Dr. Eric Westman: I am pleased to have Dr. Stephen Cunnane here today.
Dr. Stephen Cunnane: Thanks, Dr. Eric Westman. It’s a pleasure to be here.
Introduction, training and low-carb diet
Dr. Eric Westman: Thank you, and thanks for taking the time to talk to me and to people who are following low-carb keto diets or curious about them. Assume someone knew nothing about who you are and what you’ve done. Please introduce yourself, how you trained and got into this world, and why I am talking to you today about the low-carb diet.
Dr. Stephen Cunnane: I’ve been interested in science since I was a child, and that became more structured as I got a Bachelor’s degree and a PhD in physiology at McGill University. I started working in an area that’s called eicosanoids. It used to be called prostaglandins. Over time things evolve. If you’re in research, I find it impossible to stay absolutely focused on one specific thing, digging a simple hole deeper. I end up going sideways a lot of the time, and it was a chance observation about 30-35 years ago that led me, I had no interest in ketones at the time, and I was struck by an observation, that we might end up talking about, that made me try to understand how those molecules, the carbon from what we started with, end up in cholesterol and other molecules.
I ended up learning it was due to passage through ketones through intermediary metabolism, and that might have just remained a curiosity. At the same time, the ketogenic diet came on the public’s radar in relation to the treatment of epilepsy and the first Jeanne d’Arc film with Meryl Streep. (First Do No Harm.) I was struck by that, thinking, “That sounds pretty wild, maybe I should learn a little bit more about it.” Here we are, 30-some years later, and it’s been so informative and rewarding.
Dr. Eric Westman: Where are you and what’s your position now?
Dr. Stephen Cunnane: I’m a professor in the Department of Medicine at the University of Sherbrooke, which is about four hours by car north of Boston, east of Montreal by about two hours, so just north of Vermont. I went there from Toronto about 21 years ago specifically because they have a very strong imaging program, PET imaging in particular, but also magnetic resonance imaging. They committed to give me a research chair position for one thing but also to develop ketone PET imaging, which hadn’t been done before. Actually, it had been done at the Karolinska Institute, two papers came out in the mid-90s, but that program was disbanded. I spoke to the person responsible at the time and realized we were on our own and were basically going to have to reinvent the wheel and get started, which we did.
Sherbrooke is a small provincial town with 150,000 people, but with a booming university and a very strong imaging program. I was lumped into the area of brain aging, and my interests in ketones, especially in relation to epilepsy, which I was working on in Toronto, were in relation to brain development. I learned early on in that line of inquiry that ketones are actually physiologically essential for early brain development. The fact that we’re trying to use them therapeutically in adults, and perhaps in children too, is, I think, an offshoot. Underneath that, there’s a physiological need for them in the brain during early development that we have lost track of.
I keep promising myself to sequester myself for a few weeks and get a paper written on this because I’ve got all the references, and most people don’t realize the extent to which they’re important for early brain development. I thought, if they’re important for early brain development, perhaps they’re important for brain aging as well. It doesn’t get more exploratory than that, but it has moved forward.
How critical are ketones?
Dr. Eric Westman: How critical are ketones? If a child can’t make ketones, do they grow okay?
Dr. Stephen Cunnane: That’s hard to establish, but what has been shown in two different studies is that, at birth, a third of the brain’s energy requirements are provided by ketones, about 25% to 30%. That’s from two separate independent studies. It suggests there’s not enough glucose in the system to feed the brain to meet its requirements at that stage, and that requirement for ketones goes down. Ketones are supplied by medium-chain triglycerides in the mother’s milk. For infants not on mother’s milk, they’re still provided from the body fat stores that a normal-term infant has.
It becomes more of a challenge for a premature infant or a low birth weight infant to meet its brain energy requirements and grow normally. Those are the babies that have the highest risk of neurodegenerative problems, or rather, delayed neural development.
It’s empirical, but that’s the basis for that argument.
How Dr. Stephen Cunnane got interested
Dr. Eric Westman: I’ll get back to brain development in just a moment. What was the anecdote that got you interested?
Dr. Stephen Cunnane: I was studying omega-3 fatty acid metabolism in the brain, and the parent of omega-3s is called alpha-linolenic acid. We had a technique to study it with what’s called a stable isotope. It’s not radioactive, but it’s got a marker on it that allows you to see how much of that stuff you give is transformed to the end product you’re interested in, which is docosahexaenoic acid (DHA) in the brain.
The anecdote is that we saw that the conversion of alpha-linolenic acid to DHA, that wasn’t novel. We were trying to study it in living animals at the time, which was novel. What blew me away completely was the fact that most of that tracer ended up in cholesterol, palmitic acid, and oleic acid in the brain and not in DHA at all. So, there was the expected conversion, but there was this whole area where most of the tracer was actually going elsewhere. I thought, “How can that be possible? What’s the biology, the intermediary metabolism?”
The ketones are produced from alpha-linolenic acid, which is in soybean oil, flaxseed oil, and anything green that you can eat, but especially the oils. It’s got three double bonds that are relatively easily beta-oxidized, not peroxidized, but beta-oxidized, which means broken down to make energy. A lot of the carbon broken down by that process ends up being recruited into lipid synthesis through ketones.
