How Ketosis Affects Health and Longevity: Expert Insights from Isabella Cooper, PhD

Isabella: 
It’s not just ketones that begets health. What those ketones are made from, the molecules that make up your body, they really do matter. So, if you’re drinking soybean oil and canola oil, and eating pea protein isolate and soybean protein isolate, don’t actually think, no matter how high your ketones are, I don’t think it’s going to turn out into a health outcome.

Bret: 
Welcome to the Metabolic Mind Podcast. I’m your host, Dr. Bret Scher Metabolic Mind is a nonprofit initiative of Baszucki Group where we’re providing information about the intersection of metabolic health and mental health and metabolic therapies, such as nutritional ketosis as therapies for mental illness.

Thank you for joining us. Although our podcast is for informational purposes only and we aren’t giving medical advice, we hope you will learn from our content and it will help facilitate discussions with your healthcare providers to see if you could benefit from exploring the connection between metabolic and mental health.

PhD researcher, Isabella Cooper, has some fascinating studies looking at ketosis, coming in and out of ketosis, and what it means for your health and how that might impact longevity. She also ties in the evolutionary component and also likes to study what happens with women who are menstruating, the hormonal aspects, all of these fascinating aspects of ketone research.

She’s on the cutting edge, and a lot of this discussion, she does get pretty technical. Her mind is a treasure trove of ketosis and the biochemistry and the health impact. So, some parts do get a little dense and scientific, but hang in there because it’s well worth it throughout the whole journey.

Also, she’s from the UK. So, she talks about millimoles per liter when it comes to glucose. So, just so you know, when she says five for glucose that’s equivalent to 90 milligrams per deciliter or six is equivalent to 108 milligrams per deciliter and seven is 126. So, you might need that reference if you’re US based throughout this discussion.

So with that primer, let’s get on with this interview with Dr. Isabella Cooper.

Dr. Isabella Cooper, thank you so much for joining me today. 

Isabella: 
Thank you for having me. 

Bret: 
Yeah, it’s a pleasure, ma’am. I’m so excited to talk to you about your papers. You’ve had a series of publications out recently about, I guess you could say, this intersection of ketosis and longevity and is it healthy and evolutionary perspectives, and so I want to get into all of that.

But first, you’re a PhD researcher, but what led you to focus on ketosis, hyperinsulinemia? What brought you to this area of research? 

Isabella: 
My first real dive into the science of what begets health or can harm health came from being a mother. Literally, once I was pregnant with my first child and then thereafter, you just start to pay a lot more attention to things, of course, because you’re responsible for another human.

And so, my very first foray wasn’t actually food. It was endocrine disruptors. And it, so it is a different area, but that led me on into all the other things that can mess with your whole endocrine system. And then when we talk about metabolic health and insulin and ketones, insulin is part of the endocrine system.

It’s the hormonal system. And so what we knock out of whack, so to speak, how that’s subsequently harm our health. And so with young children, it was all about nappies or in America, I think you call them diapers, and the exposure to dioxins and how that can affect the endocrine system.

So, that sort of kick started it. And then, of course, it moved straight into the foods. What food should I feed my babies and as they grow up? And I really, I think many people would start off with things like, I don’t know, acidic or alkaline diets, or eat right for your blood type and all these sort of things.

And for me, it was always how can I believe what I’m reading? How can I trust that person? What’s the mechanism of action? Literally, what’s the mechanism? You should be able to work out some mechanisms that make sense and then there should be an evolutionary context behind it as well.

And essentially, it really was to me, clearly I need to go right back to school and do biochemistry and study this properly. So, I ended up going there. And then I very quickly honed in on, we know that with, you’ll hear things like diabetes or obesity increase the risk of all these chronic diseases of aging.

