Click here for the full video: Robert Lustig, MD - Food, Metabolism, and Psychiatric Disease

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Good afternoon, everyone. As part of our Emory Pharma seminar speaker series, I'm honored to present to you an accomplished speaker whose work really has had a significant mark on our comprehension of nutrition, well being and sort of the intricate connections that bind them. Today, it's my privilege to introduce Dr. Robert Lustig to our Emery Pharma series. Many of us are very familiar with some of Dr. Lustig's work, particularly on the perils of excessive sugar consumption and its implications for health. His viral lecture, the Bitter Truth, has actually gained millions of views. I've seen that myself and sparked worldwide discourse on the detrimental impacts of sugar, particularly on human health. As an accomplished author, Dr. Lustig has also penned several influential books, including Fat Chance, Beating the Odds Against Sugar, Processed Food, Obesity and Disease. It's actually a book that my wife's company actually has for all of their physicians, but really delves into again the scientific inquiries behind, or intricacies, excuse me, behind the obesity epidemic. But beyond these scholarly and advocacy pursuits, Dr. Lessig holds the position Emeritus professor for the Division of Endocrinology, the Department of Pediatrics at ucsf so University of California, San Francisco. And today he's going to delve into some of the connections that intertwine food metabolism and psychiatric disease. So please join me in welcoming a warm welcome Emery Pharma welcome for Dr. Lustig.

Thank you, Ryan. Thank you, Ron. Thank you, Anna. Thank you all again. I'm kind of like part of the family now, extended family. So I've talked to you about metabolism and systemic health in the past, and today we're going to talk about metabolism and brain health, mental health, and what the connection and what the role of food is in metabolic health of the brain. And I will make the argument during the course of the hour that in fact mental health is metabolic health of the brain. Okay. That the two are actually indistinguishable and the same processes that are going on peripherally to cause disease are going on centrally to cause disease. And the treatments, guess what? Are the same. Real food. We're gonna, we're gonna go there and you'll see why. Okay, so again, I always have to start with disclosures. Okay? So I did write these books for the general public and Metabolical has a lot of what I'm talking about today. I'm chief medical officer for these four companies and I'm a paid advisor to these other. And I'm specifically, I'm an advisor to the UC Davis Innovation Institute for Food and Health, who's looking at all of These very specifically. Okay. And I'm also the chief science officer of a non profit here in the Bay Area called Eat Real, whose mission is to get real food into K12 nationally. All right, starts here, starts with 1920. Okay. When physicians at Johns Hopkins University realized that patients who were in diabetic ketoacidosis who also had concomitant seizure disorders stopped seizing when they were in ketoacidosis, people said, well, why is that? They started experimenting with the ketogenic diet. They found, lo and behold, getting people to be ketogenic, that is lowering their insulin and inducing fat mobilization and oxidation via ketones, because ketones are the breakdown products of fat, led to a cessation in seizure frequency and seizure severity in these patients. Then people started experimenting with ketogenic diets and other things. Then of course, we had the Atkins diet. And then of course, moving on. And now, of course, everybody is just flagrantly keto all over the world for all sorts of reasons, including our colleague here, Mark, who has lost 30 pounds and had his alt go from 80 down to 24. Right. Did I get it right? Okay, so this is a good thing. And the question is, you know, do you have to be that extreme and does it work for everybody and why does it work in the first place? So that's where we're going. So it's possible that the ketogenic diet could prevent seizures through metabolic effects that are direct at the brain, or it could be through gut microbiota effects because it changes the microbiome. The ketogenic diet changes the microbiome because it provides different nutrients than were there before. So you expect different bacteria to glom onto that differently. And so there's the possibility of changing your amino acid profile, therefore changing what might be excitatory at the level of the cns. All of these things could potentially lead to changes in seizure susceptibility. Well, then people said, well, could the ketogenic diet help with other types of brain problems aside from seizures? Now, my colleague and now good friend Christopher Palmer at Harvard Medical School was the first person to recognize this possibility. He was presented with a guy who had severe manic depression, who had tried everything that was