The Silent Fuel Crisis Starving Your Brain | Dr Stephen Cunnane

[00:01] insulin resistance in the brain and there's probably insulin resistance in the rest of the body as well. And that means that the body's not able to produce ketones because the insulin is blocking that.

[00:13] The insulin is telling the fatty acids, you stay in storage because we got enough glucose. The problem is the glucose isn't getting brain. So, the brain ends up in double jeopardy

[00:26] because the insulin resistance is blocking the uptake of glucose by by several organs, muscle included, but the brain to some extent as well. But the and the liberation of the fatty acids that will become the replacement fuel as

[00:41] that will become the replacement fuel as ketones. Canada and are one of the world's leading researchers on brain energy

[00:53] metabolism and the role ketones may play in preventing cognitive decline. So, welcome to Modern Healthspan and thank you so much for joining us today. It's a pleasure to be here. So, Dr. Cunnane, I believe

[01:06] [clears throat] that you coined the term the brain energy gap. I mean, people were looking at ketones and and and how they affect brain energy before that, but kind of the brain energy gap as the potential cause for mild

[01:19] cognitive impairment and Alzheimer's was driven by yourself. So, could you explain what is the brain energy gap and and how does it kind of lead to MCI and and other neurodegenerative issues?

[01:36] what we do, Richard, the brain energy gap. I'm not sure if I coined it, but we realized that that's what we were dealing with and uh what I think is important to understand is that um

[01:50] there's a problem getting the main fuel into the brain as we get older for most people. Uh it's not universal, but it's it's quite widespread and the main fuel is glucose. But the brain is a hybrid car.

[02:06] So, it's running on two fuels that are complementary. The second fuel being ketones. Uh and the energy gap was just assumed to be a function of the brain cells that were

[02:20] supposedly dying as the the Alzheimer's disease uh evolved and progressed and advanced. Which is is logical. A dead cell doesn't need any energy. So, um if the cells are dying, then you'd expect to see less

[02:37] fuel uptake in general. But it's in general. So, that should apply to ketones as well as to glucose. And we set out to establish whether that was the case. So, how do you do that? Do you use

[02:51] what's called PET imaging, positron emission tomography, which is familiar um to to people to physicians in in who are studying cancer because it's a way of identifying cancers which are very metabolically

[03:06] And there's a a form of tracer, it's called a tracer um for glucose, which is taken up by tumors and lights up that part of the body that's got a tumor in it and it's easy to see uh where that is.

[03:20] It's also been studied we studied the metabolism of energy metabolism in the heart and in the kidney and in in the brain and elsewhere. So, it it's not just for cancer studies. And what FDG, it's called

[03:33] fluorodeoxyglucose is the tracer or FDG. And that tracer showed over 40 years ago at the dawn of PET imaging that there was a problem getting glucose into the parietal cortex just above the ears as

[03:48] parietal cortex just above the ears as Alzheimer's disease developed. fuel, then then that's a a general global problem. And we said, well, ketones can be are are generally a minor fuel, but they can be the major fuel if

[04:04] uh fasting or if you've been starved for an extended period of time. Um which has been done in metabolically in in in medically controlled studies for obesity, for instance, 40 40-day

[04:17] starvation. It's gone out of style these days, but it was relatively common um to just go into a total starvation to lose weight under medical supervision and that ketones become the major fuel of the brain.

[04:31] glucose uh and they are a a critical supplier. So, that's where the idea of the hybrid brain comes from, the hybrid car. There as a reserve uh to to replace the glucose. So, if

[04:46] there's a problem getting glucose into the parietal cortex and you have a method of measuring ketone uptake as well as the glucose uptake, establish if the cells are dead, then they won't

[04:58] the ketones either. And what we showed with the PET imaging technique for ketones and for glucose, we repeated what had been shown umpteen dozen times with the glucose, the FDG tracer,

[05:13] but the ketone uptake was normal. And we were sort of impressed and intrigued, excited, but worried as well because it seemed a little implausible. because it seemed a little implausible. And we repeated it. We also showed that

[05:28] if you gave a source of ketones with medium-chain triglyceride to an Alzheimer patient, the uptake of ketones went up in that part of the brain. It's not just that the trickle of ketones was still present, but they those cells

[05:41] could actively metabolize more ketones when they were available. Well, then we started to get excited. And then we came across studies that had used different techniques which showed the same thing. That in fact this is a

[05:54] robust observation that is not just an imaging-based method, but other types of methods as well. So, I think that's that's what drives the concept of the brain energy gap. Yes, there's a problem

[06:06] getting glucose into the brain and it gets worse as Alzheimer's disease develops. So, the ability to take up that glucose and use it goes down and that's what the gap is. And what we're trying to do is say, well, if ketones

[06:19] can be taken up normally by the brain in the same individuals in exactly the same circumstances, how can we reduce that brain energy gap by providing a source of ketones to those individuals? Is there So, I believe that the brain

[06:36] uses less energy as we get older. I mean, is there like a fundamental between the way this happens in Alzheimer's and just normal aging or is it just a kind of a scale and one side has even more

[06:52] like energy gap than normal aging? Well, it it's it's a yes, you're right. Well, it it's it's a yes, you're right. There is a trajectory downwards um in utilization of glucose and in some ways the older brain is more efficient.