And at the same time, those chronic diseases of aging, cardiovascular, Alzheimer’s, cancer, they’re occurring earlier and earlier, by the decade even. And so, that is an indicator to me that obviously it’s very largely a lifestyle factor driven. And then the other aspect is if obesity and type 2 diabetes has a strong predictor for these diseases, then they must have a very common root origin, something that’s causing them all.

And I went very quickly in biochemistry to the subcellular level, and I saw this common theme amongst all of them. It was mitochondria that being hugely dysregulated. And then, I pretty much through all my studies, always looked at things in terms of how are the mitochondria affected and what role is insulin playing in this?

And so that’s how I came up with my thesis in the end in terms of insulin. Too much insulin chronically over time is really harmful for mitochondria. And you, it’s a very life essential molecule, but essentially, too much of it just acts as an aging hormone really.

And it is the molecule that controls ketones. And obviously, I got into all the stuff about ketones as well. And that sort of led me to this whole world of hyperinsulinemia and ketosis. And then in that world, it’s a bit of a hot topic, not a hot topic, the word ketosis, ketogenic can really upset quite a lot of people.

Yeah, so yeah, that’s where it brought me into the hardcore science a bit. 

Bret: 
Yeah, from diapers to ketones. What a journey that’s, I can see the title of a book From Diapers to Ketones or something like that. But so, in your research, you’ve been very active about looking at, I guess you could say, markers of longevity, right?

Because when we talk about longevity research, is ketosis safe for decades? Is it going to improve longevity? It’s so hard to prove that because you need a 50 year study to have clinical outcomes, and that’s obviously not going to happen. So, we have to measure surrogate outcomes and pick ones that we think are representative. And can help answer or at least inform that question?

What are some of the markers that you’ve chosen to study that you think help inform that question of is ketosis safe long term? 

Isabella: 
Yeah, we can’t do, we could do a whole of life human study, but that would require multiple human researchers to track, obviously, humans over time, which we should because we don’t want to just look at an old cohort against a young cohort.

We want to see the individual persons and their change over time in their lifespan with as much information as possible. So, we have that in animal studies. And the way to ensure, let’s say, confidence in animal studies is having multiple different types of animals.

So, from dogs, cats, monkeys, all the way down to C. elegan worms, and drosophila flies, all the way down to yeast. But if we look at animal studies, multicellular animals, then the best studies for longevity with health, remember living longer with disease is not what we want. We want to live longer with health.

And so these studies, caloric restriction definitely resulted in better outcomes. But what was measured inside of the caloric restriction is that caloric restriction inherently lowers insulin and increases ketones. So, in these kind of studies where there’s been caloric restriction with an addition of ketone ketones on top, or caloric restriction being in ketosis or ketogenic diet, per se, they had an even greater effect on the longevity of these different species.

And we’re talking quite significant differences here, anywhere between a hundred percent increase, so doubling, all the way through to 1.3. So, 30% to 40% increase in lifespan with health span. So, reduction in decline in aging, biological aging, disease and just frailty, in general.

So, not having disease, per se, but your capacity to do things. This was in animal studies, a whole variety of animal studies. So. It’s common theme across these very different types of animals and insects. So with that, then obviously hyperinsulinemia is insulin and then looking at IGF-1.

So, there’s lots of really great publications out there on insulin IGF-1 showing that they are the most strongly associated with morbidity and mortality. So, earlier disease and subsequently earlier death, essentially. So, those are the two that I’m very interested in. But, of course, there’s a bunch of factors that when it comes to blood testing that you have to take into account, such as insulin has a circadian 24-hour rhythm. It has an ultradian, which is like 180 minutes, plus or minus a bit, and a pulsatile rhythm.

So, this means that as it’s doing this big 24-hour change, it’s got this every sort of two, three hour change. And then on top of it, a change that’s going on every five minutes. So, if you’re just testing insulin, there’s a chance you can be catching it at the trough of the trough.

