Jackie: [00:00:00] 

// Intro // 

Jackie: Nutrition fuels our bodies and minds. 

Jackie: Our strength, mobility, energy and even mood rely on the right nutrition and scientists are continually uncovering new secrets. 

Jackie: Welcome to Nutrition Unlocked, the podcast celebrating innovations, advancing the role of nutrition and health, sponsored by Nestle Health Science.

Jackie: In each episode, we talk to experts from around the world about the latest topics in health science. We'll bring you insights and discuss innovations that are unlocking healthier futures. 

Jackie: Our host for this episode is Anna Mohl. 

Anna: Welcome back to Nutritional Unlocked. 

Anna: I'm Anna Mohl, your host for this episode. In today's episode, we're going to dive into a topic that affects every one of us - brain health and how nutrition affects it. Our special guest today is Professor Stephen Cunnane from the Department of Medicine, where he holds the clinical research chair in Keto Therapeutics at the Université de Sherbrooke in Canada. [00:01:00] His research has given us some groundbreaking insights into brain health and we are so pleased he could join us.

Anna: Stephen, a very warm welcome!

Stephen: Thank you

// Main Chat //

Anna: So great to have you here today! 

Anna: Now the idea of feeding our brains, it sounds like a bit of a strange thing to say to some people, I think, but it's essentially what we're going to talk about today. Nutrition, or lack of it, works with the brain in many different ways and is really key to how human brains evolved.

Anna: Now you've spent a good deal of your career on this topic, and you've written on it extensively. You have a very, impressive background and very impressive contributions to the field. And you've done a lot of work around how we ended up with larger and more complex brains than our ancestors. I think it would be good for us to have a basic understanding of the evolution, and specifically how changes in diet led to advances, maybe before we start to talk about the modern brain.

Stephen: Sure. I think the links are important. It's important to think about the evolution, how we got [00:02:00] to where we are and whether in fact there's any vulnerabilities still today. Cuz we know that mental illness and neurological disorders are very prevalent, perhaps even more prevalent than they were half a century ago.

Stephen: So the brain is definitely susceptible to misfiring and it's a question of whether it's related to nutrition, I guess is part of where we're gonna go in this conversation. And so it then makes us look in the rear view mirror and say, where have we been? And how did we get here? And nutrition has definitely played an important role in our brain evolution. And one of the indicators of that is the fact that it took iodine supplementation in the diet, iodized salt was required and was finally discovered about a hundred years ago to be the cause of cretinism, which is severe mental deficiency during early development.

Stephen: So in some ways, we solved a big challenge to our mental health, a century ago with iodized salt. The [00:03:00] question then becomes,Why did that problem develop in the first place? And it developed because we weren't eating as much fish and shellfish, which are rich in iodine.

Stephen: So populations today that eat a fair amount of fish and shellfish were never susceptible to cretinism. Cretinism developed in the middle of big continents like Europe and North America. How did we avoid that problem? We ate more fish. And so iodine is one of the nutrients that is still key to our brain development.

Stephen: And we're eating less iodine now, because we're eating less salt cuz we're worried about blood pressure. And it's coming back to bite us and in some ways we're worried about fish and contaminants and fish as well. and We seem to be sensitized to certain risks, but we don't see the real benefits of fishin this situation.

Stephen: So iodine I think was really important and iodine is something that our ancestors started to consume more of by eating shellfish and fish about 2 million years ago in East Africa.

Stephen: Something that the primates, the chimpanzees never did, for instance. So the chimpanzee brain genetically is not that different [00:04:00] from ours, but it never had the opportunity to exploit its environment, because it never started, to go into that sort of food niche that we did explore.

Stephen: So if we take a step back, how has the human brain evolved as we think about the environment, genetics, time, changes that were experienced. Well, It's about three times bigger than it was 2 million years ago.

Stephen: So that's, it's a big change over time because the energyconsumption by the brain has gone up by that amount as well. So we had to supply it with some more nutrients, but we also had to supply it with some more energy, which is a topic we can come to.

