TRANSCRIPT[00:00:00] Welcome to better brain fitness hosted by doctors, Josh Turknett and Tommy Wood. In this podcast, we will explore the frontiers of how to keep our brain fit and healthy so that we can perform at our best and do the things we love for as long as possible. Let’s go.
All right. Welcome to another episode of the better brain fitness podcast. Once again, I am joined today by my always curious cohost, Dr. Tommy Wood. How’s it going, Tommy?
Yeah. Pretty sweet. Feeling sweet today?
Feeling sweet today. Alright, no, no artificial sweeteners for you.
nO. Only the real stuff.
Okay. So we are making subtle allusions to today’s topic. In a couple of prior episodes, we have talked about interesting papers that have come out and we’ve [00:01:00] decided we’ll start kind of doing this sort of thing regularly in addition to our other Q& A format. episodes. So talking about either some new research papers or classic ones that we think are noteworthy and relevant to the topic of this podcast.
And today Tommy is going to break down a recently published paper with an intriguing hypothesis regarding the role of fructose in the development of Alzheimer’s. I think it’s safe to say that both of us consider what we refer to as environmental mismatch. To play a central role in the development of Alzheimer’s and by mismatch, we mean a mismatch between our modern environment or habitat and the habitat that we evolved in for almost all of human history.
And our biology is still finely tuned and adapted for this world that we no longer live in. [00:02:00] And mismatches between today’s world and that of our ancestors drive the development of most of the chronic diseases we see today, including Alzheimer’s. And one of those areas of mismatch is our consumption of sugar.
So the average person, especially in the West these days, consumes sugar many orders of magnitude greater than what we would have in our ancestral environment. Mainly in the form of added sugars. So this is one of the most significant areas of dietary mismatch. And there are definitely strong links between excessive sugar consumption and chronic disease including Alzheimer’s.
And that begs the question as to what What might the mechanisms be? How do those particular mismatches, in this case, the consumption of excess sugar, impact us physiologically in ways that leads to the diseases that they contribute to? And so recently, earlier this year, a paper paper was published outlining a hypothetical mechanism for how [00:03:00] fructose which is half of table sugar and the sugar found in fruits, how fructose contributes to the development.
And I will let Tommy now take it away to cover what the, what the paper said, what the hypothesis was.
Sure. So this paper is called Could Alzheimer’s Disease be a Maladaptation to an Evolutionary Survival Pathway Mediated by Intracerebral Fructose and Uric Acid Metabolism? It was published in the American Journal of Clinical Nutrition, which is a very well respected…
a nutrition journal. The first author is Richard or Rick Johnson, who if anybody has ever listened to a podcast that talks about fructose, he was probably the guy talking about it or, and or fructose and uric acid in particular, because this is really his area of expertise. Other notable co authors include Dale Bredesen.
of the the Bredesen program and, you know, many papers and studies related to the conventional reversal of[00:04:00] age related dementia and the neurologist, David Palmer, who people may have heard of, who also recently wrote a book called Drop Acid, that I have not read, but it’s about uric acid rather than other acid and obviously focuses heavily on fructose, apparently.
The idea here is that, particularly in the great apes who lost the function of an enzyme called uricase, which breaks down uric acid, there is this evolutionary adaptation to fructose intake that drives a specific metabolic phenotype that is protective in times of You know, in the winter, say in times of low energy availability, but then could be detrimental in the in the setting of chronic high level exposure.
The paper is biochemically quite dense, [00:05:00] I won’t go through all of it but essentially there’s this stress response to fructose ingestion or other types of stressors like low oxygen or hypoxia that drives some of this pathway probably the most obvious example that people should kind of understand what they’re hypothesizing is in bears before they hibernate, they eat a whole bunch of fruit.
That fruit comes, and honey, comes with fructose. What happens when the fructose is metabolized is it partly some of it gets converted into uric acid that drives this pathway which decreases metabolism. We know that you need to decrease your metabolism if you want to hibernate and it also drives the accumulation of fat.
