- Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Robert Lustig. Dr. Robert Lustig is an endocrinologist. That is, he's a specialist in the function of hormones in the body and a professor of pediatric endocrinology at the University of California, San Francisco.

He has authored more than 100 peer-reviewed studies exploring how different types of nutrients, that is food, impact our cellular functioning, our organ functioning, and thereby our health. During today's discussion, we discuss the idea of whether or not a calorie is indeed a calorie and whether or not our body weight and body composition only reflects the number of calories we eat versus the calories that we burn.

We talk about how different food types, that is how the different macronutrients, protein, fat, and carbohydrates are processed in the body and the important role that fiber and the gut microbiome plays in that process. And we pay particular attention to the topic of how different types of sugars and fructose in particular can indeed be addictive to the brain and can modify the way that hormones in the body, in particular insulin, impact our liver health, kidney health, and indeed the health of all of our cells and organs.

Indeed, Dr. Lustig is an expert in how sugar impacts the brain and body. We talk about how certain types of sugars can indeed be addictive in the same way that certain drugs of abuse and behaviors can become addictive. So in other words, how sugar actually changes the way that the brain works.

And we discuss how the food industry, that is the commoditization and sale of particular types of food has altered the way that we eat and indeed the foods that we crave. Today's discussion covers all of that. And by the end of today's discussion, you'll have a thorough understanding of how foods are processed when they enter your body and how those different food choices are impacting your immediate and long-term health.

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast.

Our first sponsor is Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. I've spoken many times before in this podcast about the fact that sleep is the foundation of mental health, physical health, and performance. Now, a key component of getting a great night's sleep is that in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees.

And in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees. One of the best ways to make sure that those temperature changes occur at the appropriate times, at the beginning and throughout, and at the end of your night when you wake up, is to control the temperature of your sleeping environment.

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Eight Sleep currently ships in the USA, Canada, UK, select countries in the EU and Australia. Again, that's eightsleep.com/huberman. Today's episode is also brought to us by Levels. Levels is a program that lets you see how different foods affect your health by giving you real-time feedback on your diet using a continuous glucose monitor.

One of the most important factors in your immediate and long-term health is your blood sugar or blood glucose regulation. With Levels, you can see how different foods and food combinations, exercise, and sleep patterns impact your blood glucose levels. It's very easy to use. You just put the monitor on the back of your arm, and then you take your phone and you scan it over that monitor now and again, and it downloads the data about your blood sugar levels in the preceding hours.

Using Levels has allowed me to learn a tremendous amount about what works best for me in terms of nutrition, exercise, work schedules, and sleep. So if you're interested in learning more about Levels and trying a continuous glucose monitor, you can go to levels.link/huberman. Levels has launched a new CGM sensor that is smaller and has even better tracking than the previous version.

Right now, they're also offering an additional two free months of membership. Again, that's levels.link/huberman to try the new sensor and two free months of membership. Today's episode is also brought to us by AeroPress. AeroPress is similar to a French press for making coffee, but is in fact a much better way to make coffee.

I first learned about AeroPress well over 10 years ago, and I've been using one ever since. AeroPress was developed by Alan Adler, who was an engineer at Stanford. And I knew of Alan because he had also built the so-called Aerobie Frisbee, which I believe at one time, perhaps still now, held the Guinness Book of World Records for furthest thrown object.

And I used to see Alan, believe it or not, at parks around Palo Alto, testing out different Aerobie Frisbees. So he was sort of famous in our community for developing these different feats of engineering that turned into commercial products. Now, I love coffee. I'm somebody that drinks coffee nearly every day, usually about 90 to 120 minutes after I wake up in the morning, although not always.

Sometimes if I'm going to exercise, I'll drink coffee first thing in the morning. But I love, love, love coffee. And what I've personally found is that by using the AeroPress, I can make the best possible tasting cup of coffee. I don't know what exactly it is in the AeroPress that allows the same beans to be prepared into a cup of coffee that tastes that much better as compared to any other form of brewing that coffee, even the traditional French press.

The AeroPress is extremely easy to use and it's extremely compact. In fact, I take it with me whenever I travel and I use it on the road in hotels, even on planes, I'll just ask for some hot water and I'll brew my coffee or tea right there on the plane.

If you'd like to try AeroPress, you can go to aeropress.com/huberman. That's A-E-R-O-P-R-E-S-S.com/huberman to get 20% off any AeroPress coffee maker. AeroPress ships anywhere in the USA, Canada, and over 60 other countries around the world. Again, that's aeropress.com/huberman to get 20% off. And now for my discussion with Dr. Robert Lustig.

Dr. Robert Lustig, welcome. - Pleasure. Truly, just being here, being invited, high honor, really appreciate it. And it's not doctor, it's just Rob. - Okay, Rob, I've been looking forward to this conversation for a long time. I've seen your now famous, can we also say infamous, but famous YouTube video about sugar.

We'll put a link to it in the show note captions. It's been viewed many, many millions of times. - Yeah, and I still can't figure out why that is, you know? - Well, I can. - I didn't think my mother would watch it and she didn't, but 24 and a half million people did.

- Well, I think people are very interested in what to eat, what not to eat. And we'll start off simply talking about what most everyone believes and understands, which is that a calorie is a form of heat energy that's given off during the processing of some food bit or some thing.

If that's mysterious to people, just understand that a calorie is a unit of energy. And I was taught and still many, many people worldwide believe that a calorie is a calorie, meaning if I consume more calories in whatever form, then I metabolize by thinking, feeling, moving, exercising, et cetera, then I will gain weight.

And if I consume fewer calories than I burn, I will lose weight. And we could talk a lot about where that weight loss comes from. Does it come from adipose body fat stores or from muscle or from protein, or muscle, of course, is protein, et cetera. But let's start off with, is a calorie truly a calorie when it comes to the processing of different types of calories?

Everyone thinks that obesity is about energy balance. That is calories in, calories out. Therefore, two behaviors, gluttony and sloth. Therefore, if you're fat, it's your fault. Therefore, diet and exercise. Therefore, any calorie can be part of a balanced diet. Therefore, don't pick on our calories, go pick on somebody else's calories.

This is actually what the food industry uses to assuage their culpability for the change in the food supply and the rise in obesity and chronic disease like diabetes. Now, it is true that a calorie is that unit of energy that raises one gram of water one degree centigrade. And so therefore, a calorie burned is a calorie burned.

I don't argue that, that's true. That's the first law of thermodynamics. But that doesn't mean a calorie eaten is a calorie eaten. That's not the same. And that's where people get it wrong. So let me give you some examples of how that calorie eaten is not a calorie eaten.

You like almonds? - I do. - Me too, almonds are great. You eat 160 calories in almonds. How many of those do you absorb? 130. You eat 160, you absorb 130, where'd the other 30 go? - In the processing of that food energy? - No. Turned out, the fiber in those almonds, both soluble and insoluble fiber, and by the way, fiber's sort of the key to the kingdom in this story, forms a gel on the inside of your intestine.

The insoluble fiber, the cellulose, forms a fishnet, if you will, a latticework on the inside of your duodenum. The soluble fiber, which are globular, plug the holes in that fishnet. Together, they form a secondary barrier. You can actually see it on electron microscopy, a whitish gel, and that prevents absorption of those 30 calories.

So yes, 130 get absorbed, but many of them don't. They end up going further down the intestine to the next part, called the jejunum, and that's where the microbiome is. Now, everyone knows about the microbiome nowadays. It's all the bacteria. We always say, when women are pregnant, you're eating for two.

Well, we're always eating for 100 trillion. Now, they have to eat. Well, what do they eat? They eat what you eat. The question is, how much did you get versus how much did they get? Well, if you ate almonds, they're getting those 30 calories. So even though you count the calories at your lips, that doesn't matter.

What really matters is counting the calories at your intestinal brush border, okay? And they're not the same. So if you feed your gut, that's a good thing because then your gut will take those calories and turn it into things like short-chain fatty acids, which end up being protective against chronic metabolic disease, acetate, propionate, butyrate, valerate.

Those are actually good. They're anti-inflammatory, anti-Alzheimer's because you fed your microbiome. So even though you ate 160, you absorbed 130. So a calorie eaten is not a calorie eaten because if you ate it with fiber, it wasn't for you. It was for your bacteria, but that's not the way you count them up.

So that's problem number one. Problem number two, amino acids. So we all eat protein. Let's say you eat too much protein. You have, you know, the porterhouse steak, all right? Now, if you're a bodybuilder, those amino acids might go to muscle and you might increase your muscle mass because you're a bodybuilder, because you're putting excess force on those muscles and you're growing those muscles, okay?

But let's say you're not a bodybuilder. Let's say you're a mere mortal like me. - Or let's say you're a kid going through puberty who's synthesizing a lot of muscle, not because they're lifting weights, because they're in growth. - But because testosterone's making it happen, yeah, absolutely. But let's say you're not.

Let's say, you know, you're just, you know, just schlump off the street like, you know, Joe Schmo, okay? And you eat that porterhouse. You've taken on all these amino acids. There's no place to store it other than muscle. So your liver takes the excess and deamidates that amino acid, takes the amino group off to turn it from a amino acid into an organic acid.

And then that organic acid can then enter the Krebs cycle, the tricarboxylic acid cycle, what goes on in the mitochondria in order to generate ATP, the chemical energy that your body needs in order to power itself. Okay, now that's a good thing. It takes double the amount of energy to prepare that amino acid for burning, as it does to prepare a carbohydrate for burning.

- Or fat, 'cause when I asked about, when you asked about almonds, why the 160 versus 130, I thought it was the processing. It turned out it was fiber. You're saying for protein, let's make it realistic for a really nice big porterhouse steak, which I love, by the way.

Let's say 800 calories. - Me too. - Well, it turns out-- - How much of that is, so that's what goes in your mouth, my mouth. How much of it is actually eaten, to stay with your calorie eaten is not a calorie eaten. In the processing of that, what percentage actually goes into your total caloric intake?

- Right, so about 10% of everything you eat goes to just maintaining body temperature. It's called the thermic effect of food. But when you're eating protein, you actually generate more heat. And the reason is because it takes two ATP to phosphorylate that organic acid, as opposed to one ATP to phosphorylate that carbohydrate for consumption.

So you actually have a net loss of energy because it was an amino acid versus a monosaccharide, a sugar. Now, you brought up fat. Fat doesn't need to be phosphorylated. So it actually doesn't have any thermic effect of food at that point. So it depends on what it is as to whether or not you have loss.

- Okay, so in this, let's make it actually realistic. A 1,600 calorie porterhouse with a nice slab of-- - Butter. - Of grass-fed butter on there. I do this every once in a while, not often. - With some creamed spinach and maybe some mushrooms along the side. - Honestly, when I'm eating a porterhouse, I don't want to adulterate the taste with anything else except maybe some butter, maybe a salad afterwards.

But let's say 1,600 calories of, it's got some fat in there for sure. Let's say 1,000 of those calories is protein. The other 600 are fat. - Something like that. - Something like that, depending on how marbled it is. Okay, so based on what you just said about the thermic effect of food and protein in particular, of that 1,000 calories, how much actually can we count?

I'm not a calorie counter, but does one include as calories truly ingested? - Well, if you ingested 1,600-- - Well, that's what went in the mouth, but what is going to go against your burn deficit? - Right. So I would have to actually do the math to figure that out.

But as a guess-- - Yeah, back of the envelope. - Back of the envelope calculation, you're going to lose about 25% of that. - Wow, so we're talking 750 calories. - Yeah. - And to translate this a bit, so what we're saying here is if you're somebody who is trying to lose weight or maintain weight, or perhaps even gain weight, you eat a 1,600 calorie porterhouse with a slab of butter on it, 600 of those calories we're saying in this is fat, with the remaining 1,000 calories, that all went in your mouth.

- So you counted at your mouth. - Right. - But 700, but then when you compare it against your energy burn for that day, to maintain temperature, brain activity, physical activity, really it's only 750 calories. - That's right. - That's a huge difference. - Exactly, and another reason why a calorie's not a calorie.

Now let's take the third, let's take fats. So over here we have Omega-3s, heart-healthy, anti-inflammatory, anti-Alzheimer's, save your life. And over here we have trans fats, the devil incarnate, consumable poison, because you can't break the trans double bond, you don't have the desaturase to break that trans double bond.

So it basically accumulates, lines your arteries, lines your liver, causes chronic metabolic disease, causes insulin resistance. Omega-3s don't even get broken down for energy, because they're so important, they stay intact, because your brain needs them, your heart needs them, whereas trans fats can't be broken down because of that trans double bond.

One, save your life, other one, kill you. They're both nine calories per gram, if you explode them in a bomb calorimeter, because a calorie burned is a calorie burned, but a calorie eaten is not a calorie eaten, because one will save your life, one will kill you. And finally, the big kahuna, the one that blows everything else out of the water, fructose and glucose.

All right, now, glucose is the energy of life. - So here we're talking carbohydrates. I think most of our audience will be familiar with the so-called macronutrients. So we talked about fat, in this case, almonds. There's some fiber in there, probably a little bit of carbohydrate. - Little bit.

- Little bit. Talked about the porterhouse with butter. - Right. - You can be hungry already. That's protein and fat, very little, if any, carbohydrate. It should be zero, essentially, maybe one. - Zero, zero. - Yeah, yeah. And then now we're talking about carbohydrates, and we're gonna subdivide that into glucose and fructose.

- Right, galactose basically becomes glucose in the liver, so we can dispense with that, unless you have a disease called galactosemia, which is about 120,000, and causes neonatal meningitis, and it's a disease, as a pediatric endocrinologist, I would take care of, but we can dispense with that for the moment.

All right, so glucose, fructose. Glucose is the energy of life. Every cell on the planet burns glucose for energy. Glucose is so damn important that if you don't consume it, your body makes it. So it will take an amino acid and turn it into glucose. - That's gluconeogenesis. - Gluconeogenesis, that's right.

It will take a fatty acid and turn it into glucose, and specifically the glycerol portion of the triglyceride will turn into glucose. So the Inuit, they didn't have any place to grow carbohydrate. They had ice, they had whale blubber. They still have serum glucose level, and the reason is because you had to.

You have to have a serum glucose level in order to power your brain, in order to power your heart. Yes, you can use ketones, of course you can, but only if you're in a ketogenic state will you use exclusively ketones, and you also need glucose for structural changes in specific proteins and particularly hormones.

So glucose molecules will stud TSH, LH, FSH, different pituitary hormones in order to increase their potency. It's one of the reasons why aging leads to defective hormoneogenesis. For instance, hypogonadism, hypothyroidism is the loss of glycosylation on individual peptide hormones because of the inability to add glucose. - Because of insulin?

- No, no, it's an aging phenomenon. - Okay, we'll come back to this 'cause I think it's really important. The idea that ingestion of carbohydrates and the, as you called it, the studying of carbohydrate molecules on hormones can augment the function of those hormones, and with aging that's a less efficient process.

- It's a less efficient process, but it's not because of consumption. - Right, people are still, I see the plenty of folks who are 65 and older eating plenty of carbohydrates. You're saying a lot of them have deficient thyroid, testosterone, estrogen, prolactin, et cetera, because of the way those carbohydrates are not studying the hormones.

- Exactly, so all of those are glycoprotein hormones. - Let's tee that up for later 'cause I think that's an interesting avenue to go down. - Okay, and there's a disease in children and babies called congenital disorders of glycosylation, where you can't put glucose molecules on specific proteins, and it causes severe mental retardation, all sorts of metabolic havoc, and a lot of those babies die for that matter.

So that's an important thing. All right, but that's how important glucose is. Fructose, on the other hand, this sweet molecule, the molecule we seek, the reason why the food industry studs every food in the grocery store, and 73% of all items in the American grocery store have added sugar on purpose for the food industry's purposes, not for yours, because fructose is addictive, activates the nucleus accumbens, the reward center of the brain, in the same way that cocaine, heroin, nicotine, alcohol do, and drives dopamine receptors down, just like nicotine, alcohol, cocaine, heroin do.

That molecule, fructose, is number one, completely vestigial to all vertebrate life. There is no biochemical reaction in any vertebrate that requires dietary fructose. That's number one. Number two-- - Okay, sorry, I'm gonna just answer. So you're saying that even though we can process fructose-- - We have a limited capacity to process it, in the same way we have a limited capacity to metabolize alcohol.

Now, if you have one drink a day, you're okay. If you have two drinks a day, depends on how big you are. You know, you and I can probably-- - I would argue two drinks a week is the maximum, but let's not go there. But in terms of, you're saying, when you say fructose, processing of fructose is vestigial, what you're saying is that we don't need to do it.

It's like the appendix. It's an organ for which it has no function. - Exactly. And fructose has no function in the human body, period. - You don't need it. - You don't need it. Don't need it. But our diet is replete with it. In fact, our fructose consumption's gone up 25-fold since the beginning of the last century.

- I have to ask this now. I love fruit, I eat berries galore, especially since the price of berries seems to have come down. It used to be the only get 'em certain times a year. I'm what you call a drive-by blueberry eater. So I'll just walk past and just take a fistful.

You can't put them in front of me without me eating them. This is even difficult for me when other people I don't know are eating them. So I eat lots of blueberries, strawberries, blackberries if they're in season, I love them. - No problem. - Loaded with fructose? - No.

- Plenty of fiber, low fructose? - Low fructose. And berries, berries are the lowest fructose of all the different fruits. - I was so worried about asking you this today. - Not a bit. - Okay. - And fruit is okay because of the fiber. So the molecule, the fructose molecule's the same whether it's in a berry or in a banana or for that matter in a Coca-Cola.

The fructose molecule is the same molecule. The difference is that in the berry it comes with a whole lot of fiber. In the banana it comes with a whole lot less fiber. And in the Coca-Cola, it doesn't come with any fiber. And the fiber is what mitigates the absorption.

So when you consume the fructose with fiber, so your blueberries, you're feeding your microbiome. That fructose wasn't for you. - Got it. Such a relief. And I must say recently I had a whole body MRI as a preemptive thing. - How was that? - It was great. I got to watch a Netflix in there and I never had a whole body MRI.

I learned a few things that were useful to me. I've got a clean bill of health, so that's great. - Well, that's good. - But one of the pieces of feedback I got is that my gut was filled with this very high contrast stuff. And they asked, do you consume a lot of blueberries?

And I said, indeed I do, why? And they said, because that high contrast of it shows up white on the scan is high concentrations of magnesium that we see in people that ingest large amounts of blueberries, which is pretty rare. And yours are comparable to a bear in blueberry season.