And the main change in the brain, that accompanied that increase in size, that expansion, was an increase in the frontal cortex, the forebrain, the part just above the eyes, which helps us with problem solving. It helps us with learning. It helps us figure out how to address problems, But also language development, so [00:05:00] anatomically the big change was that we increased the number of connections between brain cells markedly compared to other animals, the synapses, which are the points of contact between neurons and with more points of contact, you have more ways to communicate between these cells. And this was a major part of increasing the complexity of the brain.

Anna: And how did we do that? How did we increase those connection points?

Stephen: I've no idea. I don't think anyone really understands.

Stephen: Butit, I'm going sort oftake a kick at it anyway. One thing that I think is critical, that is different again from the primates, is that the brain size in our babies at birth, a healthy term infant at birth, the brain is much bigger in relation to the rest of the body than it is in an adult. And its energy requirements are much, much higher than it is in an adult. It's taking 75% of the energy that mom is feeding the baby with through her breast milk. 75% is going to feed a brain, which barely works if you understand what I mean in the [00:06:00] sense that, the baby's incapable of doing anything to protect itself, for a couple of years even. 

Stephen: You ask, how did we get here? And that's a major investment in a vulnerable organ and a vulnerable organism and a vulnerable mum by consequence. And how does the brain, differ whether it's among different demographics of gender or age or even, different geographies if we see differences there.

I think the most striking difference, and it's, in a way it's a superficial difference, but it's certainly measurable, women have smaller brains than men. But it's a superficial difference in the sense that they're not less intelligent. There's no advantage necessarily to men having a bigger brain.

That's biologically been demonstrated. And it's the one thing that you can see in the fossil record, which is approximately the size of the cranium. So an indirect measure of the size of the brain. that's how we know it's evolved to be three times bigger than it was about 2 million years ago.

But [00:07:00] size isn't everything. it's complexity. it's the developmental experience and so men and women essentially, have the same cognitive potential. They have the same intelligence. They may have different vulnerabilities to different conditions. but I certainly, I can't speak to exactly how that evolved.

Anna: Yeah. I like to think of it, if women have smaller brains, but we're equally intelligent. We're just more efficient with our brains.

Stephen: Absolutely. it's clear that diet has affected the evolution of our brains, From brain development in babies and children to our older years, 

Anna: Maybe we can walk through this a little bit, starting with how nutrition affects brain development at the different life stages.  how does that evolve as you move to adolescence, to young adulthood and then through the aging process?

Wow. that's a complex question. and it's a complex process. The brain evolves, goes through what are called critical periods, so that let's say stage A, if stage A is not completed correctly because of some nutritional [00:08:00] deficiency or some genetic problem, then it has a domino effect on stage B and stage C and so on.

Stephen: Sobrain cells have to be pruned appropriately, and then you have to connect them up well with insulated wiring called myelinated fibers. And so each of those are stages that are complex within themselves. Andif you have a problem at the first stage, then it affects all the future ones.

Stephen: So neurodevelopmental progress is critical to achieving the cognitive potential of the adult. I mentioned iodine, cretinism. iron deficiency is the same problem, and these are the two biggest nutrient deficiencies in the world today still, which is, I think a critical indication of the role of nutrition. 

Anna: Omega-3 fatty acids have had a major placein the discussion about nutrition and brain development and they have an important role. in the infant, in the child, in the adolescentand in adulthood. I wanna move and talk a little bit about some of the really fascinating and groundbreaking research that you've done on [00:09:00] older people and specifically people with mild cognitive impairment, which generally affects older people. I wanna disclose here that we at Nestle Health Science have partnered with you on research in the past, and that we are a donor to the University of Sherbrook's Research Chair on Keto Therapeutics, a position which you currently hold. Now, as I mentioned before, you've done some incredible research, big contributions in the field and you've focused your career over the past decade or so on how ketones can help brain function in people with mild cognitive impairment or mci. And that's a condition that is often described as people having more memory or thinking problems than most people their age. And people with this condition as diagnosed by their physician have a greater risk of developing dementia or Alzheimer's. 

