Fructose Metabolism in Obesity, Dementia, Evolution | Richard Johnson | Episode 295

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I just want to talk a little bit about glucose versus fructose metabolism, especially in the liver, and give people a basic sense for how these things are uh used by the body, broken down and so forth. So can you give us in pretty basic terms in plain language the major differences between glucose and fructose metabolism in the liver? How are our bodies actually utilizing these two simple sugars differently? Yeah.

almost one one hundredth the concentration of glucose. So it's it's circulating at a very low concentration. Uh but it turns out to have an extremely important role in human metabolism as well. Uh fructose, the main dietary sources are honey and fruit, the main natural. And we normally many people think of fruit and honey as a very healthy types of food. But fructose is also in table sugar. And it turns out that table sugar is a dimer of glucose and fructose. They're bound together.

And high fructose corn syrup is a mixture of fructose and glucose uh free sugars, kind of mixed together. Now the reason we like sugar So much and people have a sweet taste for sugar, and our we have a taste bud that just for sweet things, and it gives us a pleasure response when we eat this. And uh it's it actually is for both glucose and fructose. Both of them activate that sweet sweet receptor.

But uh fructose is viewed as a sweeter sugar and it turns out that that extra sweetness is what makes sucrose or table sugar So delicious. And high fructose corn syrup was built on that when they made this. They they combined free glucose and fructose and they found that people actually prefer a little more fructose than glucose in taste testing.

gets into the liver. And in the liver an again, there's a very what we call a first pass effect where a lot of the fructose is metabolized in the liver before It ever sees the circulation. So in only about ten percent of the fructose we ingest will typically get past the intestinal and and liver uh metabolism. So the liver preferentially loves fruit And when the fryptose escapes the liver

Uh some of it can go will be uh passed into the urine where it will be taken up in in the kidney, uh in the tubules because they have that transporter. Some is taken up in fat cells. Some is taken up in the brain. Uh and then other places like the islets of the Pancan.

Now when its fructose is metabolized in the liver. It is metabolized preferentially by a different enzyme than the one that metabolizes glucose. And so there's a whole different enzymatic pathway. That enzyme's called fructokinase, and it's a enzyme that I have heavily studied for Okay. And that enzyme loves to metabolize fructose pretty much in an uh unregulated way. In other words, it will metabolize it as rapidly as it can with no feedback.

Now that allows when when fructose and glucose get metabolized. The m early sites, early beginning of metabolism involves a phosphorylation of fructose or a phosphorylation of glucose. So glucose gets phosphoryl pro phosphorylate at the sixth position and then gets broken down. Eventually to generate like pyruvate, uh, which uh and and lactate in the glycolytic path. But also then it can feed into the Krebs cycle and and the electron transport chain to generate a lot of energy.

Fructose theoretically can do the same. But uh what happens is when fructose gets metabolized. That initial phosphorylation by ATP is so rapid that ATP levels fall. There's no feedback system to re to to stop. And when the ATP levels fall. intracellular phosphate also falls. Mm-hmm. That activates a whole different type of enzyme reaction. that lead to different consequences.

But let me just kind of like compress and repeat some of what you said for people. And let's start in the tongue and work our way down. If let's just pretend we just eat a a a tablespoon of sucrose. So you've got glucose and fructose in there. They're both sugars. They're both sweet. We like both of them. We have a pleasure response to both of them. Fructose is actually a little bit sweeter. And the reason that something like high fructose corn syrup is 55.

fructose 45 glucose is actually because food companies did experiments, they did trial and error, and they basically locked in on that as the ratio that people sort of like the best. It's the most pleasurable sweetness ratio. And so right on the tongue, there's a little bit of a difference between fructose and glucose. We swallow it. And then once we get into the gut, there's some big differences. Fructose isn't going to make it into circulation, as you said, as much as glucose is.

It's going to get metabolized by some cells in the small intestine. It's then going to basically go to the liver and mostly get metabolized there. It's not going to go into general circulation nearly as much as glucose.

At a very high level, in very basic terms for people. Normally we think of the liver as like a detox organ and we think of the kidney as a filtration system. Why would it be that fructose is going to be mostly handled by the liver and not sent to all the other cells like glucose is? What does that start to tell us?

if you knock out fructose metabolism in the liver. So it turns out that the liver actually has a very central role

in controlling metabolic features. Now interestingly it does it through a communication with the brain. So there's a very strong liver-brain connection. that is involved in this, as well as the liver fat connection. And one could argue that the brain is also has the ma a major role, but b but when you knock out the liver you affect the brain the brain signaling. And so it actually blocks some of the changes that occur in the brain. So the liver is really central. Now what's really interesting.