refractory to all medical therapy. He also happened to be 300 pounds, and the guy wanted both help for his bipolar and also help for his weight. And Palmer didn't know what to tell him, but he said, I've heard about this ketogenic diet. Maybe that'll help your weight. And it turned out not only did it help his weight. But his bipolar resolved. Since then, he's gone on to treat numerous patients and developed case series and now is doing clinical trials with randomized control trials to determine whether or not the ketogenic diet will actually fix manic depression, schizophrenia, and multiple other CNS brainmental health problems. And in fact, now there's actually a literature on the ketogenic diet in psychiatry. Now, this talk is not about the ketogenic diet. This talk is about food, okay? In general, and how it might impact. But in it gives us a window into this issue and this problem. And the reason is because ketones don't need insulin to work. They don't need insulin to enter cells, and they don't need insulin to stimulate energy uptake. They just get in. There's no transporter for ketones. They just get in. So if you've got lots of ketones in your blood, they're going to get to your brain, okay? And don't need any help. There's no key and lock here. They just go. And so that might be a reason why it might be better, but it also might be because the insulin went down, and that might be better. We don't know yet. So the question that Christopher asked is, could food or even fasting be a psychopharmacologic therapy? And that's where we're going today. Now, many investigators, many clinicians, many scientists, many pundits have postulated a relationship between metabolic and mental health and that they might actually be the same. And here are a bunch of different books. We've talked about some of them today at lunchtime. So David Perlmutter wrote Brain Maker, Felice Jacka down in Australia wrote Brain Changer. A lot of brains here, okay? My colleague Bill Wilson in Lowell, Massachusetts, wrote Brain Drain, and I. And there Emmer Meyer, who's at UCLA and does microbiome work, wrote the Mind Gut Connection. And Christopher Palmer's new book, Brain Energy, which is actually perhaps the best of the bunch. And this hasn't escaped, shall we say, the cognoscente in academic medicine, because this is from Lancet, and here's. This is a very important quote. The emerging and compelling evidence for nutrition as a crucial factor in the high prevalence and incidence of mental disorders suggests that diet is as important to psychiatry as it is to cardiology, endocrinology, and gastroenterology. I couldn't agree more. And it's nice that somebody at Lancet figured that out, because I'd be honest with you, they haven't figured out much of anything Else. So food, what can you do to food to either make it good or bad? Okay, real food works, but clearly we're not eating real food. 73% of the items in the grocery store are not real food. They are ultra processed food. And is that ultra processed food actually impacting our brains in a negative fashion? That's the question. So what are they doing to food? Well, you can add something. You can add vitamins and omega 3s, you can subtract something like artificial colors or allergens. These are all out of, you know, ultra processed food. To make the food better, you could change the macronutrient composition or the timing. So you could go vegan. You could do time restricted eating, you know, or intermittent fasting. You could alter the microbiome, which I think is a great way to do this. And the easiest way to do that is not with a probiotic, but rather with a prebiotic. Because a prebiotic will allow the right bacteria to grow, a probiotic won't. That's why you have to keep taking a probiotic. Because after all, if a probiotic worked, you'd only have to take it once. It's a live culture. Why doesn't it just set up shop the first time? The reason is because the internal milieu of the intestine is so inhospitable. That's why those bacteria are not there in the first place. That's how they got killed off. That's why you need the probiotic. Except that you haven't fixed the milieu. So like, why would you expect it to work? Because it won't take. So fix that first. And that's called fiber, okay? And then of course, all the above. And you can do that with the ketogenic diet. Now why would these work? Why could these food manipulations have beneficial effects? In terms of psychopharmacology, CNS is central nervous system. It could alter CNS energy metabolism, that is making the mitochondria work better to make more ATP. It could alter CNS neurotransmission. We're going to talk about the glutamate GABA cycle in a minute. It could alter trophic factors in the cns, like for instance, leptin and bdnf, brain derived neurotrophic factor which cause neuronal outgrowth and in some cases neurogenesis. It could alter CNS exposures like toxins and infections. One of the big ones is strep. And I think you all know this because all you have to do is go back to 