Anna: Now, your research from 2020 showed that a ketonic drink can help people with MCI improve their cognitive function.

Anna: Can [00:10:00] you talk a little bit about this research? and, what interested you in this area and how did you come to do so much work in this area?

Stephen: Well, before coming to Sherbrook, I stumbled over the role of ketones in early brain development and I was very intrigued by their use in the ketogenic diet to control what's called intractable childhood epilepsy. So epilepsy that doesn't respond to drugs. And I heard about the ketogenic diet and I thought that was just about the craziest thing you could give a child or anyone for that matter.

Stephen: That was nearly 30 years ago now and I realized that it was a serious treatment for epilepsy in children. And I started working with epileptic children to understand a little bit more about it. And I learned in the process that ketones were really important for early brain development. And then, for personal reasons, I was interested in leaving Toronto and I saw the opportunity in Sherbrook to do PET imaging in the brain. I came here, I interviewed,they loved the idea, but there was no pediatric platform or context that we could apply it to. And they said, we have a [00:11:00] disposition in aging. And it just struck me like the light bulb going off that some of the nutritional and metabolic challenges facing the developing infant are perhaps similar to the nutritional and metabolic problems facing the aging brain.

I learned pretty quickly that as we get older, almost everyone will experience some degree of decline in the ability of brain to get its fuel, its main fuel glucose. And that for 40 years since the dawn of PET imaging, they'd known that Alzheimer's disease, there was a major problem with getting glucose into the brain, but it was always interpreted as a consequence of the cell death in the brain during the development and progression of dementia.

Stephen: So I said, well, there's, two things that clash with that. At least,there's one thing that clashed and one question we've got. The thing that clashes is that people that don't have dementia, but are at risk of getting dementia, have a lower brain glucose uptake already. It can't just be a consequence of the disease.

Stephen: People with a genetic [00:12:00] risk, people that are APOE4 carriers, people that are insulin resistant, people that have a family history of Alzheimer's disease in their sixties. so it can't just be a consequence. And besides that, the question we asked was,if ketones are the most important backup fuel for glucose in the brain, what do we know about keto metabolism in the brain and the risk of Alzheimer's and the progression of Alzheimer's. And as I started the PET ketones studies and you have to start in animals. You have to show you can make them the molecule, then you do studies in animals to make sure it's safe and you progress slowly. You need a reference group. Who's your reference group? And it turned out to be healthy, older people. 

Stephen: So we took five years before I studied the first person with Alzheimer's disease. And in the meantime, I learned in the literature that back quite a few years ago in some early work that people had two groups, one in Japan and one Sweden, had already shown that keto uptake was normal in Alzheimer's disease, brain keto uptake. I was both thrilled and [00:13:00] dismayed. I was thrilled to know that this was something we should follow up and dismayed that we weren't gonna be the first to study it, but that was okay. It turned out to be nice to know, because it was a totally different technique than the PET imaging anyway and that's always very reassuring when you have two different techniques that essentially showed the same thing. 

Stephen: So we moved forward, we started studying it in Alzheimer's and lo and behold, the pattern of declining glucose metabolism was present, has been shown hundreds, if not thousands of times before. But the ketones pattern was totally normal. And so the next question for me was, well, maybe that's just the baseline trickle ketones. If you're eating three meals a day with 50 to 60% carbohydrate in the diet, there's only a trickle of ketones going into the brain anyway. They're supplying maybe three, four, perhaps 5% of the brain's energy requirements. In a sense, who cares? That's not going to make any difference to a brain that's struggling. That's already gone down by 20% in its glucose uptake. 

Stephen: So I said, let's give a ketones supplement and see whether the brain can respond. [00:14:00] And we did. And we saw thatit was exactly the same relationship as you see in young, healthy adults.

Stephen: So we said, well, the brain is capable of using ketones. It looks like it's starving in fact of glucose, and it's not getting much ketones, because ketones are suppressed by insulin, which is increased by a carbohydrate rich diet. So in fact, the brain in Alzheimer's disease is basically in double jeopardy. It can't get enough of its main fuel and it can't get enough of its backup fuel. 