So, it can have this sort of 10 micro unit difference, if not even more. Let’s say you catch insulin at 9 or 10, it could actually be 20, the international unit, micro international units. Hence, you really want to measure a multitude of strong markers associated with morbidity, first and foremost, because a morbidity is going to decrease your lifespan, highly likely, statistically speaking.

And so with that is obviously the leptin, but also things like GGT, gamma-glutamyl transferase, liver markers, essentially very particular ones are much more sensitive. IGF-1 is regulated by the liver and regulated by insulin. Another one is leptin, very strong marker. We have a paper that’s in draft right now for that, that’s very interesting.

But our previous publication showed the huge change that we had in leptin. 

Bret: 
Yeah. So let’s talk about leptin for a second. I’m sorry to interrupt, but I’m not sure if everybody really understands leptin. So, we talked about insulin-like growth factor, but leptin, we think about has to do with like hunger, right, and satiety? And so how does leptin feed in to being a longevity or a health span molecule? 

Isabella: 
Yeah, it’s commonly known as the adipokines produced by the adipocytes. And if you think that leptin is like to do with satiety, you would therefore think, great, more leptin.

I’d be more full. So, that’s a good thing, right? But it’s not just like insulin. We need very little of it, but we need to be super sensitive to it. And where you have a situation in life where you’re constantly signaling leptin and insulin over time, it’s like your kids constantly screaming at you or you are screaming at your kids, come to the dinner table, they start not listening to you.

So, exactly the same with the hormones. The cells start to not listen for particular things let’s say. However, that’s for satiety. So, you can see there’s a relationship with hyperleptinemia longer term over time. it’s not working for the for satiety regulation, unfortunately. So, there’s a resistance to that signal.

However, leptin does a bunch of other things that your body doesn’t become resistant to. That is things like producing estrogen and increasing, so the whole, increasing the gene protein product aromatase, which helps produce more estrogen. Increasing things like vascular endothelial growth factor, VEGF, which you know, these are indicated in breast cancer as an example, ovarian cancer, these sort of things.

So, chronically-elevated leptin, and we are not even talking outside of the reference range because the reference ranges are far too broad. And having a look at your insulin, having a look at your leptin and your IGF-1, if they are moving in an upward trend year to year, that is not a good sign.

Because it’s, we always hear this thing, oh, it’s just part of aging. Oh, it’s just part of aging. No, it’s actually lifestyle. And so you don’t want to be seeing these numbers going up year on and year end. So, if you see them going up, there’s something you need to change in your lifestyle. They’re staying the same and they’re on the lower ends of the reference ranges, then you’re doing fine.

But leptin, yeah, it’s quite, it’s a very interesting one. So, we had in our last publication, we had leptin, we showed it in that paper. 

Bret: 
Let’s talk about the publication because it was so fascinating. So, you took 10 healthy women, who were in ketosis for, I think it was like up to four years or average of around four years.

They were continually in ketosis, and you took them out of ketosis and measured what changed, and then what was, I think, 21 days and then they went back into ketosis and measured what changed again. So, a really interesting experiment to say what happens when you come out of ketosis and then when you go back into ketosis.

So, with that experiment, what did you find? What were some of the main takeaways? 

Isabella: 
Yeah. Because a lot of people say that long-term ketosis, chronic ketosis is really bad for you, aside from the fact that they say it’s not sustainable. Clearly, with this cohort, very sustainable.

And they say it’s bad for you in the sense that if you restrict carbohydrates, you are going to become carbohydrate intolerant. You could say the same if If you stop drinking alcohol. You’re going to get drunk easier when you do drink a bit of alcohol, this is probably true. And temporary intolerance doesn’t necessarily mean it’s disease giving, in that temporary short time that you would have it.

But it was interesting to want to investigate. Let’s first have a look at the baseline of long-term keto people who have never had disease. Because really we’ve studied relatively well people who have disease, who have then gone into ketosis, and what they look like from that. But we don’t really know, what does long-term ketosis look like in a modern western world rather than just studying tribes and things like that.