Is that if you knock out that I'm just gonna tell you this because it's really interesting. If you give a sweet food, even like uh artificial sugar, like Splenda, sucrose. It will also activate the sweet receptors in the in the tongue. But if you knock out the sweet receptors, so if you there's no sweet receptors. Mice still like fructose.

If you knock out fructose metabolism in the liver They love sugar and But they won't get fat. And they won't drop metabolic syndrome.

The bad things that happen downstream of fructose ingestion at high levels. Let's start to talk a little bit about what's actually going on in the liver. In response to fructose ingestion. There's a number of things I want to talk about here. And so I'll lay those out and you can kind of take us through the sequence you think is the best to help people understand. But some of the things that happen are.

fat synthesis in the liver called the novolipogenesis, oxidative stress, um, reactive oxygen species related biology, and then ATP depletion and uric acid. So between those things and anything else you might want to touch on in the liver. What uh what's happening when we eat fructose inside the liver and and why is this stuff so consequential for health?

uh and then uh a period of time when the ATP levels are low. The ATP levels when they drop Initially it's from consumption, but when the phosphate falls, it activates an enzyme. called AMP deamanase, which sucks off when ATP is consumed it generates AMP. And normally AMP is recovered back to ATP. But this enzyme sweeps the AMP away to make uric acid. So ATP levels can't recover very quickly because the substrate to make ATP is AMP.

And that is removed by the activation of this enzyme that's specific to fructose. And that enzyme generates uric acid. Now uric acid is a breakdown product of ATP. But it's also a breakdown product of RNA and DNA, and we all have uric acid in our blood and it varies quite a bit in people. But when you eat fructose there's a rapid con generation of uric acid and it will increase inside the cell in the liver.

But it will also spill out into the blood. And so the uric acid levels go up in our blood about fifteen minutes after we eat a high Sugary food.

translocate or move into the mitochondria. Our mitochondria are major energy producing cells or organisms. And when NADPH oxidase enters the mitochondria. The oxidative stress knocks out or reduces the activity of various enzymes in both the grounds. the uh crab cycle as well as in the electron um beta fatty acid oxidation.

It also physically goes into the mitochondria. And that's sort of a double whammy, right? Because you've got more ROS production. And then inside the mitochondria, these are organelles that are particularly sensitive to that oxidative stress.

stunning the mitochondria and affecting recovery mechanisms. And so the ATP levels, when they fall acutely, they'll stay low for maybe 45 minutes or an hour before our body recovers. And that period of time is associated with oxidative stress of the mitochondria. And what some of our colleagues have shown is that repeated oxidative stress of the mitochondria. Damages the mitochondria over time, causes mitochondrial fission and other things, and then you start losing mitochondria.

And now you're you're you're really affecting your the way your body energy balance because the body needs those mitochondria. For energy production.

um provides additional fuel. But what's really interesting is that um Which we talked about, as well as uh lactate buildup. turns out to inhibit the classic glycolytic pathway of glucose. And so there's this there's a massive shuttling of the glucose that comes in dramatically into other pathways. And some of those include the pentose phosphate pathway and other pathways, but part of it is driving down

uh w an equivalent glycolytic pathway as normal glycolysis but without any negative feedback. So when When you eat glucose, as soon as you start producing ATP, you stop making you stop that process. The whole purpose of glucose is to

There seems to be an absence a lot of a lot of checks and balances you might expect when fructose is going through here that might be more present on the glucose side. And so we'll get, I think, later into the conversation of why. Why is the biology set up this way where maybe some of the checks and balances you might want to be there are not actually there and what that means?

But, you know, again, we talk about ATP depletion, uric acid formation, and also oxidative stress. You mentioned that this can induce de novo lipogenesis in the fat uh fat synthesis by the liver. What?

to generate energy, which is ATP. And then the idea, classic idea, is that when the ATP fills up to a certain level in the cell, the there's a signal to have the excess energy stored.

Likewise if you fast animals And you make them really skinny. I guess not giving them any food and then you stop the fast, they will go back to their weight. And what's more, they'll go back to the weight they're supposed to be for that time in their life.