- Wow. - And basically my entire gut was filled with blueberries. I suppose I need to cut back a little bit. But now I know that fruit is okay, especially if the fruit has a lot of fiber, but fructose itself, especially if it's not partnered with fiber, is first of all, not required for survival at all.

But you're telling me is problematic. - Yeah, and let me tell you why it's problematic. We haven't gotten to that yet. We're just talking about whether it's vestigial versus needed. Now let's talk about what fructose does. Turns out fructose inhibits three, count 'em, three separate enzymes necessary for normal mitochondrial function.

Now, your mitochondria make ATP. Your mitochondria have to work at peak efficiency. That's what metabolic health is. Is mitochondria working at peak efficiency? Well, there are three enzymes that are inhibited by fructose. Number one, AMP kinase, all right? Now, AMP kinase is the fuel gauge on the liver cell.

It's the thing that tells the liver to make more mitochondria, fresher mitochondria, because if your AMP levels are high, that means you've dephosphorylated a bunch of ATPs and you have to regenerate 'em, so you need some more mitochondria, so it's a negative feedback pathway. Well, you need that AMP kinase to generate that mitochondrial biogenesis signal, except that fructose, a metabolite of fructose called methylglyoxal, MGO, sits in the active site of the gamma subunit of that AMP kinase and actually binds to arginines in that active site, rendering that enzyme now dead.

It's an irreversible inhibition because of the covalent bonding of that methylglyoxal, that aldehyde, to the arginine, and now that enzyme is dead. Okay, so it basically acts like a key that doesn't turn the lock, but prevents the key that you want in that lock from entering the lock. It's like gluing a lock shut, yeah.

Got it, so that's one of the enzymes. That's one. Second one, ACAD-L, acyl-CoA dehydrogenase long chain. So this is necessary to cleave two carbon fragments off fatty acids to prepare them for metabolism. So it inhibits that one. And then finally, it inhibits carnitine palmitoyl transferase one, now CPT-1. Now that's the enzyme that regenerates carnitine.

Carnitine is the shuttle mechanism by which you get the fatty acids from the outer mitochondrial membrane through to the inner mitochondrial membrane so that they can be beta-oxidized for energy. So if you don't have that CPT-1, you're basically carnitine-less, and therefore you can't generate beta-oxidation. You said fructose inhibits all three of these enzymatic pathways.

As a biologist, I have to ask you, how potently does it inhibit them? I mean, 'cause there are drugs that block receptors, and then there are drugs that block receptors with unbelievable affinity. So I mean, mechanistically in a dish, meaning in vitro, you can see all sorts of things.

But how significant is this for obesity, for mitochondrial function in vivo in us? - All right, so the dose determines the poison, right? Paracelsus 1537. There are toxins that are parts per billion and will kill you, like sarin, ricin, cyanide. By the way, cyanide's a good analogy because it's working on mitochondria.

It's basically causing mitochondria to be completely defective, all right? Then there are intermediate toxins, like arsenic and carbon tetrachloride. Parts per million, and they take a little longer to work. They're not gonna kill you on the spot. That's why I can eat an apple seed that has a little bit of arsenic in it, but I'm not gonna die.

- Right, and then finally there, and by the tobacco smoke goes in there. And then finally, you have weak toxins, all right? And you know, where it's not one exposure that will kill you. It's, you know, 10,000 exposures that'll kill you, like alcohol. - Or toxic people. - Yeah, or toxic people.

Well, it depends on how toxic. - Sometimes it only takes one. Couldn't resist, sorry. Sometimes it only, mildly toxic people. Anyway, the point is that fructose is in that last category. So it's not what you do one day that kills you. It's what you do every day that kills you.

And if you basically eat ultra-processed food, high in sugar, for 10 years in a row, it's gonna show up in terms of your comorbidities. And ultimately, yeah, it will kill you. And we have the data to show how many years you will lose. So right now in America, we pay an eight-year longevity tax.

If you look at Japan, they have a mean age of death of 88. We have a mean age of 80, okay? We're paying an eight-year longevity tax just by living here. And we're talking about the healthy people. Now, if you have metabolic syndrome, it's a 15-year longevity tax. And, sorry, if you have obesity, it's a 15-year longevity tax.

And if you have metabolic syndrome, it's a 20-year longevity tax. That is primarily, not completely, but primarily sugar. It's also, you know, Omega-6s, it's also trans fats, you know, left over because now they're gone. But, you know, people are still suffering the ravages of the trans fats, you know, from the previous generation.

- Are they gone? I mean, I do remember as a kid when we had margarine in our refrigerator. This is actually a big debate in my home. One parent, I won't identify which, was pro-margarine. The other was pro-butter, anti-margarine. The marriage didn't last, but there were other reasons. - That's probably why.

- I went butter. - Butter is fine. In fact, time declared, you know, front cover, butter's back, you know. Margarine was the bad guy, without question. And we know now, but, you know, back when we thought it was a calorie, it was a calorie. We thought, oh, margarine, you know, it's the same, you know, nine calories per gram.

And we said, it lowers your triglycerides. Bad idea. It was, because what it did was, it lined your liver. Because you couldn't break that trans double bond. And, you know, so they're now gone from our food supply. - They're illegal. - They're illegal, they're banned. But you can make trans fats in your own kitchen by taking olive oil and heating it to beyond the smoking point.

So they're not completely gone. They're just gone from ultra-processed food. So now sugar's the big problem, because of these three enzymes that you are inhibiting. The point is, we started this with a calorie's a calorie. Well, if you are inhibiting mitochondrial function, then a calorie's not a calorie, is it?

- You're reducing the intensity of the furnace. - Yeah, exactly. So this whole calorie's a calorie just makes no sense. And it hasn't worked at any level. And there is no study that actually shows that cutting calories makes a difference. And I can show you, you know, voluminous data that shows that virtually every weight loss study that led to caloric restriction basically didn't work.

Not for any length of time. Just to round out our earlier discussion, 'cause I find it fascinating and I know other people will as well, talked about that 160 calories, that's actually 130 at the business end of things, of almonds. We talked about the porterhouse steak with butter and the 25% reduction in what's actually "eaten".

And I'll get back to this 'cause this "issue", I think the problem is there's a lack of useful language to dissociate this stuff. Even just calling fat, fat. People think it's gonna make you gain body fat. - Totally. - If we called it adipose tissue and lipids, we would have avoided this confusion.

So I don't wanna get there just yet, but I wanna make sure with- - The food industry does this on purpose. - Really? - Oh, absolutely. So they tell you a sugar is a sugar, which is not true. They tell you a calorie is a calorie, which is not true.

And they tell you a fat is a fat, which is not true. Okay, this is very specifically. So when you're talking about sugar, you're talking about dietary sugar, or are you talking about blood sugar? 'Cause blood sugar is blood glucose. - Or cholesterol. - And I never use- - Dietary cholesterol, or circulating cholesterol, or- - Absolutely, okay.

So we've done this to ourselves, but the food industry has really promulgated it because we farmed out nutrition policy and information to the food industry. So they actually use this for their purposes. It's one of the problems in this field. As we all know, quality nutrition influences, of course, our physical health, but also our mental health and our cognitive functioning, our memory, our ability to learn new things and to focus.

And we know that one of the most important features of high quality nutrition is making sure that we get enough vitamins and minerals from high quality unprocessed or minimally processed sources, as well as enough probiotics and prebiotics and fiber to support basically all the cellular functions in our body, including the gut microbiome.

Now, I, like most everybody, try to get optimal nutrition from whole foods, ideally mostly from minimally processed or non-processed foods. However, one of the challenges that I and so many other people face is getting enough servings of high quality fruits and vegetables per day, as well as fiber and probiotics that often accompany those fruits and vegetables.

That's why way back in 2012, long before I ever had a podcast, I started drinking AG1. And so I'm delighted that AG1 is sponsoring the Huberman Lab podcast. The reason I started taking AG1 and the reason I still drink AG1 once or twice a day is that it provides all of my foundational nutritional needs that is it provides insurance that I get the proper amounts of those vitamins, minerals, probiotics, and fiber to ensure optimal mental health, physical health, and performance.

If you'd like to try AG1, you can go to drinkag1.com/huberman to claim a special offer. They're giving away five free travel packs plus a year supply of vitamin D3K2. Again, that's drinkag1.com/huberman to claim that special offer. For the third category of macronutrients, carbohydrates, you differentiated glucose and fructose. If I ingest, let's say, a half a bagel since we were talking about New York, your city of origin, they have great bagels on the West Coast.

- Yeah, I know. - Yeah, it's not the same. - It's pretty pitiful. - Same with the pizza dough. It's like they claim it's the water, whatever it is, it's different back there and it's better. - Indeed. - Half a bagel, let's say 250 calories, mostly carbohydrate. This is an unlined, no cream cheese, no schmear, as they call it back there.

No cream cheese, no butter, none of that thing. Just half a bagel, 250 calories. So that's what I ate. You're saying that a calorie eaten is not a calorie eaten. How much of that carbohydrate, given that it's probably most, let's assume it's mostly glucose. Let's do it this way.

- Yeah, it is. It's polymerized glucose. - Okay, polymerized glucose. - That's what it is. - How much of that is actually utilized or burned versus the original 250? - So if you look at what happens to energy in the body, 65% of that which is ingested goes to resting energy expenditure, just to power the body.

10% goes to the thermic effect of food. And then 25% goes to activity. That's the breakdown of where the energy goes. - And that's calories from fat, protein, and carbohydrate. - Yeah, from everything together. And glucose is a perfectly good example of how that works. The point is though that when you ingest glucose, you're getting a big glucose excursion in your bloodstream.

So you're getting a big glucose spike. And that glucose spike has to come down. Well, what makes it come down? The hormone insulin. Insulin is the bad guy in this story. The higher your glucose goes, the more your pancreas will release insulin in order to bring that glucose down.

Well, it turns out that glucose rise was not benign. That glucose rise led to endothelial dysfunction. Transient, but nonetheless, endothelial dysfunction. - Could you just remind people what endothelial cells are? - The inside of your arteries, okay? And it will change blood pressure. We've got plenty of data to demonstrate how it changes blood pressure.

And over time, that will cause coronary artery disease. That will cause kidney disease, et cetera. But it's the insulin response that is really the bad guy. Now, people think insulin is good because it lowers blood glucose. After all, diabetics take insulin to lower their blood glucose. Okay, let's take a diabetic.

A patient with diabetes. Blood sugar's 300, that's bad. We give him a shot of insulin in the arm. Blood sugar goes down to 100. Blood sugar went from 300 to 100. Okay, where did the 200 points of blood glucose go? - I'm assuming that the insulin sequestered it to where?

- I'm assuming to the liver. - To the fat. - Interesting. - For storage. That's insulin's job. Insulin takes whatever you're not burning and puts it into fat for storage. Insulin is not the diabetes hormone. Insulin is the energy storage hormone. - How quickly does it do that? - Pretty quick.

- Because if I'm having a very busy day, or the diabetic person is having a very busy day and they're moving around a lot, then you've got insulin-bound glucose in the bloodstream for how long? - No, no, insulin doesn't bind glucose. Insulin binds to its receptor. - Sure, sorry.

- Insulin allows for glucose transporters to work. - So, but for some period of time, while that person is active, there's an opportunity to utilize that glucose, right? So how quickly is insulin managing that glucose? We know that the spike comes down quickly, but the glucose is not available for energy utilization after what?

It's sequestered to the adipose, to the fat tissue within an hour? Is that about right? - So about 90 minutes, yeah. But I mean, if you're active, if you eat a muffin and you're active, your muscles are going to take up that glucose irrespective of insulin. In fact, muscles are insulin independent.

They have glucose transporters, but they are insulin independent because if they weren't, then every patient in diabetic ketoacidosis would be paralyzed, okay? So glucose will end up in muscles irrespective of energy status and insulin status. - And in muscles, it's used as immediate fuel and glycogen? - Both. - Okay.

- Immediate fuel and glycogen storage in the muscle. Absolutely, all right? Now, if you're active, then you will clear glucose into muscle, therefore your blood glucose won't rise as much 'cause it went into muscle, and therefore your pancreas will put out less insulin because it doesn't have to clear as much from the bloodstream, and that's okay, that's good, right?

But let's say you didn't exercise, so you've got a big glucose excursion, now you have a big insulin response, and that insulin is going to take the excess that's in your blood, it has to clear it, and it will go to fat for storage. That insulin rise turns out to be particularly egregious in terms of metabolic disease, and I can prove it.

There is a mouse, my favorite mouse. I love this mouse. This mouse turns medicine on its head and teaches every doctor why they have to go back to medical school and learn it right. This mouse is called the PADERCO mouse, P-O-D-I-R-K-O. - Is it discovered by PADERCO? - No.

(laughs) No, it was discovered in Ron Kahn's lab, it was manufactured in Ron Kahn's lab. So this is a tissue-specific insulin receptor knockout mouse, I-R-K-O. - So it lacks the insulin receptor in the kidney. - PADERCO, glomerular podocyte insulin receptor knockout mouse. - We haven't talked too much about transgenic models and knock-ins and knock-outs, so just in 10 seconds or less, basically, these are mice that are genetically engineered to lack the receptor for insulin, specifically in the kidney.

- Glomerular podocyte, the kidney. - In the kidney, and everywhere else in this mouse, insulin does its thing normally. - Exactly, great. So these animals are euglycemic, normal blood glucose levels. These animals are normally glucose-tolerant, so they go up, they go down, just like every other mouse. These mice are not fat, these mice are not thin.

These mice are mice, except they have the worst diabetic nephropathy on the planet. - So their, oh, their kidney is degenerative. - Their kidneys degenerate to nothing. - Yikes. - Now, they have normal blood glucose levels. They have normal glucose tolerance. They have normal insulin tolerance whole body, but their kidneys are dying.

How come? Can't be the glucose, it's the insulin, because insulin's the bad guy. Insulin's actually making the kidney disease. And so these animals that are insulin-resistant, they have diabetic nephropathy without diabetes. - So the insulin is having a negative, clearly negative effect on the kidneys without binding to the receptor.

- Exactly. - So circulating insulin can do stuff without binding to its receptor. - Well, no, it binds to its receptor in different parts of the body. - Other parts of the body, but in the kidney it can't 'cause it's a knockout. - It's a knockout, right. The point is insulin does stuff by itself.

And it turns out insulin drives growth. Now, every cell in your body wants to burn at one time in its life and wants to grow at another time in its life. Every cell has those two pathways. Burning, growth, burning, growth. What determines whether a cell should be burning or whether a cell should be growing?

- I don't know what makes it burning, but presumably it has something to do with mitochondria. - It has everything to do with mitochondria. So every cell needs to burn and needs to grow at a different time in its life. Here's a way to think about it. We all start out as a zygote, a single cell.

We end up an adult. Now, that single cell had to become two cells. Those two cells had to become four cells. Those four cells had to become eight cells. And on and on and on and on. So every cycle there's a doubling. How many doublings to get from a zygote to an adult?

- What's an exponential growth? So I don't know it off the top of my head. - 41. - 41, two to the 41 doublings. - Gives you an organism? - 10 trillion cells. - We're 10 trillion cells? - We're 10 trillion cells. - Do we know that? - Yeah.

- Okay. - Two to the 41. - Okay. - Okay, now of those 41 doublings, some of them had to occur in utero. Some of them had to occur postnatally. So I need two numbers that add up to 41. How many in utero? How many postnatally? - Postnatally. - Well, way more.

You start off with a lot more than you end up with, but then you have cells that turn over throughout the lifespan. So this is a tough one. - Okay. - Because skin cells turn over. - Sure. - With neurons, it's pretty straightforward because you're gonna... - What you get is what you get.

- Right, and you're born with somewhere between three and 10 X of what you end up with, depending on the brain structure. - Yeah. - So, but for whole body wide, I don't know how you'd come up with that number. - 36 and five. - Okay. - 36 doublings prenatally, five doublings postnatally.

And I can prove that to you too. Typical baby weighs seven pounds. First doubling, 14 pounds. Second doubling, 28 pounds. Next doubling, 56 pounds. Next doubling, 112 pounds. Next doubling, 224 pounds. - Hopefully it stops there. - Obese individuals. - Hopefully it stops there. Not all people 212 pounds are obese, but some people who are certain heights or below are 212 or obese.

Point is, the cell has to know when to grow and when to burn. It turns out that the signal for that is oxygen because oxygen is necessary for mitochondria to be able to burn. In the absence of oxygen, the cell only knows how to grow. This is actually why Otto Warburg won the Nobel Prize in 1931 for the Warburg effect.

He asked the question, how come cancer cells don't need oxygen to grow? And the answer is because no cell needs oxygen to grow. In fact, oxygen is the thing that prevents growth. Famous article from the New England Journal of Medicine, 1951, Mount Everest in utero, because every fetus is oxygen deprived.

So normal, partial pressure of oxygen, 100 millimeters of mercury out here, right? If I checked your blood, it'd be about 100, right? - I hope so. - How about a tumor cell? - Guess tumor cells probably, is it double? - About 44. - Wait, you just told me-- - Partial pressure of oxygen in a tumor cell, it's about 44.

- But you just told me that tumor cells, which grow like wild. - Right, they grow like wild because they don't have oxygen. - But there are some of the, so here's what's peculiar about it. Tumor cells are some of the most vascularized cells, or tumors are heavily vascularized.

I mean, one way to try and kill one is to de-vascularize the tumor cell. - Yes, and angiogenesis inhibition, et cetera, is a big deal. Judah Folkman and all that from Harvard, you know. - So the excess blood to a tumor is the attempt to bring in oxygen that it's not getting.

- That's right. - As opposed to delivering lots of oxygen and that's why it's growing. - That's right. - Okay. - But a fetus, what's the partial pressure in the placenta? - I don't know. - Six to 31. So it's actually like a mile above Mount Everest. That's how much oxygen the fetus gets.

And it's for that reason that you've got 36 doublings. And then, as soon as you're out, you cut the cord and you start breathing and now your partial pressure's at 100, that's when growth slows down. - Has there been any effort to treat tumors by oxygenating tumors? - Yes.

- And what does that look like? - It's hyperbaric oxygen therapy. It's a thing. - Oh yeah. - Yeah. - Yeah, we'll probably do an episode on hyperbaric chambers. The reason we haven't yet is it's pretty niche, but there are people who own these things, who sit in these things.