[07:06] Uh for the same number of grams of glucose, you actually get more cognition That's one that's the positive spin on it. Um And that trajectory gets gets more acute um

[07:19] uh in in mild cognitive impairment. In in healthy older people with mildly reduced glucose uptake, we're talking about a difference of 5 to 6% less than than than a younger adult. And again, it's I was a bit facetious,

[07:33] actually more efficient or it could be that it's it's actually got less reserve, less wiggle room to to to do what it should be doing. Um So, that there's less redundancy. But in either case, that 5 or 6% is not in the

[07:48] parietal cortex, it's primarily in the frontal cortex for better or for worse. It's not in the same areas in MCI. So, it's it's quantitatively more severe, impairment develops and the regions of the brain that are affected are not the

[08:04] Uh eventually in Alzheimer's disease, it's it's a virtually universal problem except in the cerebellum, probably, and and in some deep subcortical nuclei, the deep nuclei in the brain are less affected. So, it's

[08:19] there there's a nuance that we should put on it between healthy aging and and MCI. It's it's not the same change and and it's not diagnostic either, but it is uh it is different.

[08:32] uh Alzheimer's is sometimes called the like type 3 diabetes because you you can't get glucose into the brain. Why is that specific to a region, the parietal region? So, I mean, I thought

[08:48] like diabetes, type 2 diabetes was kind of universal. Your body just didn't use glucose, not specific areas of it. So, it does the rest of the brain continue to take up sugar properly or

[09:02] not? Does the rest of the brain So, um first of all, um the glucose problem is not um disease can't take up glucose. It's still taking about

[09:17] about 70 to 75% of the glucose it should be taking up. That's that's the good news. But 70 to 75% of a you know, it's still 25% of what it should be, which is the bad news because that is definitely associated

[09:31] with the decline. But it's not that the brain can't take up glucose. Now, let's let's be clear that you you wouldn't you wouldn't survive if that was the case. And so, why in the parietal cortex? That's it's a good question. I I don't

[09:44] think anyone knows. Um I mentioned the parietal cortex cuz it's easier to the middle of the brain between the two hemispheres uh not far from the parietal cortex. It's called the precuneus. It's an area that

[09:58] is also affected. And so there are some some deep brain areas that are are guess is a bit more symbolic of of the disease rather than it being the exclusive region that's affected.

[10:14] region that's affected. So how come ketones are still taken up? And so yeah, how how do ketones work differently from glucose so that they can still be taken up by the brain and used as fuel?

[10:26] Well, they have a different transporter. It's a different type of molecule and It's a different type of molecule and the the transporter for ketones glucose. Plus ketones, it's a relatively short

[10:38] metabolic path between the ketone body and the mitochondria and the ATP Whereas glucose, it's a sequence of about 10 steps and each one of them will

[10:50] block if if it's not working. Each one of those steps would affect the glucose getting into the mitochondria. Um so the bottom line is that the the transport of ketones seems to be normal. And the metabolism of ketones from what

[11:04] we we know and that's not the PET studies, it's it's the studies that have involved in converting ketones to to carbon dioxide basically at the in into into the mitochondria and those enzymes from the studies that have been

[11:18] published are still normal. So as the disease gets worse, I could imagine the ketone uptake does get might of those cells have died and some more will die, but there's enough of them

[11:31] that are alive to to do the brain's business especially in the parietal cortex which is affected that you can slow that process down. Uh those cells are starving basically because they're not getting their main

[11:44] And I think it's perhaps the time the moment to to bring up a critical point in this story which is that utilization of glucose by the brain is dependent on the demand on the call for glucose from within the brain.

[12:00] It's not the amount that's circulating in your blood that determines how much So you can have a bowl of ice cream now and you know eat 150 g of glucose. It's not going to change the availability of glucose in the brain by one molecule.

[12:19] Ketone uptake by the brain is driven by plasma levels of ketones. helpful if we're going to use ketone supplements

[12:33] to try to correct this brain energy gap because all it depends on is getting enough into the blood. And during our evolution, it makes sense system that the second fuel be able to react

[12:48] quickly to the absence of the primary fuel or not the absence but a decline because you're trying to save that person from going unconscious which is a process that only takes a few seconds if there's not enough blood flow or enough

[13:00] Um and and same is true for glucose. So if the glucose starts to become limiting, the body's got to be reacting very quickly and the transport mechanism has to to kick in really quickly to switch over. It's not like a computer in

[13:13] your car that decides can oscillate perhaps between the gas engine and the electric motors constantly according to some algorithm. Um in fact, the computer in your brain or in the body is insulin.