So but the energy balance theory says that, oh, the food tastes so good, it's uh that that's what's driving weight gain, but then why can't we lose weight so easily? Well it turns out that the fructo story provided the insight for why this theory isn't quite right.

But one group gets uh you know a a sugar based diet and the other one doesn't. And when we did that, we actually did the experiment with equal calories, but we even did it under caloric restriction. So we put all the animals on a diet. So they're eating ninety percent of what they normally eat.

So even though they're they're eating the exact same number of calories, right, there was there was another effect going on that was independent of calories. The weight gain is really driven by calories, but All the metabolic effects like insulin resistance and so forth are not

Yeah. So but now let's get back to the the kind of the key explanation for your viewers. So it turns out that the way w you induce weight gain is to drop the ATP levels in the cell. When you drop the ATP levels, and you don't want to drop it to a crisis level. So if you drop it to like 30% of normal, the animal goes into a starvation mode and tries to break down everything it can to make energy to survive.

But what happens is fructose blocks both. It blocks the breaking down of glycogen and the breaking down of fat. And so By doing so I This uh makes you stay hungry and so you have to suddenly you'll eat more than you need. You're actually tricking yourself because your body your total body energy is high. Your body energy is stored energy plus

uh active energy. Mm-hmm. And by dropping the active energy the sensors in the body are saying we're low. Normally you would break down the fat, but if you block that Basically, it tells you you need to start storing fat.

And danoa lipogenesis is coming in and so there's this big push to make glycogen and fat, especially fat. And it's a brilliant system.

the brain will suddenly become resistant to leptin. And leptin is the main satiety hormone. So when we make, when we eat, Leptin levels go up in the blood and they activate an area in the hypothalamus that controls food intake. And what happens is when you give fructose to an animal, after about two months They become leptin resistant. And then they not only are they eating because the ATP levels are low, but once they're leptin resistant, They will just try to eat as mu you know, a lot of food

Yeah. So I want to think a little bit more about why the system is set up this way. And and we've already started to talk about it. So from an evolutionary standpoint, Um, you know, you've you've mentioned that th this is actually a great system if you're an animal that lives in a seasonal environment and there's times of food scarcity where you need to put on a lot of weight quickly to prepare for that upcoming scarcity.

Can you say a little bit more about what what you've called, I think, the uh fructose survival hypothesis and and why this whole system is set up this way in animals?

They get fat, they eat more, they get fatter, but they're also getting fatty liver, they're getting insulin resistant, and they're getting all the features of metabolic syndrome. And we were taught, I at least I was taught. That metabolic syndrome was A disease is kind of like a condition be that leads to high blood pressure and diabetes, and it does. And so it's sort of considered pathophysiologic, you know, i if you have metabolic syndrome

Um you're at high risk for developing obesity and it's not not a healthy thing to have metabolic syndrome. But these animals are purposely developing metabolic syndrome. So the question is, what was why is it w what is what is about it that could be good? And it turns out That when you are when there's no food around, like what happens during hibernation, is the animals won't have access to food or water uh for months. They won't eat, they won't drink.

Uh and and they will not and they will just hibernate. They go into torpor and they live off their fat. And it turns out that when you burn fat You not only produce calories, but you produce water. And when you burn fat you make a thing called metabolic water. There's no water in fat, but when you burn fat you produce water. And I've done a lot of work in this area, and it turns out that Animals that are hibernating use the fat to to provide them the water they need, as well as the calories.

So when you're storing fat, you're you're actually storing water in a sort of sense. Uh there's not actually water there, but it's there to protect you, just like the camel that has the hump of fat that it can use as a water source. Or uh a lot of desert animals have fat on their tail to have to provide calories and water when they need it.

whales have lots of fat. They don't drink water, so they use uh they get most of their water from their food or from the fat they burn. About a third of the water they get is from the fat they burn. So fat is a source of Energy and water. And so if you're gonna be in a period of time where there's no food around, you want to accumulate fat. Because it's gonna provide those two key things. But what about insulin resistance?

And and so you can get hypoglycemic and if you're trying to survive as a starving animal, you don't want to be hypoglycemic because you need your brain to function. adequately as long as possible. In fact, the brain is more important than the muscles. Because uh without a brain you're gonna you're gonna die with the first predator.