And it’s not fasting, per se, which is quite an intensive thing to do. And obviously, you can’t sustain over a very long period of time unless you start off being morbidly obese. This is what we wanted to answer. And also, we were very fortunate that all of these ladies were quite an age spread from 18 to 37 or 38.

None of them were on hormonal birth control, which is really important because we are looking at growth factors and hormones and all these things. And so, it’s quite important to understand physiology in its natural context. So, a lot of studies that are in females, there’s a very high exposure of the obviously birth control hormones, things like that.

And unfortunately, other kind of medications, like antidepressants and these sort of things are going to interact and change things inadvertently in a study. We also didn’t tie in the study according to menstrual cycle because we couldn’t because of the way the phases were structured. But that actually gave us something else, which was when you look at all our data, they were normally distributed with incredibly tight standard deviation, which actually indicates how strong these markers are and how strong the intervention, the phenotype of being in sustain ketosis versus out also is.

So, we saw metabolic flexibility. All our participants stayed within the under under 25 BMI, like very under. So you know, even out of ketosis for 21 days, there was weight gain, of which, half of that weight gain was water weight.

All of the weight gain was lost. But the average weight gain, I think it was like, two, two and a half kilos, of which at least one and a half to two would’ve been water. And they all lost it immediately after they went straight back to baseline.

And with that, we saw early markers that change that, some things you would think would change but, didn’t actually change. And so, things like TNF-alpha, CRP, people would think to look for these things because we want to understand what’s changing. First because if you always hear from people, it’s inflammation that causes insulin resistance and hyperemia.

So, we didn’t see anything with regards to CRP. We didn’t see anything with TNF-apha. We didn’t see anything in any of the interleukins. So, therefore, all of those markers, given that we saw this huge change in insulin, we saw a huge change in GGT, we saw a huge change in leptin. You can’t say that those kind of inflammatory markers were first movers and therefore causing the change.

Bret: 
So, you saw the insulin resistance changes without the inflammatory marker. So, there’s something else as the causative effect. 

Isabella: 
Exactly, exactly. 

Now that doesn’t mean inflammation cannot cause insulin resistance. It’s just that in the general scheme over time, if we consider that there are a lot of people who are trying to live healthly, whether it’s well-informed in terms of carbohydrate restriction and non-hyper processed foods, Were going to see change over time where you would see insulin resistance hyperemia, which essentially are one in one in the same thing really. Although insulin resistance is considered to be where you cannot regulate blood glucose into the u glycemia range, right? So this is why I often, so first and foremost.

If you’re staying in the euglycemia range, and some people say that’s a cutoff of 5.5 to 5.6 millimoles of glucose, then you are not insulin resistance as long as your glucose is staying in that range. So, you can be Hyperinsulinemic, but your insulin is inside of the reference range. So, you are already in some sort of subclinical occult level that’s actually keeping glucose in this perfect looking number, and can be quite misled to think that if I take a fasting blood glucose, I’m perfectly healthy.

HbA1C can be looking really good for 15, 20-years because the insulin’s been keeping it looking really good, too. So you can miss all of these earlier phases where you want to do some sort of lifestyle intervention or be aware of it much earlier. And ultimately, in terms of the clinical world, it’s going to, we know that doctors are pressed for time.

But ultimately a blood test and getting a blood test panel is going to take less time than going for an MRI, a CT scan, biopsies, any of these things are much more time intensive, resource intensive and expensive. So, we want to know what are all those early markers that really they, when you see in our trial, they significantly changed.

You know, these markers really significantly. Again, they were all inside of the reference range. So, you go, so what’s inside the reference range? If it moved 50% to 70% upwards in the reference range in 21 days, how about 21 years? And the fact that they all came back to their baseline shows how much lifestyle can affect these markers.

