Is fructose a driver of Alzheimer’s disease?
Dr. Richard Johnson and Dr. Rob Lustig discuss how fructose impacts the brain, gut, and immune system, and the long-term implications.
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Dr. Rick Johnson, a friend of Levels and the author of Nature Wants Us to Be Fat, is one of the world’s leading experts on fructose. He is a nephrologist at the University of Colorado. He recently sat down with a fellow Levels advisor and friend, Dr. Robert Lustig, a pediatric endocrinologist at the University of California San Francisco. The two of them discussed the cross-section of fructose, uric acid, insulin, and metabolic health.
A Tale of Two Careers: Discovering Fructose as a Key Driver of Metabolic Disease
Robert Lustig: You are a nephrologist, a kidney doctor. How did you get so far afield to study carbohydrates, and specifically sugar? What captivated you about this topic?
Richard Johnson: I tend to go far afield in my work. I basically follow my nose and follow where my research takes me. I was trying to understand the role of uric acid in hypertension. It’s known that the kidney has a really important role in hypertension and in regulating salt excretion.
I was studying uric acid, and we had this amazing surprise, because uric acid is associated with hypertension, but no one really thought it might have a causal role. But when we raised uric acid in rats, they became hypertensive. I thought, What? How can that be? We tested many more animals, and it was true. That launched me in a new direction, which was studying uric acid as a potential mediator of kidney disease and high blood pressure.
As we started studying it more, we said, “Why do so many people have a high uric acid in our population?” One of the things that can do it is sugar, and particularly the fructose component. I know you were studying this in parallel with me. We gave sugar and we also gave fructose to animals; their uric acid went up and their blood pressure went up. It seemed like sugar might be a cause of high blood pressure.
And then I thought, Wow. But the animals got fat and got metabolic syndrome. They got fatty liver and all these different things. We lowered the uric acid with a drug to see if we could affect the blood pressure, and the blood pressure came down.
But Taca, the guy working with me, comes into my office and says, “Hey, Rick, not only did we block high blood pressure, but they’re less fat. They have less fat in their liver. They have less fat in their blood. They are less insulin resistant.” We thought, Could uric acid be involved in much more than just blood pressure and kidney disease? Could it have a role in how sugar may cause metabolic syndrome?
It’s the fructose that raised the uric acid. Suddenly I was studying fructose—a kidney doctor transforms into studying metabolism. That took me into the world of endocrinology and obesity and into discovering you, Robert.
Robert Lustig: We all come at this from completely different ways. My origin story in this is totally different. I was taking care of kids with brain tumors at St. Jude Children’s Research Hospital, and I had a cadre of about 40 kids who had survived their brain tumor to become massively obese.
This form of obesity was well known in the literature, but no one knew exactly what caused it. It’s called hypothalamic obesity, and it’s due to hypothalamic damage. The hypothalamus is the hormonal regulatory center of pretty much the entire body, and also of weight.
That pesky hormone leptin had just been discovered in 1994. I moved to St. Jude in 1995 and said, “Well, let’s measure their leptin levels.” Their leptin levels were sky high because, after all, they were obese. Obviously it wasn’t because they were leptin deficient, which of course is not surprising, but they were clearly leptin resistant. The question is, why were they leptin resistant?
I was aware from my neuroendocrine training that you could lesion the ventromedial hypothalamus in a rat with an electrode and they would become massively obese. And not only that, you could block that effect by cutting the vagus nerve. The thought was that they couldn’t see their leptin because of the brain tumor. Their brain sensed starvation because they couldn’t see their leptin. They’re sending a message to the pancreas to release insulin via the vagus nerve, and that insulin is driving the weight gain. That was the first aha.
I can’t cut a vagus nerve because I’m not a surgeon, but I wondered if there was anything else I could do. We had a drug called octreotide that could suppress insulin. We gave octreotide to these kids in a pilot trial, and lo and behold, they started losing weight. But not only did they start losing weight, they started being more physically active.
This was really remarkable. This was an untoward effect that was very positive. The parents would say, “I got my kid back.” And the kids would say, “This is the first time my head hasn’t been in the clouds since the tumor.”
These were kids who sat on the couch, ate Doritos, and slept. And now all of a sudden they’re running around with basketballs and trying to swim. This was remarkable. We did a double-blind placebo-controlled trial and built a quality of life and activity questionnaire into that one. Sure enough, the same thing happened.
This taught me that the behaviors we associate with obesity, gluttony, and sloth are biochemically driven, and one of the major drivers of it is this hormone insulin. That of course has nothing to do with fructose. But what it did say to me was, “All right, these kids are very rare, but we know what’s going on with them. What’s going on with everybody else? And why does everybody else have high insulin when they don’t have a brain tumor?” That’s where fructose came in.