[13:26] Insulin is deciding whether your brain is going to use glucose or whether there's not enough glucose and therefore insulin goes down and that allows ketone production by from the adipose tissue fatty acid stores. The fatty acids are

[13:40] sent to the liver and they can be be converted to ketones when insulin is low. And you mentioned type 3 diabetes a moment ago. Whether type 3 diabetes exists as a

[13:52] separate syndrome or or or not, the problem is still that there's insulin resistance in the brain and there's probably insulin resistance in the rest of the body as well. And that means that the body's not able

[14:05] to produce ketones because the insulin is blocking that. The insulin is telling the fatty acids, you stay in storage because we got enough glucose. The problem is the glucose isn't getting

[14:17] brain. So the brain ends up in double jeopardy because the insulin resistance is blocking the uptake of glucose by by several organs, muscle included, but the brain to some extent as well. But the

[14:31] and the liberation of the fatty acids that will become the replacement fuel as ketones for the brain. So some of our work is suggesting that the heart

[14:44] situation. Uh ketones are not an important fuel for the heart normally, but they seem to be a good backup backup to but we don't need to go into the

[14:56] specific to the brain this this type of issue and this this hybrid organ concept. It's not just a brain-specific problem. we see that the brain takes less glucose as we get

[15:10] Does it also take less ketones or or they're available? So it's a question of the supply. Um and if if you if you're not in let's take the the the best-case scenario.

[15:25] You're not insulin resistant. You're 75 years old or what whatever age it is, it's going to depend on um the insulin levels postprandially. So if an excess of carbohydrate, the insulin will go up, but it'll go down fairly

[15:40] postprandial period after So postprandial after a meal of say 3 to 4 hours and the insulin will be low and ketones will be supplying energy and there will be this metabolic switch between the two fuels on a constant

[15:54] Uh and and that's what seems to be failing as as we get older because we end up with this creep towards prediabetes and insulin resistance as we get I guess over 65 really. It's it's fairly common.

[16:09] Um and and it's so it's a function of what you eat. It's a function of of the degree of exercise that you do and and those are sensitivity.

[16:21] If you keep your insulin sensitivity in a in a reasonable range how how would you Well, that will first of all allow this this fuel exchange to But how do you do that? Well, by by limiting your carbohydrates

[16:37] and by doing a certain amount of exercise and by respecting your calorie requirements which is not overeating especially refined sugar which is the main sucrose is and and fructose are the main

[16:51] culprits in contributing to insulin resistance. we get older most people. If if you're in a nursing home you know where there's desserts on the on the coffee counter all the time or

[17:06] frequently and I've worked in that that setting so I know I know a little bit Um and and you can monitor this with with continuous glucose monitoring and and we've done studies in in

[17:19] and we we've shown that you can still improve in in 84-year-olds. You can improve their glucose metabolism within days of reducing carbohydrate intake, but not radically. It doesn't have to be a

[17:33] ketogenic diet where you've reduced carbon intake on average by 80 to 90% compared to what most people eat which is more radical than most people can tolerate for for very long. But a 30% reduction from the typical

[17:47] menu in where we did the the study still meant they were getting 130 g of Um and but their ketones went up slightly. But the point was their glucose postprandial glucose and fasting glucose

[18:01] came down almost instantly. So the system is sort of overcharged with glucose and therefore overcharged with insulin and therefore undercharged with ketones and the whole thing is out of balance and and the brain suffers as

[18:15] Right. And yeah, I would love to talk about that in a bit more detail, but so the but first I'd like to talk about the Benefit Trial.

[18:28] So the So the theory is, right, that we have this energy gap and and the root cause is that the glucose is not taking up, but we can kind of address it with uh ketones.

[18:40] So you ran a trial, the Benefit Trial, where you were you were giving people exogenous ketones, well, MCT oil. So could you could you talk through the Benefit Trial?

[18:55] You know, what was the design? How many people were there? And what was some of the key outcomes? So the Benefit Trial was controlled trial of of medium-chain triglyceride in mild cognitive

[19:09] Um it was funded by the Alzheimer's Association of the USA. Um and we had a a ceiling. We had a budget that allowed us to study call completers, people who have completed the intervention

[19:24] uh in both groups. So a placebo group and an active group and I think we had 19 in one and 20 in the other. Um and it was expensive because we were doing the brain PET imaging, the glucose and the ketone uptake at the start

[19:38] and at the end of the study because the purpose was a metabolic outcome. The purpose was to establish to what extent have we improved the metabolic status what extent have we reduced the brain energy gap

[19:52] in mild cognitive impairment. Cognitive outcomes were of interest and beginning and then 6 months later, but they were a secondary outcome because we knew the study wasn't powered to uh be sure about uh whether or not we were

[20:06] onset of Alzheimer's disease in these patients. So, the metabolic outcomes showed that the ketones were getting into the brain. They showed that the uh that uptake of

[20:19] ketones was was variable. Some people had a a big improvement, some people had a smaller improvement, and the improvement in on cognitive outcomes was positively related in terms of memory, in terms of executive function,

[20:33] and in terms of language to the extent to which we reduced the brain energy gap. That's what the first paper on of of Benefit paper uh published in 20 uh 19 showed.