Stephen: So how do we provide it with more of its backup fuel? And there's basically two or three ways you could do it. You could fast, you could not eat for several days. And people have studied intermittent fasting. You can do calorie restriction. I didn't see the viability of that approach in a population that's 75 to 85 years old. You can use a ketogenic diet, which I was quite familiar with and I thought, that's probably gonna, might not even get approved by the Ethics Review Board, because of the potential to raise [00:15:00] cholesterol and the higher fat intake. And we didn't know for sure whether it would affect weight gain and other cardiovascular markers. That didn't turn out to be the case. 

Stephen: But I didn't take that approach. I took the approach that, there are ketogenic supplements, medium change triglyceride has been available for over 50 years. Both in, clinical nutrition, but also in cosmetics and for other purposes. It's available, it's cheap. All we need to do is make a kind of milkshake with it, which we tested, found it was safe and palatable and we got funded by the Alzheimer's Association to do a metabolic study. So our first foray into mild cognitive impairment was to do a metabolic study with 20 people per group. That corresponded to the maximum amount of money we could get for that type of project. 

Stephen: So we couldn't make cognition the primary endpoint of the study, cuz it wasn't gonna be powered with enough people per group. But we could do a placebo. And we did. And we took a guess as to how much mct, medium chain triglyceride, do [00:16:00] you need to produce enough ketones to correct the glucose problem?

Stephen: And we didn't have time in a sense. We got funded. So we started the project. We hadn't really worked out what that dose was. We hadn't worked out whether the product was gonna be, tolerable and so there was a very steep learning curve at the beginning of the project to get that sorted out.

Stephen: But we got lucky. We made a milkshake emulsion in lactose-free skin milk. It was tolerable at about the 30 gram dosein 80% of the participants. We did a six month intervention. We showed that we had corrected the metabolic problem with glucose by about 30%. So we didn't correct the whole problem, we corrected about a third of it.

Stephen: At this point, I met my collaborator from Nestle Health Science, Bernard Kunu and he said he was quite interested by the progress we were making and wondered if we could get involved together and start a partnership. And we did this slowly and at that point, he realized that if we were gonna show that cognition was gonna be affected in this study, we had to [00:17:00] double the sample size.

Stephen: And he agreed to fund that increase, that prolongation of the study effectively. At which point, we knew we could improve the metabolic state of the brain and we were then able to go on and show that by improving the metabolic state of the brain, we had improved cognitive performance on all the five major domains of cognition in mild cognitive impairment.

And so, we were ecstatic about this. It corresponded to some of the other smaller studies that have been published in the past. And we've gone on to do further work in this area since then.

 And how does this researchlead researchers to think about the role of a ketogenic diet in general through adulthood, in either improving cognitive health or preventing mci?

Stephen: There are some people that are definitely keen on it. I can name up to perhaps 10 groups around the world that are interested, but I think all of us recognize that there are logistical challenges. A ketogenic diet is quite hard to adapt to. I think there's a fair amount of, [00:18:00] shall we say, inertia or even resistance by the medical community. The perception that fat is dangerous for you is still very prevalent, that you're gonna gain weight, that you're gonna worsen your cardiovascular risk profile, which is not true. I think there are good enough data now to dissuade that. People are using it for weight loss and they're using it to treat type two diabetes extremely successfully, by the way. And type two diabetes is a major risk factor for Alzheimer's disease. So it shows that improving the metabolic status of the body as a whole is possible and it will definitely improve the metabolic status of the brain..

 I think that what you're trying to achieve is can you get more ketones in and can you reduce the resistance of the brain, both the insulin and glucose? Which means they're there, but they're not being used properly. What we're trying to see now is if you simply reduce carbohydrate, not dramatically, reduce it by a ballpark figure of 50%. Is that feasible in older people? Does it [00:19:00] change anything about glucose metabolism? Does it change anything about cognition? By reducing carbohydrate by 50%, we're not gonna increase ketones probably at all, but I think it's a second strategy that we can use with an MCT supplement perhaps, that's gonna make the MCT supplement more effective, I think, by reducing the glucose problem. 