1791 when Sydenham demonstrated that a strep infection caused severe chorioathetosis called sydenhams chorea due to rheumatic fever. Okay, like why would a bacteria cause a change in your central nervous system? Well, you know, we've known that for a long time and of course, all the above. And the ketogenic diet does all those. Okay? So the ketogenic diet, again, it's our window into the problem. It's not the only issue, but it's a window, okay? Could potentially have lots of different effects. It could change energy consumption because the mitochondria don't need insulin. And it gets in. So it's, you know, if you have a, you know, ketone level in your blood, it will make it into the brain and potentially you can have more efficient ATP production. Or it could change neurotransmitters over here. So it could change the GABA to glutamate balance. You know, a lot of people forget that glutamate is the precursor to gaba, okay? And so there's a glutamate to GABA cycle and that is under the control of different enzymes that are manipulable. And glutamate is excitatory and GABA is inhibitory. And so if you have a problem converting one to the other, guess what? You might go frigging crazy. And Indeed people do. GABAergic transmission, change in glutamate transport, which could lead to anxiolytic effects, etc. Okay, everybody got it? In addition, maybe more cholesterol. And cholesterol can be converted to pregnenolone, which can then be converted to allopregnanolone. And allopregnanolone binds to the progestin receptor and can cause reduction in CNS output. So it's a mild sedative, okay. And maybe even improve immune function too. All of these. Plus there are fats that matter in this story. So there are omega 3s like EPA and DHA, eicosapentaenoic acids and docohexaenoic acid, EPA, DHA. And you get these from where? You get these from wild fish, not farmed fish, okay? And these are necessary for normal neuronal membranes and normal neural transmission. And I will show you in a minute that these are very important terms of emotional well being and mental health. On the other side you have Omega 6s. Omega 6s all come from this guy over here, linoleic acid, which is in seed oils. And this is pro inflammatory because it is the precursor to arachidonic acid and arachidonic acid is the precursor to prostaglandins, thromboxanes and leukotrienes, all pro inflammatory. So we know that inflammation of the brain leads to mental health disorders, and so keeping that inflammation down is necessary. So you need a omega 6 to omega 3 ratio that basically allows for normal neural connectivity and transmission and doesn't allow for inflammation. Well, that omega 6 to omega 3 ratio optimally should be about 1 to 1, maybe even up to 3 to 1, 4 to 1. Our current omega 6 to omega 3 ratio is 20 to 1. And the question is, does that have detrimental effects? Well, we know that poor psychiatric health is linked to persistently low omega 3s. In fact, significant depression and schizophrenia too, all with low omega 3s. Now, is that an epiphenomenon? Is that a primary phenomenon? Is it correlation? Is it causation? Obviously, you can't tell from this kind of study. The only way to know that is by doing the clinical trials and seeing whether you can do that. I'm going to show you some. So this leads us to the question of what is going on in the brain? What makes a difference? And is it the ketones, is it the type of fat, Is it the elimination of carbohydrate? Or all the above, and is very specifically, because it's my interest, what is sugar's role in this? And is the reason that any of this works just because you're getting rid of sugar, which is possible? I'll show you why. We know that if you do any of these things, you will improve insulin sensitivity. Well, that will lower the amount of insulin at the level of the neuron, which is good because insulin makes the neuron do other things other than what you want it to do. Okay. Actually, basically drives energy metabolism in the wrong direction because you're in storage mode, not burning mode, and your brain wants to be in burning mode, not storage mode. And it turns out beta hydroxybutyrate, which is the primary ketone, it's not the only one. Acetoacetate is another one. But beta hydroxybutyrate is the primary one from fat metabolism. Turns out it's a signaling molecule. It stimulates the cell to make Sirtuins, in particular Sirtuin 2, which is a primary driver of mitochondrial biogenesis. So you're making more mitochondria, which is good. Okay, so is it the improvement in insulin sensitivity or is it the reduction in sugar consumption itself? We don't know because no one's ever tested just sugar reduction. Against carbohydrate reduction to find that out. So these are still open questions. And every time I go to a talk or a symposium about metabolic psychiatry, this is the question I ask, and no one can answer it yet, okay? And I'm going to be the biggest gadfly in the world asking which of these or both is is the important issue and why this matters. Don't know