, crumbs. I will, like, you know, go spend the next seven years doing residency, fellowship training, get this grant that branch. I'm like, no, I'm going to do a freaking N equals one experiment where I eat Oreo cookies to lower my cholesterol and then force this discussion to happen because I can and because there's a game that I think is important and appropriate to play currently in where we are with academia and social media, just in this incursion, this collision, where you kind of have to acknowledge the rules of the game and the engagement and use it to provoke deep discussions and ask hard questions and have these nuanced dialogues that push us to progress important science and push people to think in a way that can benefit their health. And it's a really complex art, but I'm having a lot of fun with it along the way. So I'm looking forward to the next several decades of doing this.

Is that it? You got more than in several decades.

All right. Many decades. I don't want to be too predictable to anyway cocky about it, but yeah, I'm missing at least eight years. I'm making another 70 years. It's my veter, my rookie year.

If you have the impact that you can have, it's at least 10 decades. But I'll race.

Hopefully. Hopefully we'll see. It's going to be. I mean, it's funny because this is ramped up so fast. Like I started getting serious about social media in 2024 this year while a full time researcher and a medical student and it's ramped up this fast. So like in five years, the things that are happening right now, like I got flown out to India like a week ago, first time to India, like based on some stuff that happened on social media.

Wow.

Which is like, you know, I went from in a couple periodical months, like even eating crappy hard boiled eggs like in the hospital cafeteria to being like, you know, first class guitar air as some really cool parties, like, you know, partying with famous rappers and talking to like royal families about Metavel. It's the most bizarre thing. I'm still wrapping my head around it.

It's super bizarre.

Life is changing really quickly and I'm just enjoying the ride right now.

Nice. Well, thank you.

I probably shouldn't have said all that happened. I don't know how I'm gonna get in trouble for it, but I probably will.

You won't get in trouble for it. You're fine. Thank you. See you next time on the Human Upgrade Podcast.

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