[20:46] And these were people with uh MCI. We kind of clinical which means two criteria for that, three criteria.

[20:58] They had to be over 55 years old. They had to have a subjective memory complaint, which means, "I'm worried about my memory." Yes or no. If the even if your spouse thinks that you definitely should be worried about your

[21:12] your memory, if you say it's no, then you're not eligible. And the third is that on of the five major domains of cognition uh for which we have the battery of tests that we do at at the start, they

[21:25] have to be one standard deviation below the normal value on score for the score on at least one of those domains to be considered objectively uh memory impaired. So, a a mild cognitive impairment, any

[21:41] one of those five domains. Okay. And what was the intervention that that these people were given? They were given 30 g of medium-chain triglyceride per day.

[21:55] So, when we got funded by the Alzheimer's Association, uh we had proposed that we were going to make this emulsion of a medium-chain triglyceride in um in cow's milk in in in um low-fat cow's milk.

[22:09] Um we had never done that before and we weren't quite sure how to do it. We weren't sure how long it was going to last. Uh we we got up to speed reasonably well, but we ended up with a

[22:21] sterilized product that people got an emulsi- emulsification of 30 g of medium-chain triglyceride in 250 mils of milk in each bottle. So, that's what you took per day. Uh to a cup. In American terms, a cup, a

[22:35] 250 milliliters uh of this drink, half at breakfast and uh of this drink, half at breakfast and half at supper. reasons. Our preliminary studies suggested that most people weren't going

[22:50] to take more than that, weren't going to tolerate more than 30 g a day. that and let's hope let's cross our fingers that the you know, enough people are going to finish the study that we can actually uh interpret the results."

[23:03] We didn't know the extent to which 30 g of medium-chain triglyceride would help correct the brain energy gap cuz it had never been measured. been good to know before we'd started, but you know, sometimes

[23:17] uh you don't have all the pieces of the puzzle ready to to to to ask you know, to before starting a what was for us a major clinical study. It was a still us with the PET imaging and the supplement

[23:31] blood samples. Um the it was quite an involved uh study for us to do. Did you Did you look at how much Did you Did you look at how much the energy increased, the brain energy?

[23:46] I did What was that? So, I I I'll give you the the the it has to be qualified by the what I'll say afterwards. So, the say afterwards. So, the the gap was reduced by about 30 to 40%.

[24:01] So, the glucose should be going in it's down about 7 to 8% from where it should be in in a cognitively healthy older person. And we we improved that to down by down by about 4 to 5% instead of 7 to 8%

[24:18] roughly speaking. The but that's that's difficult to um to generalize and that's why I'm sort of hesitating because when you take a dose of these ketones of of the MCT, the ketones go up and but they'll be

[24:33] back down within 2 and 1/2 to 3 hours. So, the degree to which you correct the energy deficit depends on where you are on that curve and at the peak of the ketone levels in the blood, we're correcting about 40% of the energy gap.

[24:46] But for the rest of the time we're we're correcting less than that. supplement, you get a peak maximum of maybe for 15 40% of the energy gap, but otherwise you're contributing you're correcting

[25:01] you're contributing you're correcting zero zero to maybe 20%. So, over 24 if we improve the reduce the brain energy gap by more than 10%, I'd be surprised. Right. So, I was going to ask

[25:14] Right. So, I was going to ask why split the MCT into two chunks? Was it A, to give two peaks or was it to give two peaks or was it to reduce give two peaks or was it to reduce gastric possible gastric problems?

[25:27] gastric problems, we would have split it. We would have split it more than but we were strongly advised not to try to to uh require people to take it more than twice because it's just

[25:40] too much annoyance uh during the day and if you want to go out and play golf this along with you or if you, you know, you're going out on a picnic. All All have for forgetting it or not not wanting to bother. So, two we figured

[25:55] was the most we could expect twice a a day. Um and there were would have been side effects, so we you reduce the side effects, but that could also be All of them started out of out of smaller than those than the 15 g at

[26:09] breakfast and 15 g at supper. They all started about five and within 10 days or so, they were they ramped up and and the intestine and the microbiome seems to adapt under those circumstances better than going in cold turkey.