yet. Is it the carb reduction or the sugar reduction that matters and through what mechanism I care. I think you all care, too. Okay, so when we talk about sugar reduction, what are we talking about? Well, we're talking about two molecules, right? Dietary sugar, that is sucrose, is two molecules, one glucose, one fructose, bound together with an o glycosidic linkage linking the two. High fructose corn syrup is one glucose, one fructose, not bound together. Okay? Now, the enzyme in your intestine sucrase cleaves this o glycosidic linkage in a nanosecond. You absorb both molecules separately, and they do their own thing. Glucose is the energy of life. Fructose is consumable poison. It's that simple. Well, if you consume high fructose corn syrup, you're getting the same thing. So this whole concept of sucrose versus high fructose corn syrup is just a tempest in a teapot. It is just garbage. They're both equally bad. But of course, the sugar industry will tell you it's the high fructose corn syrup, and the high fructose corn syrup industry will tell you it's the sugar because they're all competing for market share. All right, now, what is going on in the brain? Well, you got to measure. So if you inject glucose or fructose or both into somebody's vein and then do magnetic resonance spectroscopy of their brain, here's what the glucose reference looks like. Here's what the fructose reference looks like. Here's what the combination looks like. It's basically those two put together. And this is a human being, okay, who's just eating. And you see, they're both there. Okay, they're both there. And the reason is because the human brain turns glucose into fructose. This is work from Rick Johnson at the University of Colorado. And you can actually measure this as well. So this is pregnant women. Pregnant women. Here's the CSF to plasma ratio for glucose. That makes sense because the CSF glucose level is always half of what the blood level is. That's normal. Here's for fructose okay, why is there fructose in the brain and why is there more? Because the brain converts glucose to fructose. Now, why? That's a complicated story, and Rick would tell that story much better. But there's actually adaptive advantages to that. And of course, sorbitol is the way you get from glucose to fructose. This is the polyol pathway. So basically, aldose reductase makes sorbitol, and then it goes to fructose. And fructose has its own potential effects. All right, so there's fructose in your brain whether you like it or not, whether you ate it or not, all right? It's just a question of how much and what's it doing? Well, what's it doing? It's changing your mitochondrial metabolism is what's doing. All right, so impaired mitochondrial function in psychiatric disorders. So this is not like my, you know, you know, imagination. It's not my, you know, craziness. You know, other people have been looking at this, and here's mitochondrial function right here in the center. And you can see there are a whole lot of things affecting that. Okay? There's BCl2, which is oncogene, that causes cell division, mitochondrial DNA mutations, glucocorticoid receptor translocation, changes in calcium influx, okay? That all impact. Oh, and most importantly, reactive oxygen species. We're going to come back to that in a minute. All impacting on mitochondrial function. In fact, we have a paper that we've got sent out for review right now on the role of reactive oxygen species in the toxic effects of food. Okay? And why it drives obesity, not why it drives psychiatric disease, but it's the same thing, okay? And when your mitochondria don't work right, you're going to have problems with synaptic plasticity, neurite outgrowth, ATP production, apoptosis, calciumostasis, okay? Which are all going to have behavioral effects. Now, remember, the ketones get into the brain without insulin. So here's the liver making ketones, beta hydroxybutyrate right here, entering the brain right here, and basically going to both the astrocyte and the neuron. The beta hydroxybutyrate ends up going from the astrocyte, feeding the neuron, and you end up into the Krebs cycle so that you can burn it, but you don't need insulin to do that, Whereas every other cell, you know, if it's glucose, you do need insulin to do that. So that's one of the reasons why the ketogenic diet might work. Is because you don't need insulin. So ketones can substitute as a CNS energy source even when the mitochondria are dysfunctional, even when they're not working right, they will work better on ketones than they will on glucose, because getting from glucose to acetyl coa is its own process which can be affected negatively, Whereas ketones bypass that and go straight to the Krebs cycle. Okay? And you'll get less oxidative stress, less reactive oxygen species when you're burning ketones over when you're burning glucose. And it's been shown that the ketogenic diet can improve cognitive parameters in Alzheimer's disease. Maybe every patient with Alzheimer's should be on a ketogenic