So what insulin resistance does is Is it reduces glucose uptake in the muscle? significantly. So that's the muscles become resistant to insulin. And when that happens, the muscles don't get as much fuel. You actually decrease your your your energy expenditure because the the insulin resistance is reducing the amount of glucose that it's using.

benefit with that insulin resistance. Now it turns out that the part of the brain that likes glucose and is not insulin resistance is a part of the brain that's involved in foraging. seeing food. So for example like the ocular cortex Um, you know, you you want to be able to find food uh when when you're trying to when you're starving or when you're preparing for hibernation. So it turns out that fructose is a specifically activates foraging pathways.

And uh and that's the insulin independent pathways in the brain. In s when you induce insulin resistance, the areas of the brain that require insulin turn out to be those involved with recent memory and the cortex where where it's like being able to think things through things. And so what happens is um when you eat fructose you actually uh stimulate foraging So you can find food. But you you you're reducing the energy to the cortex for thinking through

Is it dangerous or not? Your your recent memory is impaired because you they don't want you to remember that they're predators there. You've got to be bold and impulsive. You've got to be able to look in all around and make quick decisions. And that's what fructose does. So if you get fructose, you know, cortical blood flow drops. You get glucose, cortical blood flow goes up.

If you give uh glucose and you inject it into the brain, ATP levels go up and the mouse and the mouse quits eating because its its satiety signals activated. You inject fructose in the brain, ATP levels fall, and the animal starts looking for food.

So if you're an animal and you wanna store fat, what do you wanna do? You wanna be increase you gotta be hungry. You've got to be foraging and looking for food. You've got to be able to Abs you know, ingest as much food as possible, like leptin resistance. My friend Marcus Goncalvi shows that fructose actually increases the vilus the villi area in the intestine so you absorb more food for the same amount of ingestance.

I mean it's just goes on and on. The list goes on and on. And fructose is the fuel that does that. Fructose is the one that stimulates denophyl lipogenesis. It's the one that blocks fatty acid oxidation. It does all those things. Now, glucose can do that. But much less. Much less. Yeah. And when it doesn't. It's likely because the glucose is being converted to fruit.

These are actually features. They can be, you know, these are these are adaptations that animals in the wild have to prepare them for the conditions they have to survive through, such as a long winter where food and water are very scarce. And so the modern environment for humans, it it's almost like we're in this kind of perpetual winter, as I think some people have called it, where we're seeing all these signals of abundance, including fructose, and our body's doing

you know what what the bear's body's doing in some sense. It's it's packing on um uh all of this extra fat because it's getting signals that signal future scarcity, of course, that never come.

And you're inducing mitochondrial oxidative stress because fructose is being metabolized in the brain. So you get mitochondrial, you get o oxidated stress, you get inflammation. And guess what? You give chronic glucose fructose to an animal? They develop Alzheimer's. They get amyloid plaques, tau protein aggregates, memory problems, all the things that you see with Alzheimer's. Yeah. And so uh it turns out that the part of the brain that's insulin dependent.

Which is where the insulin resistance is induced by fructose and where the ATP levels fall first, those are the first sites where Alzheimer's benefit. And laundering response in Alzheimer's is probably a foraging. Yeah. And so you can suddenly the foraging response becomes behavioral disorders. ADHD, bipolar disease, all these things can be seen as overactivation of this pathway. Yeah. And dementia is the uh ultimate bad outcome.

Two, the fructose is only available in a physical fibrous food matrix, which is going to limit its absorption and metabolism in ways that a lot of the foods we're exposed to don't. Can you say a little bit more about the importance of how the natural environment limits fructose both like seasonally and uh you know packages it up in physical food matrices that have fiber in them and how the modern foods that we consume that don't have those things are um tripping us up in certain ways.

Like vitamin C actually blocks some of the effects of fructose and Flavanols and epicatechin and all these things that are in fruit. But they tend to go down as the fruit ripens. So the the plant doesn't want the animals to eat their fruit until the fruit's matured and the seeds are good because then when the animal eats it, the seeds end up in the poop and help the tree. So there it kind of times the fruit to ripen as w as fall progresses, which is exactly what the animals want.

And they won't eat small amounts of fruit like we do. They'll eat as much as they can so that they get that fructose load. And they'll wait till the fruit's really ripe. So what happens is Uh nature has this taint. There's uh you know, f hummingbirds have these long bills, so they can actually pull out nectar, which is basically sugar.