Okay, so we got here by way of the bagel. - Right. - So I just want to orient us. You just had 250 calories of the bagel. We talked about glucose excursions. - But it's that insulin rise that's driving the adiposity and it's also driving the growth, okay? In the absence of oxygen.

'Cause if you have oxygen, then you don't need that much insulin. - Okay. So, because you're gonna burn instead of store. Got it. In terms of the raw metabolism of carbohydrate though, that glucose, if I eat 250 calories of glucose, how much of that did I quote unquote actually eat?

How much is used? - How much is used? - Yeah, let's assume that I'm at my desk working or I'm walking around a little bit. I'm not exercising hard in the subsequent hour. - So used for what is the question? - I'm getting back to the calories. Is the calorie a calorie?

Clearly the answer is no. But based on the processing of different types of calories, we established it for fat. The almonds, we established it for protein. The porterhouse with butter. And now we're trying to establish that for the 250 calories of bagel, which is glucose. - Right. So the glucose has to be phosphorylated.

So you're gonna lose an ATP in the process. So ATP goes to ADP. And then that ADP will go to AMP, adenosine monophosphate, which will then go to IMP, adenosine monophosphate, which will then go to uric acid. - Okay. - And that uric acid will be then released from the cell, circulate in the bloodstream, and hopefully go out in the kidney.

In the process, that uric acid can inhibit mitochondrial function, and it can also inhibit endothelial nitric oxide synthase, which is the enzyme in your vasculature that is your endogenous blood pressure lower. - Right, by expanding blood vessels and capillaries. - Exactly. - Right, this is the mechanistic foundation of the drugs that were originally used for improving prostate function, but are used to treat erectile dysfunction, which are the PDE inhibitors, which allow nitric oxide to be around longer and more of it, right?

People use it for other purposes too. Now no one will forget, if I queue it up with that example. - We, in the neonatal intensive care unit, it closes patent ductus arteriosus, which is a big deal in the neonatal world. - Well, okay, I wanna ask you about that, but so I heard two things.

One is that glucose and the insulin that goes with it increases uric acid. Uric acid, while it has certain important functions in health, too much of it, you said, can inhibit nitric oxide. - Yeah, can inhibit nitric oxide. - So that means that the blood vessels and capillaries are gonna stay more constricted, so blood pressure is gonna be higher than it would be normally.

- That's right. - And then uric acid is also inhibiting mitochondrial function. - That's right. - Okay. But eating half a bagel isn't necessarily a terrible thing if it's within your caloric requirements. - And it all depends on how much you clear and how high your insulin goes. - Now let's compare that 250 calories of glucose to 250 calories of fructose.

- Right. - Let's come up with a food example. 250 calories of fructose would be trivial to consume in the form of high fructose corn syrup, right? - So remember that high fructose corn syrup is half glucose, half fructose. - Okay, so let's not use-- - So it'd be 125, 125.

- So let's not use that. Well, so let's assume, so we can talk about a soda to get that 250 calories easily, especially if it's not a can or a European-sized bottle. - Eight ounce can of soda. - Okay, so eight ounce can of soda and maybe let's include a food item.

Let's talk like a store-bought packaged cookie, couple of Oreos, two Oreos. - Okay. - Probably get you to that 250 or maybe four Oreos. - Maybe three Oreos. - Okay, Oreo lovers everywhere celebrating. Three, 250 calories of fructose. What's the effect on uric acid? What's the effect on caloric burn?

What's the effect on anything for that matter that we should be aware of? - All right, so first of all, the Oreo has plenty of fructose in it, so keep that in mind. - Okay. - Let's say you consumed 250 calories in a bagel 'cause that's pretty much polymerized glucose versus say the soda.

So the bagel versus the soda, that's what you're-- - Equivalent calories, right. - Equivalent calories. - Or the bagel versus let's say two Oreos and a little bit of, yeah, two Oreos. - Okay, so number one, there's only half the glucose in the soda because the other half is the fructose.

So 125, 125. So your glucose rise won't be as high. Your glucose excursion will be lower. This is actually one of the reasons why there's this thing called glycemic index. And glycemic index is a canard. It's garbage. It is complete and utter BS. - The glycemic index. - Absolute BS.

Nothing is more egregious in terms of argument than the glycemic index. And this is one of the things that dieticians promote and espouse and one of the things that's gotta go. This is an idea that must die. - Okay, we'll get back to why the glycemic index has gotta die.

So 250 calories and actually can we make these equal just for sake of simplicity? Can we say 250 calories of glucose from the bagel versus 250 calories of fructose? How do we get 250 calories of pure fructose? - We don't. - You can't. Okay, you gotta bring the glucose with you.

- Lab fructose. You'd have to make it crystalline fructose in the lab. - Then let's stay with the Oreos, which is half glucose, half fructose. - Right. I mean, there is no fructose alone in nature. - Even crackers, some of the ones that are salty are also sweet. They have fructose in them.

- Yeah, absolutely. - High fructose corn syrup. - On purpose. - Yeah, that's why it's impossible to eat just one. - Indeed. - So what's happening biochemically as a consequence of the fructose component specifically? - So the fructose will, first of all, go into the intestine. The intestine will metabolize some of that fructose through what is known as intestinal de novo lipogenesis.

About 10% of that fructose will be turned into fat right in the intestine. - And that's 'cause fructose, it just wants to be fat? - Yeah, fructose wants to be fat. Fructose is the lipogenic substrate. - Here, we're not talking about body fat. We're talking about fat molecules that can potentially be used as energy.

- That's right, triglyceride molecules. Okay, so 10% of that fructose will be turned into triglyceride right in the intestine and be released into the bloodstream. And it is the reason for a postprandial triglyceride response. - Postprandial is, and I'm including myself in this group, is the nerd speak for after eating lunch.

Typically it's lunch. So that's actually one of the drivers of cardiovascular pathology, that intestinal de novo lipogenesis, turning that fructose into triglyceride right in the intestine. Now, there's a limit to how fast and how much the intestine can do that. The rest of the fructose will be absorbed into the portal vein, but not before some of that fructose will make it further down and it will nitrate tight junction proteins.

Now, let's talk about that. - Okay, portal vein of the kidney. - Portal vein goes to the liver. Portal vein goes from the visceral, from the intestine, to the liver. - No kidney, doesn't feed the kidney. - No kidney, no kidney. Intestine to liver. But fructose nitrates tight junction proteins.

Now, let me explain that to your audience. Your intestine is a sewer. Definition of a sewer. A pipe with shit in it, okay? That's its sewer. Our intestines are sewers. There's junk in the center and the job of the intestine is to move the junk through to the anus, absorbing the good stuff while you can.

The intestine is made up of cells, intestinal epithelial cells, that are bound together and they're bound with proteins that basically form a barrier. Those barriers are called tight junction proteins. - Things like Claudins and things like that? - Zonulin is the main one. Okay, there are others, but zonulin is the one that goes, is defective in celiac disease.

- What defines a tight junction? Is it like completely impermeable or semi-permeable? - Completely impermeable, unless its function is inhibited. Turns out if you alter the phosphorylation status or the nitrate status of that tight junction, it will become transiently permeable, okay? And so fructose nitrates tight junction proteins, causing them to be transiently permeable, allowing some of the junk in your intestine to get through into your bloodstream.

- So this is leaky gut. - This is leaky gut. This is what causes leaky gut. Fructose is a driver of leaky gut. - Got it. - That causes inflammation at the level of the liver, which ultimately leads to systemic inflammation, one of the reasons why high sensitivity CRP is high in patients who eat ultra-processed food.

- CRP is C-reactive protein, which is a marker of a, essentially an inflammatory immune response. - Exactly. - You don't want it too high. - And 93% of Americans today are inflamed. - Does that mean that 93% of Americans have leaky guts? - Yeah, it does, 'cause that's where it comes from.

- So in addition to limiting fructose intake, what are things that support the tight junctions of the intestinal pathway? - So there are three barriers in your intestine to keep the junk where it belongs, in the center, so that it can get pooped out your behind, all right? Three separate barriers.

One is a physical barrier called the mucin layer. So it's a layer of mucus that actually sits on top of the intestinal epithelial cells. Now, that mucin is a polysaccharide, and the bacteria can use that mucin layer for its own purposes. It will eat your mucin layer if you don't feed your bacteria.

You must feed your bacteria, or your bacteria will feed on you, okay? So you are in concert with your microbiome. If you deprive your microbiome of the food that it needs, it will use you as its food. And that's one of the reasons why fiber is so important. - So fiber to build up this mucin layer is one way to reinforce the fence that is the tight junctions, et cetera, between your intestine and the bloodstream.

This raises an interesting point about fasting. Many people, including myself, do a pseudo intermittent fasting. I eat my first meal somewhere between 11 and noon. I'm not strict about this, the 11 versus noon thing. And I probably eat my last bite of food somewhere around 8 p.m. And occasionally it's outside that window.

I've done this for a long time. It just feels best to me. But other people use a shorter eating window. One thing that I learned from a colleague at Yale who studies the gut microbiome that was surprising to me is that when you eat in that way, there's a long stretch of time, sometimes longer, for people that have a shorter eating window, longer fasting window, that is, where you're actually eating up your own intestinal lining.

So this idea that fasting is so great for us, on the one hand might be true. On the other hand, you're actually consuming components of your, you're not feeding your gut microbiome and you deplete it. But then here's where I was positively surprised. When you do eat, provided that you eat enough fiber and in particular high quality fermented foods, low sugar fermented foods, it seems that the lining of the gut and the gut microbiome is replenished to a level that is greater than if you had eaten for longer periods of the 24 hour cycle.

Do I have that right? - We do, you do have it right. And I don't know why that is true, but it does seem to be the case. And fermented foods, in part because they've got already short chain fatty acids in them, seem to help. - Is that the preferred food of the microbiome?

- Well, it's what the microbiome actually turns fiber into. So it's probably helping your intestinal epithelial cells in the same way the microbiome turning fiber into short chain fatty acids helps. So it's what we call a postbiotic. So you have prebiotic, which is the food for the bacteria. You have the probiotic, which is the bacteria itself.

And then you have the postbiotic, which is what the bacteria make in order to heal you. God, okay. And so short chain fatty acids are postbiotics. And there are a lot of people selling short chain fatty acids you know, drinks and supplements and what have you. Whether they work or not is another story.

- If I consume fructose in the form of, let's say a highly processed food, has minimal antioxidants, but it's got plenty of calories typically. And it's disrupting the tight junctions, making my gut leaky. But I'm also eating fiber. You know, I'm having a meal that includes a salad. I'm having some probiotics.

And then I want like a couple of Reese's peanut butter cups, like in the dark chocolate ones in particular. I don't do this anymore, but I used to eat like that more often. As time has gone on, I've become, I don't like to call it stricter, but more I tend to like healthier foods over time.

And I think you can get away with different things at different stages of life. Although you work with young people, so we'll get to very young people. So we'll get to this. But how much damage am I doing by ingesting any fructose in the form of a highly processed food?

- So I'll make it very simple, Andrew. I am for dessert. For dessert. I am not for dessert for breakfast, lunch, snacks, and dinner. So if you wanna have a couple of Reese's peanut butter cups as your dessert, in the same way as you might have a cognac for dessert, that's fine.

I have no problem with that. - The question is, are you gonna eat Reese's peanut butter cups for breakfast? - No, I don't eat breakfast, but no. But I do see your point. - The National School Breakfast Program, which 29% of school children today consume, is a bowl of Froot Loops and a glass of orange juice.

That is 41 grams of sugar. American Heart Association says that the upper limit for children should be 12 grams of added sugar per day. That's 41 grams of added sugar, and it's just breakfast. - And that's fructose rich. - Totally, completely. So the question is, which dessert are we talking about?

- Right, and can we adjust that morning meal to a different reality? 'Cause I agree that there are plenty of kids eating that, or a muffin that might be the equivalent. But what about the parent who says, okay, let's come up with a healthier option that the kid still likes, like, I'm thinking back to my childhood, like a Honey Nut Cheerios or something.

So not Froot Loops, which is kind of the extreme. - Take a look at the side of the package. No difference. - Now let's say they go with some waffles that are made. So with a pre-made mix, some milk, some butter, so mom or dad is making waffles. Great, it sounds healthier, but then if you do the breakdown we're still ending up at very high.

Are we basically eating dessert for breakfast in that case too? - Are we eating Eggo waffles? Or are we making waffles de novo from scratch in your own kitchen? - Let's say making- - Big difference. Okay, because the Eggo waffles replete with sugar on purpose because the food industry knows when they add it, you buy more because it's addictive.

And we actually have the demographic, the mechanistic, the imaging, and also the economic data to demonstrate that sugar's addictive and the food industry knows it. So have you ever heard of a phenomenon called price elasticity? Price elasticity is an economic term that is used to ask the question, if the price of a given good goes up by 1%, that should result in reduction in purchase or consumption because price influences consumption.

How much does it influence it? So if something's price elastic, when the price goes up, consumption goes down equivalently. A food that is price elastic, the most price elastic food is eggs. So when the price of eggs goes up 1%, consumption of eggs goes down 0.68%, meaning that eggs have a price elasticity of 0.32.

Got it? - Got it. - Now, what's the most price inelastic food? The top three most price inelastic foods are fast food. - Cereal? - 0.81. - I like a good quiz. Fast food, 0.81, soft drinks at 0.79 and juice at 0.77. - Meaning people will pay not whatever, but they're willing to pay more, more readily willing to pay more.

- Because of the sugar, because it's addictive, because it's hedonic. So many, many years ago, Andrew, you probably remember something called Keynesian economics. And Keynesian economics was based on this concept of the rational actor. And the rational actor can determine value, which is utility over cost. And if you're a rational actor, you should be able to say, yeah, I'll buy that, but I won't buy that, right?

Okay. In 1979, Daniel Kahneman and Amos Tversky, Nobel Prize winner, Daniel Kahneman, described the irrational actor. Now the irrational actor cannot determine value. And the reason is because he is risk averse. So the cost is always too great. So the utility may be the same, but the cost goes up because that's why they have, you know, aversive tendencies, the irrational actor.

Jeffrey Sachs has described the hedonic actor, who also cannot determine value because it doesn't matter what it costs. They need their fix. And this is what's going on and the food industry knows it. And that's why every food in the store has been spiked. - I'd like to take a quick break to acknowledge our sponsor, Element.

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Frankly, I can't pick just one. It also comes in chocolate and chocolate mint, which I find tastes best if they are put into water, dissolved, and then heated up. I tend to do that in the winter months because of course you don't just need hydration on hot days and in the summer and spring months, but also in the winter when the temperatures are cold and the environment tends to be dry.

If you'd like to try Element, you can go to drink element spelled element.com/huberman to try a free sample pack. Again, that's drink element.com/huberman. - We talked about dessert for breakfast in the form of cereals, some of which are disguised or couched as healthier. You know, I think of like honey nut Cheerios.

It seems healthier than Froot Loops. It looks healthier like just by way of color. It looks kind of weedy, you know, color. So, but let, and in terms of lunch, I mean, one of the things that I love about Europe is that the breads are amazing. - Yeah, that's a terrific pair.

- And I like them because they're not as sweet. - Exactly. - And so a sandwich from not every deli, but from a typical sandwich shopper that one makes with store-bought bread, sliced bread in the US has a lot of fructose. I looked this up prior to our discussion today.

So in some ways, dessert is being woven into foods that are, that parents and or kids, everyone thinks are savory, we're actually eating sweets. - Exactly right. - But we can't, but we don't taste them as sweet at a conscious level necessarily, right? - But our taste buds do.

- Right. - That's exactly right. So the question is why do they do that? So question for your audience. You buy a loaf of bread at the local bakery. How soon before it stales? - Two days at best. - Yeah. - If it's really great bread. - That's right.

- The better the bread, the quicker it stales. You buy a loaf of bread at the neighborhood grocery store. How soon before it stales? - You've got probably a week and then there's moldy pieces at the end that you, you know, if you're in college and you were maybe trying to scrape that off.

(laughing) - It can last up to three weeks, depending, right? - You could throw it in the freezer. You probably do that with the bakery bread, but it's never the same. - Never the same. - It's never the same. - So the question is why is that? And the answer is sugar.

The answer is sugar. So the grocery store bread had sugar added to it on purpose because when you bake it, the sugar does not evaporate. It stays in the bread and the sugar is hygroscopic, meaning it holds on to water. This is a phenomenon that the food industry uses called water activity, okay?

And so it will hold on to water and so it will stay spongy and will not stale as quickly as the bakery store bread, which did not have that sugar added to it. So even something as benign as bread has been turned into something that ultimately leads to chronic metabolic disease.

- We've pivoted somewhat from carbohydrate divided into glucose and fructose to a discussion of sugar. Could you tell us the link between sugar and fructose? - So table sugar, what percentage of table sugar is fructose? What percentage of brown sugar is fructose? What percentage of the sugar that's added to food is high fructose corn syrup on average?

You know, just because here what we're talking about is what you're describing as an intentional lacing of food with something that's addictive, but that's also processed very differently at the level of the kidney, at the level of the liver. And it's bad, it's a bad situation. - So when we talk about sugar, I think we need to be as careful in describing what we really mean as when we talk about a calorie.

- I completely agree. So for your audience, let's be very, very clear on definitions. Let's not use the word sugar because it has multiple definitions. Let's use sucrose. Sucrose is what you put in your coffee. It's the crystals, right? It's cane sugar, beet sugar, you know, the stuff that you, teaspoons of, right?

This was all that was available for many, many years. That is one molecule of glucose, one molecule of fructose bound together for the chemists out there in O-glycosidic linkage, okay? The enzyme in your intestine called sucrose cleaves this O-glycosidic linkage in about a nanosecond. You absorb the two molecules separately.

The glucose goes to the entire body, generates an insulin response. The fructose goes straight to your liver, generates fat. That's sucrose. High fructose corn syrup is essentially one molecule of glucose, one molecule of fructose, not bound together. No O-glycosidic linkage. So they're free. The enzyme sucrose doesn't care because the blond's already broken.

Ultimately, they do the same thing, and that's why high fructose corn syrup and sucrose are indistinguishable metabolically. What they are is they're very different economically, and the reason is because high fructose corn syrup is half the price of sucrose because sucrose we get from importing, and high fructose corn syrup we make at home.

Sucrose is in bags. High fructose corn syrup is in barrels. Sucrose you can sell at the store. High fructose corn syrup you sell to the ultra-processed food manufacturer. You can't buy high fructose corn syrup at the grocery store. So they're very different in terms of what they're used for.