diet. Well, Dale Bredesen, who wrote the End of Alzheimer's, thinks that that's true. Okay, now, hasn't been tested in a formal fashion. Needs to be. Okay. But in his case series, which he has just published, that's one of the things that allow for survival. Alzheimer's was going on a ketogenic diet. Now, why is this a problem? I mean, what's going on to alter the mitochondria? Well, that's in this slide here. And I think I've shown this slide at Emory Pharma before. I love this slide. It's one of my favorite slides. Okay, here's glucose. Here's fructose. They are not the same, okay? The food industry will tell you calories are calories, sugars of sugar, garbage. Total, complete trash, okay? They say that on purpose because that's how they assuage their culpability for putting all the fructose in the food in the first place. They are not the same. And this slide shows that they're not the same. Glucose actually stimulates mitochondrial function. So you'll notice beta oxidation up arrow in green. Hooray. That's good. Glucose increases mitochondrial function. How does it do it activates two enzymes. Right here. Activates AMP kinase. Adenosine monophosphate kinase. This is the fuel gauge on the liver cell. When your cell uses up ATP, it makes amp, right? Because the phosphate bonds get broken, and that's where the energy is is in those phosphate bonds. That's what the electron transfer support chain in your mitochondria do, is they basically release the energy and you turn NAD into NADH and then go back and forth, etc. You know, that's the whole oxidative phosphorylation that powers cells. Everybody familiar with the concept, right? Okay, well, AMP kinase, okay? If you have more amp, it fits into the active site. And what that does is that tells the cell not enough energy. We're energy depleted because I've got AMP instead of ATP. And so we need to make more mitochondria. So it increases mitochondrial biogenesis, which is good for burning more energy. In addition, it increases this enzyme here called HADH hydroxyacel CoA dehydrogenase, which is also involved in increasing the rate at which two carbon fragments get converted into energy. Thus, beta oxidation going up. So glucose, for lack of a better word, is good. Fructose, on the other hand, is another story. Fructose does the opposite. Fructose inhibits three enzymes that are necessary for normal mitochondrial function. It inhibits AMP kinase. It inhibits this one down here called acad L, Acyl COA dehydrogenase long chain, which is necessary to cut up those two carbon fragments. And it also, through uric acid, inhibits this guy over here, CPT1A, carnitine pulmidoltransferase 1A. And this is the enzyme that regenerates carnitine. And carnitine is the shuttle mechanism by which the fatty acids get from the outside into the mitochondria for burning in the first place. The sum total of which is that beta oxidation goes down, glucose beta oxidation goes up, fructose beta oxidation goes down. They are not the same. Clearly, Ron Kahn, CEO of Joslin, who was the senior author on this paper, famously said about this paper, the most important takeaway of this study is that high fructose in the diet is bad. It's not bad because it's more calories, but because it has effects on liver metabolism to make it worse at burning fat. As a result, adding fructose to the diet makes the liver store more fat. And this is bad for the liver and bad for whole body metabolism. And that's just the molecule itself. Never mind what it did to the insulin, right? Well, that's one problem. There's another problem, okay? And it's on this slide. And I've shown this slide here as well. You're all familiar with this concept. Now, here are five pictures of food. They all share one thing in common. What is it? They're all delicious. Brown. Brown. Yes, but they're all brown. They are delicious. And the reason they're delicious is because they're brown, okay? That's the caramelization or the browning or the Maillard reaction. The Maillard reaction. And this is, of course, what causes hemoglobin A1C. Okay? So the way to think about this is you can roast your meat at 375 degrees for an hour, or you can roast your meat at 98.6 degrees for 75 years. The answer is the same. You're browning. And if you don't believe me, here's newborn rib cartilage, nice and white. And here's 88 year old rib cartilage, nice and brown. Okay? You are browning as we speak. And if you had orange juice this morning, you are browning seven times faster. And that browning reaction is the aging reaction. It is what causes wrinkles, it is what causes cataracts. It might even be what causes Alzheimer's disease. Might. How does it work? Well, as you know, glucose has a ring form and a linear form. This is the linear form. When glucose is in the linear form, it has an aldehyde at one end at position one. And that aldehyde will bind to an epsilon amino group of lysine at position one of the hemoglobin molecule forming a shift base which will spontaneously decompose to this covalent linkage which then