Ketones supply about 90% of the carbon that you need to make lipids in a newborn as well, so they’re not just an energy substrate.
Dr. Eric Westman: So, a child needs ketones to make cholesterol in the brain, is that right?
Dr. Stephen Cunnane: Yes.
Cholesterol and ketones in the brain
Dr. Eric Westman: Tell me about this cholesterol in the brain. What does it do, and why can’t you make it without ketones?
Dr. Stephen Cunnane: You can make it without ketones. Cholesterol is part of the lipid structure of the brain’s nerve cells, whether it’s an astrocyte, a neuron, or the myelin itself. These have long-chain fatty acids in what’s called phospholipids, that’s the way they’re put into membranes. But there are also molecules of cholesterol in there. The brain is largely autonomous in relation to most of the fats it accumulates; it makes them itself. So, you don’t have to eat cholesterol to get cholesterol into the brain. You can take a statin, and it will presumably reduce your blood cholesterol. In fact, some early statins that block cholesterol synthesis in the brain are extremely dangerous for malformations. So, women who are at risk of pregnancy and need to take a statin have got to be on contraceptives to avoid that huge risk.
Cholesterol is extremely important for early brain development, and ketones are a major substrate to make cholesterol in the brain. They’re not the only ones, but they are the main ones, at least in the first two years of life.
How else is cholesterol made in the brain
Dr. Eric Westman: How else can you make cholesterol?
Dr. Stephen Cunnane: Glucose, we know, can be converted. Most people stop inquiring where the carbon for cholesterol comes from once they stumble upon glucose, but in fact, ketones are a much better substrate for cholesterol synthesis in the brain. It’s not just cholesterol, it’s saturated fats, too.
So, to make myelin, absolutely. This applies to aging because myelin deteriorates with age as well. I hadn’t thought about whether you could correct hypomyelination in childhood genetic disorders, but we are seeing evidence of improved myelin structure in older people who are on a ketogenic intervention. So, it’s consistent.
Multiple sclerosis and low-carb keto diets
Dr. Eric Westman: Diseases like multiple sclerosis could theoretically improve?
Dr. Stephen Cunnane: Absolutely, and I don’t know if anyone has started looking into that, but it’s definitely worth a go.
Dr. Eric Westman: I had the great fortune to travel around the U.S., and once to Vancouver, so it includes Canada. I talked to people, and on Saturdays, people would come out and talk about low-carb keto diets. This was before the pandemic. Several people told me their multiple sclerosis was better, but I know just enough about the disease to know that it comes and goes and that it’s difficult to know for sure unless you really stick with it, or better yet, randomize people to the intervention or not.
I asked one of the people to create a Facebook group, to get people who are doing keto to see how many people would gather at that site. Last I checked, some people think they do get better, but it really needs a touch of science, a good formal study with controls because of the disease itself.
Dr. Stephen Cunnane: Absolutely.
Dr. Eric Westman: Same thing with Alzheimer’s and Parkinson’s as well.
It’s so great to be talking to a physiologist. I didn’t know there were any left!
Dr. Stephen Cunnane: There aren’t many.
Further research
Dr. Eric Westman: Thanks for reaffirming that because most students know very little other than what’s on the test for them to pass the boards. I’d say there’s more curiosity now among the students and residents that I see.
How did this initial foray into discovering something unexpected lead to further research?
Dr. Stephen Cunnane: It led to me wanting to continue what I was doing, which was to work with some animal models. But I also became jaded. The reality check with animal models is that they rarely deliver on translation. I was firmly committed to trying to do whatever we could in humans, perhaps do some exploratory stuff in animals, but not be too dependent on those results.
If you want to study ketones in humans, you can do blood measurements, and we developed a breath acetone measurement, which is very hard to do, actually. We went to the keto clinic at the Montreal Children’s Hospital and St. Justine’s Hospital, where they were treating kids with epilepsy. We moved all our equipment from Toronto to Montreal, which is over 300 miles away, set it up in the lab, and when the kids came in, we didn’t have to take blood samples. We could make these breath acetone measurements because we’d shown that acetone was tightly correlated with blood measurements if done correctly. It was a good proxy.
This was a good example of not only working with humans but also working with people who had a serious disease and were benefiting from an intervention. The point was to see the relationship between the ketone levels in their breath and their seizure control. They were all in good seizure control. Interestingly, they had about a 50-fold difference in breath acetone levels, some had quite low levels, and some had quite high ones. We couldn’t be sure that they were well correlated with blood levels because we didn’t have access to blood in the children, but we did in the adult studies leading up to that study. This was my first chance to say, “There’s a lot we can learn if we just make the effort to study these problems in humans with the tools that are available and ethical to use.” That’s why imaging became an important pillar of what I wanted to do next because even with breath acetone measurements and other interesting data, we still didn’t know what was going on in the organ most affected. Let’s get in there. The techniques exist; it’s not difficult, dangerous, or that expensive. Let’s just do it.
Dr. Eric Westman: Did you know that keto diets were used for weight loss and diabetes treatment?
Dr. Stephen Cunnane: I learned that, but no, I didn’t know for sure. I’m talking mid-90s here. I moved to Sherbrooke to start the imaging in 2003, and at some point, I became aware of the expanded horizon and the potential for keto control of type 2 diabetes.