So the production of new fatty acids and storing of those fatty acids. So we know bears get fat and they decrease their metabolism so they can hibernate. And before they do that, they have a continuous period of foraging. So they’re just like, they’re single mindedly eating [00:06:00] in order to accumulate fat so they can then hibernate.
And the hypothesis is that, you know, The high ingestion of fructose is kind of driving this because when you when you metabolize fructose, uric acid, you decrease ATP levels. So energy levels in the cell, you decrease mitochondrial energy production capacity. So you’re decreasing metabolic rate. And then within the brain, what they’ve seen.
Both in terms of some, some animal studies and then also in humans when they give you a large bowl of sufructose. What happens is the patterns of activity change in the brain. So it looks, so your brain is activated in areas that are activated during foraging. So say the occipital or visual cortex.
But then you decrease activation in other areas like the hippocampus which is associated with things like memory, with the idea being that you will be singularly focused on finding food and less worried [00:07:00] about other things that are happening around you. So it’s kind of driving this, this foraging behavior, as well as driving hunger.
There are some studies again in humans suggesting that if you give somebody a certain amount of glucose or a certain amount of fructose, you know, it’s the same amount of sugar, the same number of calories, the fructose will give you less of a glucose spike, a less of an insulin spike, but will drive more relative hunger.
You’ll be, you’ll be less satiated with the amount of fructose given relative to glucose. So all of these things saying that if you eat a lot of fructose, it can change activity patterns in the brain. It can create this sort of drive to eat more, as well as changing metabolism such that you accumulate fat and you develop insulin resistance, which is this kind of what we would need if we were going to hibernate long term and would also be protective.
So if in the summer this was happening to humans, we were accumulating body fat maybe decreasing metabolism a little bit that will allow us to survive the winter better because during that period of time, you know, at least evolutionarily, we would have had [00:08:00] less access to food. However, this no longer happens in a cyclical manner, which would probably be, you know, reasonably healthy because you would accumulate fat and then you would lose it during the winter when you have less access to calories.
Now we have access to calories continuously, and lots of them come in, in terms of refined fructose or sucrose, which is half fructose. So this idea is that not only Due to this particular metabolic effect of fructose, we’re driving things like insulin resistance and fat gain, we’re also making people hungrier and it’s changing activity patterns in the brain, and those activity patterns in those activity patterns in the brain um, look similar to activity patterns in Alzheimer’s disease, as in you’re losing activity in some of the areas that typically we see less activity in Alzheimer’s disease, like the hippocampus and some of the medial temporal lobe.
So their hypothesis is that high ingestion of fructose and the way we respond to it chronically is, is affecting. insulin sensitivity and glucose uptake into the brain, which is something else we see and then activity in the brain as well as driving sort of systemic insulin resistance, which we know is a contributor to Alzheimer’s disease.
So that’s essentially the summary of what they said. And I think it’s, I think it’s very interesting. It’s certainly likely that some of this is [00:10:00] contributing to Alzheimer’s disease and age related dementias. The ex whether it’s all happening via this pathway, it’s going to be really difficult to figure out.
And I will say that some of the sentences in the paper, when you then dig into the references, the references don’t quite say You know, don’t quite support the statements. The statements are probably much stronger than the evidence suggests. However, this is almost written as a hypothesis paper. They’re not saying, right, there’s a question mark in the title.
They’re not saying this is happening, they’re saying, you know, we need interventional studies in humans to better understand what’s going on. And I think that’s a perfectly reasonable suggestion. There are some things that I kind of, thought about as I was reading this. And the first is how can I shoehorn this into the demand model of age related cognitive decline and dementia, which is obviously what you and I subscribe to.
And actually it’s very easy to do that, I am happy to say. So if we sort of put [00:11:00] aside the sort of the greater metabolic effects, insulin resistance, type 2 diabetes, right, and how fructose contributes to that, we know that maintaining insulin sensitivity and metabolic health is critical for maintaining brain health.
However, there are some very specific things that are mentioned in the paper in terms of cognitive demand. So, one of the things is that they suggest… That by changing activity patterns in the brain fructose then leads to changes in those areas of the brain because they’re not being used, right?