I was giving a talk at the National Institute of Environmental Health Sciences at their 100th anniversary. It was a two-day symposium. The first day was going to be on successes—lead poisoning and pollution and asthma. The second day was going to be on new challenges—obesity and metabolic syndrome in the morning, ADD and autism in the afternoon.
They asked me to come to this meeting at NIH and tell them what I thought was the biggest environmental factor involved in obesity and metabolic syndrome. I figured they probably thought I was going to come talk about bisphenol A or PFAS or PBDE, a flame retardant, or phthalates, plasticizers—something in the environment we could remove easily. I thought that just wasn’t it.
I said, “I’m a pediatrician. What are the two diseases children get today that they never got before?” Children are always the canaries in the coal mine for everything, including Alzheimer’s. The two diseases were Type 2 diabetes and fatty liver disease. When I started medical school, that was unheard of in children. It was even unheard of in adults unless you were an alcoholic.
I opened up my Lehninger biochemistry textbook from 1974 from college, and turned to the alcohol page. Then I turned the page and there was fructose. I started looking at the pathways and saw they were exactly the same. There was no difference. But of course that made sense because, after all, where do you get alcohol from? Fermentation of fructose. It’s called wine.
I went to this meeting at the NIH and said I thought fructose was the driver. It is the environmental obesogen—which is now a real term—driving this obesity metabolic syndrome epidemic, particularly in children.
I gave my talk, and as soon as my talk was over, it was the coffee/bathroom break, and nobody came back into the room. I had to use the bathroom. I went out to the bathroom and a bunch of toxicologists tackled me. They were screaming at me saying, “Oh, my god. He’s right. Fructose is a toxin. You have to tell the world about this.”
I’ve got to tell you, I have never been tackled by a bunch of toxicologists before.
Richard Johnson: That’s a fantastic story. When we found we could lower uric acid and prove this fructose theory, we realized we were dealing with something that was working independently of calories, because lowering uric acid isn’t part of the caloric pathway of fructose. It’s involved in this side-chain reaction of fructose metabolism.
Fructose gets metabolized like a calorie, but when the uric acid is generated from fructose, it’s generated because the ATP levels fall on the cell and the ATP turnover leads to the uric acid. Just like you were thinking it was a toxin, I thought, Oh, my gosh. This suggests fructose is causing metabolic syndrome through a pathway that does not involve calories.
> We showed that fructose actually induced the leptin resistance in the brain, but a high-fat diet alone did not. It was specific to fructose. That was a big breakthrough.
But it was true these animals were eating more. And when we measured it, we found, just like you did, that leptin levels were high, but they weren’t responding to leptin. If we injected leptin in the rats, they kept eating. Normally, if you inject leptin, animals will quit eating. We also realized most people with obesity have leptin resistance as well.
We showed that fructose actually induced the leptin resistance in the brain, but a high-fat diet alone did not. It was specific to fructose. That was a big breakthrough. We realized fructose makes animals eat more. That is one of the reasons you gain weight.
If we pair-fed them so they couldn’t eat more, they still gained a little weight because of the resting energy metabolism. They really didn’t gain much weight. but they still developed diabetes. They still developed fatty liver. They still developed visceral fat.
Fructose is working independently of calories, but also is driving calorie intake. You and I converged with the concept of the leptin resistance being involved and that insulin levels go up. That’s very interesting. We keep converging throughout.
Robert Lustig: We’re both on the same track and have benefited from each other’s work. We’ve never published together, but I think we have to fix that, Rick. I really do.
Richard Johnson: Let’s fix that. I would love to publish with you.
Fructose in the Brain May Be Behind Cognitive Decline
Robert Lustig: The thing that got Levels excited and the reason we’re talking right now is because of the paper you published with David Perlmutter and Dale Bredesen on fructose and Alzheimer’s.
This is something that has been a bee in my bonnet for years. And when I say years, I mean years. I didn’t have a weigh-in per se, but I actually have talked to several people about it, including Dale, and I’ve also talked to Stan Prusiner, the Nobel Prize winner who discovered prions.
I have my own pet theory about why this is and why sugar might be a root cause of Alzheimer’s disease. Since you are an author of the paper—in fact, first author of the paper— why don’t you give us the TL;DR version of why fructose might be a bad guy in your brain.
Richard Johnson: When most people think about Alzheimer’s disease, they think about the fact that this is a terrible, terrible disease that leads to atrophy of the brain and the building up of amyloid plaques in the brain, and also a thing called tau protein aggregation.
