FoundMyFitness - #022 Peter Attia, M.D. on Macronutrient Thresholds for Longevity & Performance, Cancer & More

Episode Date: March 13, 2016

Dr. Peter Attia Peter is the founder of Attia Medical, a medical practice with offices in San Diego and New York City, focusing on the applied science of longevity and optimal performance. In addition to being a medical doctor, Dr. Attia has done research on the role of regulatory T cells in cancer regression and other immune-based therapies for cancer. Regulatory T cells have also been, in the past, referred to as suppressor T cells because of their role in actually attenuating or reducing the inflammatory response. Dr. Attia and I share interests in all things related to longevity and healthspan, which includes the role of diet, nutrition, sleep, exercise, and stress. Dr. Attia is a medical doctor and specializes in implementing these strategies in clinical practice. You can learn more about that at his website www.attiamedical.com. In this episode, we discuss... (00:00) Introduction (05:39) The difficulty of identifying longevity compounds (08:41) The mTOR and IGF-1 growth/longevity pathways  (19:11) Preventing cell and tissue damage to live longer (22:28) Dr. Attia's ideal diet for prolonging lifespan (25:45) Measuring gut microbes is challenging  (35:34) Alzheimer's disease risk is more lifestyle than genetics (42:05) Environmental triggers of Alzheimer's disease (55:49) What prolonged fasting teaches us about metabolism (53:36) Healing brain injury and concussion with metabolism If you're interested in learning more, you can read the full show notes here. Join over 300,000 people and get the latest distilled information straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Welcome back for another episode of the Found My Fitness podcast. It's been a while. Did you miss me? I know you did. Okay, let's get down to business. Today's podcast is with Dr. Peter Atia. Peter is the founder of Atia Medical, a medical practice with offices in both San Diego and New York City, focusing on the applied science of longevity and optimal performance. You may have first heard about Dr. Tia from his two interviews that have been on the Tim Ferriss show or from any number of popular presentations that he's given. that were filmed and put online. In addition to being a medical doctor, Dr. Tia has done research on the role regulatory T cells play in cancer regression and other immune-based therapies for cancer. Regulatory T cells have also been in the past referred to as suppressor T cells because of their role in actually attenuating or reducing the inflammatory response. Dr. Atia and I share many interests in all things related to longevity and health span, which includes the role of diet, nutrition, sleep, exercise, and stress.

Dr. Atia is a medical doctor and specializes in implementing these strategies in clinical practice. You can learn more about that at his website, www.atiamedical.com. That's A-T-T-I-A-M-E-D-I-C-A-L, Atia Medical.com. In this hour-long podcast, we talk about eating to delay the aging process and what the drivers of aging actually are. The challenge is inherent in trying to figure out what the best diet is. diet is for longevity. Some of the test or clinical assays, Dr. Atia, is most enthusiastic about or is hopeful to see developed in the next few years. The manner in which some of the biochemical pathways relevant to aging, hypertrophy, and even cancer are regulated by amino acid intake,

especially branched chain amino acids, as well as insulin through the intake of carbohydrates. And some of the interesting interventional strategies that may allow us to one day achieve the perfect balance of activation of these various pathways to achieve peak physical and cognitive performance, while still achieving longevity and ultimately cancer prevention. Dr. Atia's thoughts on what the sweet spot is for branch chain amino acid intake when used as fuel for workout, and more generally, his strategy for trying to optimize macronutrient intake in a way that ensures muscle growth and maintenance, but without reaching into the outer threshold of what might compromise long-term health. The influence of diet, particularly

carbohydrate restriction, on free testosterone levels. The health dangers, of refined carbohydrate, particularly added sugar, looking at cancer through the lens of a twofold problem. The first being cancer initiation from DNA damage, and the second being the presence of growth signals to an already aberrant or damaged cell. The power of the immune system to protect us from cancer cells that most of us are carrying around at any given moment, but which failed to manifest themselves as a tumor because we're able to defeat them without or even knowing it. The gut as a source of inflammation in the body and the need for better interventional and analytical tools to understand how to apply emerging research to actually have a clinical application.

One of the biggest genetic risk factors involved in Alzheimer's disease and the bizarre disconnect between the slight increase in longevity over the last 50 years and disproportionate and substantial increases in the incidence of Alzheimer's disease over the same time period. Lactate in ketones as brain fuel and the ketosis producing effects of multi-day fasting. If this part interests you, make sure to check out my conversation with the pioneer of the lactate shuttle theory, Dr. George Brooks, and lots more on the biology of cholesterol and cholesterol transport, probably more than I'm forgetting it to mention. This conversation is a great one, but it can be a little technical at points. I suggest checking out the YouTube video that accompanies it because it includes dictionary definitions for most of the things we talk about. So, for example, when a shorthand like MI is used, an annotation will pop up on the screen and it'll let you know that it stands for myocardial infarction and clarify, that means heart attack.

Or if Dr. Atia says OGTT, then it'll pop up on the screen that he's talking about an oral glucose tolerance test. And it will explain how that is used to diagnosed type 2 diabetes. You can go to foundmyfitness.com forward slash YouTube to see all the found my fitness videos, which includes the vast majority of podcasts, but with helpful annotations. Okay. Now, before we get started, just two more things. If you're not on my email newsletter, go get on it.

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That's FoundMyFitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R crowd sponsor. Now on to the podcast. Hello, everyone. I'm very excited to be sitting here with Dr. Peter Atea, who has a medical degree from Stanford University, and he has done a residency in surgery, I believe, and also some research in surgical oncology with Dr. Stephen Rosenberg, I believe. Very interesting background, broad interest. I know of him from being on Tim Ferriss podcasts, where he talked a lot about some of his self-expermentation using a variety of different dietary techniques. But

I'm really excited to talk with Peter today because we have a lot of overlap in our interest in longevity, particularly the role of diet, nutrition, and other lifestyle factors like sleep, exercise, stress in longevity. So thanks for being here, Peter. Sure. So maybe we can start a little bit with what are you eating then to try to delay the aging process? So diet obviously plays a very important role in aging. And I'm trying to figure out exactly the best diet to eat and talk a little bit about what I've, what I think. But I'd love to get some of your thoughts. So, I mean, I think the short answer is we don't know definitively. And I don't think we're going to know definitively. If you define definitively as a randomized clinical trial of longevity in humans.