So that is essentially saying that fructose is changing demand in different areas of the brain. So it’s almost a contributor to how demand is distributed in the brain, which again would kind of fit in the, in the model. It doesn’t mean that it’s everything, but it could be one thing that contributes to changes in brain cognitive demand that then could drive or part of it.
Yeah. drive long term neurodegeneration. The other part that I thought was [00:12:00] interesting is that they mentioned some studies where even in the setting of localized instant resistance in certain parts of the brain or hypermetabolism in certain parts of the brain, which we know Sort of happen early on in the disease process of age related dementia and Alzheimer’s disease.
Even in that setting, which could, which may or may not be driven by fructose, if you create cognitive demand in those areas, you will up regulate metabolism and you will respond as normal. So even in the setting of some change in these patterns due to what we’re eating or other things, you can overcome that with adequate cognitive demand with those, in those areas of the brain.
So, while I think there are a number of reasons to say, yes, we shouldn’t have a ton of refined fructose in our diet, and they do specify that eating fructose from fruit does not have these effects in general, because we’re just not eating enough of it. This is, you know, sodas, and cakes, and sweets, and all those [00:13:00] things.
So even if some of this, you know, fructose in the diet is driving some of this, we can probably… you know, still get benefits of cognitive demand because it overcomes these changes in brain metabolism driven by fructose. So, so again, the, the demand model kind of explains and supersedes some of what is happening here.
You know, the sort of the systemic metabolic effects I think are still worth. considering. There are a couple of other things that I think should also be taken into account. One, which they don’t really mention, is the contribute like how other nutrients contribute. So there are certain studies that suggest that things like choline magnesium, copper, all of these things are really important for proper fructose metabolism in a good way and that high levels of fructose intake can negatively affect those things, particularly copper.
But when you’re thinking, when, when they’re talking about the production of fatty acids, so like you’re generating new [00:14:00] fats, they get deposited in the liver. This is one of the reasons why sugar, high amounts of sugar intake are associated with non alcoholic fatty liver disease, at least in animal studies.
And there’s some human evidence that suggests this, if you have adequate choline intake, You don’t get that accumulation because coding is needed to to shuttle those fats away to be stored in a, in a better place. So, I think there’s an interaction between sugar intake and Other nutrients in the diet.
And that’s important because if you’re eating a whole bunch of refined sugar that is displacing foods that have nutrients in it, it is completely, you know, usually those foods are completely nutrient free on there. So not only could they have a negative effect themselves, they’re also displacing foods that have you know, important nutrients.
So that’s one of the reasons why you would try and focus on more of a nutrient dense nutrients. Whole food based diet, not only you’re reducing sugar and fructose [00:15:00] intake, but you’re also increasing nutrients that help you metabolize these things when you do eat them. So that’s, that’s an important factor to take into consideration.
I think that was everything I was going to talk about up front. Is there anything in particular that you came up with or any questions that you had? Based on your reading the paper, you hit most of the things that I was thinking about that I was gonna, that would have said as well. And it was, that was great.
Review everything. I guess the big picture concept here is that fructose can trigger this sort of hibernation mode that we are this sort of less extreme version of hibernation that that we can go into and that that was an adaptation for uh, helping us to adapt to times where food was less available and an adaptation for times of famine.
And so we’re triggering this adaptation that’s supposed to be helping us in [00:16:00] times of famine. Yet we’re not we’re not reducing our, we’re not experiencing that at all. So that’s a big problem, you know, and certainly that makes a lot of sense. And there’s good, I think there’s, you know, there’s some pretty interesting, the effects of fructose are interesting and sort of do coalesce around that particular idea in some ways.
I think one of the potential pitfalls here is, is in. Sort of number one, thinking this is the only thing, right? If this hypothesis is at least partially true, it’s still going to be one factor amongst many that I think that drive risk. And so I think that this can certainly fit within a broader model.