For the last 50 years, Alzheimer’s disease has really been thought to be due to these amyloid plaques.There’s been this huge movement to try to find out what’s causing the amyloid plaques and how we can reverse it. Pharmaceutical agencies and companies have generated all these different ways to try to block the amyloid plaques. And as you know, it’s weak. The data show maybe a little bit of improvement here and there, but it’s nothing like what we were hoping for.
Robert Lustig: I’m now really concerned because of this whole scandal Science uncovered. There’s actually been some doctoring of some photos back from the 2002 paper that originally identified amyloid as the problem. Maybe amyloid is not really the problem.
I’ve also heard amyloid might be the body’s defense against the problem as opposed to the problem itself. Just because amyloid shows up on the scene doesn’t mean it’s the cause. It might be the innocent bystander.
Richard Johnson: Right. But the movement has been that the amyloid plaques can’t be the primary cause; there must be something underneath. There’s been a lot of interest in the last 10 years on three key findings people see early in Alzheimer’s.
The first finding is that there tends to be insulin resistance in the brain. A lot of the brain doesn’t need insulin. Some areas of the brain will take up glucose, independently of insulin, but there are certain regions that are insulin dependent. You can show in animal models as well as in humans that there’s a degree of insulin resistance. There are even people giving intranasal insulin as a potential way to help treat that, with some possible benefit. But it’d be much better to know the cause of the insulin resistance in the brain than just to give insulin.
Robert Lustig: We now know there are specific trophic factors in the brain. People often think of the brain as fixed: it grows, and then those synapses are fixed, and there’s no regeneration, there’s no remodeling. It’s a static structure.
My very first project in science back in 1984 showed that estrogen, a different trophic factor, remodeled synapses in the hypothalamus. This was unheard of, and I got a lot of flack for it at the time. Now it’s common knowledge.
> The fact that you are insulin resistant in your brain is clearly not a good thing, not just from a metabolic standpoint, but from a neural architecture standpoint.
The brain is plastic. Things can change what’s going on in the brain. There are trophic factors, and the ones most relevant to this story are insulin, leptin, and brain-derived neurotrophic factor, BDNF. They are altering synaptogenesis. When they’re not working, synapses can fall out. Guess what? That’s Alzheimer’s. The fact that you are insulin resistant in your brain is clearly not a good thing, not just from a metabolic standpoint, but from a neural architecture standpoint.
Richard Johnson: Exactly. Insulin resistance is one of those factors you can see early on in Alzheimer’s, and some people call it brain diabetes.
A second finding is that the neurons seem to have some dysfunction of their mitochondria, the little energy factories that make ATP, and ATP levels fall early on. There’s this mitochondrial dysfunction and then there’s inflammation. These are the three major things—neuroinflammation, mitochondrial dysfunction, and insulin resistance.
When I was studying fructose in the animals, I was showing that they induce insulin resistance systemically, induce mitochondrial dysfunction, reduce the ATP levels, suppress the mitochondria, and cause inflammation. I thought, Wait, this is the same biosignature as what’s going on in the brain. Fructose could be doing this.
What’s very interesting is that, if you eat fructose or sugar, most of it is removed in the liver. Only a tiny amount gets to the brain. It seemed like there was some paradox, like there was some problem. Why is it that very little fructose gets to the brain if fructose is driving the disease in the brain, as I was thinking?
Then we had these discoveries that the body can make fructose and that you don’t have to necessarily eat fructose. But when you eat sugar, the body makes fructose. The body makes fructose in response to sugar, and the body makes fructose in response to high-glycemic carbs like potatoes and rice. It also makes fructose in response to salty foods, and all three pathways are due to a particular enzymatic reaction I call the polyol pathway.
Glucose can be converted to fructose. When you eat a lot of high-glycemic carbs, the glucose levels go up in the blood. That’s why CGM is so helpful. That’s why Levels is such an important group—they provide these CGMs. But when the glucose goes up in the blood, fructose starts to be produced in the brain. This has even been shown by a group at Yale in humans: If you raise blood glucose, fructose levels go up in the brain in humans after about 40 minutes. It’s very significant.
We found that high-glycemic carbs and salt trigger that reaction of glucose to fructose. There are these foods we eat which can generate fructose, and when it goes up, it goes up in the brain, as well as in other tissues.
This led me to think that perhaps what’s going on is we’re eating foods that are raising fructose levels in the brain. Then I started looking at it and realized there are all these data that show that sugar intake is a risk factor for Alzheimer’s. It’s a risk factor for cerebral atrophy. High-glycemic carbs are a risk factor. Salty foods are a risk factor. All the things that generate fructose are risk factors for Alzheimer’s and obesity and diabetes, which are signatures for fructose production or intake. Then we had this connection: the risk factors for Alzheimer’s are the same risk factors for raising fructose in the brain.