Of course. We have to pause it that we're never going to figure that out. So instead we have to rely on proxies. So we look at proxies and animals where you can do virtually anything you want in a totally controlled setting. But then, you have to pause it. you run the risk of two things. One, are you identifying diets that are clinically and biologically meaningful to your host? For example, if you put a humanized diet into a mouse, what you learn may or may not extrapolate to the human. And then secondly, you're really hindered by the idea that you're studying that animal in an artificial environment. And when you reduce the risk of a subset of metabolic, or a subset of death, a subset of, you know, causes of death, which is effectively metabolic disease, you're often unable to measure what, in my opinion, is an underappreciated risk that comes on, which is sort of the more sudden and traumatic causes of death that we take

for granted, especially in the case of caloric restriction. So that's the problem with animals. Then what we do in humans is we can rely on our best proxy biomarkers that we think reflect the systems that drive aging, and we can measure those things over time and sort of estimate what we think is the effect of this dietary change or that dietary change or this lifestyle change or that drug change on those things. And so I basically try to focus my efforts on those, on sort of converging those two worlds, but acknowledging that we're never going to know the answer for certain, and we're going to have to use our best judgment around those things.

and hope that in time certain other things do become available. For example, it would be really great if there was a way in the blood to measure the activity of EMTOR. We don't have that. It would also be great if we could, you know, measure other growth pathways like the RAS pathway without having to rely on, you know, tissue biopsies and things like that. So just for people that don't know what MTOR is,

can you explain why that's really important? Yeah, so there are probably, depending on who you talk with, I would say there were two or three major growth pathways in the body that are kind of responsible for growth, both in the positive sense and in the pathologic sense. The two that I focus on the most are the IGF pathway and the EMTOR pathway. Now, mTOR stands for mammalian target of rapamycin. I think for the sake of time, I will not tell my favorite story, which is a story that is both the discovery of rapamycin. and perhaps more interestingly, the elucidation of how it worked. But suffice it to say, the compound rapamycin was identified first long before a really

amazing guy named David Sabatini as a PhD student at Hopkins in 1993, 94, as a side project in a lab made the discovery that this thing, rapamycin, was actually working by inhibiting a protein complex of which Tor, target of rapamycin, as it became named, was the central piece. We now know today that it conform into two complexes. One is called mTOR complex 1 or mTORC 1, and the other is mTORC 2, torque 2. And we also know that it exists in different tissues, and it has different activities in different tissues. And like most things in the body, too much or too little is a bad thing. So if you have no mTORC 1, for example, in your muscles, you'd wither away. And that would be a debilitating condition. In fact, for people with

muscular dystrophy, one of the things you want to do is figure out how to alter that pathway. But similarly, we know that over-activity is predisposing us to aging and, of course, certain diseases of aging like cancer. So for people that, you know, when Peter mentioned that, if you don't have any m-tork, one activity, you might, you know, cause muscle wasting. Well, that's because m-tort does play a very important role in protein synthesis. And what's very interesting is that both the two pathways that you mentioned in being involved in aging, MTOR and IGF1, IGF1 actually increases mTOR activities. So, you know, they're...

Yeah, these aren't independent pathways. Right. And what's also very interesting is that they're both regulated by amino acid intake, right? So IGF1, one of the major... So IGF1 is also a growth factor that you do need as well. So it's one of those things where you don't have any IGF1, well, you know, you're going to and not, you're going to be in trouble. I mean, there's a lot of positive things about IGF1, muscle growth, muscle repair, neuronal growth. But too much IGF1 also can allow damage cells

to continue growing. But are you familiar with like any of the dietary nutritional research on IGF1 and EMTOR and specifically with amino acids and how? Yeah, I mean, that's sort of my biggest obsession, I think, is probably around those topics. So it's, it's, complicated. I think we have probably a better understanding of mTOR. I mean, I think it's very clear that mTOR is amino acid driven. In fact, what's today? Last Thursday, eight days ago, David Sabatini and his group at MIT published a paper in science that identified the amino acid sensor for mTORC 1. Now, it's always been suspected what it was, which was leucine, was the highest affinity. But in fact, He's now crystallized that structure.

So if you even think about it through the lens of like, why do bodybuilders or people who, you know, love lifting weights want to take branch chain amino acids while they're exercising, the reason is largely through this empirical observation that it enhances muscle growth and or prevents muscle degradation during exercise. What I think is really interesting is that, you know, we now know exactly what's going on. So the branch chain amino acids, there are three, lucine, iselucine, and valine. it turns out that isolucine and valine are virtually irrelevant. It's pretty much all leucine. And what's really clever, just from an evolutionary perspective, is that mTORC in muscle has a much higher affinity for leucine than mTORC 1 in fat or in hepatocytes.

Now that's a good thing because you'd like to believe that in times of nutrient deprivation, even a trace amount of leucine should preferentially provide the muscle with its growth signal before providing the adipocyte or hepatocyte. So from a nutrient sensing pathway, what you could infer from that is too little lucine, probably a bad thing. Too much lucine, probably a bad thing. Now, what too much and too little are, I think, remains to be seen. The other thing to keep in mind is, you know, because one of the questions a friend of mine asked me recently,

actually a mutual friend, Tim Ferriss, is, you know, can we, can we, can we take too much lucine during a workout? And again, I don't think we know the answer, but extrapolating from the animal data, I think five grams of lucine during a workout, probably not harmful. And it also doesn't stick around very long. Because when we take amino acids in a workout,

if you sort of sip them throughout the workout, you're taking a free amino acid, so it's got a relatively short stay in the body. In fact, one of the pharmaco interests on this front, which is to treat diseases of muscular wasting, is to actually come up with molecules that are not necessarily more potent agonists of the lusine receptor, but would stick around a lot longer. Because that's actually the problem with the nutrition side.

We can't keep lucine around long enough to stimulate muscle growth. Okay, so that's the easy story. Right. Now the hard one. IGF. Yes. Okay. So two schools of thought on this.

I am in one camp, but I will acknowledge the other camp. One camp says IGF1 is driven exclusively by amino acids. The other camp says, no, it's actually driven by amino acids and carbohydrates. Yes. And carbohydrates indirectly via insulin. Yes. So... Why are those mutually exclusive?

Oh, the way I define it. There's certain people who I will not name that are prominent in the field who I will argue with, that will argue that the carbohydrates play no role. It's virtually all protein. But there is a role that they do play. That's been shown. I believe it has been shown. I mean, there are wonderfully erudite people in this field who believe it is entirely an amino acid issue. And it is true.

Methyane has probably been shown to be the most active amino acid in driving IGF pathway. However, as it sounds like you agree, it's pretty clear that as insulin levels go down, IGF BP3 goes up as IGFBP3 goes up as IGFBPPPP. sorry, IGF binding protein three goes up. Maybe it's worth me taking a moment to explain why that matters. So most of these things, as maybe the listeners know, you know, when you have hormones floating around the body, whether it be testosterone, whether it be cortisol, whether it be, you know, thyroxine, these things, they don't, because they're typically hydrophobic, they can't just travel through the bloodstream freely. They have to be bound and carried, just as cholesterol does. And so it's these binding proteins that we often don't think about that play an important

role in determining how much active or bioavailable hormone is free. So in the case of IGF1, it gets trafficked by this IGF binding protein. And most of these binding proteins actually bear an unbelievable relationship to insulin. So sex hormone binding globulin goes up when insulin goes down. It's very interesting. There's always this complaint that free testosterone levels will drop all things equal in someone who restricts carbohydrates. And I remember sort of hearing that empirically and not really thinking much about it until I started to, one, observe it and two, understand why, and it's quite obvious. Because, again, all things equal when insulin goes down, which is usually what happens when you were stick carbohydrates, sex polymer binoglobulin goes up. That means if you

have no change in testosterone level or even estradial level, free testosterone will go down. Less testosterone is around to be unbound to the sex hormone binoclobulin. So it's for that reason that I think that insulin and carbohydrate do play an important role in the IGF pathway. And I also think empirically, not that I like to refer to ecology or epidemiology, but when you look at the ecology and epidemiology of cancer, to my knowledge, the content of highly refined carbohydrate and sugar is more predictive of cancer in a society than the variety and protein content. In other words, there are cultures that have consumed larger and lesser amounts of protein that have been without mass amounts of cancer, but the same cannot be said with large amounts of these things. Now, the problem, by these things, I mean sugars and high glycemic glyphic acid are high.