High fructose corn syrup is particularly egregious because it's so miscible, because it's already a liquid. So you probably remember Chips Ahoy cookies in the old days. They often would seem like the sugar in the cookie had crystallized 'cause the sugar content was so high. - It's been a while since I've had one.

They weren't particularly good. - Yeah, well now-- - But you eat two of them, and then you think they're good, and then you want to eat four. That's what's so odd. The first bite is kinda like the, and then it's bombs away. - There you go. Well now it's a chewy Chips Ahoy cookies.

- Oh, I remember the chewy Chips Ahoy cookies. - Remember chewy chips? Well that, that's high fructose corn syrup because the two molecules are free, they don't crystallize. So you can actually up the dose. Several times throughout today's discussion, you've been talking about the quote unquote food industry. Okay, so I'm not a conspiracy theorist.

- I am. - But I understand, you know, that most businesses exist to make money. Many businesses start off with good intentions and drift in order to stay competitive. And many, many businesses, as we know, not all of which are entirely bad, such as the pharmaceutical industry, right? There are bad, there are instances of like the opioid crisis, but then there are drugs from the pharmaceutical industry that help save lives.

I mean, that's my stance. The food industry, I think there are good actors and there are bad actors, but we're talking about the food industry. Okay, well, we can talk about the exercise industry, we talk about the podcast industry. I mean, you got good actors and bad actors, but what you've alluded to several times here, and you're more informed than I am, is a concerted effort to lace food with a form of sugar that makes people crave more of that food, and that is causing metabolic illness, disrupting mitochondria, and on and on.

- Exactly. - And you're the physician, not me. You've worked with patients who struggle with obesity and for various reasons, not me. And so we could probably spend hours, if not days, talking about all the terrible things that the quote-unquote food industry has done, but what do you think is the pure motivation, right?

I don't think that they want people to be sick, but they wanna sell product and this sells more product. So then it raises two questions. Why is it that more people don't know this information, although many more will know after today's conversation, but, and certainly in government, it's a mix, regardless of what side of the aisle you're on, or if you're right in between.

There are clearly people that care about the health of themselves and others. So I can understand how things might've gotten to this point, but what do you think are the barriers to getting people to appreciate just what a problem this is, and getting people to change their choices in terms of what they're eating?

Are they truly addicted to the point where they are sick, they can't make good decisions? Like a drug addict who's highly addicted to heroin is a sick person, they have an illness and they need treatment, but until they get that treatment, they can't make good decisions. - Let's take an analogy, alcohol.

40% of Americans are teetotalers, never touch this stuff. - 40% don't drink. - 40% don't drink. - Great, I'm not a big fan of alcohol. I've never seen it make anyone better at anything that really mattered. - No, because it's- - Except drinking. And that doesn't really matter. - It's also completely vestigial.

There's no biochemical reaction in the body that requires alcohol, okay? For the same reason, by the way, fructose. 40% are social drinkers. Yeah, you can pick up a beer, put it down, I'm in that category. 10% are binge drinkers, and 10% are chronic alcoholics. Okay? Now, do you deprive the 40% of social drinkers because of the 20% of binge drinkers and chronic alcoholics?

- Well, I believe people should be in choice, but I believe people should know what they are doing so that they can be in choice, right? Like, do as you, I always say, and I said this about the alcohol episode, which turned out to be one of our most prolific episodes, where I said that more than two drinks, zero is better than any, and more than two drinks per week, you need to do other things to offset that, and it's problematic.

Those are what the data say. But I would say, do as you want, but know what you're doing. - Well, so I would say that that's exactly what the food industry wants you to think. That is the food industry's mantra, is you have your own choice, personal responsibility. So the question is, does personal responsibility work?

And the answer is, no, it doesn't. Every public health debacle in the history of mankind started out as a personal health issue before it became a public health crisis. And you can pick your personal responsibility issue, whether it be exposures, whether it be addictions, whether it be infections. Bottom line is, ultimately, it required a societal response, okay?

We can talk about syphilis, we can talk about tuberculosis, ultimately needed a public health response. We can talk about teen pregnancy, we can talk about-- - Tobacco. - Tobacco ultimately needs a public health response because the sheer enormity of it and the egregiousness of it requires that public health response.

Well, turns out, this is no different. In order to exercise personal responsibility, four criteria have to be met. Those four criteria are the following. Number one, knowledge. You have to have the knowledge because if you don't have the knowledge, then how can you exercise personal responsibility? Well, in fact, the public's being kept from the knowledge.

We're doing this now in part to entrain that knowledge, to get people to understand what the problem is. - Yeah, I consider myself pretty informed about nutrition and health, but already today I've learned two dozen facts about processing of fructose in calories generally that I had no knowledge of prior.

- Well, that's good, okay? 'Cause it's not about the math, it's about the science, okay? They want it to be about calories. So we have this thing called food science, we have this thing called nutrition, and we have this thing called metabolic health. They are not the same. Food science is what happens to food between the ground and the mouth.

Nutrition is what happens to food between the mouth and the cell. Metabolic health is what happens to food inside the cell. But all of the chronic diseases that we are suffering from, type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, cancer, dementia, fatty liver disease, polycystic ovarian disease, those eight diseases, which make up 75% of healthcare expenditures in this country today, are all inside the cell, because they are all mitochondrial dysfunction, and there is no medicine that gets to the mitochondria.

- Although you and others at Stanford, Harvard, et cetera, are starting this with metabolic psychiatry being one instance, right? - Indeed. - And UCSF as well, forgive me, I should have mentioned UCSF up front. Your home institution, wonderful institution right up the road from Stanford. So, you know, things are changing.

People are starting to think about mitochondrial health. - They are. - Okay, so you listed off the first thing. You said there are four things that stand is bare. First one was knowledge. - Knowledge. - Second, access, because if you don't have access, then how can you exercise personal responsibility?

- Access to healthier alternatives. - Exactly. - Which means cost-effective. I mean, I love berries from the farmer's market more than I love berries from the store. I love the farmer's markets generally, but it takes time, energy to go there, and the cost is actually lower at the level of what you hand the vendor, typically, but volume is tough to achieve.

- They actually have me at a quota. I'm not allowed to buy as many berries as I want because obviously there are other people who want berries. So there's that, right? People have to feed their family that, you know, and we're used to eating a lot of volume. - But you're able to at least go there.

- Sometimes, yeah. - We're talking about people who live in, quote, food deserts. We're also talking about people who live in food swamps, okay? When we're talking about food swamps, we're not talking about a plethora of healthy foods. We're talking about all the junk. That's what they, they live in the swamp of junk.

So if you live in the swamp of junk, how are you supposed to exercise personal responsibility? Number three, or affordability. So you have to be able to afford your choice, and society has to be able to afford your choice. And right now, we can't afford that choice because healthcare costs right now are at $4.1 trillion a year.

- But like so many things in behavioral economics and health, it's so hard for people to see that the immediate choice is leading to a higher cost down the road. There are just too many nodes of separation for people to realize, hey, when I'm reaching for this cereal, as opposed to making waffles for my kids from scratch, or, you know, they're thinking time efficiency, cost efficiency, volume, the kid's not throwing tantrums 'cause they're no longer getting the cereal.

And it's very difficult to see this is the reason why healthcare costs are going up. There are just too many nodes of separation. - Well, couldn't agree more. But ultimately, it's because the government separates and silos food industry profits from healthcare costs. If you actually combine those, 'cause they ultimately are the same, you would see the problem.

So globally, the food industry grosses $9 trillion a year. Healthcare costs globally cost $11 trillion a year, dietary related healthcare costs. Environmental costs cost $7 trillion a year, and productivity costs cost $1 trillion a year. So when you do the math, nine minus 11 minus seven minus one means that there is a $10 trillion a year deficit because of us cleaning up the mess that the food industry makes.

- And while numbers like that- - That's not affordable. - Right, I agree. And while numbers like that land really hard, I find that for myself and for many people, statistics like that are hard to keep in mind in a way. There's something about the human brain that hears that and goes, whoa, where like that war costs that much and this food issue costs that much.

And then we go to the store and we're hungry. And the kids are hungry. And so those nodes of separation, it's almost like a neural slash memory slash prefrontal cortex issue to me. And of course I look at everything through the lens of neurobiology. - Me too. - Not everything, but most everything.

And so how could I not, how could we not? But then the issue is, well, there's still food on the shelves. And so what do we do to bring closer together these nodes? What would the government do? So the question is, is there food on the shelves? Let me finish the fourth one and then I wanna come back to that point.

Let me just finish a concept. So affordability. And number four, externalities. Your choice can't hurt anybody else. But what if your choice does hurt somebody else? So like for tobacco, secondhand smoke. - Right. - Four, alcohol, drunk driving. - But what's the argument for teen pregnancy that someone else was gonna have to raise the kids?

- Exactly. - But what about for food? Well, how about the fact that your employer, Stanford University, has to pay $2,750 per year in obesity-related healthcare expenses that they have passed on to you even though you're not obese? That is affecting you. So that guy's obesity right there, that is affecting you.

But there, nowadays, it's especially tricky even to have the conversation. I'm willing to have it now, which is that there's this whole concept of fat-shaming, right? So if somebody's obese, whose fault is it? And if we even talk about it, are we subject to attack, legitimate attack? So calling someone obese at a clinical level, like I mean, you're an expert in endocrinology.

Don't talk about obesity. Let's talk about diabetes. - Okay, so talk about the consequence of obesity. - Yeah, let's talk about the metabolic health issue itself. The fact is that diabetes is now 11.4% of America. - What was it 20 years ago? - It was, 20 years ago, it was about 8%.

- I was wondering this earlier. 20 years ago, there was a lot more margarine in refrigerators, but people were thinner and there was less diabetes. - Everything you told us about margarine and trans fats is that it's bad, bad, bad. Now butter is back, as Time magazine and you said.

So clearly can't be the transition away from trans fats. That's increased obesity. So it's gonna be the increase in sugar and these hidden sugars in the foods. - Exactly, that's right. The key though is Pakistan and India and China, they are not fat, but they have 14% diabetes rates and they're thin and the reason is because of ultra processed food.

- Are there any countries in the world that don't allow high fructose corn syrup or at least not at the level that we do? - Oh, boat loads, okay. There are boat loads of countries that don't import high fructose corn syrup or don't make it. - So Scandinavian countries?

- Scandinavian countries, most of Europe. Other than the Asia Pacific Rim, so Japan has it. In fact, it was invented in Japan, 1966 Saga Medical School, Takasaki, et al. Korea has it, but Australia does not have it. Thailand does not have it, but they have just as much of obesity and diabetes problem as we do because they have sucrose.

Because high fructose corn syrup and sucrose are no different metabolically. So it doesn't really matter. - Is that one to one? - It's the one to one thing, exactly. - Of glucose and fructose. - So here's the question, Andrew, okay? So I wanna go back to that. You said all this food is still on the shelves.

Is it food? What is the definition of food? - Can I give the definition I think most people would give? That's not necessarily the one I would give, but something that contains caloric energy. Or like I could eat this microphone, but it's not gonna provide much useful energy. - The definition of food straight from the dictionary, and believe me, I looked it up and memorized it.

- I believe you. - Substrate that contributes to either growth or burning of an organism. - Interesting. - That is the definition of food. - So I'm pretty scientific. - 100% correct, growth or burning. So any substrate that passes your lips that contributes to either growth or burning, that's food.

Okay, let's do it. Let's do burning first. I just showed you that sugar, which is the marker of ultra-processed food, and 73% of the items in the grocery store are spiked with sugar, inhibits burning. It inhibits those three enzymes involved in mitochondrial function. Now let's do growth. My colleague, Dr.

Efrat Monsonigo-Ornan, who is the chairman of nutrition at Hebrew University Jerusalem, actually looked at this question and showed that ultra-processed food actually inhibits growth. It inhibits cortical bone growth. It inhibits trabecular bone growth. It inhibits cancellous bone growth. It inhibits linear bone growth. It hijacks growth for cancer because it inhibits mitochondria.

And so you have to then grow instead of burn. - And this was work that was done in in vivo or in vitro? - In vivo. - In vivo, so these are people that are eating high amounts of highly processed food. - Exactly. - How did you find those in the Middle East?

- They found, in Israel, they found them. So bottom line is if a substrate does not contribute to growth and does not contribute to burning, is it a food? - I see the answer is no. - Well, that's 73% of what's in the grocery store. So I would argue, you said the food's there.

No, it's not. That's not food. In fact, it's consumable poison. - So this leads to an important question of what's left. You remove all that, what's left. Just anecdotally, and what I sometimes call anecdata, you know, I've had several friends in their 40s and early 50s say they wanted to lose weight and get in shape, and the thing that's worked every single time for them to lose significant amounts of weight quickly and keep it off, and many of them were already exercising, but then also increase their exercise, was I just, since I'm not a dietician, nutritionist, or anything, I just say, eat meat, fish, eggs, vegetables, fruits, you're not gonna eat starches.

You're not gonna drink alcohol. You're not gonna drink soda. You can still have coffee, tea. You can still have artificial sweeteners. I will get to artificial sweeteners in a little bit. - We have to go there. - And the reason I say no starches, even though I personally eat rice, oatmeal, pasta, things of that sort, some in moderation, depending on what sort of exercise I'm doing and how much, is because of the fact that nowadays many of those things contain fructose, and inevitably, every one of those people is blown away by the fact that it, quote unquote, works, and assumes that it's all because of reduced calorie intake overall, and they lose like anywhere from 30 to 55 pounds and keep it off, and they're like, hey, this is great.

I can actually still eat ribeye steaks and salads, but they're not eating croutons. And so in some sense, it looks extreme. It sounds ketogenic, but it's nothing like that. You're just saying basically stay away from, you're eliminating processed foods, you're eliminating liquid calories in general, and on and on.

And so there's nothing sophisticated about it. And my question to you is how much of that weight loss effect do you think is a calories in versus calories out effect? 'Cause they're eating a lot of food, in some cases. And how much of it do you think is the elimination or near elimination of this fructose or this glucose, fructose combination?

- It's nothing to do with the calories. It has everything to do with the insulin. If you get the insulin down, you're not shunting energy to fat. You can lose weight. Your fat will give up the triglycerides stored in it as soon as your insulin goes down. Insulin is pushing on your fat cell all the time.

And as long as your insulin's up, your fat cell can't release it. The minute your insulin goes down, you can now engage in what we call lipolysis. Hormone sensitive lipase is an enzyme in the fat cell that is inhibited by insulin. As soon as the insulin's gone, hormone sensitive lipase can turn that stored triglyceride into free fatty acids and glycerol and release it and you can lose weight.

So get the insulin down and it all works. So the question is, what makes insulin go up? Well, two things, refined carbohydrate and sugar. Those are the two things that make insulin go up. In addition, branched chain amino acids make insulin go up as well. Leucine, isoleucine, valine, which is in corn-fed beef, chicken and fish, processed food.

All right, here's the deal in one concept. My colleague, Dr. Carlos Montero, who is a professor of public health at the University of São Paulo, has done the world a great service. He has developed a system for categorization of food processing. It is called the NOVA system, just means new.

But he has basically categorized every food anywhere in the world into one of four classes. Easiest way to explain this would be an example. Let's take an apple. NOVA class one would be an apple picked off a tree. NOVA class two would be apple slices. De-stemmed, de-seeded, de-skinned maybe.

NOVA class three would be apple sauce. Cooked, macerated, possibly a preservative added, maybe some extra sugar, maybe not. NOVA class four would be a McDonald's apple pie. Now, does that McDonald's apple pie look anything like that apple? No. Is there even any apple in it? Maybe a tiny bit.

Maybe not. Maybe a tiny bit. It's all flavor enhanced, et cetera. Turns out, and this is epidemiologic data, but nonetheless, prospective epidemiologic data, so it's not useless. That NOVA class four, that ultra-processed food category, which is 73% of the American grocery store, is the class that is associated with all of these chronic metabolic diseases.

NOVA class one through three, no problem. - Now, when you say associated, what percentage of one's daily total caloric intake needs to come from NOVA class four before that statement you just made is true? Because I love the recommendation you made earlier, or the, let's just say, the contour of a, you don't have to avoid dessert.

You can enjoy dessert, but don't eat dessert at other times of day. And maybe you don't eat dessert every single night. I mean, is there a rule that people have to eat dessert every single night? - So the answer is about seven to 10% would be at the upper limit.

- So you can get seven to 10% of your caloric intake, daily caloric intake, from these NOVA class four foods, and still- - And still be okay. - And still be okay. - Yeah. - So this is, I know- - But that's not what's happening. - Right, I know some very healthy physicians who I used to observe how people, A, moved, 'cause I would pay attention in our field, right?

I was like, oh, you know, people all around me at Stanford, UCSF, et cetera, were successful, or else they wouldn't be there. I was like, you know, who looks healthy? Who can make it up the stairs and doesn't have to take the elevator? How much exercise are people doing at a given age?

Are they fanatic, you know, like four in the morning runners? I'm not gonna do that consistently unless I have to. And I observed that, you know, many of the healthiest people I know, they move a lot during the day, they eat very well. Many of them skip breakfast or lunch, not always.

And then I also noticed that they would drink very little or no alcohol, but they would enjoy like a, there's one physician at UCSF in particular I'm thinking of who really enjoyed his dark chocolate Kit Kat after lunch. And he's sort of very ceremonial about the unraveling of the foil and the end of the day.

And I was like, okay, so you're talking about that small percentage of calories. If that's all you do, hey, you know, God bless you. But that's not what people are doing. That's the problem. Bottom line, that NOVA class four is where all the action is in terms of chronic metabolic disease.

So the question is, how can you avoid that? How do you know which is which? We have a solution. So my colleagues and I have developed a web-based tool that is available to the entire world right now. And you'll put it in your show notes. - Yeah, we'll put a link to this.

- Absolutely, it's called PERFECT, P-E-R-F-A-C-T. And you can find it at PERFECT.CO. And what it is, is it's a recommendation engine, not AI. We're gonna talk about AI in a minute. But it is a recommendation engine based on the science of human metabolism that categorizes foods based on not their nutrient content, but on their metabolic effect.

- Interesting. - And so there is a NOVA filter, which will filter out all the NOVA class four stuff. And it will go to your grocery store and will tell you what you can buy that will be in NOVA class one through three, which turns out to only be 20% of the grocery store.