Robert Lustig: You know another way to make fructose in the brain? Be pregnant.
Richard Johnson: Yes, absolutely. And also trauma. Trauma is a risk factor for the brain. When the brain gets a concussion, there’s what we call a little bit of ischemia, and the ischemia generates fructose in the brain in response to a concussion.
How Fructose Acts on the Brain
Robert Lustig: Normally, the food industry tells you, “Fructose is fine. It gets converted to glucose in the liver.” That can be true. That’s why they put the high-fructose corn syrup in Gatorade. It was because, in fact, the fructose can become glycogen through a backdoor pathway—through fructose 1,6-bisphosphatase—and ultimately be diverted away from the mitochondria and toward glycogen. That is true if you’re glycogen depleted. Ostensibly, that’s the reason fructose is in sports drinks.
However, and this is credit to you, glucose can also be converted to fructose, and it’s through this thing called the polyol pathway. The polyol pathway is not known to everybody. It’s worth taking a moment to talk about why this happens.
By the way, the polyol pathway is the reason for cataracts, because glucose gets converted to sorbitol, which is a sugar alcohol, and that’s an osmolite, which holds on to water. That ultimately is the nidus for cataracts.This occurs in the eye, occurs in the brain, and then that sorbitol gets converted to fructose.
Why does this pathway matter? Why is it there? Why didn’t we develop a mutation to get rid of it instead of the uricase mutation you’re famous for?
Richard Johnson: That’s a great question. When we were looking at this, we said, “Why is it that fructose can do all these things?” It’s true: If you give fructose to a starving animal, the fructose will be converted to glucose because it wants immediate fuel. But if you give fructose to a fed animal, it will lower the ATP and activate this process that leads to obesity and metabolic syndrome.
It’s really interesting that animals will eat fructose to prepare for times when there’s no food around. The bear will eat fructose in the fall. It’ll eat thousands of berries. It doesn’t eat one natural fruit, it’ll eat thousands. And that will activate this switch by dropping the ATP, reducing mitochondrial production of ATP. It induces insulin resistance and all these things as a mechanism to aid survival.
> The risk factors for Alzheimer’s are the same risk factors for raising fructose in the brain.
One of the really cool things we’ve discovered, or at least have looked at carefully with others, is that fructose stimulates foraging. When fructose goes up in the brain, for example, or when you give sugar, you’ll stimulate a foraging response. That foraging response turns out to be very important in Alzheimer’s.
To forage, you have to go into an area you’ve not been. You’re looking for food. You have to be willing to go into areas where you’ve not searched for food. You have to look quickly. You can’t spend a lot of time, you can’t deliberate, you can’t have a lot of self-control. You need to just be able to plunge in and do it—get the food, get out, go into that lion’s den, et cetera.
Robert Lustig: Sounds like every convenience store I’ve ever been to.
Richard Johnson: Exactly. It turns out that to do this foraging, you have to suppress certain areas of the brain. The cortex is really involved in self-control, especially the frontal cortex. When you give fructose, you inhibit the activity of that area so that you have less self-control—sort of like alcohol, actually. Likewise, if you give fructose, you’ll inhibit the area for recent memory because you don’t want to have vivid memories of how dangerous it is, where you’re going to go.
It will also stimulate impulsivity in all these things. Fructose works on certain regions of the brain. And guess what? Those are the insulin-dependent regions of the brain. The anterior cingulate, for example, is a part of the brain that’s important for foraging, and fructose stimulates that. But it inhibits other areas.
When you look at that, you find this amazing thing. Alzheimer’s affects the areas of the brain that are inhibited by fructose. The areas that are stimulated by fructose are preserved. The occipital cortex, which allows you to see the food, is not affected very much in Alzheimer’s. The anterior cingulate, which drives the foraging, is not really affected in Alzheimer’s. But the cerebral cortex, the hippocampus, the entorhinal cortex—all these different areas that are inhibited by fructose are actually the signature of where it occurs. These are the same areas where insulin resistance occurs.
Robert Lustig: We had a hypothesis a long time ago. My colleague Dr. Alejandro Gugliucci at Touro University and I talked about why fructose does this. It’s in my book Metabolical, and it’s in your book Nature Wants Us to Be Fat.
There’s this enzyme responsible for how cells and neurons burn energy. That enzyme is called AMP kinase. AMP kinase is basically the signal to your cell that there’s not enough energy around. Why? Because the substrate that contains the energy is this molecule called ATP, adenosine triphosphate. The energy is in the phosphate bonds. When you need energy, you cleave off a phosphate, and then the electrons from that get diverted through the electron transport chain to generate true energy.