[26:23] Right. So, I believe the MCT had So, I believe the MCT had uh eight C8 and C10. Um Yes. Yeah. Can you go into any more detail? What What were the percentages and

[26:36] What were the percentages and how kind of sure are you that this is or how how strongly do you feel that this is perhaps the best mix to uh create ketones? But because basically the MCT goes into the liver, right? And

[26:51] then you create ketones from it. Yeah. I So, well, it it it So, and back in 2015 when we started the study, when we got funded, uh there were no alternatives.

[27:03] There was nothing that was available um to to replace them or if they were, they we weren't aware of it in in Canada at the time. And we have a regulatory Canada, which regulates the use of of of

[27:20] natural food products, they call them. So, a ketone ester or a ketone salt would have to receive Health Canada approval to be used in a clinical study, whereas MCT were already on the market in Canada. So, the those are the two

[27:34] logistical reasons why it it it was the it was the the product of choice. The mixture that we used, I didn't know at the time that C8 and C10 actually had a different ketogenic effect. The C8 is moderately more ketogenic than C10.

[27:48] Uh but the two of them together were over 90% of the MCT. Uh 55% and and 35% I think were the ratios for or the percentages for C8 and C10. So, again, we learned in our first study, it's sort of thing you should we

[28:03] didn't actually know that C8 was more ketogenic than C10. Um and but I'm glad we ended up using that product. Um and we were able to produce a placebo, which is is is um

[28:17] absolutely essential in this sort of study because so much of the evaluation is is not subjective, but it's it's open to influence. When when you're sitting across the desk from me doing your test your memory test, your trail making

[28:29] your memory test, your trail making test, um for instance, um it's it's unconsciously it's easy for you to look for help from me or for me to offer help for help from me or for me to offer help from you to you whether it's time or uh

[28:42] something and it if and that's going to happen. you're on and I don't know and you don't know which product you're on, then it it all comes out in the wash. Uh and and the the subjective effects of

[28:56] having a person-to-person evaluation uh is is is reduced and and the again, the placebos are not available for for more ketogenic uh um exogenous ketones

[29:08] that are available today. Um you you can make your own placebo for the ketone uh and for the for the salts um in-house as we did with the MCT, but anyway. So, we were one of the first to do this.

[29:28] And you also checked you checked the the ketone levels. So, they were it it was ketone levels. So, they were it it was successful in raising the ketone levels. Um Correct. And so, the

[29:41] the patient could still have glucose at the same time as as this ketone that the ketone increase. We didn't have any advice except to eat eat as you would normally eat. And and so yes yes they would have been

[29:56] consuming carbohydrate for sure. And and glucose would still have been by far the the main fuel getting into the brain. Just a little bit more on the on the cognitive test. So I understand that what what you you said that it

[30:11] wasn't powered due to I I guess funding. I I guess funding. To be able to really see the cognitive differences. But I think some of them were significant. I mean the P values

[30:24] were significant. I mean the P values were under 0.00 0.05. So can you talk about what you saw in terms of people's improvements in the cognitive tests? Yeah. So let's be clear that the original funding

[30:37] the million dollars that we got from the Alzheimer's Association paid for 19 in one group and 20 in the other group to complete the study. And yes there was cognitive results and yes some of them were statistically significant.

[30:49] halfway through that study we started a partnership with with a subsidiary of Nestle called Nestle Health Science that was quite interested in keto therapies if you will.

[31:04] And they they were aware I think they saw the one of their team spoke to me at a conference when I was talking about the interim results for the for this study of benefit. And we we quickly came to the decision

[31:19] together that it would be interesting to double the sample size of of that of the benefit study in order to get results that would tell us whether the cognitive outcomes were were relevant or not. Whether they could be

[31:35] confirmed by doubling the sample size and if so they'd have we'd have a more robust result. So Nestle Health Science paid for an extension of the study to double the sample size. Those results were

[31:47] published in 2021. They confirmed what the first study had shown and and they extended it as well but there was no imaging done in the second phase of that study. So the metabolic stuff was all done in the first phase.

[32:00] It's fairly fairly expensive part of the project and the project. So we do have the sample size to refer to the cognitive outcomes and we do have the sample size to refer to the metabolic outcomes.

[32:15] And it's a blend between two phases of that project. that project. Okay. So what cognitive improvements did Okay. So what cognitive improvements did you see in the second part of the trial?

[32:28] We confirmed that the episodic memory scores were better in the MCT treated group that language scores were better and that executive function problem solving was improved. We also that was um

[32:44] that was clear. What we also confirmed from the first part was that our different types of imaging that you can do one's called functional connectivity do one's called functional connectivity using MRI scans and and another one that

[32:56] looks at the white matter in the brain. And we showed that of the five major mentioned were robust observations for memory executive function and language. And when we looked at those other imaging

[33:11] techniques we could see effects on the connectivity between brain regions which has an impact on attention which is the fourth cognitive domain. And it also had an impact on the white matter integrity. So the the quality of

[33:26] the white matter in your brain was going up on those participants that had been on the MCT. And that affects the fifth cognitive domain of the of five called processing speed.