- It means basically staying on the periphery of the grocery store, right? - Well, that's a lot of it. - In general. - In general, yes. - Yeah, the produce, the meat, the dairy, the-- - All the things you mentioned, in fact. So I'm not low carb, I'm low insulin.

And there are a lot of ways to get to low insulin. Get rid of the refined carbohydrate, get rid of the sugar, increase the fiber, get rid of the branched chain amino acids, okay, so eating fish is a good place to be. Even eating a steak is okay if it's a pasture-fed steak.

So let's talk about your steak. - Right, which is also better for the animals, right? - It is, absolutely. So you mentioned marbling before. We love our marbling, right? We can cut our US grade A steaks with a butter knife because they're so tender, right? You ever been to Argentina?

- Yeah, my father's Argentina. - Oh, right, that's right, you're Argentinian. - Yeah, they only know grass-fed steak. The idea that cows would eat anything but grass is sort of like the idea that fish would fly. - Absolutely, New Zealand, same thing, okay? The meat is gorgeous, it's homogeneous, it's pink, it's delightful.

I've been to Argentina, the meat is fantastic, but you have to use a steak knife. You can't use a butter knife. - And it takes more chewing. - And it takes more chewing because there's sinew. It's a different experience entirely. It's delicious, but it is kind of a little bit tougher.

Turns out that marbling is intramyocellular lipid. That animal has metabolic syndrome. - The American corn-fed. - The American corn-fed animal because that corn is filled with branched-chain amino acids, leucine, isoleucine, valine. Branched-chain amino acids are what's in protein powder. That's what bodybuilders put in their smoothies to build muscle.

And if you're building muscle, that's okay because 20% of the amino acids in muscle are branched-chain. So if you've got a place to put them, have at it. - Yeah, there's a need there 'cause they're breaking down muscle. - Yeah, fine. But if you're not, if you're, again, a mere mortal like me, you consume those excess branched-chain amino acids, they're gonna go to the liver, they're gonna be deamidated like we talked about earlier, and they're gonna end up as branched-chain organic acids.

They're gonna flood the mitochondria. The mitochondria are not gonna be able to deal with the volume. And so they're gonna divert the excess and turn that into fat. And so now you've got hypertriglyceridemia and chance for fatty liver disease and insulin resistance. So what kind of meat you eat has a lot to do with your metabolic health.

- What about the egg, the whole egg? Near perfect protein score in terms of its bioavailability. - Eggs are terrific. - Okay, great. - There's nothing wrong with eggs. Now, there are better eggs than others. So there are-- - Pasture. - Well, there's yellow yolk eggs and there are orange yolk eggs.

What's the difference between a yellow oak egg and an orange oak egg? - I'm guessing that something about the feed of the mother chicken. And I'm guessing it probably also has something to do with choline content? - Omega-3s. - Ah, interesting. - The orange yolk egg has a lot of omega-3s in it.

- What are other great sources of omega-3s? I know some off the top of my head, but I'd like to hear it from you. - Okay, so marine life is number one, fish. - Provided you're not bringing in heavy metals with it. - Well, yes, so that's always the argument.

The question is, is it the mercury or is it the omega-3s? Ultimately, I think it's the omega-3s that is more important but yes, I do understand the mercury issue. Ultimately, there are three omega-3s. There's ALA, alpha-linolenic acid, which you can get in vegetables. There is EPA, eicosapentaenoic acid, which you can only get in marine life.

- Fish oil, cod liver oil. - Right, and finally, DHA, docohexainoic acid, which you also get from marine life but you can get from algae. So you can get algal oil, which the vegans will use. - Do you personally take anything to increase your omega-3 intake? - Yeah, I take fish oil.

- I know that there's even prescription omega-3s. - I take fish oil. - You take a fish oil, yeah. - I only take three supplements. - Okay, I'd like to know what those are. I will say that I always, always, always say behaviors first, right, do's and don'ts. Behaviors, nutrition, then only if needed and one can afford it, then supplementation and prescription drugs.

And I'm a big consumer of supplements and always have been, frankly. So what are the three? So you take-- - Fish oil. - And do you take to get above a certain threshold of EPA? - About 1,000 milligrams. - So you say about a gram a day of EPA, okay.

- Vitamin C. - How much vitamin C do you take? - A thousand milligrams a day. - You and Linus Pauling. - Yeah, well, it's actually from my rosacea. I've got a skin issue that helps with that. - Interesting. - And finally, vitamin D. Now I will tell you, vitamin D is a complicated one.

All right, and we can talk about vitamin D and how either important or non-important it is 'cause there's a quirk to vitamin D and it's important for your audience to know about it 'cause everybody and his brothers, you know, touting vitamin D as the cure for everything. - It's sort of funny because you have your supplement, lovers, haters, and agnostics, but vitamin D somehow made it through the chute.

Like everyone's like pro vitamin D. It's really interesting. Somehow vitamin D, people are comfortable taking a vitamin D gel cap, but like other supplements where you say, oh, like maybe this might be good for, you know, like Omega-3s and fish oil, then people are a little bit like more standoffish.

It's really interesting that the kind of psychosocial stuff around this. How much vitamin D do you personally take? - I take 5,000 units a day. - Okay, so do I. - Vitamin D is complicated though. Here's the problem. If you look at the literature, vitamin D deficiency is associated with all of these chronic metabolic diseases.

However, supplementation with vitamin D has not fixed any of those. So if you're vitamin D deficient, why wouldn't supplementation fix it? Couple of reasons. One, one of the reasons for vitamin D deficiency is 'cause everyone's drinking soft drinks. That's one reason, but there's a more important reason. - Sugar and artificially sweetened soft drinks?

- Yeah. - Can deplete vitamin D, utilize it? - Well, you're not consuming dairy 'cause you're consuming soft drinks. - But I can't tolerate milk anymore. - Well, then you take vitamin D. But here's the real nugget of truth. And this is a little complicated, but the endocrinologists in the audience will get it.

Vitamin D is a pre-pro hormone. It's not active at all. Vitamin D is converted in the liver first step to a compound called 25-hydroxy vitamin D. That is a pro hormone. It also is inactive. It has no activity whatsoever. From there, 25-hydroxy vitamin D can be metabolized one of two ways.

It can either be one alpha-hydroxylated in the kidney to the active form, one alpha, one 25-dihydroxy vitamin D, which will then do all of the business of vitamin D, such as calcium absorption from the gut, suppression of the immune system at the toll-like receptor four. - That sounds like a bad thing.

- No, that's a good thing. - I know, but I had to bring that up because when you say suppression of the immune system, people go, "Oh, I'm immunosuppressed." That sounds like AIDS. - It suppresses inflammation. It's a good thing, okay, suppression of inflammation. And that's actually the point that we're getting to.

So there are a lot of good things about one 25-dihydroxy vitamin D. However, that 25-hydroxy D that came out of the liver can be metabolized a different way. It can be 24-hydroxylated in inflammatory tissue, like tuberculosis, sarcoid, gut inflammation. And so you will end up taking your 25-hydroxy D, which is a prohormone, and turning it into the inactive 24/25-dihydroxy D, which then just gets excreted out.

So in other words, you consumed all this vitamin D and it didn't go where you needed it to go. And the reason was because you're inflamed. You have to fix the inflammation before the vitamin D can be effective. And 93% of Americans are inflamed. So giving them vitamin D is not gonna do a damn thing.

- Got it, is reducing fructose intake one of the primary ways to reduce systemic inflammation? - Absolutely. - What are some others? - Reducing oxidative stress in general, so heavy metals like cadmium. Cadmium is very high in chocolate, especially South American chocolate, sorry. - No, I'm not a fan of chocolate.

I occasionally like a little dark chocolate, but so if people are going to eat chocolate, they should be careful how much chocolate they eat. - Well, especially if it's South American chocolate and processed chocolate. I mean, the really good stuff. - We're gonna be on the hit list of so many industries after this episode comes out.

- All I can tell you is I've been on the hit list for a decade and I'm still here. - You're just one big target. - Yeah, right. I gotta, it's on my back, you know, kick me. I already got that. There are, the main thing is to make that gut work right.

So fiber, short chain fatty acid production from fiber is a huge, you know, boon and benefit. - To reduce inflammation. - To reduce inflammation. - How about improving sleep? Is there any evidence that, you know, chronic slight sleep deprivation can increase inflammation? - Well, what it will do is it'll increase cortisol and chronically increased cortisol will definitely lead to increased inflammation.

You know, which is funny 'cause cortisol is usually considered the anti-inflammatory, but only acutely. Chronic cortisol elevation does the opposite. - If we can contribute to, I have this secret agenda, which is not a secret, which is that people think cortisol is bad when in fact acutely cortisol does wonderful things provided it's happening at the right time of day.

Late shifted cortisol, bad. Too much or too frequent cortisol, bad. But cortisol, you need it. It's so essential. And I think most people just hear cortisol and it's been associated with all things bad and maybe we can help shift that narrative. - Yeah, I'm very happy. I mean, as an endocrinologist, you know, this is, you know, this is my wheelhouse is where I live.

Cortisol is a good news, bad news deal like so many things. Short-term gain for long-term pain, okay? So when you are in what we call allostasis, that is perturbation of homeostasis, that is a stress, an acute stress, cortisol is one of the things that helps you manage that bodily and mental stress.

So an English test, a car accident, running away from the lion, you know, the famous, you know, pygmy running away from the lion. All of those require cortisol in order to manage and mitigate that stress. - The upcoming 2024 election. - That's chronic stress. That is not acute stress, that's the worst.

- That'll be the only mention of politics on this podcast. - And we don't have to go there. But we're all chronically stressed. And we can talk about why that is and what's going on. And I'm actually very interested in that. And a colleague of mine in Paris and I have built a computational model of the limbic system, which focuses on the stress center of the brain, the amygdala, to understand how chronic stress is different from acute stress and how that chronic stress ultimately leads to metabolic and mental health disaster.

- Very interested in learning more about that. Before we touch on that, you've worked a lot with kids. People age, as you put it, zero to 19. I don't know about the exact numbers, but when I was growing up, there were some kids in school that were overweight, but it was the occasional kid.

- Right. Now it seems, depending on where one draws the threshold for overweight, it seems that there are a lot of kids that are overweight. - How about 25% obese and 40% overweight? - Okay, so obviously a serious problem. - Serious problem. - Now and going forward. What about adults in the U.S.?

I remember seeing at a meeting a map of obesity in the U.S. and over time, and it very quickly filled in from very few people were obese to very many. Colorado was this beacon of fit people, but now it's no longer- - And that's bullshit too. - Oh, okay, cool.

- I'll tell you why. There are four things that can increase mitochondrial biogenesis. - Are you gonna tell me altitude is- - Cold, that's why Colorado is less obese. Altitude, that's why Colorado is less obese. And what were the other two? But those were the reason. It had nothing to do with being more fit.

It had to do with cold and altitude. Example, Switzerland compared to Germany, they got the same crappy food, but Switzerland has half the obesity that Germany does. Because Switzerland is higher. - Oh, I love the food. When I go to Munich, I love the schnitzels and the sauerkraut. - Yeah, it's wonderful.

They got that in Switzerland too. - Okay, so they have great food. - Switzerland is less obese. Same way Colorado is less obese. It's because of the altitude. - You mentioned cold. Many listeners of this podcast are at least interested in some also practice deliberate cold exposure, cold showers, cold plunges, mainly for the, I think the best data are the increase in catecholamines, epinephrine, norepinephrine, dopamine that are long lasting.

People feel a big state shift. They feel better. But when one looks at the effects on metabolism, they're pretty slight. - They are slight. - They're slight. However, studies like that, to me, always seem short-sighted in the sense that if there's a longer arc of effect on the mitochondria that's affecting other things in terms of how calories are processed or how calories are feeding into mitochondrial function or dysfunction, there I could see how it might shift the scale, so to speak.

I mean, cold is an amazingly powerful stimulus. And I think of light, cold, food, movement. It's kind of like the core four ways in which you can shift physiology easily. - All of these things are eminently manipulable and for almost zero dollars, okay? But you have to know what you're doing.

And right now, we've been actually kept from that knowledge. And if you're addicted, it's really hard to unaddict yourself. - So that brings us back to this thing about food industry conspiracies, government conspiracies, and the rest. Boy, this is going to be an interesting section. But what do we do?

So if you and I go up to Capitol Hill. - Which I've done. - Yeah, which you've done, and maybe I'll join you someday. And you're at UCSF, I'm down at Stanford. You're a clinician, I'm a scientist and a public health advocate, podcaster. And we explain to people, hey, listen, the food is laced with a drug, it's not even really food.

- That's right, it's not food. - It's an aggregate of food and non-food parts that make you think it's food. It's sort of like telling people, hey, your kids are, they're swimming in a swimming pool, looks like water, but it's actually part poison and it's harming them. It's giving them, if you say those kinds of things, I mean, congressmen and women are, they're like reasonably smart people, right?

I mean, aren't they gonna do something about it? - No. - So where is the conflict? Is it that the food industry has the government by the short hairs? - That's exactly right. - And they have them by the short hairs where? I mean, is it, are they lining their pockets?

I mean, where is the leverage actually exerted? - Okay, so they are lining their pockets, that's number one. That is absolutely true, and we have the data to support that. Blanche Lincoln, who was a senator from Arkansas, who was the chairman of the nutrition committee, you had to see her campaign contributions every time she was up for reelection.

- So it's all about getting reelected, or it's about them having a third home in the Hamptons? - I think it's the third home in the Hamptons more than anything. - Okay, so it's really as bad as some of the documentaries would make us believe. - Without question. Without question.

- Goodness. - And we have the data. There is an organization that I absolutely wanna call out because they are the most egregious political organization on the face of the earth. They're called the American Legislative Exchange Council, ALEC, or A-LIC, and they write bills. They are a bill mill, okay?

And they are for whoever gives them money. And who gives them money? Big pharma, big agra, big oil, and big food. - So you're including big pharma. You're a physician. You've written scripts before. You've written prescriptions for patients before. Isn't that pharma that provides the drugs that allows your patients to feel better?

- Well, the question is, do they? Do they feel better? This is a big question. You wanna go there? We can go there. - But you're writing the script. I mean, I'm not trying to challenge you, but I see. So you don't, there have to be instances where someone's thyroid deficient and you give them a drug.

- Absolutely, so if you've got a disease and a medicine will replace what's missing, sure, okay? So for deficiency diseases, which as an endocrinologist, that's what I do, absolutely. And I did that with no compunction of impropriety whatsoever. But that's not what we're talking about here. Let's talk about what we're really talking about.

Let's start with statins, statins lower LDL. Okay, do statins reduce heart disease? Yes or no? - I seem to be whiffing today on all the quizzes and it's kind of becoming fun for me at this level. I'm gonna go with no, but I will say, you know, my friend and I think his expert physician as well, you know, Peter Attia and others, you know, has talked about some of the positive attributes of statins in certain cases for certain patients.

- In certain cases, that's exactly right. And I completely agree. And by the way, Peter's a friend and, you know, someday we'll, you know, all, you know, go out drinking together. - Well, I won't drink, but how about if we share a steak? - Share a steak, absolutely. You got it.

- You guys, I don't know if he drinks a little bit. - If you're listening, okay. - He drinks a little bit. - Porterhouse on me. - Yeah, I don't do the dessert or the alcohol anymore. But I'm, and it's not so I can live to be 120. It's so I can wake up the next morning and keep up with you guys.

- It's fine, yeah, I get it. So for primary prevention, that is your LDL's high, you need a statin. That's primary prevention. You haven't declared yourself. You haven't had an event. For primary prevention, the mean increase in lifespan for being on a statin is four days. - Four days?

- Four days. - Four days. Sorry, I have to chuckle. That's a-- - And the risk for diabetes is 20% increase. - What about any improvement in quality of life? - Done. For primary prevention. Now for secondary prevention, for secondary, in other words, you've already declared yourself. You already have a problem.

For secondary prevention, that's where statins shine. So there's a value to them. I'm not arguing that. And if you have familial hypercholesterolemia, which is one in 500, okay, not only do you need a statin, but you need a low-fat diet and a priest, okay? So there is definitely a value to statins, but not for primary prevention.

But that's what every doctor's doing. Oh, your LDL, it's over 80, you need a statin. That's ridiculous. That is absolutely a joke. And the data show that. In fact, in fact, my colleague Asim Malhotra in the UK participated in an analysis where they took the entire UK population, and they took out everybody under age 65.

So you're looking at people 65 to 90. And it turned out that the LDL level correlated with longevity. The higher the LDL, the longer they lived when you took out all the people who had problems. So LDL is not really the problem. And the reason is 'cause there are two LDLs.

There's one called large buoyant. There's one called small dense. Turns out dietary fat raises your large buoyant. Your large buoyant is irrelevant. It is cardiovascularly neutral. But that's the one that statins affects. The small dense, that's the atherogenic particle. When your small dense LDL is high, that means you are not clearing triglyceride peripherally because that's what small dense show you.

That's what happens to triglyceride, they become small dense. - Can I take a guess and say that the best way to reduce small dense is to reduce insulin? - Yes, by reducing sugar. Because that triglyceride is made in the liver. It's all palmitate and that's the only fat that the liver knows how to make.

And so triglyceride is your liver output of carbohydrate. That's how you have to look at triglyceride. So triglyceride turns out to be much more important as a cardiovascular risk factor than LDL ever was. - So does big pharma and big food, do they know all of this? - Yes, I know they know 'cause they've told me so.

But they have statins to sell. - And foods in the NOVA class four. - They know this too. - So I'm an optimist or what's it gonna take to really move the needle? I mean, you described the four barriers. We're trying to add to the knowledge component now. What's it gonna take?

Going to take having a president in office or congress people in office that really understand and care about this stuff? - Yeah. - I mean, to really revamp the whole system. - So right now, the system is completely and utterly broken. Completely and utterly broken. And there's a reason why it's completely and utterly broken 'cause the food industry likes it that way.

- Well, it's profitable for them, obviously. - There are 51 different federal agencies that manage our food, 51. And none of them know what the other one's doing. And the food industry likes it that way. - So communication across these 51 organizations would help? - Well, if we had a centralized food czar or food, if we split the food off the FDA, because it's not the FDA, it's the DA, or the FDA is not the Food and Drug Administration, it's the Federal Drug Administration.

They spend a lot of time on drugs. They spend almost no time on food. - Well, let's think about where there's been success. So I can recall when people smoked on planes. I actually recall going to a gym in Europe and there was an ashtray molded into the squat rack.