The problem with that is, of course, you can't infer a cause from that, but the negative to me is suggestive that at the very least carbohydrate content matters when it comes to IGF1 signaling. Absolutely. And the way I like to think about it, actually, when you're discussing these two things is, you know, IGF1. is not a cancer initiator. Like, it's not going to cause the initial damage that can make a normal cell abeyrant, a normal cell that acquires whatever problems it acquired to make it, you know, turn into a cell that's not cancer. What IGF1 is really good at doing is taking that cell that's already acquired the damage.

Right, and saying, here, keep growing. Like, no, don't die. I know there's signals in your body that are trying to kill you, but don't die. You know, whereas the refined carbohydrates, the way I always think, about it is, you know, that leads to a variety, a plethora of physiological processes in your body. Inflammatory processes, you know, a lot of different pathways that are causing damage, that are initiating the type of damage. So it's like, well, if you have someone that's eating a terrible diet, they're eating refined

carbohydrates, they're, you know, they're releasing endotoxin in their gut, they've got this constant inflammatory process going on, they're releasing hypochlorite damage, you know, they're damaging mitochondria, damaging DNA, blah, blah, blah. Well, and then, you know, so they've acquired all these damaged cells, and then they're eating, you know, a bunch of protein and activating the IGF1 pathway. It's like dynamite. It's like, here, here's the damaged cell and here's the signals to, like, keep living and keep growing. So I kind of... Yeah, I mean, I think...

So you obviously alluded to this, and I think many patients, when I talk to them, are sort of surprised to learn that every one of us has cancer. I mean, at this moment, I have millions of cancer cells in my body as. you. The good thing is virtually all of the time the problem gets eradicated, right? So either we talk about the apoptotic pathways that you describe, but even when those pathways fail, our immune system is remarkable. I did my postdoc in immunotherapy. So I spent about two and a half years working with T cells, specifically regulatory T cells, I'm looking at this problem. And, you know, we just take for granted how good the cellular immune system. is rather. So for those, again, maybe not familiar with the immunology, you know, you have your

B-cell system, your T-cell system. These T-cells, which are the ones that fight viruses, are unbelievable. When you think about how many antibiotics we have in our arsenal to fight bacterial infections, it's remarkable. Think about how many antiviral drugs we have relative to antibiotics. We have very few. And we certainly don't have them for the most common viruses we acquire. And yet, virtually all of us recover, in the end, unharmed from the typical viral infection we get two to three times a year. That's a testament to how amazing our immune system is. And when you unleash it against cancer, it's effective 99.9% of the time. So, yeah, the name of the game is avoid the amplifiers. Now, the other reason why I think this is an important thing, an important

concept that goes beyond cancer, but now gets to the broader aspect of aging is when you look at the people who live the longest, when you look at these people who live to 100 and beyond, for the most part, they die of the exact same diseases as the rest of us schleps. They just get them later. That's really important because I think it offers an insight into longevity that is often overlooked. So if the people who live to 100, 105 were all dying in car accidents and plane crashes, you might make the argument that there's two classes of citizens, right? There's the people who get chronic disease, and then there's people who will never, ever, ever get it, and eventually they just die of something else. Because remember, the fourth.

leading cause of death or the fifth leading cost of death starts to become accidental stuff once you get outside of the chronic stuff. But that's not the case. The point is we're all sort of pre-programmed to go through this process. But if you want to live longer, the name of the game is delaying the onset of the big three. The big three being the diseases that will kill 75% of us. So cerebrovascular and cardiovascular, cancer, and neurodegenerative. And so that brings us back to why we don't, why we've got to have IGF and mTOR in check, because we've got to prevent them from being able to sort of amplify that. Right. And, um, so I still haven't answered your question, which is how do you do this with diet? But, but, but, but, but, but, so I think, I will

explain conceptually how you do it, how you do it at the individual level, um, is, is, is empirical, and I think prescriptive, meaning you have to be able to try something, iterate on it and make a measurement. But here's the conceptual way to do it. The, conceptual way to do it, at least the way I do it, is you consume more or less the least amount of protein you can consume to maintain and grow muscle mass. But you don't need any more than that. So it depends on the individual. It depends on the timing of that protein ingestion, the quality of that protein, and the type of metabolic and conditioning stimulus you put into it. But there's an amount. But for most of us, I think we're probably over-consuming protein

relative to that actual need. So we raise protein level until we hit that amount. Carbohydrate, we do the opposite. Carbohydrate, we are basically lowering it until we reach the highest point, or pardon me, the lowest point that we can tolerate, where we can maintain, and again, this is quick and dirty, but it's the lowest possible fasting insulin. And in my mind, I typically like to see that at below three or four,

as IU of insulin. And you want to limit sort of post-meal glycemia. And I actually use a standardized test, which is an O GTT, which has its limits because it's liquid. You're drinking liquid glucose. I like to limit that post-pranidial hyperinsulinemia to a number. And I use a reference. I use a checkpoint of 30 that I want to be able to see within one hour of a 75 gram glucose

challenge if you can keep insulin below 30. So in my mind, because I can't do what's called an AUC, an area under the curve. So the really rigorous way to do this would be I'd put a catheter in your arm, and I would sample your blood every 30 or 60 minutes over the course of a day while you ate. And I would say, I'd integrate that function, and there would be an area under the curve of insulin. And that's actually the number I care about. But since I can't do that outside of a research setting, I rely on these other proxies.

So the bottom line is your carbohydrate content is highly variable by the individual, by their insulin sensitivity, by their muscle mass, and their capacity to dispose of glucose and a host of other factors. But the bottom line is you don't want to consume any more carbohydrate than you can without blowing through those parameters. And you don't want to consume any more protein

than you need to to preserve that. And then basically fat becomes the fill. And so the point here is that that becomes a highly different diet for different people. For some people, that's 40% carbohydrate and 20% protein in the remainder fat. For others, that's 20% carbohydrate and 15% protein in the remainder of fat. So what about...

So your approach seems to really look at, you know, insulin response. It's looking at, you know, obviously the IGF-1, M-TOR, things that are dietary, nutritional factors that are, you know, influencing those pathways. And then, of course, the rest being fat. For me, I like to think about food as a... what you're putting in your body, not only to activate these pathways or try to keep the pathways from being too active, but also I like to think about it at the level of the gut, because the gut, one, regulates the immune system, big time.