[33:40] the metabolic results confirmed that all five domains in fact were responding to five domains in fact were responding to the presence of MCT versus placebo. Um and and that was the outcome of that both

[33:54] studies that we did in the first half of that project. And then stand alone cognitive results without imaging were based on a larger sample size as I mentioned. But I didn't have the imaging to further assess those those the

[34:08] of the brain. Okay. So that was using external ketones really to try and raise the the ketone levels but not changing other things. However you you referred earlier to a study

[34:24] which you did in in a home care and I think it's this is the sage study where you reduced the amount of carbohydrates that people had. So I could you talk a little bit more

[34:37] detail about what you actually saw there and and what um seems that just reducing carbohydrates a little bit would I I don't

[34:50] I'm I'm I'm I'm impressed that it made so much difference. So the the idea behind this was first of all in in a in a residential setting where people are in the same

[35:03] building eating at the same place if you do want to make a at the same counters as it were same menu. If you do want to make a dietary change it's it's an environment where they're all eating the same thing. So that that

[35:17] facilitated the logistics of making a dietary change. So so why make why make this dietary change? Well the benefit study showed that we and that we could have an impact on cognitive function.

[35:30] were eating. I knew they were still mildly insulin resistant. having a negative impact on the brain that we weren't changing.

[35:45] on insulin by reducing some of the carbohydrate in the diet? come into the laboratory and are living each one in their own home setting but it's it's a lot more work as I mentioned than than trying to do it in a

[35:59] eating the same menu. So that was the reason for the context. And a lots of people uh pass their latter years in in in a home >> in a retirement home or a nursing home anyway. So that that tends to be the

[36:14] destination for a for a lot of So it's very practical to know whether their health and perhaps their quality of life. Um and the goal was to do something modest and that was achievable in terms

[36:26] of what the kitchen could accomplish and was achievable in terms of making radical changes that that most of them weren't interested in in making. And and so what would a modest change look like? Um and we had no specific

[36:41] objective except to hopefully see an improvement in the way that the blood sugar was was metabolized. So that's what I mentioned in terms of the continuous glucose monitoring. People wore one of those monitors that has a

[36:54] 10-day lifespan for the one we used the Dexcom. Uh and for the last four days before they made the dietary switch they were they were wearing this so we knew what the their regular diet what their

[37:07] like what their fasting glucoses were to six days once they started the glucose reduced diet what was the impact. And then we did the same thing at the at the other end which was two

[37:21] months later. So wear the the glucose patch for four five days before you stop the reduced carb diet and then continued wearing it while they go back to the the regular diet. And at both ends we saw that the

[37:36] glucose came down well and went up at the end but when it came down the the postprandial glucose after the meals and the fasting glucoses came down in those that were hyperglycemic. And they went up in those when they went

[37:53] back onto the regular diet when they went back to eating more carbohydrates. The goal was also to see whether or not reducing carbs was safe. I mean are we going to induce hypoglycemia in anyone at this age? The last thing you want is

[38:07] for them to lose consciousness when they get up from the table and fall over and and bash their heads and have a you know the the consequences of that we we needed to establish whether that was a risk. Um nobody had a glucose

[38:21] lower than 3.9 millimolar which is on the low end of normal and that you know with thousands of measurements from these Dexcoms over 10 days in in 20 people. Um so we were very confident that

[38:34] hypoglycemia was not occurring because of being on this diet. The other concern was that if you reduce carbs you have to raise something else or they're going to lose weight. So if they're going to be in calorie neutral

[38:47] something's got to go up. Protein went up a bit but so did fat. And you know the perception is that fat is is the boogeyman is the troublemaker is bad for cardiometabolic health and and we wanted to get some data to

[39:00] establish whether that was the case. And in fact all the cardiometabolic markers that we looked at from from weight to to waist circumference to triglycerides to HDL to insulin to hemoglobin A1c they were all

[39:14] within the normal range and they didn't there was no signal that we were inducing some sort of cardiometabolic risk by raising bit. So this was really a feasibility study

[39:27] more than anything. It was the goal was not to look at cognition. We didn't we didn't even measure cognition because that wasn't the point. The point is can we do it? Will it will they participate and is it is it dangerous?

[39:41] And and the answer is to all of those was no, let's go ahead and and take it take it out longer on a larger number of people establish whether there's an effect on quality of life and on on cognition.