Dr. Eric Westman: I think it was around that time, and I thought it was at Hopkins, where they figured out that the children who respond to the keto diet are the ones who don’t have the glucose receptor that helps glucose get into the brain, the GLUT1 receptor.
Dr. Stephen Cunnane: No, I haven’t done any of that. That was done in Germany, I think, and elsewhere. You and I met, I think, in Tampa, probably in the early 2000s, when the first metabolic summits were organized. I’m sure you probably put type 2 diabetes on my radar as soon as anyone did.
Concerns about ketosis
Dr. Eric Westman: I had been exposed to the ketogenic diet for epilepsy in medical training, but the idea of using a keto diet for diabetes and obesity was not from straight medical training. It was from people doing it on their own. Two of my patients lost over 50 pounds reading the Atkins book, and as an internist, I thought, “That’s nice.” I thought this would be really easy, we do a few studies, show you can cut carbs, and we won’t have obesity and diabetes anymore. That was 25 years ago!
The Metabolic Health Summit was a great and still is a great meeting that brings together researchers and clinicians who study epilepsy, the brain, and diabetes reversal. That whole physiology thing. Last year, the ketogenic textbook came out.
This metabolism affects every organ, and it seems like in a helpful way. It is like the default mode, perhaps, on a computer, or low-energy mode on a phone, where if you’re not eating, everyone goes into ketosis. From your vantage point now, did you have concerns? You saw children who were sick being put on keto diets. Do you have any concerns about ketosis in your sphere?
Dr. Stephen Cunnane: Concerns that it has negative effects or that there’s a risk associated? Initially, I had the classical risk concern, which was that the fat was going to be dangerous. I was naive, and everyone was taught that at the time, so it wasn’t unusual. To me, it was a question for the parents. It’s a question of risk priorities, and the seizures were far more important to them to get under control than an increase in LDL cholesterol.
With time, I also understood that the LDL might go up a little, but the LDL was a bit more of a bogeyman than it should be. We put a lot of energy into controlling this molecule, this complex molecule, and perhaps some of it’s misguided. That hasn’t been my focus on cardiometabolic health, but I realized in the process that LDL doesn’t necessarily go up on a ketogenic diet either.
What does LDL do
Dr. Eric Westman: The type or its character can change from small to large. What does LDL do for those who, I ask this for residents, students, and even doctors who come to my office, because they’re not taught what it does. As a physiologist, what does LDL do?
Dr. Stephen Cunnane: It’s not my field, so I’m on thin ice, but in simple terms, it’s a way of getting cholesterol from one place to the next. It’s a transport complex molecule. It’s like a transport truck with cholesterol on it that gets dropped off at some point. If the transport system isn’t working well, cholesterol will accumulate and may become part of an atheroma, and so on. That’s not my specialty, and I don’t want to say something that would paint me into a corner.
Alzheimer’s and Parkinson’s disease
Dr. Eric Westman: Let’s get to the brain. What have you learned? What can be some take-home points for people watching? Everyone is worried about Alzheimer’s, Parkinson’s, and dementia, the tangles and the plaques. What have you learned that might enlighten us?
Dr. Stephen Cunnane: I’ve spent 20 years working on Alzheimer’s disease since I came to Sherbrooke. At first, we had to make the tracer, and then test it on animals. Then we had to ask, “What’s the control group for this project?” A young healthy adult is not the same as an older healthy adult. How do we define “older healthy adults”? There’s no standard definition, but Alzheimer’s is generally associated with aging, so what’s the control group going to be?
That’s where we said, let’s do the classical cognitive tests, and if they’re within the norm for their age, that’s called normal. Let’s just start there. We don’t care if they’ve got a BMI of 28, 29, or 24. That’s not going to be the criteria. It’s whether their cognitive health, according to standard measurements, seems normal.
At the time, I wasn’t even focused on Alzheimer’s. It was more to say, “What do we know about brain energy metabolism and healthy aging?” There were reports saying that glucose metabolism goes down, it’s the main fuel for the brain, while others said no, it’s normal. The imaging wasn’t done by the same approaches, so I found that a bit of a mess to start with.
We did the measurements as well. We found that there was a bit lower glucose metabolism in the frontal cortex in healthy older people, but no difference in ketone metabolism, which intrigued me. Then we said, “Well, we’ve got 20-30 people we’ve studied; let’s look at Alzheimer’s disease.”
We found the same thing, the classical problem with glucose metabolism in the parietal cortex, here above the ears, but no change in ketone metabolism. I thought, “Well, ketones are only supplying about 3% of the energy requirements of the brain in healthy individuals, so who cares, in a sense, that there’s no change with that low level of ketone metabolism?”
But then we gave an MCT (medium-chain triglyceride) supplement to the Alzheimer patients, just a single dose, and that produced more plasma ketones. The ketones went into the brain at exactly the same rate as younger healthy adults. So, we said, “When ketones are available, they’re getting into the Alzheimer’s brain.”