The ATP is the substrate for energy production, but when your cells run out of energy, they turn the ATP into ADP, adenosine diphosphate—two phosphates—and then finally AMP, adenosine monophosphate, which has only one phosphate. Every time a phosphate comes off, energy is released. But it also leads to energy depletion.
Like I said, AMP kinase is the fuel gauge on the cell. It is the stimulator of new mitochondria. It is the thing that tells the cell, “Hey, there’s not enough energy around here. I need to make more mitochondria in order to be able to make more energy.” It is the signal for mitochondrial biogenesis.
That AMP kinase is unique. It has three subunits: alpha, beta, gamma. In the gamma subunit is the active site for the AMP, the adenosine monophosphate, in order for it to turn that enzyme on.
There is a molecule, an intermediate metabolite of fructose, called methylglyoxal, or MGO. Lots of people have worked on this—people in England and people here at the Buck Institute for Research on Aging. That methylglyoxal has an aldehyde on it, and it fits right into that active site in that gamma subunit. When it does, that aldehyde binds to an arginine and basically kills the enzyme. It doesn’t just inhibit the enzyme, it kills it; it irreversibly inhibits it.
Basically, through this metabolite, fructose is depleting your ability to generate mitochondria. Your energy’s on its way down and your ability to create new energy is now knocked out. This notion of Alzheimer’s might be due to a depletion in neuronal energetics.
Richard Johnson: We have the same hypothesis, because when we give fructose to animals, we inhibit AMP kinase, but we do even more than that. The fructose consumes ATP acutely, but then it generates oxidative stress that suppresses the mitochondria from making ATP. The ATTP levels can’t go up because the mitochondria is not making it.
The rescue system, the AMP kinase, is inhibited as well. Fructose lowers the ATP in the cell through all these pathways—the oxidative stress, the inhibition of AMP kinase—just as you say. We actually found that uric acid inhibits AMP kinase as well. It drops the energy in the cell, and that is the signal to eat more, to forage.
Robert Lustig: By the way, one of the earliest signs of Alzheimer’s is increased food intake and obesity.
Richard Johnson: Yes. To wrap our hypothesis up: Basically, if you give sugar to animals, which has fructose in it, after about eight weeks, they have trouble walking through a maze. Normally they can get through a maze, and the more times they go through it, the faster they go. If you give them fructose, when they go through the maze, they don’t get faster. They continue to have trouble getting through the maze.
> There’s only one nutrient that lowers ATP in a cell, and that’s fructose. Fructose levels are high in patients with Alzheimer’s—five to sixfold higher than in normal age-matched controls.
Then, if you look in their brains, you find insulin resistance, mitochondrial dysfunction, a drop in BDNF (your nerve growth factor), a drop in ATP. It is exactly what we’re talking about. If you go out to 16 weeks, they start developing amyloid plaques and tau protein.
Robert Lustig: Many years ago, I talked about this to Stan Prusiner, the director of the Institute for Neurodegenerative Diseases at University of California, San Francisco. I came to him and said, “Could fructose be a driver of Alzheimer’s?” He said, “Well, maybe.” He told me why he thought that might be true. He said, “You have this thing called amyloid.”
It’s there. It’s not like you make the amyloid. It’s in a different form. It’s intracellular amyloid polypeptide, IAPP, before it becomes amyloid, which is this gunk that forms the plaque. But it’s a protein before that.
Before the IAPP becomes gunk, it’s an alpha helix, just like DNA. And when it’s an alpha helix, it’s soluble. But in order to maintain that confirmation, the alpha helical structure requires energy. That’s an energy-dependent process. It’s one of the things the energy in the neuron is used for: maintaining these proteins in their correct confirmation.
When the energy in the cell goes down because of the mitochondrial dysfunction—because of the AMP kinase and all the things we just talked about—and the levels of energy in the cell are going down, those alpha helices in the IAPP can’t stay alpha helices anymore, because that’s an energy-dependent process.
They go from an alpha helix to a beta sheet. Beta sheeting is a collapsing of those coils onto themselves. When that happens, it’s kind of like dominoes. More proteins become part of the new problematic structure, which of course is exactly what happens with prions. This is why Stan Prusiner was so excited about this. This is something that happens in neurons routinely when there’s an energy problem.
Richard Johnson: It looks like you and I are getting to the same place, but we took separate roads. We both took roads less traveled. A drop in ATP is probably the key issue driving Alzheimer’s. There’s only one nutrient that lowers ATP in a cell, and that’s fructose. Fructose levels are high in patients with Alzheimer’s—five to sixfold higher than in normal age-matched controls. Your idea about inhibition of AMPK is fantastic. I wish I’d written the paper with you, Rob. Would’ve been a stronger paper.