I mean, that's, you know, you've got more immune cells in your gut than you do in any other organ in your body, and your gut bacteria, the interaction between your gut bacteria and your gut are also, you know, regulating the types of immune cells that you're making, regulatory T cells being put in that. And also because it's the major source of inflammation, and inflammation, even very recently, has been identified to be a driver of the aging process. So, you know, eating things that are good for your gut like fiber

and avoiding things that are going to cause a lot of gut damage. So I think about those things as well. Do you, do you, and then micronutrients, which is also very important. Micronutrients are co-factors for a variety of enzymes and proteins in the body, make sure they're, you know, functioning proteins that are involved in, you know, these processes we're talking about keeping cancer cells in check, you know, like, you know, P53 is zinc-dependent proteins, magnesium, which is important for repairing damage, things like that. Are those things

that you consider at all when you're thinking about the influence of diet on the aging process? I don't think about it as much as a lot of people do, and I would hate to use the term I'm a gut skeptic because I don't, I think that conjures up a whole bunch of negative images. But, So I'm going to be a late adopter on this one. Right? So there are a whole bunch of facts that everybody can rattle off about the gut. A lot of them, by the way, are kind of BS. So the cells in the gut outnumber the cells in our body 10 to 1.

That actually turns out to be false. You mean bacterial? Yeah, sorry, the bacterial cells versus, yeah, sorry, the bacterial cells within our gut. So putting all that stuff aside, there are a whole bunch of really interesting facts. But it reminds me of, you know, what a good friend of me. mine once told me when I was trying to rationalize something I needed to do or thought I needed to do to him. He said, why are you doing this? And I said, blah, blah, blah, blah, blah, blah, blah, blah. And he said, that's a fact, but is it a reason? And so that's kind of how I feel a little bit about the gut.

Like, there's a whole bunch of really interesting stuff, but I don't know that it actually matters that much, right? It's like, I'll give you a sort of a really idiotic example. The number of ants on this earth outnumber us 10 to 1. I'm making that up. Ergo, we should be doing more to protect the ants by avoiding climate change. Yeah. And I'm saying, no, that might be true. There might be more ants than us. Yes.

But we're the species of interest. So the point is, so that's my first sort of kind of lack of interest. The second is I don't really know what to do with it, right? So I've been through it all. I've gone through all the sequencing. I've done it with patience. And I have found that it's like there's a very crude set of tools that I can use in really obvious cases. So I had a patient that came to me two years ago who, you know, had a

history of sinusitis, horrible history of sinusitis. So this is, she was, you know, she probably had to do an augmentant course six times a year because of recurrent sinusitis. She had three surgical procedures, just couldn't get better. So started working with her, became pretty clear to me that there was something in her diet that was creating an inflammatory environment that wasn't a structural problem. So we made a lot of dietary changes. Things got better. But in parallel to that, I sort of suspected that 10 years of six cycles of augmentin probably altered her gut. And so, yeah, she's an example of someone where I would do, you know, a sequence and look and be like, lo and behold, you're all yeast, right? Not surprisingly. And disproportionate bacterial overgrowth.

Okay, so she's an example of someone in whom the signal was so big that I felt like there was an intervention I could make, which was both fixing her diet, but also utilizing agents that could alter that. But for the most part, I don't have a clue what to do. And all the people I see who claim to know what they do, like, they can't convince me that they're knowing what they're doing. Now, that doesn't mean, I'm talking outside of a couple of really amazing examples. So we're familiar with how C-diff colitis works and the reversal of C-diff with dual transplant. So those are remarkable examples. But some of the other stuff I'm still not clear of. So I guess what I'm saying is, I'm happy to be convinced, but I'm not convinced yet, that this is like the, that this is a reason and not just a fact.

So I think that focusing on the gut microbiome and the number of, you know, bacterial cells are supposedly outnumber our human cells and all that. I don't think that's the important point. My, you know, so I've become very interested in the gut, mostly because of a colleague of mine, Mark Shigganaga, who's been working, doing gut research at Children's Hospital in Oakland is brilliant. He's been showing me data and I've just been convinced more and more that gut health, making sure that you're keeping the mucin, which your gut goblet cells are producing, you know, that disgustingly slimy mucus-like material that's keeping and separating the immune cells in your gut from all the microorganisms in your gut. And that's very important because when that starts to break down, the immune cells recognize

bacteria. And I'm not asking this rhetorically, I just don't know. Is there an effective way to diagnose that in patients? So the problem is that endotoxin release into the blood system would be the way to measure it into the diagnosis. So you could measure it through the lack of barrier, basically. You can measure the endotoxin levels in someone's blood, which is a marker or a proxy of the throughput.

Yeah, yeah. But the problem is, is, is that. that getting that there's also a lot of false positives. That's right. So that's the only concern. Until that test, that diagnostic test can be... Because it seems to me a stool test would be a more effective way to measure that. Endotox?

Oh, mucin. Muson. Yeah, there might be, there might be a way to do that, to measure it in a school. That would be an interesting thing to explore. because the, so, you know, what I'm getting at here is, I'm also a very, I'm a scientist, you obviously are a scientist and like to be, you know, understand mechanism and see solid data before you, you know, think something is true. And I have become more convinced that literally, like the endotoxin released from the gut, which is a constant, I mean, really the major source of inflammation in the body is. And to be clear, Rhonda, I'm not disputing that. So to be clear, I bought that thesis back actually when I was a surgical resident because we would see endotoxemia. Yeah. Right.

Surgical procedure gone bad, endotoxemia, ICU, death. I know what that looks like in its most extreme state. What I think I'm more of a skeptic of, and again, a skeptic waiting to be convinced is that I can intervene through, that I can make that diagnosis in a non-catrophic case, which is basically the chronic case, and make an intervention. either through, you know, some alteration in the, in the microbiome itself, or meaning directly or indirectly through diet or other variables. So, and I think that will be a very interesting sort of sort of path to go down. But, but again, I, I just, I'm trying, there's so many things I don't know at the moment. I'm just trying to focus on the ones I do know. Yeah, yeah. There is, There is some interesting work coming out of, like Justin and Erica Sonenberg Lab, over at Stanford.

I recently had a discussion with them. I'm looking at the role of fiber and certain types of fiber in fueling different species of bacteria in the gut and how those are generating short chain of fatty acids and other signaling molecules, which are regulating hematopoices, they're regulating, you know, the number of T-regs that we're making. So it is very interesting that feeding our gut certain things. types of fiber, which are present in vegetables and a variety of fruits even, do have a positive effect on the immune system via these signaling molecules that are being made in the gut. So that's very interesting. It is one thing that I consider when I'm thinking about the effects

of diet on longevity. Because I think that these, while, you know, I've focused on insulin for a long time. I've been very interested in insulin when I first, um, I was doing research at the Salk Institute in La Jolla. Before I went to graduate school, I was working on aging and specifically doing different genetic manipulations in Cialigans to look at the effects on aging. So insulin signaling was like obvious. Decreased insulin signaling, you're going to increase this worm's lifespan by like up to 100%,

which is like very profound. So I've been very focused on insulin for a long time. And reducing the insulin signaling pathway, reducing the insulin response, you know, all that. However, I think that as I continue to look in humans and we're very, you know, complex organisms and there's lots of interactions between things going on, between, you know, different things that are happening in our diet, in our lifestyle, that are affecting the way we age. And one of those I do think is gut health. I sort of began to become interested in what sort of diet is good for my gut and what is not

good for my gut. And I think we were talking a little bit about this before we started filming this. And that is one thing I'm also very interested in is the effects of fat on the gut, because fat can be very hard on the gut. But I think that it also depends on a variety of factors. If you're eating it with protein, if you already have an unhealthy gut, if you're not exercising or you are exercising, things like that. Also, genetic factors play a very important role. you know, certain polymorphisms in... Don't ask about APO-E. P-P-A-R-Gama.