That’s interesting, and I wanted to be sure. We looked at the data upside down and back to front, and we did everything to be sure because I knew this was going to be controversial if it was true. And it stuck. In the meantime, I found there was an older paper from the 1980s that didn’t use PET imaging but used what’s called arterial-venous difference. With this method, you can measure what comes into an organ through the artery and what goes out through the vein. You can then deduce what’s being used by that tissue based on the difference. You can do this in the brain, and researchers in Sweden had shown that ketone metabolism was normal in Alzheimer’s disease using that method, but brain glucose metabolism was down.
So, that’s two methods showing the same thing. Since then, there have been two more studies. In total, there are now four methods that demonstrate that in Alzheimer’s disease, glucose metabolism starts declining in the parietal cortex and progressively worsens as the disease advances. However, none of the studies so far indicate that brain ketone metabolism has changed.
This suggested that if we could increase the ketone supply, we could get them into the brain. The obvious next question was whether that would make any difference to memory, learning, attention, language, or other major features of cognition.
We got funded by the Alzheimer’s Association of the USA to do our first foray into this. We almost panicked because we hadn’t thought about how to provide enough MCT (medium-chain triglyceride) to people daily for them to comply with the protocol and complete the project six months later. We ended up making a milkshake, essentially, lactose-free skim milk with MCT, providing 30 grams of MCT per day.
Lo and behold, when we did the PET imaging (both the glucose PET and the ketone PET) before they started and at the end, we could show that when they had taken their dose of MCT, the ketones were going into the brain exactly as we had seen earlier in Alzheimer’s disease. This was mild cognitive impairment, by the way. I should have specified that. If you’re going to try and change the course of the disease, starting early makes sense. On the other hand, the deficit is smaller the earlier you start, so being able to see an effect six months later was pretty difficult.
We ended up with 40 people on the active treatment and 40 people on a placebo. We did the imaging on all of them and showed that you could improve all five major cognitive domains, and it was related to the ketone levels getting into the brain. That seemed to be proof of the principle that ketones are not just a secondary effect, they get into the brain, but they also play an important role in helping the brain fill what we call the “brain energy gap.” As the glucose level goes down, ketones are not just produced magically, even if the brain is crying out for them. This is because insulin, our famous friend, is actually blocking the endogenous production of ketones. Most people, as they get older, become a little insulin-resistant and tend toward diabetes, which puts the brakes on the replacement fuel.
The fortunate thing about MCTs, and other exogenous ketones, is that they don’t depend on insulin to access the heart, brain, or other major organs. We could bypass insulin resistance without needing to correct it, though it would have been beneficial to correct it as well.
Dr. Eric Westman: These were all carb-eaters? They were eating what they normally ate?
Dr. Stephen Cunnane: Yes.
How much energy the brain gets from ketones if one keta-adapts and does not eat carbs
Dr. Eric Westman: When someone eats carbohydrates, the brain uses about 3% ketones for energy. If someone keto-adapts and doesn’t eat carbs, how much energy does the brain get from ketones?
Dr. Stephen Cunnane: If your ketones are at 3 to 4 millimolars, which some people might reach on a ketogenic diet, we didn’t have much difficulty, at least in the short term, getting young adults up to 4. At that point, the brain is running on about 35 to 40% ketones, like a newborn infant actually.
Ketogenic diet and neurodegenerative disorders
Dr. Eric Westman: Very interesting. Going back to Alzheimer’s, I guess the thought process is that glucose fueling has some issues, so let’s give ketones because they still seem to be helpful at that point. What if you run someone on ketones the whole time? Do you think theoretically that might prevent dementia or other complications?
Dr. Stephen Cunnane: Theoretically, I think for sure it would. If someone starts a ketogenic diet in their 20s, 30s, 40s, or 50s, they have a much better chance, I think, of resisting any neurodegenerative disorder, whether it’s Alzheimer’s or Parkinson’s, which we’re working on. So yes, I think it would be beneficial.
I knew at the same time that Russell Swerdlow, who’s the director of the Alzheimer’s clinic in Kansas City, was doing a ketogenic diet intervention in Alzheimer’s disease at the time we started doing our brain imaging, and I was friends with Russell Swerdlow, who was conducting similar research. I was sort of monitoring how his work was going, and the big challenge for him was compliance. They struggled for a long time to get, I think, 15 people through an 8-week intervention with a ketogenic diet.
Dr. Eric Westman: Consult with me, I can help with that.
Dr. Stephen Cunnane: I also realized that there was a lot to learn. At the time, I was worried that ethics probably wouldn’t allow me to do such a study because they might be concerned about causing a heart attack or hypercholesterolemia. This was in 2015. I hedged my bets and thought, “Let’s get around insulin with the MCT and see what we can do.”
Other anecdotes
Dr. Eric Westman: Keto diets aside for the moment, just giving MCT, coconut oil, or ketones in some form was the basis of Mary Newport’s story. She’s the pediatric neonatologist whose husband had dementia. The classic clock-face drawing was disorganized, and she started reading about ketones. She didn’t know much about keto diets aside from their use for epilepsy, so she started putting coconut oil on his cornflakes.
He didn’t follow a keto diet, so he had insulin around presumably, but the ketosis in that instance helped him organize the clock face. She tells the story that he was himself for at least another year or two before they entered a clinical trial, and things went sideways, and he eventually passed away.
I wonder if there are any other anecdotes like that. Are you able to administer ketones or coconut oil, or are your folks focused on MCT?