- Yep. - That was telling. - Yep. - I don't see people smoking cigarettes around Stanford Hospital anymore. But I remember when they initially said that people couldn't smoke anywhere except in this one little designated area. And that's typically what you see nowadays. And my understanding of the anti-smoking campaign, at least for kids, for people 18 and younger, was that telling people it was bad for their health didn't work.

Showing them lungs that were decrepit didn't work. What worked was showing them commercials of cackling, hand writhing white guys who were talking about how much money they were making off of these naive kids who were buying cigarettes and other tobacco products. So it became the effective campaign to end smoking in young people was to hijack their inherent rebelliousness of youth.

And then they were like, "No, we're not gonna smoke. "Stick it to them." Like, you know, as my friend calls it, like the two-finger business card, like no. And so that worked. That worked. - Vaping's making a comeback. Vaping is a separate episode. We won't get into that. But because nicotine is still addictive.

But you don't see a lot of people smoking cigarettes. So it worked. Like something that you would never imagine could ever work, worked. - Well, so yes, no. I mean, that's part of it. I'm not gonna tell you that it's not. It is part of it. And we actually have an example of how that could be applied to another toxic substance, sugar.

We had Berkeley versus Big Soda. You know, that's how Berkeley ended up with its soda tax. That dates back to 2015. - The city of Berkeley. - City of Berkeley. We just celebrated the five-year anniversary of the Berkeley soda tax. And we've been able to actually look. Gestational diabetes, way down.

Obesity, down slightly. Not a lot, but a little bit. Cardiovascular disease, down. Dean Schillinger and Chris Madsen at UCSF and UC Berkeley just presented at San Francisco General just three weeks ago. - So a soda tax like the cigarette tax. - Like this-- - Just makes soda expensive. - Exactly.

- So you're telling me that a can of Coke that I buy on Shattuck Avenue in Berkeley costs more than a can of Coke that I buy on University Avenue in Palo Alto? - It does. - Huh, okay. - Buy a dime. - And that was sufficient enough to create this kind of change?

- Well, yes, it is. - 'Cause money hurts. - 'Cause money hurts, exactly. So, Andrew, there have been four, count 'em, four cultural tectonic shifts in America in the last 30 years. And they're all undeniable, here they are. Number one, bicycle helmets and seat belts. - Everybody uses those.

- Two, smoking in public places. - Nobody does that. - Three, drunk driving. - Hopefully fewer people are doing that. - Four, condoms in bathrooms. - Condoms in bathrooms? - In bathrooms, in public bathrooms. - Yeah, you see those more available. - Okay, all right. 30 years ago, if a legislator stood up in a state house and proposed legislation for any one of those four, and I don't care if it's in a state house or in Congress or in Parliament or in the Duma or anywhere else in the world, they'd have gotten laughed right out of town.

Nanny state, liberty interest, get out of my kitchen, get out of my bathroom, get out of my car. Okay, today, they're all facts of life. All right, nobody's bellyaching about any of those. The point is, we were able to solve those for public health tobaccos. How did we do it?

How did we solve those four? No one could imagine that we would ever solve smoking, right? But we did, sort of. I mean, we brought consumption down by half. Okay, that's pretty good when you think about it. For an addictive substance-- - How many fewer people are dying of lung cancer nowadays in the US?

- It's like 80% lower. - Well, there's also been improvements in treatment, but-- - Yeah, but no, it's the incidence-- - But diagnosed with the incidence. - Incidence has gone down. - Amazing. - Okay, because tobacco's gone down. So the question is, how did that happen? The answer is very, and why did it take 30 years to do it?

We taught the children, the children grew up, and they voted, and the naysayers are dead. That's how you make a cultural tectonic shift. So, we now have this real food movement. We have people who are arguing against ultra-processed food. We have kids who are demanding different in their schools.

And by the way, what is the biggest fast food franchise in the United States? - I'm gonna get this wrong, so-- - Try me again. - I don't know, I've never tried it, but I've heard of, is it Chick-fil-A? - Nope. - Is it McDonald's? I don't know. - It is this nation's public schools.

- Ah. - You can add up McDonald's, Subway, Burger King, Chick-fil-A, and Wendy's, and every other fast food franchise, Jack in the Box, every fast food franchise in the entire country, and it would only be half our nation's public schools. - Wow, so could you imagine a world where there were no class three or class four NOVA foods allowed in public schools?

- And we're doing it. So I am the chief science officer of a nonprofit, and put this in the show notes, called Eat Real, eatreal.org, and we have a new business model for public schools. So in 1971, the Department of Education issued an administrative ordinance called Resolution 242, and they did this purely on monetary reasons.

This was under Nixon, and what this Resolution 242 said was that all school cafeterias all throughout the country had to make book. They had to basically cover their costs. They couldn't be loss leaders for the school. They had to fend for themselves. Well, this sent every food service director in the country scurrying for how am I gonna do this, 'cause I got all these lunch ladies, which personnel and food preparation equipment and costs that they're mounting, how am I going to break even?

They couldn't do it. So in walks Aramark and Cisco and Guggenheim and McDonald's, and they say, "Hey, we'll do it for you. "We'll provide every kid in America "with a nutritious meal every single day." - Hot lunch. - Well, they didn't say hot. They just said lunch. Nutritious, they said nutritious, and I put that in air quotes too, 'cause it wasn't nutritious.

And here's the added benefit. You can take your food preparation facilities and your footprint in the school, and you can turn that into classrooms 'cause you're gonna need 'em. And that was the goal. Because as soon as you've moved the food preparation facilities out of the school, you are now hostage to the food industry for the rest of your life.

- And I could also see how that allows room for them to use these commoditized foods, foods that have very long shelf life. - Exactly. - Right, because you wanna make sure that if you only sold 2/3 of the lunches that were prepared that on next Tuesday after the weekend, that you could still give them food that isn't moldy.

- Exactly right. And I will tell you, so that's how it happened. And you can actually trace IQ scores and reading and math scores in this country down from 1971 to today. - When I went to school, I was allowed to get, I called it hot lunch 'cause it was usually hot.

I was allowed to get the school lunch one day a week. - One day a week. - Two days, I had to bring my lunch. That one day was pretty special, like you felt like you were getting a treat. It was usually like corn dog or a hamburger. The hamburger was pretty paltry, but the- - It's a commoditized hamburger.

- Yeah, a commoditized hamburger. You had to go looking for the patty portion and the bread was sweetened. And so it was different, but I don't remember nearly as much obesity. I went to high school in the early '90s. So you're saying that now, if I went to a high school, it would be a lot more sodas and donuts and pizza and- - Got it.

Yeah, pizza's a vegetable, didn't you know? - They claim it's a vegetable. - Congress said pizza's a vegetable. Amy Klobuchar made pizza a vegetable. - Maybe they need their eyes checked. - Because the biggest frozen pizza producer is in Minnesota. - I mean, the ketchup is a vegetable was a stretch, but at least it made sense on the Nova system of going from tomato all the way to ketchup.

- To ketchup. - Since high fructose corn syrup is the primary ingredient in ketchup. - Indeed. - So the point is that our kids are suffering under the weight, the burden of this chronic disaster of ultra processed food, which is not food. And no wonder they're all obese and sick and doing so poorly in school.

And by the way, also depressed. Ultra processed food has now been shown in three separate studies to correlate with depression in teenagers. - So what is the relationship between processed food or maybe we call it Nova system level three, four foods and depression and other psychiatric challenges? And if you could, you separate out metabolic syndrome from obesity in answering that.

Like, is there something inherently depressing about carrying excess adipose tissue, setting aside any kind of aesthetic stuff, you know, how people want to look or perceived, you know, just, is there anything bad about carrying a lot of body fat independent of the metabolic syndrome for mood and overall sense of wellbeing?

- No, I'm really glad you asked that, Andrew. And we should have actually covered this earlier. Everyone thinks fat is fat. As we've learned, fat is not fat. And a fat is not a fat, but body fat is not body fat. There are three fat depots and they are metabolically different.

The first is the, does this bathing suit make me look fat fat? By the way, never answer that question. That's called subcutaneous fat or big butt fat, if you will. So here's the question. How many pounds or kilos of subcutaneous fat do you have to gain before you become metabolically ill?

- I have no idea. - About 10 kilos, about 22 pounds. - Okay. - Why? The reason is because that subcutaneous fat drains into the systemic circulation. So you have to have a lot of cytokines coming from those subcutaneous adipocytes to raise the blood level of cytokines to the point where it starts doing damage at the level of the liver.

- So fats are releasing cytokines, which are pro-inflammatory? - Exactly. - And they're doing that at rest. Any fat cell? - Any fat cell. - Okay. - Any fat cell. But if it's going to the systemic circulation, you have a volume of distribution of six liters. So you have to lose, you have to have a lot of cytokines to get the concentration up.

- Now, just out of fairness to the fat, how many cytokines does a muscle cell release? I mean, are we unfairly picking on adipose tissue? 'Cause why would adipose tissue be pro-inflammatory? I mean, a single fat cell. I've got a fat cell sitting in my shoulder someplace, right? I mean, I'm not zero fat at my shoulder.

Why would it be pro-inflammatory? - So in fact, the fat cell itself is not. Here's what happens. The fat cell has a fat vacuole. It has a storage place for this lipid droplet. You stuff it, you stuff it, you stuff it, the fat vacuole gets bigger, bigger, bigger. The perilylipin border that encompasses that fat vacuole, that borders the space, ultimately can't get any bigger, and it starts breaking down.

When that happens, it spills the grease into the fat cell. The fat cell dies, becomes necrotic. That calls macrophages in to clean up the grease, and it's the macrophages that release the cytokines. So in fact, the fat cell is not the problem. It's the breakdown of the grease that leads to the macrophage activation.

That's the problem. But when you do it in subcutaneous fat, it's going into this six-liter tank, and so the concentration doesn't go up very much. So 10 kilos before you start seeing some effect. Fat depot number two, visceral or big belly fat. Now, how many pounds or kilos of big belly fat do you have to gain before you get metabolically ill?

- I don't know, but I'm guessing it's less than 22 pounds. - It's way less. - Oh, for once I got an answer right today. - Yeah, that's right. (laughs) About five, about five pounds. Now, the question is why? Number one, the visceral fat does not drain into the systemic circulation.

It drains into the portal vein, which goes straight to the liver. So you're getting a bigger load going straight to the liver of cytokines. - Not to the kidney. - Not to the kidneys. - The good thing about getting an answer wrong, folks, is that you never forget the correct answer.

That's what I always tell my students, right? So I'll never forget that. - Indeed. - Got it. - And the question is what made the visceral fat in the first place? Was it calories? Nope. It's cortisol. It's stress. It's the combination of the sympathetic nervous system and cortisol. And the reason we know this is because you can take patients with major depressive disorder, with endogenous depression, who are suicidal, who have to be admitted to the hospital to keep themselves from killing themselves, stick them in a scanner, and they are losing subcutaneous fat like crazy 'cause they're not eating, but they're gaining visceral fat because of the high cortisol and the stress.

- So there's something about the adrenocorticoid receptors in that area that just preferentially depot fat there when cortisol is high? - Indeed. Because that's the metabolically active fat, right? And five pounds will do it. And then finally the third fat depot, the liver. Now, how many pounds of fat can the liver store before you become metabolically ill?

- Oh, I gotta be even less because the liver's not nearly as large as the sort of abdominal region. - Half a pound, quarter of a kilo. How much does a healthy liver weigh? - Healthy liver weighs 1,500 grams, okay? So it's not very-- - I'm trying to translate quickly to pounds, so we're going metric, we're going as standard to metric.

- So 1,500 grams would be three pounds. So basically half a pound, okay? So not very much. Because that's where the action is. And so when you have fat in your liver, it causes metabolic dysfunction right away. And the question is where did that fat come from? That came from alcohol or sugar.

So alcohol and sugar, most metabolically egregious 'cause it affects the liver directly. Stress, second most because it affects the visceral fat. And subcutaneous fat, the least important in terms of metabolic derangement. So yes, it may not look good in a bathing suit, but from a metabolic standpoint, it is actually the least important.

So the question then becomes, all right, what are you trying to fix? If you're trying to fix liver fat, it's really easy. Get rid of the alcohol and the sugar, except of course they're both addictive. - Will that also liberate any fat that's already in the liver? - Absolutely, and that's one of the reasons why intermittent fasting works is because it gives your liver a chance to basically offload what it's already stored.

That's one of the things that intermittent fasting will buy you is a little less liver fat. So that's a good thing. All right, now stress on the other hand, as you know, and as we've talked about and as you know, you've had Dr. Les Appel on your podcast before, stress is tough, trying to mitigate stress, especially in today's environment, and I hope you'll invite me back some time to talk about the role of stress on the amygdala.

- Yeah, gladly. - And then finally, the subcutaneous fat. So when people go on diet sweeteners, what are they doing? Are they really reducing the fat? And the answer is no. - When are you talking about artificial sweeteners? - Diet sweeteners of any sort. You can pick your artificial sweetener.

So aspartame or sucralose, stevia, monk fruit, the new ones, you know. - Yeah, the one that people are more excited about nowadays is Allulose, it's expensive, it tends to have less of an artificial sweetener taste that people can detect. So you're saying that regardless of, oh, and we should, I'm remembering from the comment section, I do read them, artificial sweeteners and non-caloric sweeteners.

Because the moment you say artificial, people say, what about stevia, what about Allulose? So let's just say non-caloric sweeteners can wrap our arms around that entire category unless we need to distinguish among the different participants in that category. So you're saying that even though people can lower their total caloric intake, pretty effectively, I've seen the studies that show if, you know, dieters who consume water only as their main liquid versus diet sodas with aspartame typically or stevia, the diet soda drinkers actually lose more weight.

We know that, but you're saying there may be deposition of fat in the liver in those individuals, specifically because of the artificial sweetener. - Because of the insulin. Turns out there's still an insulin response. So a very famous study done in Copenhagen, 100 normal individuals, 25 in four different groups.

One group, one liter of sugared soda per day for six months. - One liter, that's a lot of sugared soda. - Yeah, one group, one liter of diet soda per day for six months. - I probably did that in graduate school. - One group, one liter of milk per day for six months.

- I probably did that when I was an infant. - And finally, one final group, one liter of water per day for six months. - I do that now. I do more than that, but yeah. - The one liter of soda per day in six months gained 10 kilos.

- The sugary soda. - The sugary soda. - 10 kilos. - 10 kilos, no surprise. The one liter of water per day lost two kilos. Also no surprise, those were the easy ones. Now let's do the ones in the middle. One liter of milk per day, no change. - Presumably that was full fat milk.

We're talking about Europe. - Full fat milk. - Yeah, they like their full fat milk. - No change, why is that? They're taking on an enormous increase in total caloric intake. - I'm guessing that there was a blunted insulin response due to the fat in the milk. - And also because lactose is not a very big driver of insulin response.

And because there's a satiety effect. - That's like food. - They eat less. - Yeah, it's like food. - Like food. And finally, the key, the kicker to the whole thing, diet soda, the one liter of diet soda. What would you predict their weight would do? - More weight loss than in the water group based on my understanding of the literature.

- They gain two kilos. - A child, because they ate more. - Well, you tell me, why did they gain two kilos if they were consuming a liter of diet soda, which are zero calories? The answer is because they still generated an insulin response. - And that insulin response generated more hunger?

- More weight and more hunger, exactly. And that's the key. So they didn't gain the 10 kilos, they gained two kilos. So it looks better compared to the sugared version, but it looks like a problem compared to the water version or even the milk version. - So unless you bootstrap calories and hold that constant, you're gonna see a weight gain due to artificial sweetener intake.

- Exactly right. And that's been shown 50 ways from Sunday at a whole bunch of different studies. So compared to sugar, yeah, it's better. But compared to water, it's way worse. And the reason is the insulin response. You put something sweet on the tongue, message goes, tongue to brain, sugar's coming, message goes, brain to pancreas through the vagus nerve, sugar's coming, release the insulin.

And so tongue doesn't know if it's sugar or not. It releases the, the pancreas releases the insulin, which drives energy into fat, whether it was from the diet sweetener or not. - I saw some really interesting data from Dana Small's group at Yale showing that when people have a diet soda with food, so this is like the Diet Coke with the sandwich or with the burger, maybe even with the pasta, the insulin response from the food and the insulin response from the diet soda are compounded, but there's a classical conditioning effect, Pavlovian effect, such that then later, if they just drink the diet soda, they get an even bigger insulin response just to the diet soda than they would have originally if they'd only had the diet soda separate from food.

So in other words, the insulin, the food-induced insulin response is conditioning a greater insulin response from the diet soda. - And we actually have another study that demonstrates the same thing out of Singapore, Tay et al in American Journal of Clinical Nutrition, 2018, I believe, that looked at a similar paradigm.

Here's what they did. They took a bunch of people and they admitted them to their clinical research center four times a week apart, and they did them in random order. And each time they started the morning, they're fasting, and they did either a sucrose tolerance test or an aspartame tolerance test or a sucralose tolerance test or a monk fruit tolerance test.

So two hours, ingesting one of the four and measuring glucose and insulin over the course of the next two hours. - Fasted. - Fasted, okay. Then it was time for lunch, and they let them have whatever lunch they want. It was a metabolic buffet. They could eat whatever they wanted off the buffet except that they were being clocked, and the same for dinner.

They were being clocked, but they could eat whatever they wanted. - In a given period of time. - In the 24 hours, or from 7 a.m. to 7 p.m. whenever they went home. Turned out the sucrose tolerance test generated an insulin response as you'd expect. The monk fruit, the sucralose, and the aspartame did not.

But then when they ate lunch, if they had had one of the three diet sweeteners in the morning, they ate more at lunch and more at dinner and generated an increased insulin response both at lunch and dinner so that the area under the curve for the whole day was exactly the same.

- So they ate significantly more. - Yeah, yeah, because they had the diet soda in the morning. - Wild, well I drink drinks that contain stevia, and I don't worry about it too much, but what you're saying is even if I bootstrap my calories, there's a possibility that the insulin response could have direct effects on the liver.

- Exactly right. - And not for the better. - And not for the better. Now, having said that, we have undertaken an interesting project, which I don't know if you know about. In 2020, during the pandemic, I was approached by a food company in the Middle East called Kuwaiti Danish Dairy Company, KDD.

It's the Nestle of the Middle East. Now they make all sorts of junk. Frozen yogurt, flavored milks, ice cream, confectionery, biscuits, tomato sauce, okay? Kuwait has an 18% diabetes rate and an 80% obesity rate. - Eight zero. - Eight zero. - Wow. - In the adults, all right? Now, the company recognized that they wanted to be a metabolically healthy company and they knew they weren't.