Like, like you said, we consider kind of the demand coupling model to be that, to be sort of the big picture and then how do these different pieces that we know would be relevant fit within that framework. So one question I had was, was your thoughts about fructose consumption from fruits, and I think your position would be probably not worth worrying about, right? And like you [00:17:00] said, potentially compensated for by, if there is an issue, compensated for by sort of a cognitively demanding lifestyle, anything more that you
would say about that? Yeah, that’s essentially where I’d land. And I will say, so there’s two things, or there’s actually a few things, but we’ll kind of keep going into them, I guess.
But one, one point to make is that they stay up front, that there are other dietary components that can still drive this sort of stress or adaptation pathway that they think are important. So it’s not just fructose consumption, it’s also eating a lot of eating a lot of salts, which then can create a relative dehydration or increase in blood osmolality.
So the concentration of sodium in the blood, which can then also drive this. So they think that large intakes of salt may be a contributor. And they also mentioned very high, you know, glycemic diet. So if you’re eating a lot of refined carbohydrates, then the blood sugar or, you know, the blood sugar that gets, gets released, that can also be converted into fructose and then through the polyol [00:18:00] pathway.
And then that sort of drives the same thing. And then they also talk about umami foods. So in the, they cite a couple of papers that use monosodium glutamate that kind of show some of these effects. Although, kind of historically, we talk about these foods high in purines, which often, you know, meats and seafood, and how they may increase uric acid and gout risk.
Although, I will say that, both in terms of the body of literature in general, and what’s presented in this paper, I think that the evidence is far less convincing than, say for fructose. But these are all things that are part of that. And then for fruit in particular I, I see no issues with fruit consumption in general.
Both it’s actually has some nutrients as well as water and fiber and, and other things. So the, the total intake is decreased as well as the sort of the pharmacokinetics or how it affects the body as well as the things that come along with it. [00:19:00] And sort of as part of that, I think there’s been this sort of demonization of And I don’t mean that, I think that’s not a bad thing, I just mean that the dose probably, the dose really makes the poison, right, so, so, like, to give an extreme example, I’ve seen people complain about added sugar in bread, right, and so, it’s probably like a little, it’s like one teaspoon of sugar in a whole loaf of bread.
The problem is the bread, it’s not the teaspoon of sugar that you added, right, and that could be the case for any food, right, so, say you have a salami, which is 99. 9% meat and fat, and then maybe some spices. If you add a little bit of sugar to that as part of the curing process, you’ve seen, I’ve seen people go crazy because the sugar added to this salami, but like, just the total [00:20:00] dose is so small, it doesn’t make any difference.
So I think we do need to think about the dose and how it’s coming, rather than just saying don’t eat fruits, it’s got fructose in it, or, you know, don’t eat this. Salami because somebody added three grains of sugar at some point in the curing process, you know, I think we have to think about the whole context.
Yeah. And that little bit of added sugar. The bigger issue probably is the hyper palatability that’s created from doing that. Right? Rather than the impact of that little bit of sugar. And it’s, you know, in many cases been precisely calibrated. So we know the exact amount that will get you to eat more.
You know, one of the questions around fruit is the fact that we’ve cultivated it to become far sweeter than its wild ancestors. I think Dan Lieberman’s book, the story of the human body, he mentioned that. That the sweetest fruit that would have been around in our ancestral habitat has the sweetness of a modern day carrot.[00:21:00]
So that would be like the sweetest thing we would encounter. So I’ve generally hedged towards the sweetest stuff being more moderation. and things like berries, which have been less modified and are less sweet on their own to be a little bit safer. But again, you know, I don’t know how significant of an effect that is.
And I think the general rule is proportions that are found in nature are going to be the most likely, the ones we can deal with the best in terms of proportions of nutrients.
Yeah, I think there’s, there’s certainly a lot to be said for the coupling of what a food Tastes like and contains to how our body expects to respond to it versus how it actually responds and the more processing and the more sort of adulterated for want of a better word right into making that food the bigger the mismatch mismatch again between what like the expectation of a physiological response based on you know the calorie and macronutrient [00:22:00] content versus what actually happens.
So, you know, taking a, you know, some berries. Versus some kind of highly processed berry juice, right? It’s a very different response. And so, and that’s, that’s where some of the issues come in, in terms of how the body senses those, those calories and what to then do with them. Right.