And they can get fat in a day. They just from they eat up mainly sugar and they get the fattest liver of all birds and they get insulin res they become diabetic during the day. But during the night when they when they don't go out for They they can't I g I don't know, but they do they they don't eat at night. Yeah then they burn off all the fat because they have such high metabolism and in the morning they can go again and their their blood sugars will drop. And if they drops too much

They'll go into torpor. They go into kind of a sort of hibernation for three or four hours. They'll just sit on a branch. Wow. So the nature has got it all worked out. But we we learned how to make Refined sugar and high fructose choring cells.

And because we have a taste for it, we have a craving for it. we mix it into all these foods and we mix it into processed foods and we we coat it on sugar sugary

And uh and and so the animals uh started starving and he actually confirmed that there was starvation going on in our ancestors and certain regions of the world where our ancestors were actu they actually went extinct. But um a mutation occurred around that time then uh allowed us to process fructose more effectively. And we showed that we resurrected the extinct gene and we did a lot of studies to prove this. But yeah.

We talked about the ATP depletion, the uric acid formation, the unique sort of um sensitivity we have and other apes have on that side due to our evolutionary history and the oxidative stress burden that fructose metabolism can place on our mitochondria, which can break them over time if we're eating a lot of fructose all the time.

One thing that's interesting to me here about all of this fructose stuff is it kind of lines up in an unfortunate way with something I know about one of the other big ingredients in the modern food environment, which is the omega-6 polyunsaturated fat. Those fats can be obesogenic and promote fatty liver. They can promote food intake via endogenous cannabinoid signaling. And they can render mitochondria more sensitive to oxidative stress.

which, as we discussed, can go up in response to fructose intake. And it seems to be uh, you know, probably not a coincidence that two of the major features of the modern industrial food environment are high omega-6 content and high fructose content. Do you think that the combination of high omega-6s and fructose is particularly problematic?

Leptin resistance is associated with increased craving for fats, especially polyunsaturated fats like omega-c. And so there is this kind of Uh stimulation. fat intake that goes along. Now the reason that has a survival benefit is you know you're trying to put on fat.

If you're on a keto diet and you're eating a high fat diet, you don't gain weight because you're controlling your appetite. But if you have your appetite affected by fructose so that you're hungry, then when you're exposed to a high-fat diet, you will eat more fat and you'll get more calories because you're not regulating your weight. So in other words, if you take animals and you make them give them fructose and make them leptin resistant,

And then you give them fat, they get really, really fat very quickly. You can even stop the fructose and they'll get fat because the leptin resistance carries over for a few weeks. But if they are not left in resistance and you give them uh lard or something like that, they don't gain weight. So it turns out that Um, you know, a big part of gaining weight with fat is to have lectin resistance present from fructose.

Now, when you give fructose to animals or or if you particularly when we did these studies were mainly with raising uric acid. It turns out that you s you start activating enzymes and in the prostaglandin pathways that are associated with inflammation.

But the modern food environment is characterized by high omega six and high fructose content. Are you back, Rick?

And so there's this literature where people are saying, Oh, you know, Omega Six aren't bad But if you put give omega-6 in the setting where fructose and uric acid are you know are involved, um there's it's gonna the omega-6 are precursors for the prostaglandin. And the enzymes there are good prostaglynins and bad prostaglynins, but fructose and uric acid activate the bad enzymes. So when you take omega-6,

With fructoseneuric acid, it's gonna be pro-inflammatory. But if you gave omega-6 to people who have are very healthy you may not be able to see that because the omega six is just the precursor.

And then the question is how but how does that interplay with in an evolutionary basis and how does it interplay with what we've discovered? Um and and it's fantastic how they all kind of fit into pieces. I wrote a paper just this last year or maybe two years ago, where I took all the main obesity hypotheses and I put how they work on one piece of paper, uh one figure, and showed how they all interact.

Uh and that how the fryptoseurvival pathway actually can explain the protein sparing and the Energy balance and the carb insulin models and it it I think everyone is everyone is partly right, and probably I'm only partly right too.

And interestingly, uh here's a fantastic thing. If you raise blood glucose, like in a diabet a person with diabetes. Or if you give a high glycemic meal, like um if I eat pancakes and I I have a glucose monitor so I can actually Look at my own glucose. And see it go up. I don't like it going up because when it gets over about 140, I know much of it's being converted to fruit. including in the brain, because the high blood glucose is certain remember it circulates everywhere.