Robert Lustig: It’s quite alright. We can still do it.
How Fructose Affects the Gut and the Immune System
Robert Lustig: ATP is the linchpin in this story. However, there’s even more. If it was just one thing, we could get a drug to stop this from happening.
Here’s why I think it’s more than that. A paper came out recently. The first author is Ivanov, and the paper came from the ElinavLab at the Weizmann Institute of Science in Rehovot, Israel.
They said, “Everyone says a high-fat diet causes metabolic syndrome, but it also causes Alzheimer’s. It causes all the chronic metabolic diseases. But a ketogenic diet, which is the highest-fat diet, doesn’t.”
The question is, What’s going on at the level of the gut? They found that the gut has three separate barriers in it. Your gut’s a sewer. There’s a lot of you-know-what in there. Your gut’s not the cleanest place in the world. You want all that stuff to stay in your gut and not end up in your bloodstream.
There are three barriers in your intestine to keep the junk out. The first is the physical barrier, the mucin layer. The second is the biochemical barrier, the tight junctions, the proteins that bind the cells together, the most famous of which is zonulins, which is what goes wrong in celiac disease.
But there’s a third barrier, the immunologic barrier. As you know, there are more immune cells in the gut than anywhere else in the body. The reason is to keep the junk out. One of the major cell types that does this is a cell called the Th17 cell, and it makes a protein called IL-17, interleukin 17, specifically to maintain intestinal integrity.
Ivanov et al. exposed animals to a regular diet, a high-fat-with-sugar diet, and a ketogenic diet, which is a high-fat-without-sugar diet. They showed that the Th17 cells and the IL-17 in the intestine were perfectly fine with the regular diet, and with the ketogenic diet. But with the high-fat diet with a little bit of sugar—in other words, our diet, the cafeteria diet, the standard American diet, the SAD diet—the Th17 cells were completely depleted, the IL-17 was low, and the junk in the intestine made it across and into the bloodstream.
Richard Johnson: It’s the fructose that causes the leaky gut syndrome. We showed we could disrupt the tight junctions just by giving fructose to a mouse and increasing the gut leak.
I’ll tell you a cool story. I was aware sugar could cause leaky gut, and a leaky gut is really important for food allergies. Little children are getting allergies more often. They’re getting these anaphylactic reactions more often.
An immunologist, Steve Dreskin, was speaking at the university. He had created a model of anaphylactic shock to peanuts. He would give cholera toxin to animals to make the leaky gut, and then he would give peanut antigens that would trigger an anaphylactic episode. I went up to him afterward and said, “I think I can have you do this experiment without giving cholera toxin. Why don’t you just give fruit juice or fructose?”
We did some studies together, and when he gave fructose, it caused the gut leak and then the animals’ anaphylaxis. We never actually published the paper because we needed to study more animals. But basically, I think the reason food allergies have been so prominent in the last few decades is because of giving fruit juice to toddlers and stuff.
Robert Lustig: There’s actually data to support that. It may be an effect on the intestinal cell itself, or it may be an effect on the specific microorganisms in the intestine.
We know the bacteria that causes tooth decay in your mouth is strep mutans, and it loves fructose. It has very specific enzymes that make fructose a preferential substrate. It’s what burns the hole in your tooth because it can metabolize the fructose, and none of the other bacteria can.
Well, it turns out there’s a group A strep in your intestine that loves fructose just as much, and they create toxins. Strep is famous for creating toxins. After all, what is rheumatic fever? What is PANDAS, this new autoimmune neuropathic disease associated with strep. It was what Sydenham’s chorea was way back when. The point is, all of these end up having neurologic manifestations—because of what went on in the gut, because we fed the wrong bacteria the substrate they love.
Richard Johnson: It’s amazing how complicated fructose is, and how, in excess, it leads to morbidity. It’s really fun talking to you about how we can learn more and more about what fructose does and how it probably has roles in not just obesity and metabolic syndrome, but neurologic diseases and ADHD and bipolar disease and Alzheimer’s and seizures and GI illnesses and anaphylaxis. Really, it’s such a major driver.
Robert Lustig: I’ll throw another log on the fire: response to COVID.
Richard Johnson: Yeah, it’s the inflammatory response. One of my friends did some studies on COVID and found that the hallmark for long COVID syndrome is mitochondrial suppression, low ATP, and this biosignature of increased glycolysis. Decreased mitochondrial oxidative phosphorylation is what you see with cancers. But it’s also what you see with fructose and long-term COVID. It’s a very interesting observation.