Yeah. Our influence saturated fat versus polyunsaturated. Yeah, APO-E, yeah. I've actually got one APO-E-4 all. So I'm very interested in APO-W, I'm actually writing a paper on APO-E-4 and it's role in Alzheimer's right now. Well, I'll tell you my take on that, which I'm sure you've seen the literature on it, but I actually think it's the phenotype that matters more than the genotype.

So in other words, I think it's the, it's the, amount of APOE that's expressed that matters, not the APOE, not the genotype. In other words, just as we measure APOB as a surrogate for LDL particle number in VLDL and VLDL and REMRMVL particle, we can measure APOE. Now, there's no clinically used or CLIA approved assay for that yet, but there are labs that are doing it for experimental purposes. And there's a paper that I saw maybe six, nine months ago that actually showed that the, if you take the APOE3-4s and 4-4, so as you know, I'm sure, better than I do,

a 3-4 genotype, just on a hazard ratio is about a 2x increase over the 3-3 in terms of Alzheimer's disease. A 4-4, of course, is anywhere from 10 to 20x depending on the series. Okay, so if you're out there and you've got an 8-O-E-3-4, especially if you've got a 4-4, you're worried, right? And I'm worried for my patients who are 4-4s. I have four-facients who are 4-4s. But when I saw this paper, what it showed was,

actually, and just so the listener would know, the majority of people with Alzheimer's do not, are not 3-4 or 4-4. They're still 3-3. The difference is this, because remember, the 3-3 is the majority of the population. I mean, the 3-4 is actually pretty big. It's about 20%, but the 3-3 is the largest one. So having a 3-3 doesn't protect you from Alzheimer's, and having a 3-4 doesn't guarantee you're going to get it. And by the way, even a 4-4 doesn't guarantee you're going to get it. So the key is, is there something else that's more predictive?

And I think it's the phenotype. So when they measure the serum level of APOE, it turned out to be more predictive of Alzheimer's disease than the genotype. So my hope is that we can get a clinically approved assay in a relatively short period of time that will allow us to actually do that, especially for the patients who are 3-4 and 4-4, which says, are you able to reduce your risk? So let's say I could measure you today. And your APOE level was here.

And then we could say, well, look, there's some intervention. We believe that reducing, you know, or increasing insulin sensitivity of your brain, you know, reducing the probability that pyruvate dehydrogenase is going to cause an energy shortage in your neuron. It's going to improve your odds for delaying or eliminating AD from the list.

And then we could measure your APOE at a point in time, and it were lower, that would give me some confidence that we were moving in the right direction. Because... Lower? So you're saying that the higher the APOE... The higher the expression, the higher the risk. That's what this paper. In the plasma.

In the plasma, the higher the risk. Okay, so a couple things. One is... Happy to show you the paper. Yeah, that's interesting because most... From my understanding, you make APOE in the liver, you make it in the astrocytes. But one of the important things is that it plays an important role in bringing cholesterol

from the estrogates to the neurons, but also in repairing damage that's done. So you need to have neurite outgrowth to repair any sort of damage that's done, damage with normal brain aging. or traumatic brain injury, which is like damage in real time. But I was into the impression that there's less, so there's less APOE expression in APOE4, and so there ends up being a problem because the LDL receptor is very important

for bringing the cholesterol to the neurons, getting it there. And so the plasma, I don't know. Yeah, yeah. And the other thing is I think the, and by the way, I could be wrong. It's been nine months since I read this paper, so I could have it backwards. But I think the more important thing is I think there's two separate things going on, right? So the APOE4 gene also plays a role in,

because my real interest clinically is, of course, lipidology. That's my clinical obsession. And that's the place where I think we're becoming pretty clear now that the APOE4 or the 3-4 is not a death sentence in cardiac disease, especially the 4-4. The 4-4 was really viewed as, boy, you're guaranteed to have an MI before 60. And I think the evidence today, suggest that once you normalize and correct for LDL particle number or APOB, it stops mattering. Yeah, those are definitely probably more important. Yeah.

And so, so with the, so loosely speaking, this is an oversimplification, if you're a 3-4 or a 4-4 in theory, you should have a harder time clearing LDL particles from circulation. Right. And, but I think that that's not entirely the issue that you're alluding to, right? I think there's two issues you're talking about. One is the clearance issue, and then one is the cholesterol transport, the central part. Yes. There's, I mean, and there's also the different issues in the, well, in the brain versus the liver.

So, I mean, we're talking about, like, the astrocytes are almost like little livers in a way, but not really. I mean, so there's, like, you know, there's, I think looking at the effects on the brain and looking at the effects on, you know, recycling LDL and all the other things going on in the periphery are different. But by the way, I did just want to mention that between 65 and 80% of all cases of Alzheimer's disease, at least, you know. At least one has a four. Between 65 and 80% of all the Alzheimer's cases. So the majority are three-fours then. The majority of them have at least one allele. Yeah.

Yeah. But again, that's based on the hazard ratio, we know that that's just a numbers game. It is 20 to 25% of the population is three. Right. It's 25 or 20. Exactly. So, but the point is that there's something... But the 33 doesn't protect you from AD. No, it doesn't. So someone walking around the 3-3 shouldn't assume that, well, I'm never going to get AD. No, it does not protect you, but there is definitely something... Does the 2-2 protect you? The 2-2 does actually protect. Yeah. Yes. I'm curious. I'm sure that some paper has the histogram of 2-2-3... It's protective. Yeah. It is. And so it's very... Because in cardiac disease it does, and in cardiac disease, the 2-4 is

about the same as the 3-3. The 2-4 cancel. Wait, say it again? So the 2-4 is... The 2-4 is... The 2-4 is... Again, just in hazard issue. I found out my mom was 2-4 and I was for the cardiac problem. I was kind of worried. Anyways, okay, that's very interesting. So we're totally going off on this apoe tangent, but it's something... No one's even watching it this point.

You know, I'm very... I'm very interested in... But there's a huge, huge component for lifestyle in risk for Alzheimer's disease. particularly with having an APO4 allele. And that's where I've become obsessed. I see, you know, looking, I've been looking at mechanism, but also looking at, you know, the epistudies, looking at epidemiology, you see certain lifestyle factors, you know, for example, drinking, if you're drinking in your APO4, because you're inducing damage that you can't repair as well, you're going to fare worse, you know.