Dr. Stephen Cunnane: Yes, we’ve published on this, and Mary and I have discussed it at length. We’re good friends. I was curious about the coconut oil effect, so we conducted some controlled studies. It turns out that coconut oil doesn’t contain enough MCT of the ketogenic length (C8 and C10 carbons) to make much impact on ketone production. However, if you add C8 or C10 to it, the ketogenic effect increases. Coconut oil alone, though, has a very low ketogenic effect.
I’ve always emphasized, and I will again, that this doesn’t mean coconut oil can’t be beneficial for Alzheimer’s disease. First of all, there aren’t any good controlled studies, but I think there are other effects of coconut oil that are just as important as the ketogenic effect. For example, coconut oil may help control xenobiotics in the body, such as microbes. It’s antiviral and antibacterial. Most of us have different forms of viral infections in the brain, like cytomegalovirus or herpes simplex, and the neuroinflammation that results from trying to control those infections can be combated with the C12-length MCT in coconut oil, which is lauric acid (the basis of soap). Maybe coconut oil is helping the brain from within when you take it, probably also helping to reduce gingival infections and other problems. Again, it’s not very ketogenic.
I would suggest that combining a form of MCT that is ketogenic (C8 and C10), or a ketone salt or ester, with coconut oil and a low-carb diet would be complementary and increase your odds of better control for the brain.
Dr. Eric Westman: Fascinating.
I would like to go back a little bit to physiology. We now have the technology to measure ketone bodies, either beta-hydroxybutyrate in the blood, acetoacetate in the urine, or acetone in the breath. Back in 2000, all we had were the urine strips for acetoacetate. I want to share the story of a company called Invoy. The CEO was trying to find a clinic with patients in ketosis but couldn’t find one until she came to mine. That’s when they could finally see how well their monitor worked in humans – by visiting a clinic that actually had people in ketosis.
Some clinics claimed to be keto clinics, but they didn’t truly achieve ketosis. So now, the question is, which ketone measure should we follow, and does it matter? We did a couple of investigations looking at acetone, beta-hydroxybutyrate, and acetoacetate, and they seemed to correlate pretty well. However, there was great variability. Some people returned to ketosis after a carb meal in two days, while others took a week to get back into ketosis. This wasn’t something we were expecting, but it’s clinically validated by patients telling me how hard or how long it takes them to get into ketosis.
My general teaching for Keto Made Simple is to not measure anything; just keep the carbs super low and you’ll be in ketosis. But are there instances where you’ve learned that measuring ketones might be necessary? Is one method better than another?
Ketogenic responses
Dr. Stephen Cunnane: A couple of points you already mentioned: one is that even if you put everyone on exactly the same diet and they don’t have access to any other food, they won’t all have the same ketogenic response, whether they’re healthy or diseased, young or old. Whatever it is, that’s something we need to learn a lot more about.
Beta-hydroxybutyrate is stable when you freeze it, so if your doctor, for instance, takes a blood sample, you can get beta-hydroxybutyrate measured on it even a couple of years later, and it will still be a valid number. This is not the case for acetoacetate, which is in the blood as well. There is roughly a 2:1 ratio of beta-hydroxybutyrate to acetoacetate in the blood, but acetoacetate will spontaneously degrade. We do the measurement on fresh blood when we have a participant or patient coming into our project to get the most robust number possible.
I don’t think acetone, from my personal experience with urinary measurements, is worth much. The urine volume can vary significantly from one moment to the next. If the urine is concentrated, the value will look high, and when it’s diluted, it will look low, but the level in your blood or breath could be the same. I saw this frustration in the parents of children with intractable epilepsy on a ketogenic diet. They thought they were doing something wrong because they couldn’t see any values in the urine on some days. I’m not sure there’s any good logic in using the urine measurements, at least from my experience.
Measuring ketones or not
Dr. Eric Westman: For adults with diabetes and obesity, I teach that any ketones are good – trace is as good as large – because of that urine dilution issue. Having them check in the evening rather than the morning gets rid of the dawn phenomenon, which sometimes causes ketones to disappear.
Would it help if someone had mild cognitive impairment or diabetes, which may be considered pre-Alzheimer’s, to measure their ketones? You mentioned a correlation between symptom improvement and ketone levels. Was that the throughput of ketones, and how can we separate that? It might be that the ketone is not being used as well, which is why the level is a little higher.
Dr. Stephen Cunnane: Ketones go everywhere. Interestingly, the heart takes up ketones more avidly than the brain. We’re doing PET imaging of ketones in the heart and kidneys now to assess whether the same metabolic failure in the brain applies below the neck as well. We’ll see where that takes us.
Some people want or need that feedback, but they might not be very satisfied because they’ll say, “My values aren’t going up. Maybe if they’re at three, they should be at four,” and so on. Some will say, “Dr. Westman, if you tell me I should do it this way, I’ll follow your guidance and won’t need to take a blood sample.” They’ll be satisfied with that uncertainty. I guess it depends on the patient and their personal needs for feedback, and whether they’ll worry that they’re doing it wrong because their values are low or perhaps high.