Robert Lustig: You can get COVID, but that doesn’t mean you’re going to die of it. Who dies of it? The three demographic groups: the BIPOC community, people with obesity, and people with preexisting conditions. What do those three demographic groups share? Processed food: high-sugar processed food.
We now know—we’ve known this actually since 2020—that it’s not the virus that kills you; it’s the immune response to the virus that kills you, the out-of-control immunologic response. The chain reaction gets out of control. There are brakes on the immune response. The immune response is one of the few things in the body that has a positive feedback cycle. Normally, everything in the body is in homeostasis. With a negative feedback cycle, you get a stimulus, and then that actually ratchets down our response to it.
> Basically, fructose is an immune activator. Fructose releases the brake.
But the immune response is one of the places where there’s a positive feedback cycle, where a little makes a lot. The reason, of course, is to get rid of the infection. But ultimately, there has to be something to reign it in, otherwise it’s an atomic bomb that blows up and you’re dead. That’s basically what the COVID immune response is: the lack of brakes on the immune response.
It turns out that if you glucose to immune cells, they do what immune cells do, which is not much. If you give immune cells like macrophages fructose, which inhibits an enzyme in the immune cell called glutamine synthase, this apparently is one of the things that generates that immune response. The TNF alpha levels go sky-high. The interleukin 6 levels go sky-high. Basically, fructose is an immune activator. Fructose releases the brake.
Richard Johnson: And the high uric acid also contributes, and may be involved in that process. When I was working on the wards, and the COVID patients came in, the young people who died tended to have metabolic syndrome and obesity. We found a relationship of serum uric acid with morbidity and poor outcomes. Uric acid is a reflection of the processed foods and the fructose and the metabolic syndrome. I agree with you.
Fructose is a big animal that does a lot of things to a lot of systems. I know you have this interest in fructose in cancer and in alcoholism. We’ve also linked fructose to driving the Warburg effect, for example—fructose is the perfect fuel for cancer cells. Fructose is involved in alcoholism, too.
When I started seeing how fructose could be involved in so many processes, I looked in the mirror and said, “Am I tricking myself?” There seemed to be too many diseases in which fructose was important. But then you do the studies and it seems like we’ve discovered a really important pathway.
Fructose is the only nutrient that lowers the energy in a cell. Most foods, when you eat them, increase ATP, and the excess can go into fat. In fructose, you drop the ATP, so the energy that comes in to maintain energy balance goes directly into the fat. You maintain a low ATP but high fat program. That’s what people with metabolic syndrome have. That’s what people with diabetes have. That’s what people with Alzheimer’s have. We’re looking at a signature, and fructose is the artist that signs the letter.
Robert Lustig: I couldn’t agree more.
Sugar, Addiction, and Its Potential Downstream Effects
Robert Lustig: All of these diseases that are now prevalent in our world—Type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, cancer, dementia, fatty liver disease, polycystic ovarian disease—are the components of metabolic syndrome. All of them don’t have a drug treatment. All of them are going up in our society, and really any society that has adopted the Western diet. All of them are due to mitochondrial dysfunction. The problem is there’s no drug that gets to the mitochondria.
Richard Johnson: But there is a dietary approach we can recommend. It’s not to never eat sugar, it’s just that we have to reduce it dramatically. It’s going to be impossible for a lot of people, because it’s in so many foods. Casey Means has talked about ways you can block the glycemic response. There are a lot of things we can do to make our diets healthier, and to make healthier choices.
Robert Lustig: I agree with that in principle, but the problem is the practice. There’s education and there’s implementation. The problem that dissociates those two is another phenomenon, which we did not get to, but maybe we should: It’s called addiction.
Richard Johnson: I totally understand addiction. That is the great spoiler, isn’t it?
Robert Lustig: It is. It’s the thing that makes this so problematic. I liken it to alcohol because fructose and alcohol have such similar signatures in the body, and also in the brain. About 36% of Americans are teetotalers. They don’t touch the stuff. About 40% are social drinkers. They can pick up a beer, put it down—I’m in there. One in six American adults are binge drinkers, and about 10% are chronic alcoholics.
What makes somebody a social drinker and somebody else a binge drinker or a chronic alcoholic, we still don’t know. We still don’t know what distinguishes those phenomena. But what we do know is that you can consume a little alcohol and it’d be okay. But if you consume a lot of alcohol, it’s not. And if you are addicted, you can’t consume a little.
Richard Johnson: Exactly. It will trigger you to eat. It’s not enough. You’re right. That’s a great analogy.