So anything that's going to damage your body worse, anything that's going to create inflammation, refined carbohydrate, eating a bunch of, you know, refined carbohydrate. hydrates, a bunch of sodas with added sugars, like all this stuff that's terrible for you. That's not, you know, whole food. That's not something that's nutritious. That's going to cause inflammation, inflammation, inflammatory molecules get across the blood-brain barrier. You know, so blah, blah, blah, all this damage can continue to occur. So obviously, diet, lifestyle play a very important role in your Alzheimer's risk. And I think that understanding the biology of what APOE4 is doing because not only, now there's, you know, research, a lot of it coming

out of UCSF, Gladstone Institute, showing that in addition to a loss of function with APOE4 allel, there's also a dominant negative effect. So apparently the APOE4, there's just two amino acid substitution. And structurally, if you look at the structure of the protein, it starts to get cleaved. And so it itself starts to accumulate these like aggregates that then, you know, keep, you get more activated microglia and it keeps like spiraling out this whole inflammatory process in the brain. So there's also this dominant negative effect that's going on. That's interesting. And you want to understand that as well. But yes, Alzheimer's disease is one of the neurodegenerative diseases that are up in the top four or five, like you mentioned, cause the death. Well, it's the

top. It's the only neurodegenerative disease that's on the top 10 list of death. Top 10, yeah. So cardiovascular disease. So cardiovascular is far in a way number one. It's not even, I mean, cancer in an aggregate is number two, but as an oncologist, I sort of take an issue with that because cancer is a completely heterogeneous form of diseases. So, you know, to put this in perspective, right, so breast cancer, who's not afraid of breast cancer if you're a woman? breast cancer accounts for 3% of deaths in women. I was shocked to learn that.

Very low. I would have thought much, much higher. Now, cancer in women, all cancers, 20, 21%. Cardiac disease, 22, 23%. So if you're a woman, if you ask anyone on the street, are you more afraid of heart disease or breast cancer? I think most women would understandably say breast cancer. And yet, it dwarfs.

It's dwarfed by cardiac disease by a fact, of seven and a half to one. And we definitely know that diet and lifestyle play a major role in your, you know, risk for cardiovascular disease. Yeah. I mean, I think there's no place where that's more obvious than actually an Alzheimer's disease for other reasons, which is a thing. Oh, really?

Yeah, I think so. Yeah. More than cardiovascular? Well, I mean, I say that just based on what I call the existence principle, right? So cardiac disease, I mean, I think that's entirely true. I think cardiac disease is inevitable, right? And while we've had a deterioration in our lifestyle over the past 40 years, pretty precipitated and accelerated, sort of move in the wrong direction on that, it's been largely offset by

pretty amazing medical advances. So there's three things that have, I think, allowed cardiac disease to remain. In fact, it's actually come down. If you look at the death rate from cardiac disease, it's come down. So it's still the number one killer, but it's actually on. a downward slope. I mean, it's sort of plateauing. But when you look at what sort of the three biggest drivers are of cardiac disease, the first one is not disputed. It's smoking. So the data are really clear that if you could only make one behavioral change to reduce your risk of heart

disease, it's don't smoke. The next two are actually, because they are so cross-correlated, you can't actually distinguish which one's more important, are hypertension and elevated APOB or LDL particle number. And again, APOB is the single best biomarker or LDLP to distinguish your risk of cardiac disease. It trumps LDL cholesterol. It trumps non-HDL cholesterol. It triglacelides. H. Del cholesterol. Those things don't hold a candle to LDL particle number APOB. Well, think about it. Think about the advances we've made in the last 40 years on all of those, right? So smoking has gone from, you know, 45% of the population to 18% of the population. we reduce smoking.

In the U.S. In the U.S., that's right. Obviously, we haven't done the same across the, in the developing world. Think of the litany of drugs we have for controlling hypertension. And think about the litany of drugs we have to bring down APOB. So despite enormous improvements in the three big picture drivers, it's still the number one killer.

So it's got to be lifestyle driven, but we're blunting the effect of that. Whereas in Alzheimer's disease, we don't really have any pharmacotherapy plays. Like, we're still arguing about what the environmental trigger is. Is it all diet-driven? Is it sleep-driven? Is it stress-diven?

What's the combination of factors? Is it a virus? Is it preons? I mean, I've heard every other end of the sun, right? But here's what we do know. We know that in the last 50 years, the prevalence of Alzheimer's disease has gone up about 2.5%. Whereas the increase in our lot, per year, by the way, I'm sorry, that's per year.

whereas we know that our longevity has increased at about 0.6% per year over that same period of time. Now, over a 50-year period, a 2% spread per year of prevalence, actually, I think it might be incidents now that I think about it. I think it's incidence. And longevity suggests that Alzheimer's disease isn't just the natural response of getting old. There's something driving it. And even if you accept that part of that increase in incidence is a greater appreciation for the diagnosis, it's hard to argue that makes up the full 2% spread. And so that's why I think that, to me, that's the most convincing case for why there is something in our environment that's triggering Alzheimer's disease,

and it is not just the natural consequence of aging. Yeah. So what are your thoughts as to what are triggering Alzheimer's disease in terms of our... Yeah, I mean, I think it's probably a combination of things, but the most compelling evidence to me, and again, this is probably because I'm just a simpleton and I like to start with Occam's Razor, is it's very hard to dispute the high association between Alzheimer's disease and type 2 diabetes and hyperinsulinemia. And so I'm in the camp of which some neurobiologists are, but not all. This is still far from being settled.

I sort of view Alzheimer's disease as brain diabetes. And I think of the ACE, Apoe genotype is basically just a susceptibility. So I think anybody can get Alzheimer's disease with any genotype if there is enough insulin resistance. If there's basically enough difficulty in getting glucose through pyruvate dehydrogenase and into the Krebs cycle. So I think it's a neuronal energy problem more than, and I think all of the other things we see are results of that.

But I think in terms of what the driver is, I think it's a neuronal energy problem. And I think that's, I think all of the tau plaque, the neuronal, the synapse stuff, I think Those are byproducts. And I think in animal models, there's some very convincing data that you can, you know, I mean, you've seen this stuff, I'm sure more than I have, right? Simultaneous insulin, you know, injection of glucose and insulin can transiently overcome deficit. Administration of exogenous BHB can overcome the deficit by bypassing and going straight through alpha hydroxybutyrate into the Krebs cycle.