Is fructose doesn't quite get there, but high glucose does. And so it turns out that oh these rise in blood glucose is the best way to increase fructose levels in the brain. that the brain does not do well with high glucose. And uh there's a guy at Yale who showed the inhumans that if you clamp blood glucose levels to elevated levels, the brain starts making a ton of fruit.

And and fructose levels are are high in the brains of people with dementia and f high in the brains of people with bipolar disease and so forth. So I think Yeah, I think that this is another but a again it's a survival mechanism. If you if you become insulin resistant, not only are you Is that a survival mechanism? But the high glucose allows for more fructose production, so it's an amplifier.

Part of what that does is limit the absorption rate, but also part of what it tended ha actually happened to do was stimulate the microbiome in a way that, long story short, It actually stimulated the glutathione pathway in the body to help buffer the body against the oxidative stress induced by fructose and prevent lipid peroxidation in the liver. So it was another example to me of how some of these things tie together fructose biology, lipid biology, and fiber.

And these fructans are mainly levens, so they're not inulum, they're a different type. But if you feed those fructans to animals, to horses, they will develop uh metabolic syndrome and laminitis. And uh it turns out that mammals can't break down fructans, but some enzymes in microbes can. And uh it's been discovered that there's a strap species. in horses that breaks down the fruit dance to fructose.

And um can induce likely has a role in inducing metabolic syndrome and that's the And um I've written a little bit about this but So the trouble is is uh Inulin is a fruit dan too, but it's not the one that's in those rich grasses, the blue g the blue grass of the Kentucky, you know. Um, and so not all fruit bands are good. So anulin may be good, but we also don't know if maybe at high doses. So the horse will eat huge doses.

I want to spend the rest of the time we have talking about brain stuff because I think this is important and I know that you've got a lot to contribute here. Say a little bit about endogenous fructose to get us to the brain. Remind people, where does this endogenous fructose come from in our bodies?

So diabetics who have high glucose in their blood. They have high levels of this enzyme, so they're making a lot of fruit. Likewise, salt salty foods will activate the sense. Alcohol activates this enzyme. We recently showed that the fatty liver from alcohol is actually from fruit. The alcohol doesn't make fructose, the alcohol activates the enzyme that converts glucose to fructose. So when you're drinking

It's those pretzels that you're eating with the alcohol that are being converted directly into fructose because it's salty g glucose. Salt and glucose. and alcohol. So it turns out that you can activate this pathway even with stress. Um it can be activated with trauma, with ischemia, or like a heart attack will induce this pathway in the heart.

intake is strongly linked with obesity. And ultra-processed foods mix salt and sugar together. French rice mix salt and carbs together. So you've got the salt and the oil, the fat and the carbs. The glucose and the carbs gets converted to fructose. It's like the perfect food. 'Cause it's convert you know, y raises the glucose rapidly, converts to fructose.

Makes you, you know, like the fat all the more. The salt stimulates. So that's why there's a big difference between salt salted potatoes and non-salted potato.

It's like amazing. Uh I looked at umami and I looked at foods associated with, you know, that raise uric acid and they're they're they're the same. It's the same group. So I think that the um and it turns out that when you raise uric acid you activate

this uh this uh fructose pathway, the Ldose the the polyol pathway. So unfortunately When I started reading this, I go, oh my God, and putting it together and doing studies, we kind of realize that this survival pathway is a very central pathway for that animals have have evolved from So to find foods that can help you store fat is something that animals like. And then because we have taste buds for those. we end up not unwittingly uh eating foods that can activate the

And the big the big activator for sure is sugar. High flutose carried sugar that's by far the biggest.

Absolutely true. High fructose corn syrup is worse. We d we actually did a s another study where we did this and we where we gave high fructose corn syrup what fifty-fifty glucose fructose. versus sucrose and we parafed animals and we got worse fatty liver with the high fructose corn syrup.

with with just increasing the salt, but it takes like three times the time. Instead of two months, it takes like five months. And uh Umami is actually quite potent. But we don't eat enough umami. So if you on a gram per gram basis, umami is probably worse than sugar, but we eat one tenth, one fifteenth of umami compared to sugar. So uh Umami is not a big player l unless you like uh in certain regions of the world, like uh China maybe where Umami is probably

and now it's like a w a major cause of death and it's probably one of the worst diseases to have, not only because you of what happens to you for those who love you, uh,'cause there's nothing like seeing you lose your cognitive