[39:56] And by the way, one of the conditions of the patients cuz they all signed a consent form was they wanted two desserts per day. One at lunch and one at supper. And and this was not negotiable. So and

[40:11] so we said, "Okay, we will design this the dietary plan with that proviso in taken into consideration." The brownies weren't quite as big, the scoops of ice

[40:23] is you can eat sugar and reduce your carb intake. It you know, those are compatible concepts if you if you if you're selective components, you can do it. You can it's still

[40:37] The nobody dropped out of the study. And and so it's feasible and ketones went up a bit. apart from the tolerability and safety was that the glucose metabolism

[40:54] Right? And that suggests that insulin resistance was going down and that's good news for most of the body including the brain for all of the body including the brain. Right? So

[41:08] what kind of percentage change for for like carbs to fats was it? it I think it's in the in the manuscript, but the percentage change in glucose, but overall

[41:24] said suggest the glucose came down by 11%. Right. Which is is not a huge amount, but it it's it's more it's not it's it's more it's not to be blown away by an an exaggerated

[41:38] change that's not sustainable. We believe that this is a sustainable change and I think an 11% drop in glucose for the rest of your lifetime is a is very good news. And and in in this residence where we're

[41:51] hoping to set up an extension to this study, the two-month period was the window for the menu cycle. So the menu cycle restarts after 2 months. You don't have to reinvent this carb reduction because

[42:04] figure it out. It's it's it's a repeating. In fact, we're going to do it by the same have the same owner because they all have the same menu plan. So now we can extend in time, but we can

[42:18] extend in the number of participants without going to a a great deal more difficulty in in making the analysis of how where we're going to reduce the carbs in which meals in order to to do this.

[42:30] So I think it's a complimentary thing. Ketones there's no magic in ketones. And we still even even if we we got a lot more ketones into the brain than than we can do with MCT we still need to reduce insulin

[42:45] resistance and the two of them ketones don't do that by themselves. The lucky thing is the ketones can be produced from MCT whether or not you've Right. So a type two diabetic will still make ketones from MCT even if they're

[43:00] insulin resistant. And that that's the good news, but it should still encourage them to correct their type two because it's correctable. it's correctable. Yes and

[43:13] care home care home diets could definitely be improved. So anything you're doing in that area is great. Thank you. Yeah. So if we

[43:26] I love the bit about the you got to have two desserts. Uh so if we were thinking about practical steps that people could take, what what can we take away from from kind of these

[43:40] two studies and your work overall? Um if because one of the things is we do take up less glucose as we get older. So potentially having more ketones around would be helpful and in any case

[43:56] lowering carbs would help keep insulin down. So what would what would your key takeaways be if somebody wants to kind of implement a more brain-friendly

[44:11] brain-friendly lifestyle? but it's it's a it's one of the components and it it's it it seems like an obvious component. It would be an obvious component even if it didn't have

[44:24] an effect on brain ketone uptake. But the interesting thing is it does have an effect on brain ketone uptake in Alzheimer's patients. So I'll come to the take-home message in

[44:36] just a sec, but I want to mention that this is an effect that we never expected, but we were able to measure. And we thought, "Well, if we've got a a medium-chain triglyceride supplement plus they're doing some exercise

[44:49] then for for for whatever given rise in blood levels of ketones, you're actually brain if they're also doing exercise the same day." So that's part of the recipe. So what is the take-home message?

[45:03] Try to reduce your carbs. Get rid of the the the carbs in in your soft drinks, in your fruit juices, in in your candies and and in your fudge brownies to some extent. You know, if you still really want two desserts a

[45:17] day, you can do it, but go with the highest quality of chocolate or or candies or or whatever it is that you really are are stuck on. Reduce it in in your coffee if you can, but try and get rid of the the table

[45:29] sugar basically in your recipes and in what you eat. going to we don't know whether reducing the carbs is actually it's it should be

[45:42] utilization insulin sensitivity in the energy gap? We don't know that for sure. So I I would hedge my bets and say, "Well, reduce your carbs to get make insulin

[45:55] more effective, but still take in a medium-chain triglyceride supplement or a ketone ester if you prefer. You have the budget for it then you have strong enough taste buds to handle the very bitter nature of those supplements,

[46:11] by all means. Don't forget about exercise. Don't forget about sleep. Don't forget about your your social environment because ultimately you know, sleep is important for the reparative process to the brain. And

[46:26] it's underrated, but it's it's crucial in terms of fatigue and the impact life-changing events in in our you know, affect us as we get older. Our spouses and and members of our family die and so on and get sick and it's it's

[46:41] it can be very depressing. It can be a very depressing stage of life. So then you eat less well and then you sleep less well and and you're more tired and These comorbidities all gang up on you in a in in a way.