They contacted me and said, would you put together a scientific advisory team to advise us what we need to do to change the food in order to be a metabolically healthy company? And we wanna lead. And I said, I'd be happy to do that with one proviso. We get to publish what we did so that it can serve as a roadmap for the rest of the food industry.

And they said, fine. And so I convened a scientific advisory team with my colleague, Wolfram Alderson, who started the very first farmer's market in Los Angeles and is now actually the director of sustainability and nutrition for KDD. Tim Harlan, who is the head of culinary medicine at George Washington University.

Rachel Gao, who is a fatty acid expert who ran the omega-3 for ADD trial at the NIH. And Andreas Kornstadt, who's actually a computer scientist from Stanford. And we basically stripped down every single thing that KDD did in terms of procurement, in terms of ingredients, in terms of packaging.

We submitted every single ingredient to biochemical analysis because you couldn't trust what the vendors were basically telling KDD was in the food. We had to actually know what was in the food. And that was a half a million dollars all by itself. I mean, this was not a cheap little sojourn into the woods.

This was a big deal. We basically re-engineered their entire 180 item portfolio. And they have now turned over 10% of their products to be metabolically healthy. And the precepts that we set in this paper, which is in Frontiers in Nutrition in March of this year, 2023, three things, three principles.

If you adhere to these three principles, you can turn any food healthy, including ultra-processed food. Number one, protect the liver. Number two, feed the gut. Number three, support the brain. If you have a food that does all three of those, it is healthy. If you have a food that does none of those three, then it's poison because it's not food.

- It's not, I was gonna say, it doesn't sound like food is the right descriptor in that case. - Exactly. And if it does one or two but not all three, then it's gonna be somewhere in between. So the goal was to take all of KDD's products and move them from the lowest tier up to the highest tier by adhering to these three principles.

And we came up with some very simple things. Number one, gotta get rid of the sugar. Number two, gotta add fiber. Number three, gotta add omega-3s. Number four, gotta do something about the emulsifiers because the emulsifiers are causing the gut inflammation because after all, emulsifiers are detergents. They hold fat and water together.

They burn a hole in the mucin layer. So they're actually contributing to that gut inflammation and emulsifiers are strewn throughout ultra-processed food-dom. - We've heard about hidden sugars a lot during today's episode and elsewhere, but based on everything you told us about artificial, excuse me, low-calorie sweeteners, it makes more sense to me now why foods that are not touted as diet foods would be laced with things like sucralose because it should drive the craving for that food through increases in insulin and craving of other foods later that day and later that evening.

Is that why non-caloric sweeteners are added to all sorts of foods now that because typically one thing's non-caloric sweeteners probably only added to quote-unquote diet foods, low-calorie foods, but that's not-- - You're right, that's not the case. And they are adding diet sweeteners to foods that you didn't know had diet sweeteners in them.

That's right. There are two reasons that this happens. One is insulin because insulin blocks leptin signaling at the level of the hypothalamus and the nucleus accumbens. So if it blocks leptin, leptin is the hormone that your fat cells make that tells your brain you've had enough. So if insulin blocks leptin, it makes you hungrier and it also extinguishes, it stops the extinguishing of reward by that food so that you want more of it.

So it does both because leptin normally suppresses food intake and reduces craving. - The analogy that comes to mind is a slot machine that encourages you to feed more money and hit go to pull the lever, but that also blinds you to the outcome. So even if you win, you don't even know that you have wins.

It's also blinding you to your losses. You're effectively becoming an automaton of just eating without any kind of conscious understanding of what you're bringing in or tasting the food any longer. - Exactly. - Right, it's not this like, Anna Lemke when she came on the podcast, author of "Dopamine Nation" and obviously head of our dual diagnosis addiction clinic at Stanford, talked about these consumptive behaviors where people are scrolling social media or consuming porn or consuming drugs or alcohol in a way that like, they're not in touch with the pleasure of the substance or behavior anymore.

They become automatons. But if they don't do it, they feel lousy. So the pleasure is gone, the pain is definitely awaiting. - Tolerance and dependence, that's the definition of addiction. So dopamine is an excitatory neurotransmitter. It excites the next neuron always. There is no such thing as dopamine inhibiting a post-synaptic neuron.

Dopamine stimulates the next neuron. And it doesn't matter which dopamine receptor it is, one through five, it's always excitatory. Now, neurons like to be excited. That's why they have receptors. But neurons like to be tickled, not bludgeoned. Chronic overstimulation of any neuron, and you know this, leads to neuronal cell death.

And the reason is because the neuron needs energy. The neuron is the most energy-dependent tissue in the body. It needs those mitochondria to be pumping out ATP like crazy to engage in neurotransmission. Well, when you're firing nonstop, you risk cell death. So the excitatory neuron, the post-synaptic neuron, has a plan B.

It down-regulates the receptor. It down-regulates the dopamine receptor. So there's less chance that any stray dopamine molecule will find a receptor to bind to. And this is its plan B in order to try to mitigate the risk of dying. Well, what does that mean in human terms? It means you get a hit, you get a rush, receptors go down, next time you need a bigger hit to get the same rush, and receptors go down, and you need a bigger hit and a bigger hit and a bigger hit until finally you need a huge hit to get nothing.

That's called tolerance. And then when the neurons do start to die, that's called addiction. That's what we've got. And that's what's happened in terms of food addiction. So the question is, what's addictive? Is fat addictive? No, because if fat was addictive, then all the people on the Atkins diet or on the ketogenic diet would be gaining weight, not losing it.

- And I'd be craving rib-eyes all day. I like a rib-eye pretty often, actually. But I know, I know, people say no. But hey, look, my lipids are in line and I don't eat many starches and I certainly avoid sugar. Although now I'm thinking I might want to really reduce my low-calorie sweetener intake.

I don't see myself reducing my stevia intake to zero 'cause it's in some things I really like. - Andrew, I am not the food police, you know? - I always say that to people, I'm not a cop. But data are data and health data are interesting. - The data say that that's not helping you any.

That's what the data say. Point is that the fat's not the problem. The salt's not the problem. The caffeine's a problem. - Really? - It's a classic addictive substance at every level. - Yeah, but in terms of-- - And the sugar's a problem. - But if one can cut out caffeine by the early afternoon or even sooner in the day and it's not consumed to excess and it's in the form of coffee, yerba mate, some other form that's healthy, is it really that much of a problem?

I love coffee and yerba mate. - Me too. That's my addiction. - Like with a capital L underlined boldface highlight. - I feel your pain. And the answer is no one has shown that coffee is toxic. It is addictive, but it's not toxic. Now, if you mix the coffee with alcohol, now you got four loco, now it's toxic.

But in and of itself, caffeine is not toxic. And that's why there's a Starbucks on every street corner. - But it is highly reinforcing. I did an episode on caffeine where it covered some data that was published in the journal Science, one of the three apex journals. And if you put caffeine, unbeknownst to the consumer, into plain yogurt, people will crave plain yogurt much more.

I mean, people like the feeling of being caffeine as long as it's not creating anxiety levels of energy. - Exactly. - I'm gonna stick with caffeine. - That's fine, and so will I. - We've been talking a little bit about the hypothalamus as well as some peripheral gut-based mechanisms for hunger and satiety.

This is a great opportunity to talk about some of the GLP-1 agonists that are now widely used. So typically called ozempic, but GLP-1, glucagon-like peptide-1, originally discovered in the Gila monster, which eats very seldom. And some really smart biologist, I love biology like this, said, "How come they don't have to eat very much?" Well, their blood is loaded with GLP-1.

- Right. - And so they only have to eat one, whatever Gila monsters delight in, per year or something outrageous like that. Humans make GLP-1 as well. My understanding is that GLP-1, not that it's injected, but that one makes naturally, is acting on both the brain and the gut to increase satiety.

- So it is acting on the brain, no argument, but the primary action is on the gut. GLP-1 decreases the rate of gastric emptying. - That is its primary driver. Yes, it does affect the brain. I'm not arguing that it does, but the primary effect is to reduce the rate of gastric emptying.

So you stay fuller longer because the food doesn't move through the stomach and the intestine. - Interesting, in South America, in Uruguay and Argentina, it was long thought that yerba mate consumption, which we know very modestly increases GLP-1, and by the way, a lot of other things do too, that people were taking it after meals for its laxative effect, partially, but that's, you know, it's not pleasant for- - But that's also at the colon.

- That's at the level of the colon. - Rather than the stomach. - But it is used fairly effectively for people to space their meals without snacking. And maybe it's the GLP-1, maybe it's something else, but people are injecting themselves with GLP-1 analogs now. - And it's $1,300 a month, yeah.

- Is that what it costs? - That's what it costs right now. - And it seems to be pretty effective at inducing weight loss, although a significant amount of that weight loss seems to be from skeletal muscle tissue. - And we need to talk about that. - So what are your thoughts on ozempic as a primary, earlier you talked about primary and secondary control.

You referred to it a little bit differently in the context of statins. So a kid comes in who's obese, who's slightly overweight, and it's like, "Mm, I don't know what to do. "I'm trying to eat better exercise." Or a person comes in and says, "Hey, I've had a really hard time getting "that last 29 pounds off for so many years.

"Will you prescribe me ozempic?" - So the short answer is number one, I'm retired, so I'm not prescribed on anything. But let's go there. The data show that GLP-1 analogs like semaglutide and now terzepatide, which is Lily's version, Monjaro is the diabetes version, Zepbound is the obesity version in the same way that Ozempic is the diabetes version for Novo Nordisk and Wegovy is the obesity version.

- But they're all GLP-1 analogs. - They're all GLP-1 analogs. - They're synthesized in a lab. It looks like GLP-1, smells like GLP-1, acts like GLP-1 when injected. - Terzepatide, the Lily one, actually has a dual function. It binds to the GIP receptor, so it might have double duty.

And the data show that it's actually even slightly more effective at weight loss than the Novo Nordisk version. So we'll be seeing a shift in terms of consumer preference soon, no doubt. But here's the thing. You look at the data, one year of treatment, 16% weight loss. Now that sounds great.

And I'm not saying it's bad. It's good. - And people are not craving food all the time. Is that because people are feeling full longer? - Right. - So they're eating less. - They're eating less. - This is the calorie in, calorie out model. - They're eating less. And so they are losing weight.

I'm not arguing that. - And they might be craving alcohol less, according to some recent reports. - Yes, yeah. Well, we can go there for a minute too, in a second. Here's the problem. When you look at that 16% weight loss, as you just said, when you put people in a DEXA scanner, they have lost equal amounts of fat and muscle.

Now, is it good to lose muscle? No. It is not good. Ask any little old lady who breaks her hip if she wishes she had a little bit more muscle. - Or somebody who dieted lost a lot of muscle 'cause they weren't offsetting the weight loss with resistance training or some other form of exercise.

And the amount of food that they can eat in order to maintain that weight, to put it in scientific terms, sucks. - And we mentioned Peter Atiyah earlier. In Outlive, he's made it very clear that sarcopenia, lack of muscle mass, is one of the drivers of mortality. So losing muscle is not a good idea.

But you lose equal amounts of fat and muscle. What else causes loss of equal amounts of fat and muscle? Starvation. In fact, the reason that all these GLP-1 analogs work is because you stop eating. - Like the Gila monster. - It's starvation. Yeah, just like the Gila monster. - Although the Gila monsters look pretty chubby to me.

- Well, ask another Gila monster. - I did, but unfortunately whatever answer it provided was not interpretable. - Indeed. The point is that starvation is not so good. And if you think about why it's working, it's reducing the rate of gastric emptying, all right? Well, it turns out that that's the reason for its side effects, the reduction in gastric emptying.

That's why you get nausea. That's why you get vomiting. That's why you get pancreatitis. And most importantly now, gastroparesis. Your stomach turns to stone. And you can't move any food through your intestine at all. And worse yet, when you stop the medicine, the gastroparesis doesn't get better. This is not a good idea.

- This is like the opposite of the Yerba Monte induced effect, which has a sort of prolaxative gastric emptying, maybe GLP-1 agonism. Gosh, okay. So it's obvious why people who've struggled to lose weight like it, especially if their struggle to lose weight was, at least in their mind, the consequence of being hungry all the time and needing to eat more.

- Or was it because of the reward and their dependence? Because in fact, yes, these GLP-1 analogs reduce reward. And that's one of the reasons why they've noticed that reduction in alcohol consumption as well. And that sounds like a good thing, except there are also numerous cases now of major depressive disorder in response to these drugs.

- It's almost like naltrexone or something for the treatment of addiction, which sometimes can be useful, but attempting to remove the amplitude of that reward signal. I mean, on paper it makes sense, but it doesn't always play out. - And in practice it doesn't play out, that's right. And so I'm gonna refer you now to an old literature that was from 2006.

There was a drug that was approved in Europe called Romanabant, okay, a trade name Acomplia. And it was approved in Europe for weight loss. And it was pretty good at weight loss. It caused about 20% weight loss. It also caused severe depression and 21 suicides. - So it's no longer available.

- Because it was pulled from the European market, never approved in the United States. And the reason this happened was because this was the anti-marijuana drug. This was the anti-munchies drug. This was an endocannabinoid antagonist. Well, when you reduce reward, you also reduce your desire to live. And that's why this concern about reduction in alcohol consumption, we've already seen major depressive disorder in patients receiving Ozempic.

So are we gonna see the same thing play out as we did for Romanabant? I'm worried about it. - Or Fen-Fen. - Well, Fen-Fen didn't have-- - No, it was cardiac. - It was cardiac, right. We had cardiac problems due to the fenfluramine because of the serotonin 1B receptor agonism.

- Right, I'm just referring to the fact that these quote-unquote blockbuster drugs for obesity, they tend to follow a contour of very promising, very exciting, a lot of people losing weight suicides, or very promising, a lot of people losing weight, cardiac issues, very promising, losing weight. And now you're saying the stomach turns to stone.

It sounds so biblical. - Well, indeed. So that's the question. And then finally, we can really talk biblical. If everyone in America who qualified for Ozempic got it, that would be 2.1 trillion to the healthcare system, which is currently at 4.1 trillion. So that would be a greater than 50% increase in healthcare costs at 1,300 a month.

Conversely, if we just got sugar consumption down to USDA guidelines by basically putting some limits on how much added sugar the food industry can put into any given product, like Froot Loops, we could reduce weight by 29% and save $3.0 trillion. So we'd get better weight loss and we'd save $5.1 trillion, which makes more sense to the U.S.

government. - Well, earlier you were alluding to government, big food, big pharma relationships. I mean, there's a huge win here for whoever's manufacturing these GLP-1 analogs. - Indeed. - But the question is, who's paying the tab? - Well, we are. Now, the question is, why can't the government see that?

And the answer is because the government's on the dole too. Because the government, through tariffs on U.S.-made foods, okay, grosses $56 billion a year. So they're a player. They're not just a regulator, they're an actor. - To play devil's advocate a little bit, listen, I'm gonna be the last person to step in and try and defend government as a unified body.

I'm not qualified to do that, but you could see how if you looked at it like checkers instead of chess, you'd say, okay, here's a drug that's going to allow many millions of people to reduce their overall body weight. Overall body weight is a risk factor for a number of things.

And there will be savings on the back end as a consequence of that weight loss. I mean, so that's the checkers version. The chess version is how you're describing it. And I think that, I mean, clearly people in government are, well, most, some perhaps are smart enough to play chess, not checkers, or to at least understand it, but there's very little incentive for the chess model.

So what would quote unquote solve this problem is the same thing that happened to Fen-Fen or this romantic, which is if suddenly there's a major issue with the drug, then everyone stops taking it. And traditionally that's how it's gone. It sounds like these GLP-1 analogs are gonna make it through the chute though.

- Yeah, I mean, there is a very clear downside to these medicines. On the other hand, you know, there's an upside. And so I'm not sad that these medicines exist. I'm for them, I'm not against them. I'm for them for the right patient. And right now it's not the right patient who's getting them.

- Just like the statins. So what if somebody who's taking one of these analogs makes it a point to do resistance training? And here, you know, you mentioned bodybuilders early. I'm not suggesting they become bodybuilders, but we now know, and I think Peter or Atiya and others would agree that everybody should be doing some form of muscle loss offsetting resistance exercise.

- I agree. - At least past, you know, they're reaching their adult height or something. You know, I know there are those that say weight training doesn't blunt your height, but anyway, let's just say that from early twenties onward, doing something. - Especially if you're on these medicines in order to maintain muscle mass.

- So that's a different picture, right? People are drinking less alcohol. Again, I'm playing devil's advocate here. So if we look at these compounds, not in a vacuum, but okay, the person who's been carrying that extra 30 pounds is now only carrying a few extra pounds of adipose tissue.

They've lost a lot of muscle, but now they feel well enough to exercise. The depression part worries me, but anyway, I'm just trying to round the contour of it. - What we've seen in children, 'cause that's who I took care of, was that often they needed a jumpstart, okay?

And there were different ways to get them to jumpstart. - Stomach stapling. - Well, that's not jumpstart. That's way down the line. - But that was what a lot of people did. I have a friend, he was and sadly still is really big. And he always talked about the stomach stapling, like if I could just get 50 pounds down quickly, then I could exercise, but exercise is painful, this kind of thing.

And sadly, he's continued to maintain or creep up in a very excessive weight. - And that's the point, is that this concept of jumpstart, actually, if you're only doing it yourself, doesn't really work. And the question is, why is his weight creeping up if he's had the stomach stapling?

The answer is 'cause he's a sugar addict. - Yeah, he's definitely addicted to the super big gulp soda. - If you drink your calories, it doesn't really matter, does it? - No, and he's got such terrible psoriasis and joint pain and all this, that the prospect of exercising is like a, you might as well tell him to like flap his wings and go to Mars.

- You know, fructose is a driver of immune dysfunction. If he got off, you can tell him from me, if he got off the sugar, his psoriasis would get better, his weight would get better, his arthritis would get better, and he could have then that jumpstart. - This is a perfect example to bridge to the brain component of all this, because I've long wondered, based on what I understand about neural circuitry and neuroplasticity, I know we share in this knowledge that at some point, carrying a lot of adipose tissue means that the brain sort of represents the body differently.