So where you can reverse the signs and symptoms. Now, I'm not particularly in this space. though I find it really interesting. There's a guy by the name of Richard Isaacson. Do you know Richard? He's a neurologist at Cornell. And he has a practice that focuses on early cognitive decline that utilizes very low-glycemic index diets

coupled with MCT and stuff. So it's basically like inducing ketosis without a full-on ketogenic diet, which obviously for many people is challenging. And he's seeing very promising results. I think he's in, he's running a couple of clinical trials as well. And there's a whole sort of, I don't know what the word to describe it is, but there's a whole network of people out there with, you know,

all of their interesting data that are, because we don't have controls, we just don't know if this is like a performance bias we're seeing or if there's a true impact. But anyway, that's sort of my hypothesis, which is I don't actually know what's causing Alzheimer's disease. I don't know how to treat it. I don't know if it's treatable once it's in a late enough stage. but I firmly believe that if you can be as insulin sensitive as possible,

for you as an individual, you reduce your risk. Now, that doesn't mean that the risk ever goes to zero for any of us, regardless of APOE genotype. But I know that if I have to choose between being very insulin sensitive and not so insulin sensitive, I'm going to be better off in this camp. And I think that's frankly true for every disease state. There are other things. There's subtle things going on, of course.

IGF, of course. Just to bring it back to where we were, IGF's really interesting because centrally and peripherally, you may actually want them to be in opposite directions. You probably know this, but Amgen had a drug that was an IGF receptor antibody. It went into clinical trials, phase two trials, in pancreatic cancer, advanced pancreatic cancer, and it failed. Now, it failed despite reducing IGF levels at the receptor. by 50%. You could argue that that failure implies that reducing IGF is irrelevant. Reducing IGF is

irrelevant once the tumor burden is established. Reducing IGF to only 55% is irrelevant. You could argue 100 different things. What's most interesting is that antibody does not cross the blood-brain barrier. And so today there is ongoing research. It's all in animals at this point in time that's looking at giving a diet that actually increases IGF. but giving it in the presence of this IGF receptor antibody. The point being is can we raise IGF levels totally, primarily centrally, and then block the receptor peripherally? So we ward off cancer and diabetes, but we ward off dementia. And actually, there's even evidence, though, I think this evidence isn't as strong,

that elevated levels of central IGF also are protective against diabetes. Oh, really? Yeah. But again, the problem is these are animal data. So you've got to sort of take everything with like a lot of speculation. So to just kind of bring it back to the briefly back to the type you were talking about diabetes in the brain being Alzheimer's. What's really interesting to me is the fact that neurons are actually mostly using lactate from astrocytes. Astrocytes are glycolytic.

So the astrocytes are sporing cells in your brain, which are using glucose, mostly. are what using glucose to generate lactate, lactate then gets shuttled into neurons. And then the neurons, and the reason why neurons like that is because it's thermodynamically favorable, much like beta-hydroxybutyrate in which you mentioned, B.HB,

because it can shunt right into the TCA cycle and the mitochondria. By the way, how does the brain out compete the liver for lactate? So, like, if you go out and, if I made you go out there and do a bunch of burpees, right? Yeah. So you're, the blanking on the name of the transporter. MCT, one or two, which one is the transporter out of the muscle?

Oh, I don't know which one or two. But the majority of lactate is going to be generated in the muscle. So then that MCT is going to transport that out. Yes. And remember, it's got to go through the portal system. Yes. It actually doesn't go through the portal. It passes through the cave, but it's still passing through the liver.

how does the brain manage to get any out of, without the liver taking it all into the core cycle, which seems to me the preferential place to undergo gluconeogenesis? Yeah, so what's weird is that, I don't know, the answer to your question. I know that many tissues, and this has been shown through the work of George Brooks at UC Berkeley, who actually pioneered the lactate shuttle hypothesis in the theory. But it's been shown that it gets taken up by the liver, it gets taken up by, the muscle gets taken up by the brain. In fact, exercise itself has been shown to preferentially cause the brain to tick up. Can we measure? I don't know if you read this literature,

but there was a lot of really interesting work back in the 60s done at Harvard with real fasting experiments. I mean, 40-day fasts. You have inpatient subjects given nothing but water and minerals for 40 days. And it was done to basically demonstrate what the steady state fasting levels of glucose insulin, BHB, and acetoacitate would be. And it's actually quite interesting, right? So you take a normal person, we take you, and let's say your insulin level is, you know, 10. Your glucose level is 95. Your BHB level is unmeasurable because you're on a normal diet, and your acetoacetate level is unmeasurable. And then we just fast you. And it turns out that within about seven days, you'll be at a ketone level of five to seven millimolar.

Glucose will be down to three to four millimolar, which is call it 60 to 70 milligrams per deciliter. And you will stay at those levels in, you know, sort of for a very, you know, until at the end of the 40 days, they're still in those levels. So the glucose, so glucose never really goes away. What's changing is the consumption. by the neuron, which goes from at the initial state being about 100% glucose. Of course, I don't think they were measuring lactate then, so we don't actually know. Were they looking at neuron or just brain? Was it astrocytes or neural?

They were probably just looking at brain, yeah. But it would fall to maybe 40 or 50%, the rest of it being made up by the combination of the ketones. And it's interesting that it never went to zero, right? So even to your last day of life, if you're being starved to death, you still have glucose in your blood. Yeah. And so it's kind of interesting that, like, what percentage of overall brain metabolism do you think is driven by lactate? It must be very, very small and reserved for, you know, a very, very specific subset of neurons or astrocytes or... Well, the astrocytes are using the glucose and they're generating the lactate.

So the lactate doesn't have to gain. So that might be the issue. So that's probably why the liver doesn't matter because it's... Well, yeah, during exercise, I mean, but it has been shown that lactate will cross over the blood brain barrier during exercise as well. But that is why it doesn't... But the dominant source is... The astrocytes. Yeah, the estrocytes are making it in the brain. And what's fascinating... So, astrocytes don't have mitochondria. They do. So why do they make all the lactate? I think they make the lactate because the neurons, that's how the neurons are getting their energy. I think

that's just the way it's worked out. So it's sort of a Warburg effect. The Warburg effect, of course, to me is interesting because I don't buy the argument that the Warburg effect is due to defective mitochondria. It's not. That was, Warburg showed that, I mean, he... No, there are still a lot of people who think that it's a, that cancer affects the mitochondria, and that's why the warfax. But I think it's just that the cancer cell is smart enough,

and it's optimizing for cellular building blocks. And it sounds like the astrocytes doing the same thing. Okay. We have to talk about this. For a different reason. Yes. different reason. It's really interesting.

Okay, so we're totally just hopping around all these interesting topics. But, okay, to finish on the lactate thing, fascinating work, traumatic brain injury. You know, also brain aging real time, people with TBI are much more likely to get Alzheimer's, especially if they have 8-0.4, you know, up to 10, 20 times, depending on how many alleles they have. I used to do work with some professional athletes. And for guys in the NFL, if I saw that they were APOE-3-4, and again, this is, completely bogus, but it's the best I think you can do.

I would advise somebody who is an APOE 3-4 entering the NFL that your number of concussions should be fewer than what is recommended. Yeah, I would actually go as far to saying if you are APOE 3-4, that head trauma in general is putting you at high risk. Yeah, no, no, I completely agree. But of course, when you got a guy who's about to make $20 million to go play football and he's willing to, like, play until he gets six concussions, maybe you make a three. Yeah.

So back to the lactate thing. Very interesting. Yeah, so read up on this. You know, George Brooks, a friend of mine, he's working now with some other physicians at UCLA looking at the effects of actually exogenous lactate on helping treat TBI because TBI. But why not just exogenous B.HB? Or, yeah, or that.