[46:58] So you need some kind of structure to resist that and and I think lower carb intake modestly lower carb is still going to be helpful. The keto supplement of your choice is going to be helpful. It doesn't have to

[47:10] be MCT. But it is less expensive with MCT. It's more flexible in terms of how you take it whether you take it as a drink >> or put it in your coffee as some do or put it in into soups or or into salad

[47:24] dressings. You don't get it as much as you can into a drink, but don't drink milk, I mean you're not going to put it in milk even though it's emulsion to to make. If you don't drink

[47:37] you know, I understand. So people need to adapt to their own style. If you've your hips, you're not going to be able to walk as much. So what kind of exercise can you do that that you can accommodate and and

[47:51] could do on a relatively regular basis because it's good for your cardiac health, but it's also good for your brain health. Yes, lifestyle always first and and exercise is great, but

[48:05] exercise is great, but so for an MCT, so MCT actually means so for an MCT, so MCT actually means like between six and 10 chain carbons. What what is a good source of MCT? Do you need like an MCT supplement? So

[48:20] there is coconut oil. What does does coconut oil contain enough MCTs and which MCT do you think is like the most effective?

[48:33] 12 to 14. Some exclude the 14s. It's a bit of a chemical definition, but the majority there isn't much 14 in the diet in in any form and there's essentially zero six in the diet of any. So we're boiling

[48:46] it down to 8 10 and 12 carbons primarily. primarily. What's called MCT and you know when you buy it in the store, it's a liquid form. It could be it could include the 14.

[49:00] There won't be any six. I don't think there's any natural sources of six. So it could be a various mixtures of 8 10 12 and 14. In all. The eights and 10s are more ketogenic

[49:14] The eights and 10s are more ketogenic than the 12 and 14. That's for sure. So if you're looking for the ketogenic effect, you need to either eat a lot of coconut oil or you need to to get a specific source of of MCT that has eight

[49:27] and 10 carbons in it. That doesn't mean the coconut oil is inert even if it has a relatively modest ketogenic effect because it has the the fatty acids the medium chain

[49:40] you know when they're converted to salt to soaps that's what we wash our hands with they're an antibacterial so coconut oil is an antimicrobial within the body it does you don't have to eat soap but the

[49:54] the active ingredient in soap is the fatty acids and they are present in coconut oil and so they're antiviral antimicrobial antibacterial and a source and they may be helping reduce neuroinflammation I don't think there's

[50:07] data to to show that for sure but it it's logical so I'm not trying to that coconut oil is is useless Newport and I have a couple of occasions and I I insist on the fact that coconut

[50:22] oil and MCT are not opponents they're they're actually synergistic and the MCT that are making ketones can't do as good a job of oil can so the two of them together are are good

[50:37] partners in this in this story Can you just can you help me with so you did this the study the benefit study on MCT oil will you be taking that

[50:49] forward are you looking at MCT or ketones in any other form with Alzheimer's Yes in two two parts of the answer one is that that Nestle has is running a

[51:02] multi-center trial in Europe right now with about 350 people in it in seven using exactly the same protocol if you will as we did in benefit 30 grams a day it's actually for for 12 months with a six-month open

[51:18] label afterwards it's called CogniKet and that that you can find on the clinical trials registry so that's a very significant sequel to benefit in terms of taking things forward

[51:33] I've just received an important donation and I'm going to be using that donation towards the study in MCI where we will combine exercise MCT reduced carb as we've just been talking about plus a source of omega-3

[51:48] fatty acids as a multi-modal intervention so I'm going to take this in in a relatively big trial we think we'll be recruiting about 700 people into that study here in Quebec starting perhaps as early

[52:04] as late this year but if not next spring Okay really looking forward to that so if I want to keep up with you where where can I go for updates on these where can I go for updates on these trials

[52:22] good a source as any I'm not very good at updating my website and we usually use the videos for that purpose anyway so I do give conferences now and again that get get recorded and and become public domain that's probably the best

[52:36] thing I'm not privileged to see the results of CogniKet until they until results and I obviously don't have any results from the project that we're going to start sometime later this year so

[52:49] at the moment benefit is you know it's out there it's published we're we're trying to do better than making it bigger and making it part of of a multi-domain a multi

[53:03] but it's the story since we published it going on seven years ago now Yeah six years ago Yeah Dr. Kunin I love what you're doing and this it just seems to

[53:19] be that you know Alzheimer's has been stuck and for so long and using your method of trying to use seems to be really

[53:33] forward quickly whereas some of the other solutions seem not to be so effective anyway thank you so much for joining us today it has been wonderful talking with you

[53:47] just add to that point that yes there's been no no notable success with the pharmaceuticals and and I I I often about the energetic side that the drugs

[53:59] that have been at best modestly successful but mostly failures might well have been more effective because the energy problem is still there you can get rid of the amyloid but the cells still need a spark to talk to each other

[54:13] and you need you need something to generate that spark so eventually I'm not saying there's any magic in ketones in fact I've said there there isn't but there could be a synergy between certain

[54:26] I hope someday that that's going to get tested Yeah So thank you for inviting me to chat with you today it's been a pleasure Thank you Dr. Kunin great talking with you