Professorship designed for ketone research
Dr. Eric Westman: I’m so glad you’re starting to study organs below the neck. As an internist, I know we have snippets of knowledge, such as when someone cuts out carbs before a PET scan and the heart disappears from the image. On a keto diet, the heart isn’t using glucose. If you use radiolabeled glucose, the heart disappears because it’s using fatty acids primarily. The heart always uses fatty acids.
Do you remember the physiology study where the cardiologists measured every possible fuel source and said in the abstract, “We were surprised that the heart muscle didn’t use glucose”? No, it uses fatty acids. Every Department of Medicine chair who trained with heart muscle in a petri dish learned that the heart uses fatty acids because the heart needs high ATP levels for energy.
I encourage trainees who come through to avoid writing abstracts that express surprise about things we’ve known for years. It’s like being surprised that people fall when they jump out of an airplane. The physiology of the heart has always been the same, but the field of cardiology has become so focused on non-physiological things, unfortunately.
I remember that some years ago there was a professorship designed for ketone research. Has that progressed?
Dr. Stephen Cunnane: Yes, I’m very proud that we obtained the necessary endowment to launch a clinical research chair in ketone therapeutics here at the University of Sherbrooke. I am the current holder of that chair. Part of the goal is to transition to a new chairholder, a younger person who isn’t at the end of their career, who can carry the ball forward while we have the skill set and all the acquired knowledge we’ve gained over the past 15 years. I’d like to transfer that to someone else’s hands.
Dr. Eric Westman: Tell me the name of the chair again.
Dr. Stephen Cunnane: Research Chair in Keto Therapeutics.
Dr. Eric Westman: Is this a first?
Dr. Stephen Cunnane: I think it is a first.
Financing for research
Dr. Eric Westman: That’s exciting. Dr. Yancy and I changed the name of our clinic to the Keto Medicine Clinic. I think it’s the only one. Leadership is when other people follow, so I’m waiting for the second Keto Medicine Clinic. They are named other things, like Lifestyle or Dr. Smith’s Clinic.
Is there a specific focus now? For those who aren’t researchers, they probably don’t understand that a large amount of your time is spent trying to get funding for your job, your position. To have a chair means it defrays some of the day-to-day need to secure money for your job so that you can think big thoughts or not have to worry so much about funding. Does it come along with money to do some research, too?
Dr. Stephen Cunnane: There’s an endowment, which means there’s an amount available annually to do research. The total amount isn’t huge right now in terms of the annual payment, but it’s there for the rest of my career and for the person who will follow me. It’s a capital endowment, which won’t be touched, so I think that’s good news. It allows for research, and it’s not focused on a specific area of research.
My interests are mostly above the neck, but not entirely. The heart and kidney, as I mentioned, are areas where we’re doing some exploratory work. If a cardiologist, for argument’s sake, were to take over the chair, the direction of the research could change. But it would still focus on keto therapeutics. I think the potential to improve heart function is as important as improving brain function, and possibly renal function. There’s a huge amount we can do with metabolic improvement. We call it Keto Therapeutics now, but we may end up calling it something else eventually.
The point is to give ketones their due, without trying to create anything magical about them. They’re not a miracle, but they are an important part of our energy metabolism and overall health. Let’s give them their due, and that’s what we’re trying to do.
Do kidneys create ketones
Dr. Eric Westman: Sometimes we learn from new drugs and their side effects. For instance, SGLT2 inhibitors, which allow the kidney to leak glucose, can also cause ketoacidosis, which wasn’t an intended outcome of creating that drug. I don’t know if anyone truly understands the mechanism yet. I remember a young endocrine fellow I crossed paths with a few years ago. He said that in animal models, when they gave animals that drug, the animals died, and they didn’t know why. I thought we needed to figure that out. What he started to suggest was that the kidneys were creating ketones. Is that right? It’s not in the textbooks.
Dr. Stephen Cunnane: I don’t know if that’s true for SGLT2 inhibitors. The kidney can produce ketones and probably does in people who are in ketosis through carbohydrate or energy restriction. It’s probably the case.
Dr. Eric Westman: Is there any research going back to starvation studies where they might not have been looking for ketones but could see how much was being created?
Dr. Stephen Cunnane: It’s obviously difficult because it’s quite invasive to find out what the kidney is metabolizing. I don’t think anyone has done arterial-venous difference across the kidney. With PET imaging, we can get some insight into this almost non-invasively.
I think there are two sides to the SGLT2 inhibitor story in relation to ketones. There are cases where people go into ketoacidosis, but would they have anyway? I’m not sure. What’s clear is that cardiovascular mortality is going down in people on these drugs, so the ketones aren’t killing them. I think the ketones might be part of the beneficial effect.
There’s also interest in studying SGLT2 inhibitors in Alzheimer’s disease. I’m not sure of the scope of all the studies, but there’s enough momentum around this area that there will be some fatalities, and there will be issues. Some people shouldn’t be on these drugs for good reasons, but a lot of people will benefit from better glucose control. The question is whether they could achieve it by a different means than using an SGLT2 inhibitor, and that’s still something to figure out.
Dr. Eric Westman: In the clinic I’m in, I get the liberty to be very patient-focused, so if I can try something lifestyle-related without a drug, I can do that. I don’t create a policy and worry about using drugs and their side effects, but I never saw ketoacidosis in a keto medicine clinic until the SGLT2 inhibitors came out.