Stephen: So I think you can attack this problem from several angles and I think there's a lot of excitement in the Alzheimer field. 

Stephen: So as we look into the future of nutrition and the brain, what research do you see happening in the next five to 10 years to further support brain development. And what role do you think nutrition will play?Well, if we focus on aging, there is a multimodal approach that's going to be needed. My vision is that, so we know something about the fuel problem in Alzheimer's disease and how it starts in healthy aging and you slide slowly towards MCI. So it's not just that we throw another supplement at you, but we try and change your dietary pattern for [00:20:00] the better. 

Stephen: We need to show that the sciences makes that worth addressing in the first place. And so there are tools that we have access to now that we need to apply and that's my main preoccupation is to see other people pick up and run with these sorts of studies. It's developing, it's not developing as fast as I'd like to see it happen, So we simply have to accept that progress is what it is and we're not going backwards. People are commercially using low carb diets to treat type two diabetes. There's a successful business model in the US right now that is helping thousands and thousands of people. It works, it's safe and it's economically viable. It applies to older people as well. We just need to turn our attention,and we'll get there.

Anna: Yeah. It's incredible that we started the conversation about brain health and we're of course discussing metabolic health. I think, the linkage between them and the role that nutrition plays and the benefits that you can get from certain types of diet across your body and across your health, I think are just fascinating.

Anna: We could probably [00:21:00] spend the next couple of hours discussing all the kinds of research that it would be exciting to do And I think to your point, it's fantastic the advances that you've made and I think how you've probably sparked, you know, interest, passion, opportunityfor further research to continue to learn and to continue to explore and continue to make important findings in this field and to come up with more breakthroughs in terms of how we treat brain health, the evolution of brain health and specifically MCI.

Anna: So,a big thank you and congratulations for everything that you've done. I know there's always more to do, but I think you should be excited about,some of the accomplishments you've already achieved.

I am, I guess researchers are never satisfied! 

Anna: That's good though. That's good. That's what makes you, that's what makes you great, right? That's how, how you keep discovering new things.

 And one thing I've discovered in the past year or so is that there's an emerging field called metabolic psychiatry. So it's not just cognitive health that is benefitting from a correction of the metabolic syndrome,but mental health as well. It's not a field I know hardly anything about, but I'm starting to be [00:22:00] aware of some of research that's being done on this and addressing some of the serious mental health issues that we have in our society and how intimately they are related to our metabolic health as well, which simply adds another argument to the fact that metabolic health underpins so many aspects. Not only cardiovascular health, cognitive health, but probably mental health aswell and it's in its infancy, but it's a field that is going to take its place on the research stage over the coming years.

Anna: Oh, that's absolutely fascinating. 

And now we know that there's a group in Denmark that I'm starting to collaborate with that's looking at ketones in the heart and in relation to other fuels that the heart can useand it's very exciting to see how the field is growing and this expertise is becoming available elsewhere.

Stephen: So,in that sense, I'm very satisfied and I'm just impatient to see progress go even faster.

Anna: It's good. We need inpatient researchers. Thank you!

Stephen: You're welcome. Thanks for, organizing this podcast with me.

// OUTRO //

Anna: Thank you so [00:23:00] much, Stephen. It has been an absolute pleasure and absolutely fascinating learning from you. We look forward to more insights from your research in the future and wish you great success in all the research that you do.

Anna: Professor Stephen Cunnane is from the Department of Medicine, University de Sherbrook in Canada, where he holds the Clinical Research Chair in Keto Therapeutics. 

Anna: Thank you so much for listening to this episode. We hope you'd enjoyed it. And if you haven't already, please rate, review and subscribe to Nutrition Unlocked wherever you get your podcasts, so that you can make sure you don't miss an episode and you can tell others that you know all about the podcast.

Anna: We look forward to sharing more insights on the science behind nutrition with you soon, and we look forward to seeing you next time on Nutrition Unlocked. 

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