I mean, have you seen what Dom Degistino's done? I have, I think I've read one of his studies. on cancer. You should see Dom's work in TBI. So this, oh, in TBI. Oh, yeah. That's how he got started. They're the same.

He's a neurobiologist. Oh, okay. The only reason he's in cancer now is because he started out working in neurobiology. Interesting. And using TBI models. I didn't know that. Yeah, but it's the same thing. Lactate, beta-hydroxybutyrate, it doesn't matter.

They're going to the MCT. They're completely overcoming trauma. They're both doing similar things. They're both thermodynamically favorable. They allow glucose sparing and they allow glucose to then be, you know, used to make glutathione, which is important in the brain when you have damage. But what's interesting is that TBI also disrupts astrocyte's ability to make lactate. And what I'm wondering when you were talking about...

But those two might just synergize. They might. Because I also think the trauma causes an oxidative stress. I think what's happening is pyruvate dehydrogenase is getting interrupted. And all of a sudden you were having a transient but violent interruption of energy to the brain. Yes. And so this is obviously of high interest to the military because of blast injuries. And Dom would know this.

So it's absolutely worth talking about this to him. I'm sure the DOD is all over this. I hope the DOD is all over this. Because the interesting question is, do you have to have the BHB or the lactate in your system at the time of injury to prevent it? Or can administration be done immediately following the trauma? Or is there a kinetics? Is there a certain time? I think because of the fact that it allows glucose sparing, which if you have a trauma is,

and this has been shown in animal models for TBI, that if you can prevent the, and this, but this was done by putting glutathione transcranially, which obviously is not going to happen. But anyways, they could prevent like over 50% of the damage because they were able to sequester the reactive oxygen species that start to damage, cause all the damage and the inflammatory pathories that start to get out of control. So I think that if you allow that glucose to be used for the pentose phosphate pathway within a certain time frame, I don't know what that time frame is, it was something within a couple of hours, then independent of the, you know, allowing your neurons to get, you know, this easier

sorts of energy. If your neurons are using glucose because they need energy, but the glucose, you know, can't be used to repair that damage through the pentos phosphate pathway. I think that's one component of it in terms of the temporal effects, like how soon after the damage. But anyways, your Warburg thing, I have to just quickly tell you. So I also spent six years doing cancer metabolism at St. Jude, Tulin's Research Hospital,

and I wanted nothing more than to believe that mitochondrial dysfunctional. And that was, yeah. Because that would have made my whole thesis, like, so much easier. and I wouldn't have taken six years. But I couldn't find that. I couldn't find that cancer was causing mitochondria to be so dysfunctional that that's why they're glycletic. Yeah, there's an amazing paper that Matthew Vanderheiden wrote in 2009 in science with Lou Cantley

and Craig Thompson on it. That was really, that was the time when I, that's when I sort of shifted my point of view on that. Yeah. Well, you mentioned that cancer cells are using it for, I agree with you with the fact that, you know, cancer cells, the reason why they're glycolytic, I think also is because it's quicker and they don't really give a shit about, like... Well, they're optimizing for the building blocks to make more cellular machinery. Right.

They're not... They're basically saying, I'm willing to do an inefficient process of getting ATP in exchange for something else. Yes. But here's my other insight onto this, my other sort of theory. By the way, I'm interested in how to exploit that. In other words, you don't have to know why that's happened. to figure out how to exploit that. That's what I'm interested. Well, here's what I think, another reason why they've figured out not to use their mitochondria. I think the reason they figured that out, and this is why I also think why things like

anything that'll activate pyruid dehydrogenase or anything like beta-hydroxybeter rate, anything that's going to force the mitochondria to work, right? So like, whatever it is, because the mitochondria are, for the most part, not as active in cancer cell. I think that anything that's going to force them to work, the reason why cancer cells don't want them to work is because cancer cells are primed to die. So this is the whole basis, most of the basis, behind how chemotherapy drugs work. Cancer cells are primed to die in the sense that our body has increased the amount of all these pro-death signals, pro-apopotic proteins to say, die, die, die, cancer cells have increased all the anti-apopotic proteins and signals that, no, I'm not going to die yet. So they're like balances here. You know, they're primed to die.

They're ready to die. All they need is a little push to the pro-death side, right? So if they have a chemo that's another activating more pro-death, it's enough to push them the balance into pro-death, right? Well, mitochondria, when they're active, when you're highly metabolic, using your mitochondria, you're generating reactiv-option species, which are a pro-death signal. And I think that is one of the main reasons why giving DCA, activating the pyrube dehydrogen, complex can kill cancer cells. I think that's why ketogenic diets, which are basically forcing the cell to use oxidized fats, you know, which require mitochondria, I think that's also why they're, you know, very effective. So that's interesting. So you would think then that all

things equal a ketogenic diet would produce favorable cancer outcomes versus exogenous ketones. In other you could produce the same hormonal milieu with both, but in one of them you don't have to undergo the machinery. So, maybe, maybe. And the reason I say maybe... And I find that interesting. I don't know the answer. The reason I say that is because cancer cells also want lipids.

They like to build more cells, and you need lipids to build some of them. So I'm worried about that component of it. However, forcing, if you think about it, normal cells aren't primed to die. So normal cells, anything that's activating your mitochondria, normal cells, isn't going to kill them. And I think that's why it's a much better cancer therapeutic strategy than chemo, because chemic therapeutic drugs also kill normal cells, proliferating cells. You've got your hair, your skin, whatever, is proliferating fast like a cancer cell. So I actually think that it's possible that whether that's, you know, fat oxidation through more of a ketogenic diet,

I think it's someone that needs to be tested more. Like I said, I do have concerns just because you are giving, you know, a cancer cell building blocks for more cells, which, of course, is always a concern. But I think that anything that is going to force some mitochondria to become active and generate that signaling, you know, reactive oxygen species signaling to death, you know, to kill it is good. It's also why taking dietary antioxidants, supplemental dietary antioxidants when you have cancer is very dangerous, because you're blunting that whole signaling pathway, right? You're basically blunting all the reactive oxygen species that are usually signaling for your cells that are primed to die, for the cancer cells to die, and you're sequestering it. So it's like, you know, and that's been shown.

But it's something that's interesting to think about. And I don't know it's a possibility. It hasn't been proven, but I think that it's certainly an interesting hypothesis that should be looked at. And for all those people out there that are researching cancer and mitochondria, maybe they will. We'll be looking at it. Great, great. All right, so I think we've talked about a lot of interesting things, and, you know, is there anything else you want to discuss or talk about? I mean, I think we could talk about ISIS, but I feel like it takes us a little bit off course.

So probably not. Yeah, probably. Okay, that's it for this podcast. Thanks for listening. Learn more about what Dr. Peter Atia is up to by going to atiamedical.com. And once again, to get awesome articles, podcast announcements, and much, much more, go to foundmyfitness.com and sign up for my email newsletter where I regularly send out exclusive content, not released anywhere else.

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