So, the drug raises the risk of ketones and ketoacidosis in those on a keto diet. I use that as a caution, and the Virta company just makes sure that people measure their blood beta-hydroxybutyrate ketone levels while they’re on that. I haven’t talked to them lately, but I don’t think they stop it altogether. However, I will explain that the diet is stronger, and you just need to be more patient. These drugs, which are the darling of cardiologists and other doctors, don’t always understand the power of lifestyle change. I can explain this.
The Department of Defense has funded Dr. Phinney and Dr. Volek to do a study on ketone administration and a keto diet for heart failure. I think this awareness came from the fact that they used a drug to find out the mechanism, and then they circled back to the keto diet as a possible mechanism.
Dr. Stephen Cunnane: You mentioned a few minutes ago that one of the signs of success in research or in the clinic is when someone else starts doing what you’ve been doing. I’m sure you’ve seen that. You mentioned heart failure and this funding from the Department of Defense for Dr. Phinney and Dr. Volek. I think what stimulated them was an interesting trial that was run in Denmark a few years ago. They have started using ketone PET imaging since we were doing it. They are primarily looking at the heart, and they’re showing that the heart’s energy dynamics improve a lot with a ketone infusion. They started with an IV infusion, but that’s helping to show some of the physiology, metabolic aspects, and performance benefits for the heart under essentially normal conditions.
This is a second site doing ketone PET imaging, and we’re starting to collaborate with them and work on projects together. It’s been very rewarding.
Benefits from following a low-carb or keto diet and potential concerns
Dr. Eric Westman: How would you suggest someone benefit from following a low-carb or keto diet, knowing you’re a PhD and not an MD? Are there any potential concerns from your perspective? What practical advice could you offer? The researcher I spoke to, who was doing IV ketone administration, didn’t know much about a keto diet. So, there’s a lot of siloed information; it’s kind of crazy.
Dr. Stephen Cunnane: I want to tell you a short anecdote to prepare my answer. Older people seem to struggle a little bit. Most of my work involves older people and the diseases that affect them. I thought, in a retirement home, for instance, where everybody is eating the same thing, you should theoretically be able to change everyone’s diet at once. If it’s ethically possible, is it logistically possible? And if so, how long do you do it for?
We started with something simple. You and I had a conversation about this a couple of years ago, and I told you I was going to start with a 30% reduction. You asked, “Why go halfway?” But for better or worse, that’s what we did. The paper has just been published, or at least accepted last week. This was in a retirement home with 83-year-olds, and most are very particular about what they eat. If there’s too much of something one day and too much of something else the next day, they’re never happy. So this was a good test case.
For two months, we had 83-year-olds on a 30% reduction in carbohydrate intake. Their LDLs went down, triglycerides went down, and insulin and HbA1c levels went down. They wore glucose monitors for 10 days at the beginning and 10 days at the end. Their baseline glucose went down, and their postprandial glucose went down. And they liked it.
You asked for practical advice, and I thought, well, 83-year-olds are a population at high risk for Alzheimer’s disease, and their ketones doubled. It wasn’t exceptional, but by improving insulin control, you allow for a bit more of a trickle of ketones to be produced.
So, practically speaking, it shouldn’t be that difficult to reduce your carbs. These folks had two desserts per day – lunch and supper. It was a non-starter for them if they couldn’t have that, but we found ways to make it work. A 30% reduction isn’t dramatic, but it’s a start.
It’s feasible, and it’s feasible in this environment where you’re at a higher risk. Eventually, you should presumably be able to reduce your dependence on insulin if you are type 2, or on other medications, like anti-glucose-lowering medications, which we haven’t gotten to yet. The proof of principle is that it’s doable. Their meals are on a two-month cycle, which means we can repeat that cycle every two months, and the kitchen has figured out how to do it, which is a significant challenge.
That’s a simple, practical thing. You don’t have to be 83 years old to do it, you can be 33 years old and do it. Just think about consuming less refined sugar and start there before you get type 2.
Is Alzheimer’s disease type 3 diabetes?
Dr. Eric Westman: A patient of mine asked me to speak at his retirement center recently, and half the people there had type 2 diabetes. My final question is, is it really true that Alzheimer’s is type 3 diabetes? What does that mean, anyway?
Dr. Stephen Cunnane: It’s diabetes affecting the brain, and whether it’s type 2 or type 3, I don’t think it matters to most people. The problem is that the glucose is not getting in, and part of it is because insulin has been blocking that process. Insulin is part of the problem, not only blocking glucose but also preventing the production of the backup fuel at the same time. The hybrid car is breaking down, and what we’re trying to do is get the hybrid car to work better on both fuels.
Latest on keto diets for neurodegenerative diseases
Dr. Eric Westman: I get a lot of questions about whether a keto diet can help a loved one with clinical symptoms of Parkinson’s or Alzheimer’s. What’s the latest on keto administration or keto diets for neurodegenerative diseases?
Dr. Stephen Cunnane: I’m preparing an abstract for the next Alzheimer-Parkinson meeting on 10 Parkinson’s patients. I wasn’t able to find any good data on whether there’s a problem with brain glucose in Parkinson’s, but in fact, our study shows it’s actually more severe than it is in Alzheimer’s disease. It’s definitely present, and type 2 diabetes is a big risk factor for Parkinson’s disease.