Robert Lustig: This is what I see with sugar. We absolutely need to eat less of it. I totally agree. I dedicated my retirement to trying to fix that. But addiction is the obstacle. I’ll be honest, it’s not just the obstacle for the individual or for the metabolic-syndrome patient; it’s an obstacle for the politicians to be able to help us with this, in the same way it took so long to fix tobacco.
Richard Johnson: I agree with you on that. If you’re a sugarholic, and many of us are, you eat that one ice cream cone, and that alcohol drink suddenly triggers a binge. It is something we have to work on.
When we give alcohol to animals, the alcohol actually triggers the polyol pathway and generates fructose. Other groups, too, have shown that alcohol can stimulate fructose production. We’re making inhibitors for fructose. We’re still a long ways away, but when we give these inhibitors, it reduces the craving for sugar. Interestingly, it also reduces the craving for alcohol. The craving for alcohol is linked with the fructose. We’re beginning to think that craving is due to ATP depletion in the brain, in the nucleus accumbens.
Robert Lustig: It actually may be ATP depletion in the tongue. You might look at the work of Dr. Monica Dus, who’s a neuroscientist at U of Michigan. This is her bailiwick, and she actually redid her lab to study this sugar phenomenon, because of my work, your work, et cetera.
Richard Johnson: That’s interesting. If you block the taste, animals still get addicted to sugar. We did that. We completely knocked out taste in the tongue. And animals will still be addicted to fructose. They won’t be addicted to artificial sugars, but they will be to fructose. They may still be getting ATP depletion in the tongue. That’s a really interesting question.
Robert Lustig: Well, unfortunately, from a public health standpoint, we have a long way to go. But the good news is we have the science. Now, turning the science into policy is the alchemy of public health. But we have the science, and 20 years ago we didn’t have anything. We had calories and saturated fat. Today we have a very different paradigm
Richard Johnson: Your book really lays out a lot of that science. My book also kind of details these fructose-based pathways based on the science, from our group and others as well.
Robert Lustig: We should mention the name of your book, Nature Wants Us to Be Fat. Now, I’ve got to tell you, I don’t know why anybody would want to read that one.
Richard Johnson: I admit the title may make you think, I don’t really want to read that because I don’t want to know more about that. But the book tries to teach you which foods are good, which foods are bad, which foods drive this switch, which foods counter this switch.
One of the great powers of the book is the evidence that hydration is a very powerful tool for blocking fructose effects. Who would ever think that? It turns out that water intake can be very beneficial, and that it suppresses some of the mechanisms by which fructose causes obesity.
We also identified vasopressin, the hormone from the brain activated by fructose. When you block the vasopressin from the specific receptor called the V1b, you can block the effects of metabolic syndrome and so forth from fructose. Vasopressin, which is suppressed by water, has a role in metabolic syndrome. That’s why people who are obese tend to have high vasopressin levels.
Robert Lustig: Let me throw a different line of thinking at you: Oxytocin is the safety neurotransmitter.
Richard Johnson: Right.
Robert Lustig: Vasopressin is the threat neurotransmitter. If we are turning the vasopressin in our brain on by consuming sugar, then we think we’re constantly under threat, which of course is what we see in society today. It has many ramifications in terms of both behavior and continued consumption, because one of the ways to assuage that threat is more consumption. This is sort of pie-in-the-sky, but do you think that if we could get the sugar in our diet down, we could solve some of the violence we’re seeing in our society?
Richard Johnson: I do think it has a role. I always worry about blaming food. There’s the murders in San Francisco 20 years ago that were linked with Twinkies—the Twinkie defense. I don’t want to completely blame sugar for the mass shootings and so forth, but there is no doubt that fructose decreases self-control. It increases impulsivity.
If you happen to be a person who’s quite impulsive to begin with and you’re eating a lot of sugar, it may make you more impulsive. It may make you have a little bit less self-control, kind of like a drink, and then you do things you may not normally do.
> We’re looking at a signature, and fructose is the artist that signs the letter.
My belief is violence would decrease if we could reduce sugar intake. In my book, I talk about it a lot. I quote lots of papers that link sugar intake and high fructose corn syrup and fructose intake with violent acts. I don’t want to go there, but I do think it’s a contributor.
Robert Lustig: Maybe we can convict the food companies instead. After all, if you can convict a bartender for letting somebody out after too many drinks, maybe we could convict a soda company for supplying the substrate in the first place.
Richard Johnson: I’m all for it if the argument can be made strong. It’s something I hadn’t thought of, but I do think it could be a contributor. I’m going to not try to make a committed response to you on that one. But it’s very good thinking.
Richard Johnson: It’s just a delight talking to you. I have to tell you.
Robert Lustig: It is so my pleasure. We go way back now, and we’ve been riding this train in different cars, but going in the same place. It’s truly been a pleasure.