I mean, we know there are these somatotopic maps of self, but that the neural machinery and the hypothalamus, sure, which is responsible for motivated states, et cetera, but also just the entire mapping of the self changes. In other words, if one is fat long enough, that it becomes increasingly hard to get to a healthy weight because of the way that the neural circuitry is impacted.

It basically remaps to maintain that fat person, not necessarily even just at the level of appetite, but just in terms of what do big animals do? I had a bulldog that weighed 90 pounds, bulldog mastiff. He was very economical with his movement, right? He was extremely powerful. - Indeed.

- He could run, at least when he was younger, but if he could be still, he was still, as opposed to certain smaller animals that are peripatetic, right? - Because he was leptin resistant. So leptin, as we talked about briefly, is the hormone that tells your brain you've had enough.

If you are leptin sensitive, you are happy to burn. If you are leptin resistant, your brain thinks you're starving, and if your brain thinks you're starving, it's going to affect your behavior in two ways. It's gonna make you wanna eat, and it's also gonna make you wanna conserve because the goal is to try to increase the leptin levels in order to overcome that resistance, which, of course, you can never do because all you're gonna do is lay down more fat and make more leptin.

- That makes so much sense because leptin comes from the adipose tissue. - Exactly. So that leptin resistance is what you have to be able to break through. You have to fix the leptin sensitivity. Well, what's the driver of the leptin resistance? Insulin. Insulin inhibits leptin signaling, and it does it at three separate places in the POMC neuron, the pro-opium melanocortin neuron in the hypothalamus.

It does it at IRS2, insulin receptor substrate two. It does it at SOX3, suppressor of cytokine signaling three, and it does it at PIP3, phosphatidylinostole triphosphate. Those three separate arms of the leptin receptor are all basically put to sleep by high insulin. Insulin blocks leptin signaling. So the higher the insulin goes, the more your brain thinks you're starving, and the more your brain thinks you're starving, the hungrier you get and the less you wanna move.

So the gluttony and sloth that we've been talking about all in our podcast is really biochemical. It is secondary to this phenomenon of insulin blocking leptin signaling. You gotta fix that first. Get the insulin down any way you can, and the best way, get rid of the refined carbohydrate and sugar.

That's where you start. - It makes so much sense. - It works too, how about that? - That's always good. - It is. - I once heard you say, I think it was in a conversation with Peter Attia on his podcast, and this really stuck in my mind, that when a person consumes glucose, that it activates a number of different brain sites.

You know, neurons loving glucose, but that when one ingests fructose, that it preferentially activates neurons in the reward pathway. At maybe seven times the magnitude or something like that. - Glucose activates the basal ganglia. This is work from Wollner House in Switzerland, and also Eric Stice at Oregon Health Sciences.

- It's for movement and planning and execution. - Exactly, okay. Fructose basically stimulates the nucleus accumbens, the reward center. It is just like heroin, just like cocaine, just like nicotine. It activates the reward center. It doesn't do anything for the basal ganglia. So it is addictive. Anything that stimulates the reward center in the extreme is addictive.

So we have chemical addictions, heroin, cocaine, nicotine, alcohol, sugar. We have behavioral addictions, shopping, gambling, internet gaming, social media, pornography. Doesn't matter. They all stimulate dopamine in the reward center, and in the extreme, they are all addictive. So the question is, if you are addicted, is that personal responsibility?

- Well, it's a very, it's a question I think about a lot, because I know a lot of people in the addiction recovery community, both from the treatment end and the addict end, and this always comes down to this question when somebody is suffering from an addiction of any kind and they're resistant to getting treatment.

If you look at them as being sick, at least in that moment, is a sick person in the best or worst or at least diminished position to guide their own treatment? So for instance, somebody with dementia, would you ask them, do you wanna go see a neurologist? You might ask them that, but are they the best person to make that decision?

- Well, this is the problem. So this is where personal responsibility falls down. So personal responsibility, as we talked about four criteria have to be met, none of them are met. That's the first issue. Second one is a little bit, shall we say cheekier. Who invented personal responsibility? Any idea?

- I'm definitely gonna get this one wrong. - Yeah, you're gonna get this one wrong. Are you ready? - Yeah, I don't know. - The tobacco industry. - The notion of personal responsibility? - They invented it. There was no personal responsibility until tobacco in 1962, 'cause they were getting killed on the science and they needed to invent another reason for you to smoke.

In fact, there's a paper that came out, Dorfman et al, that looked at the New York Times and the Washington Post and they did an entire lit search of the entire, all of the output of those two newspapers for decades to look for the term personal responsibility. And the very first time it was ever mentioned was 1962.

And it didn't pick up in speed until 1986, which was the same year as Cipollone v. Liggett at the Supreme Court, which basically said that the cigarette industry was guilty of plying people with an addictive substance. So this is very specifically industry-driven and we have the data to prove it.

- Amazing. Well, I wonder, along the lines of personal responsibility, given that many listeners to this conversation are going to be thinking about their own food intake and food choices and that of their children and other relatives, that we could play a little, not a game, but a little rapid-ish fire Q&A.

Never done this before in this podcast, but I think it's particularly appropriate for a discussion like this that weeks out into so many areas and I absolutely will invite you back and perhaps along with Alyssa Eppold to talk about some of the exciting work you guys are doing, 'cause there's so much we could cover, but people are going to wonder in a very practical sense whether or not they should or should not be consuming certain things.

And I know you're not the food police. - I'm not the food police. - And I'm not a cop and I do believe people should be in choice about these matters. But I also believe that, because you're a guest on the podcast and you're highly informed and I've done clinical work and research for so many years in this area, and you have such a clear stance on the role of big food and we really, really appreciate your honesty and directness, but now you'd be willing to provide a comment about a couple of different terms that I'll throw out.

And if you choose to say really nothing to say about that, fine, that would be a quick pass. So here we go. And we covered a little bit of this earlier, but fruit in whole form. So has fructose, but has fiber. So thumbs up, thumb sideways or thumbs down for fruit consumption.

- Fruit is fine. - Fruit juice is not. - Great, thank you. White rice versus brown rice. And among the white rice is the sticky rice and the rice is with added sugars, which you find in a lot of restaurants. - Brown rice because of the fiber. White rice, polished, you know, number one, all the vitamin B1 gone.

And of course, a much larger glucose excursion. That glycemic index thing, which of course I hate, it's glycemic load that matters. And that is a very high glycemic load. So brown rice. - So brown rice is better than white rice. - Yes. - Okay, in a meaningful way. - In a meaningful way.

- Okay. Earlier you mentioned tomato sauce. I love tomato sauce that's made from just tomatoes. Can tomato, so are most tomato sauces filled with sugar? - Perfect. Our little recommendation engine looked at this question and it turns out that only 10% of the available tomato sauces out on the market don't have added sugar.

So you have to know which ones. Well, you can look yourself or you can look up perfect and it will tell you which ones you can buy. - If people chose to consume bread, which many people do, is there a way to just across the board without just baking your own or looking at the ingredients list to make a better choice?

Is it like sourdoughs tend to have less sugar than blank? - Well, sourdough has been fermented so it will have actually consumed some of the sugar so it would be a better choice. But really the best choice is the highest fiber breads. Now, if you look at a wheat berry, it is 25% of fiber.

The husk is 25% of the weight of that wheat berry. That means that the carbohydrate to fiber ratio of a wheat berry is three to one. So a good bread should have a carbohydrate to fiber ratio of somewhere between three to one to five to one tops. Anything above that means that they've stripped the fiber away.

So that's something you could do. But the easier way is to actually look it up on perfect. - You mentioned meat and meat sourcing, egg and chicken sourcing earlier. Maybe we just revisit that. Meat, fish and eggs, thumbs up, thumb sideways, thumbs down, or it depends? - It depends.

It depends on where the meat came from. It depends on whether it was pasture raised. Depends on whether it's organic or not. If the animal was injected with antibiotics, stay away from it because those antibiotics are in the meat. They're gonna basically sterilize your gut and then the bad bacteria are gonna take over.

We haven't really talked much about the microbiome today, but that's a whole podcast all by itself. - We can touch on it a little bit more. Low sugar fermented foods, thumbs up, thumb sideways, thumbs down. - Fermented foods, short chain fatty acids, all good. - What are your favorite sources of fermented foods?

- I like kimchi. - Yeah, I like kimchi too. I like some of the live sauerkrauts. - Yeah, that's also good, but with the right accoutrement. The one thing I would be careful about is yogurt, okay? So there are yogurts with live cultures and there are a whole lot of yogurts with dead cultures.

And if it's a yogurt with dead cultures, it's kind of irrelevant and the chances are they've actually covered up the sourness with sugar. So large commercially available yogurt, be very, very careful, okay? If it's an artisan yogurt made by people you know or trust, that's a very different story, yogurts with live cultures.

- Intermittent fasting, do you practice it and what do you think about it? - I don't practice it, but I am for it, for the right patient. Turns out who's the right patient? The patient with liver fat because the reason it works is 'cause it gives the liver a chance to basically burn off the fat that it's stored.

- Zero calorie soda, got it, definitely no. And I don't even have to ask about sugary soda because that's basically just poison in a can. - Food combinations, I have a feeling I know what your answer is, but the glycemic index, which we know your feelings on now, asserts that if you combine some fat with a sugary, like eating ice cream, you have a more blunted insulin response than if you were to eat pure sugar of equivalent calories.

But what are your thoughts on food combinations as a way to blunt the insulin response? - Food combinations are great if there's some fiber associated with it. - Comes back to fiber again. - And by the way, and by the way, full disclosure, I am the chief medical officer of a fiber company.

- What is it? - It is called biolumen and it is a proprietary fiber. It is a microcellulose sponge, seven microns in diameter, so the size of a red blood cell. You swallow it, it goes to your stomach, it expands 70-fold over its original size, and so it'll give you a feeling of fullness 'cause it's taking up space in the stomach, but more importantly, when it expands, the nooks and the crannies in the sponge become available, and embedded in those nooks and crannies are a set of proprietary hydrogels, soluble fiber, which sequester glucose, fructose, sucrose, simple starches, and render them unavailable for early absorption in the duodenum, thus reducing the glucose response, reducing the insulin response, protecting the liver, and moving it through the intestine so that microbiome can chew it up for its own purposes, feeding the gut.

We can reduce glucose absorption by 36%, fructose absorption by 38%, sucrose absorption by 40%, simple starch absorption by 9%, and increase short-chain fatty acid production by 60% without an increase in gas. - When do people take this? - With meals. - Okay. - So it comes as a sachet, one teaspoon, sprinkle it on your food or take it in a drink, just mix it in and slug it down, and then eat breakfast, lunch, or dinner, and it will basically act like you ate real food.

It will turn processed food into real food in the intestine. And we have clinical trial data that demonstrates that. - Is it available as a commercial product? - It is available. It is called Munch Munch. Now, I hate that name. I didn't make it up. - Well, I'm gonna-- - The marketers did that.

- Your marketing team sucks, but the product sounds amazing. - Yes, biolumin.tech. - Great, thank you for that. Sorry, Munch Munch marketing team, but you got a Munch Munch to a new product name. But it sounds like a very interesting product, and it actually answered my next question, which was about fiber supplements.

- Fiber is good, but there are two kinds of fiber. There's soluble and there's insoluble, and they are not the same. So soluble is what goes into fiber one bars, you know, that's psyllium, inulin, pectin, like what holds jelly together. That's good. I'm not saying it's bad, but you need the insoluble fiber, the cellulose, the stringy stuff in celery, the cardboard, if you will.

Together, they form this gel that we talked about earlier. If you only consume the soluble fiber, which is what the food industry will add to food, 'cause the insoluble fiber is not miscible. If you only add the soluble fiber back, you're not getting the benefits of the entire fiber complement.

- Earlier, when talking about the Nova system and how most all of our foods are nine, let's say, I know it was seven to 10%, let's say 95%, let's say are on the side of better. 95% of our foods should come from Nova system class one or class two foods.

- Or three. - Or three, okay, staying away from those Nova class four foods. Could you give us some examples of Nova class one and class two foods, just broadly speaking? - Okay, Nova class one is any food without a label, period. If you see a label on a food, it's a warning label.

- Well, there's ground beef has a label. Okay, so that's-- - Well, does it? - So you're talking about apple. Well, when I buy it, it has a label. I'm asking this because people are gonna wonder. - Well, it doesn't have a nutrition facts label. Is there a nutrition facts label on a thing of ground beef?

- I buy that ground beef where I consume venison where if you flip it over, it says how many calories, how many protein. So there's a label, but it's just B for venison. - Okay, and that's class one. - Okay, egg? - Egg is class one. - So, and then of course, fruit, apples, orange.

Okay, so it doesn't matter if it has a name tag as long as it doesn't have an ingredients list. - Got it. - Real food does not need a label. It's only if they did something to it that it needs a label. So you have to look at every label as a warning label.

Now, the problem with the label is it only tells you what's in the food. What you really need to know is what's been done to the food because it's the ultra processed food that's the problem. They don't wanna tell you that. That's secret. Okay, secret from a proprietary standpoint, but also secret because if you knew what they did to it, you wouldn't eat it, you would never buy it.

And they don't want you to know. So they only tell you what's in the food. That's not what's important. It's what's been done to the food that's important. And that's why this NOBA class four is so important and that's why perfect is so important because it'll do the work for you.

- Great, we'll definitely provide links to all of these. So if you could pick one thing to recommend to people that want to improve their health. - Get rid of the sugar, period. - Very clear. - That's number one. Number two, go for a walk. - The exercise piece.

- Go for a walk. - And if you could recommend one thing that the general public can do to try and assist in this advocacy for not redefining, but actually clearly defining what is food and what isn't and making people aware at the level of policy and change and school lunches.

I mean, if there were one thing, what can we do? I mean, you've clearly activated my neurons surrounding like the set of problems that exist and the paths to correct them, but should we be writing to our Congress people? Should we be getting angry at hospitals because they've got all these fast food machines and that the cafeteria food is like illness promoting?

- At UCSF, we've gotten rid of all sugar beverages. We have the healthy beverage initiative. So you can-- - No Coke machines at UCSF? - No Coke machines at UCSF. - Oh, Stanford, check that out, 'cause people always send me pictures of the Coke machines in the school of medicine.

I'm like, listen, I didn't put them there, but I-- - We have to model for the public. I mean, where was the first place that smoking was banned? Hospitals, okay? Because we knew. So if you get rid of the soda, if you get rid of the sugared soda at the hospital, you're telling people something.

So yeah, I think that every hospital and really every public venue in America needs to clear out the junk. - So post photos of junk that are supposed to be in health promoting institutions, and I guess we're trying to cancel junk food. - Shame, shame. - We're trying to cancel junk food.

I'm pretty opposed to cancel culture, but here we go. We're gonna cancel. Marvelous, it's actionable, it's straightforward, it's low cost, low time investment. Zero cost, very low time investment. So thank you for that. - And look up Eat Real, because we're doing it for your kids. So you need to help support it.

Any school district in America can do it. So what do we do? We have a business model whereby the food services director either purchases or rents a dilapidated factory in the center of the district, repurposes it into a food preparation facility. They can make 27 to 30,000 meals a day, okay, with a skeleton crew, and you control what's in it.

And because you're buying in volume, it actually reduces the cost, so it's cheaper than buying it from Cisco or Aramark or Sodexo or wherever. And then you farm it out via truck or bus to all the different schools. So every kid gets a hot meal made from scratch, each day, and we can solve this problem.

- Can't help but ask this one last question. For people that want to cut out sugar, which you clearly stated is the most important thing to do for one's health, how do we know how much sugar is in something? So should people be looking at labels and just looking for how much sugar, how much carbohydrate, or could we even go so far as to say, if it says high fructose corn syrup, then it's on the no-fly list.

Don't eat it. - So the problem is that there are 262 names for sugar, and the food industry uses all of them. And the reason they use all of them is because they can include a different sugar as number five, number six, number seven, number eight, number nine on the list, and when you add it up, it becomes number one.

They hide it in plain sight, and they do it on purpose. Now, do I expect everybody to memorize all 262 names? No, of course not. Can you figure it out yourself? Well, the answer is no, unless they have the line where it says added sugars. If it says added sugars, it is either sucrose or high fructose corn syrup.

No one's adding lactose, okay? That's not-- - Or glucose. - They're not even adding glucose, because glucose isn't that sweet. Glucose is not that interesting. You don't see people going around chugging carose syrup, do you? Okay, that's glucose. Who cares? Yeah, it might be good in the molasses cookie, but that's it, all right?

So it's fructose. So you need to know what's been added. So if it says added sugars, that's a good place to start. No greater than one teaspoon per serving. No greater than four grams per serving of added sugars. Anything greater than that, leave it at the store. - And aim for those Nova type 1, type 2.

- Aim for Nova types 1, 2, and 3. And if you don't know whether it's Nova type 1, 2, or 3, you can use perfect, and if you don't look at that, then go look at the Nutrition Facts label, and anything that has more than four ingredients is Nova Class 4.

- Robert Lustig, thank you so much. You've provided such an incredible education in nutritional biochemistry, the processing of fat, protein, carbohydrate, sugar, fructose in particular, the clear detriments of consuming fructose on so many different organ systems. I love, love, love that you separated out food science, nutrition, and metabolic health.

That's a gazillion dollar delineation for people to understand and to shape their understanding of all the information that's out there and bins into these different categories. You've given us so many actionable tools, new conceptual frameworks. You've given us a real tour de force today in just oh so clear language.

So I want to thank you. I've learned a ton, and I know everyone else has as well. And if people have questions, they can of course put them in the comment section on YouTube, that's the best place. We'll provide links to all the companies and websites that you referenced and some of your other work.

And listen, I'm so grateful that you exist and that you've done the work that you've done and your passion and your advocacy for health is just oh so clear. So thank you so much. - So I want to thank you. And the reason I want to thank you is first of all, inviting me, that's nice, that's good.

But the reason is because people need to understand science. I am completely in agreement with you. The public needs to understand science. They listen to you because you number one, provide the science and number two, you don't talk down to them. You treat them as equals. And that is truly remarkable.

And so I want to thank you for your service. - Well you're most welcome. It's a labor of love and I think it was the great Max Delbrück that said when teaching assume zero knowledge and infinite intelligence. And I do believe that humans are infinitely intelligent, although sometimes as a whole we mask it.

People deserve the knowledge. So thank you so much for sharing that knowledge today and let's absolutely have you back. - My pleasure, thank you. - Thank you for joining me for today's discussion with Dr. Robert Lustig about nutrition and how sugar impacts the health of our brain and body.

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