And I think at one point there were twenty-six or more uh compounds being tested and the vast majority failed to show a benefit. Some of them show very mild benefits, but nothing to write home about. And so the realization was that the amyloid Deposition is probably a late manifestation of dementia, and we should look at earlier stages. to see if what what it what actually is going on before the amyloid plaques becomes so uh prevalent. And three major uh findings were made. One was that the

brain becomes insulin resistant. And as mentioned, the certain areas of the brain are sensitive to insulin, some of the areas are not, but the areas that are normally sensitive to insulin become resistant to insulin. The second issue was that uh there were mitochondrial uh uh dysfunction and mitochondrial oxidative stress that was seen, and the third was that there was the discovery of inflammation in the brain. What we call neuroinformation.

an activation of the macrophagia of the brain, which is called the microglia. So these three uh became the focus of the next range of attacks and people are looking at giving drugs to block inflammation or to improve mitochondrial function. Or to try to find ways to improve the insulin resistance and even things like intranasal insulin was being given in in Seattle, where you are. And uh and so there are all these kinds of uh approaches. But um I I was studying fructum.

And I found that, you know, systemically, the key feature of fructose is insulin resistance. That is what drives insulin resistance systemically. That is the main nutrient. And we show that in so many different ways. And it causes mitochondrial oxidative stress. In fact, that's key to how it works. And it causes inflammation. So I realized that there was a parallel. So when we started looking at

People with Alzheimer's and other groups did most of this epidemiologic work. It was not surprising to see that the foods that are associated with fructose, like sugar, high fructose corn syrup, Sweets, carb, high carb diets. were also linked with an increased risk for And not only that, but uh even things like h high salty foods were linked and all these kind of things that we were identifying, alcohol.

And um and so the next step was to see what happens with animals when they're fed fructose. And if you give fructose or sugar to an animal, they have trouble getting through a meat. Or if they're um diabetic, for example, their glucose levels are high, which we know can generate fructose.

that you can show cognitive dysfunction. They they can't learn. Normally a mouse, if you put it in a maze, the first time it can't find its way very well, but they learn each time how to get there a little bit quick. But not if you feed them high sugar. And not not only that, but um my friend Gomez Pinilla uh did some studies where he showed that if you give sugar to animals, that they develop mitochondrial dysfunction, insulin resistance, and neuroinflammation.

And then a group in Egypt showed that if you give the fructose for eighteen months, they actually get neurofibrillary tangles and tau protein aggregates and amyloid in their brain in addition to cognitive. So pretty strong evidence. And and then a group recently showed that if you had a diabetic animal with cognitive dysfunction, if you just injected an inhibitor of fructose metabolism into the brain, you can improve the cognitive disorder.

And so that all that was pretty strong evidence that this pathway is involved. So what about humans? So in humans it turns out that you can find high fructose levels in people with Alzheimer's is like sixfold higher than than the age matched controls, along with elevations in sorbitol, which is another metabolite. As well as activation of AMPD aminase, which is the key enzyme.

And uric acid is found to be uh linked with Alzheimer's by Mendelian genetic studies, and was found to be the only key metabolite that really predicted Alzheimer's in two studies.

And so I think that there we've got a pretty strong case that this is it. And then there's that evolutionary thing, which was really cool. So with David Perlmonter Neil Predison and others, um, we started thinking about this and realized that the areas of the brain that are affected by fructose are also the areas of the brain that um are the first to go with Alzheimer's and also are the areas of the brain where inhibiting blood flow and causing insulin resistance stimulates foraging.

That is a hypothesis that is. So for those of you who are listening, uh know that it's it's uh but it's just it's based upon this data.

Would you how what would you say around added sugars versus whole foods versus timing and seasonality and things like that? So

Cut out liquid sugar, reduce your alcohol intake, because that can be converted to fructose. Um and you know, try to cut back on sugar and high fructose corn syrup. Number one. Number two. All fructose comes from carbs, including endogenous fructose, or fructose you make is coming from glucose. And the main way that happens is by eating high glycemic carbs. So things like pancakes, rice, potatoes, bread, especially if they're salty, salted pretzels, you know, cut those way back.

And in fact, if you are on a keto diet, you are you are lucky because that will block The the a keto diet will block glucose and fructose pathways. So you basically block the survival You blocked that pathway by just going on a keto. But can you maintain a keto diet? Many people can't. Can I? I cannot. Yeah.

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