has to be cleared by the spleen. And that takes three months. And that's why measuring your hemoglobin A1C basically tells you about your glucose burden over the previous three months. That's why diabetics can use it to monitor their efficacy. Okay, everybody with me so far? Well, not only does it occur in glucose, and every, by the way, every time that reaction occurs, it releases a little reactive oxygen species, a little oxidative stress, which has to be quenched by an antioxidant or it will do damage. It will cause lipid peroxidation or protein denaturation, ultimately causing cell dysfunction, ultimately cell death, ultimately organ death, and ultimately human death. Okay, Just does it over a long period of time. Like one cigarette won't kill you, okay? 100 cigarettes in one day won't kill you, but you know what? 10 cigarettes over 20 years will most definitely kill you. Okay? Takes a while, but nonetheless, it's still toxic. Even if it's not an acute toxin, it's a chronic toxin. Same idea here, okay? This is a buildup, slowly of damage. And it turns out that glucose will do it and you can't stop it. It will happen. If you're alive, it's going on, but you can slow it down. And fructose does it too. And it does it seven times faster. And you can actually measure this in not just the body, but in the food. Because when you heat ultra processed food, the fructose in the food Binds to the epsilon amino groups of lysine in the food to create advanced glycation end products in the food itself. And there's a receptor for the advanced glycation end products called rage. Receptor for advanced glycation end products. And when you stimulate that rage with an advanced glycation end product, you generate reactive oxygen species all by itself. So eating food that has been that had sugar in it and bound is also problematic. Okay. And it correlates with cardiovascular disease in patients with obesity. Now, why does this happen? And why is fructose particularly egregious for having this happen? That's here. And this is our paper from our kids study. Okay. This is the important term right here. D lactate. Now, you've all heard of lactate. Lactate is what your muscles make right, when you exercise, right? Lactic acid, that's L lactate. This is D lactate, the isomer. Right. The epimer. Okay. Delactate only has one source and it's not exercise. I will show you. So there are a lot of different things that affect that AMP kinase, right? It is the master regulator of all of these pathways and it promotes all these good things and it also inhibits all of these bad things. So turning on your AMP kinase is a good thing. That's why metformin is now being utilized for type 2 diabetics and possibly even as a longevity promoting agent. Near Barzillai is, you know, running this metformin trial out of Albert Einstein to see whether or not metformin can promote longevity by increasing AMP kinase, by increasing mitochondrial function. Okay, so there's a theme here, if you will. Okay, so AMP kinase is pretty important, and I agree, it is. So let's look at AMP kinase a little closer. Three subunits, Alpha, beta, gamma. That gamma subunit is the. Where the active site is. That's where the AMP fits in to the pocket. Okay. And that pocket over here has three arginines. Three arginines. Three places where something could bind and form that Maillard reaction. Well, turns out a compound that is made from an intermediary metabolite of fructose called methylglyoxal. Methylglyoxal is the breakdown product of dihydroxyacetone phosphate. Okay. Can fit in that active site. And it is an aldehyde. And what happens when an aldehyde and an amino group find each other? Amine, Right? So here's the Maillard reaction. If glucose is. If the rate of the glucose at the Maillard reaction is 1, fructose is at 7, methylglyoxal is at 250. So methylglyoxal is a bad guy, okay? Because it is binding to proteins whether you like it or not, okay? And it fits in the active site. So it fits in that argin, you know, finds one of those arginines in that active site. So the methylglyoxal gets made from dihydroxyacetone phosphate from fructose, fits inside there, and. And then you turn off your AMP kinase irreversibly. You have basically killed your AMP kinase. So your AMP K goes down. What does that mean for mitochondrial biogenesis? Means it's in the sewer. Means you have decreased your mitochondrial function. And if you decrease your mitochondrial function, what does that mean for your cell? Means your cell's starving. And is that going to have any behavioral effects if it's in your brain? You bet it will. Everybody got the idea, okay? Now, methylglyoxal has a way of being detoxified to de lactate. Remember I told you D lactate was important? This is the source of D lactate is methylglyoxal detoxification by an enzyme called glyoxylase 1. Glyoxylase 1 is in all your cells, but different people have different levels of the glyoxylase 1. It's genetically determined. So some people will be able to get rid of their mgo and some people won't.