The capacity to use ketones is still intact in Parkinson’s patients, based on this study. When you combine a ketone supplement with exercise, you enhance the ketone transport into the brain, both in Alzheimer’s and Parkinson’s. So, don’t put all your effort and money into a ketone supplement. Get out and walk if you can. If you’ve got Parkinson’s disease, you might be walking with a cane, or maybe you’re unable to walk. You should talk to your doctor about what type of exercise you can do, but if you’re able to get out and move, it’s going to be part of the solution.
One quick anecdote about this: I met someone who was 61 years old at the time and had had Parkinson’s disease for 14 years. I ended up talking about the work we were doing and asked if he wanted to see the lab. He said, “I’d like to know what I should be doing.” I told him to meet our dietitian and reduce his carb intake. I suggested trying a 30% reduction to start. Within two weeks, he was on a fully ketogenic diet.
He would have been one of your disciples in the sense that he didn’t go halfway, he went all the way. His cognitive performance improved, his balance was better, and the vocal problems he had, such as the cadence of his voice, became much stronger. I’m not saying we solved the disease, but it’s clear to me that reducing carbs and increasing ketones seem to be part of the solution, potentially for Parkinson’s as well. We’ve got the scientific proof that we’re addressing an energy problem, an energy deficit in the brain, that is clearly present and hopefully can be corrected.
Dr. Eric Westman: Can I put on your list of research and studies to figure out which cells in the human body require glucose, which cells can use ketones, and which cells can use fatty acids? It’s basic physiology, but no one seems to care. Especially when it gets so far afield that a heart doctor thinks the heart muscle uses sugar as its main source of energy. There’s some basic physiology about what cells do that we need to blaze a trail on.
Dr. Stephen Cunnane: Absolutely. Things get labeled as good and bad, it’s very black and white. Ketones are seen as bad at the moment, like lactate; they’re the black sheep of metabolism.
Dr. Eric Westman: No, I’m way beyond that language. Ketones are great, they’re fine.
Dr. Stephen Cunnane: That one-on-one interaction in a clinic, with that sort of demeanor and emotion, is important because patients go to other doctors who have panic attacks when their LDL goes up 10%. I think one area that is emerging is in metabolic psychiatry, where antipsychotics have a devastating effect on brain energy metabolism by the looks of it. People are trying keto interventions with some success in some cases. It’s very early, and we’ve just been funded by the Baszuki family to do a small pilot study to look at the brain energy status, the ketones and glucose, in people before treatment, people with first-episode psychosis, and then after starting whichever drug is preferred by the patient and the psychiatrist. We aim to see what the situation is with the brain when they are actually experiencing this type of psychotic situation, and to what extent that is made worse by the antipsychotic. Again, we are trying to see inside the brain in order to optimize treatments that could be used.
Dr. Eric Westman: Thanks to the Bazuki group for funding these studies. They’re funding more research on ketones and the brain than is fully accumulated at the moment.
The final thing I’d like to say to those who are listening is, when we talk about brain energy, where it is makes a big difference. It was explained to me once that imaging of a brain sometimes is kind of crude, and it would be like having a microphone in a stadium of 30,000 people trying to figure out the signal from one person. The brain is heterogeneous, where dopamine and substantia nigra would be the areas in Parkinson’s disease, but parietal regions, as you’re saying. What a wonderful way to break down based on ketone and just fuel use energy metabolism.
It’s exciting to see, but would you say this research is in its infancy?
Dr. Stephen Cunnane: Well, it’s a hundred years old, and so, if we’re still toddlers at 100, we’ve got a long way to go. Yet, the sad thing is that I think we have enough information to make these changes, but there’s still cultural resistance, especially among the baby boomers who are getting these disorders, and perhaps the medical establishment as well. We’re not using the information we have, and we’re saying we need to do more research. Sometimes I’d like to say that’s BS because we’re not using what we have. The tools we have now are sufficient to justify these changes, and yet there’s resistance, and that’s unfortunate. In some ways, we’re in toddlerhood for sure because that transition is happening extremely slowly.
Dr. Eric Westman: It seems like we’ve gone through an era of carb-centric, glucose-centric metabolism and all of the damage that it does. Researchers and clinicians, being in a position of power, can say, “You need to do more data.” When I look back, Jeff Volek and I did a review in 1998, and there were no studies saying a keto diet was bad. Yet we still felt defensive, like we had to assemble the data behind it. Now studies have been done all over for obesity and diabetes, and hopefully now in mental health and other neurodegenerative diseases.
I’m excited. I think there’s great potential, and yet there’s also a lot of potential for misunderstanding, getting this information directly to the consumer. Again, I’m thrilled to know that you have a beachhead, if you will, a place where you can study freely. Hopefully, the cardiologists aren’t giving you grief.
Dr. Stephen Cunnane: We’re doing a study with a cardiologist in heart failure and his patients. It’s just an acute study, but just start one thing at a time, first things first. So, it’s coming.
Dr. Eric Westman: It’s great to see you and talk to you again.
Dr. Stephen Cunnane: I’m delighted. Thank you for inviting me; it’s been a pleasure chatting with you.
You can watch the full video here.