And it’s all, all relative, even the sweetest.
Mango is probably far better than a can of soda. So, you know, if it helps to get, you know, the lesser evil, you know, is often very helpful. Alright, anything else to add there, Tommy? No, I
don’t think so. If people are interested in this, I would encourage them to read the paper. I did like sort of at the end, they said, like, what, how might people challenge these ideas, what are the limitations?
I think they could have leaned into it a little bit more, because some of the challenges I don’t think were sort of fully [00:23:00] addressed, but there are some things like, in in Alzheimer’s disease, in general, when they’ve looked, uric acid levels are lower than sort of healthy populations, and there’s a number of reasons why this might be, there’s a possibility that uric acid is an extracellular antioxidant and they do.
They, they mentioned that, but they don’t really address it. So, so, you know, maybe it has some benefits, rather it’s, it’s not all bad, right? There are certain contexts where, where uric acid can be beneficial, and there’s some interesting information on how the loss of uric A is the increase in uric, in circulating uric acid may have helped drive human brain evolution.
That’s kind of interesting. And, you know, maybe partly through its function as an antioxidant, um, but then sort of the idea, you know, the way that they suggest their model works is that, You sort of accumulate uric acid early on in the disease process, it drives some of these negative changes and then eventually you decrease function and metabolism so much that uric [00:24:00] acid production drops so that they kind of This inverted U shaped curve.
But again, there’s just like so many questions here that I think is still worth still worth digging into. And my guess is, if you’re you know, if you’re going to test this in a clinical trial, what will your intervention be? Would it just be restricting fructose? Because, you know, by their hypothesis, this could still be driven by high, any carbohydrate, any glucose intake umami foods, salt, but then as soon as you start changing those things, then it’s kind of difficult to isolate the effects.
I think if you ate a lower sugar, higher, you know, less refined diet, I am certain, you know, we would both agree that you would see better health outcomes, including better brain health. But isolating the effect of fructose here is going to be. really, really difficult.
Yeah, that’s, that’s kind of, in a nutshell, the challenge of like a whole of biology, which is everything’s [00:25:00] interconnected.
You can’t isolate any one component because that changes the whole everything else. But yeah, so the test, like quote, unquote, proving any of this is just like, It’s all about sort of increasing the likelihood of its plausibility rather than like definitively saying anything, but yeah, and I think to your level of confidence changes, depending on what level you’re talking about, right?
In terms of this, these explanations at the level of like evolutionary forces, we would say, I think there’s the chances that are the mismatch of sugar in the diet. I think from now to, from now compared to our ancestral habitat, the likelihood that that’s the, you know, a quote mechanism I think is high, you know, the further you drill down into the, into the lower levels of description and the molecular interactions, the less confident you become, the harder it becomes because the complexity increases so [00:26:00] much.
I think we could. But like, a good takeaway would be that, so this is like mechanistically and evolutionarily fascinating. It’s a really interesting paper, hypothesis, there’s, you know, I’m a big biochemistry nerd, I love reading about this stuff. In terms of practical applications, I am confident, and I think we would both be confident, that a diet that reduced, like a western style diet that reduced the intake of highly refined sugars and carbohydrates.
Is going to improve the health of your body and your brain. Right. So, even if what’s described in this paper isn’t exactly what’s going on, the implications of it are probably still going to result in improved health outcomes. So, which is what we really care about. Absolutely.
So. Right. This is why it’s so important, too, to think about the different levels, because if this explanation is totally wrong, it doesn’t change at all.
that the mismatch is driving the problem. It just means we’ve got the mechanism wrong, but this, this [00:27:00] largely academic and even the question of how much, you know, where, where is your intervention likely to make the most difference? It’s going to be upstream, you know, at the level of not mucking around with one of these potential pathways, you know?
Yeah. So, and we already know. Enough to say that intervening with a reducing added sugars is a good thing. Okay well thanks Tommy. If you guys have any questions about what we covered today or anything else on the topic of brain health and fitness, send it our way at brainjo.academy/questions.
Okay, thanks Tommy. Thank you.