And given that, we look at some studies and we understand insulin is predictive for this hyperinsulinemia, HOMA-IR is predictive for these disease. GGT predictive for these disease. Leptin predictive for these disease. How about in our study? We got all of them. We saw them all move in that direction, and we were able to bring them all back once they went back into a lifestyle that didn’t suppress ketogenesis.

Bret: 
Yeah, so you bring up so many fascinating points there that they were still within the normal range. So, pushback would be what is that truly reflective of a disease process? And you bring up such a good point though. It was 21 days, and so what’s going to happen down the road? You couldn’t do a 20-year study, but it’s clearly a move towards higher insulin, higher IGF-1 resistance to those.

So, something you definitely do not want long term. And so interesting that they came right back into the normal range because, like you said, there’s always this question, this is insulin resistance. Keto gives you insulin resistance, but really it doesn’t because it’s not pathologic, right?

It’s not the pathologic insulin resistance. It’s just we’re using the same framework of interpreting the blood test as if you’re eating high carb or if you’re eating keto. We, and we can’t do that. So, that’s my little soapbox. But anyway. 

Isabella: 
It’s also because that idea of insulin resistance is understood in the context of just glucose regulation.

That’s it. And so what’s been shown quite nicely is the fact that where glucose is not being taken up mainly by muscle cells, let’s say, and therefore, one would say your insulin resistant. That’s only resistant to insulin getting that glucose out of the bloodstream. It’s not, the rest of your body is not resistant to the insulin, and everything else it does.

And it’s actually quite arguable that insulin’s primary job is not regulating blood glucose. That is an acute job for an emergency situation. So, whether it’s because you decided to eat a whole load of honey, or come across a very stressful event that, whether you’re evolutionary running from danger and you have a spiking blood glucose, then you know insulin’s going to come into action again.

If you accept that restricting carbohydrate to one’s personal threshold, the threshold being that doesn’t suppress ketogenesis, then you under start to understand insulin has this whole other job. That’s really actually what its real job is, which is regulating growth and division.

Things like that because we know, no insulin is equally dangerous. It’s pathologically dangerous. We see this in type 1 diabetics. So, insulin makes sure that we can grow our muscles, make sure we can have body fat. Remember our body fat stalls fat soluble vitamins for the winter of times of fasting where we can’t find food to be able to become pregnant and have a baby and be able to nurse that baby.

So, insulin’s incredibly important for growth and division. But as we know, in a pathological condition, growth and division can be super dangerous. So, that’s in the case of cancer. It’s uncontrolled growth and division, and insulin is going on in the background, constantly stimulating that pathway whilst glucose is providing the food at the same time.

It’s unfortunate that insulin resistance is only understood in the context of poor glucose regulation. Of course, we want healthy glucose re regulation. But insulin is not the only thing that regulates glucose uptake. Glucose, first of all, every cell in your body that requires glucose can take up a fair amount of glucose without insulin completely.

Although, again, like I said, we’re not talking about situation with no insulin. So you know, they can take up, this is using GLUT1 receptors. There are other hormones that also sensitize cells to insulin. And taking up glucose without insulin, that would be osteocalcin from your bones. So, osteocalcin significantly affects muscle cells ability and adipocytes to take up glucose without insulin.

But with insulin, it actually potentiates insulin, which means the less insulin you have. But with osteocalcin there, that insulin’s going to do a better job, which is insulin sensitivity. So, less can do more, which means you’re not getting it, the overstimulation of growth and division. 

Bret: 
Yeah. That’s so interesting.

I was curious why you checked osteocalcin in your study, but that makes a lot of sense. But so the way you phrase it, I think it’s perfectly summed up as it’s a necessary, beneficial evolutionary process that just in our current lifestyle environment becomes pathologic.

Which brings to the question about the evolution, I think is so interesting. And you’ve done so much work in this area that people will say, we evolved, we were always in ketosis. And somebody say, maybe we weren’t always in ketosis, but maybe we were in and out of ketosis? And then someone will say, yeah, but then there are populations like the Inuit who are not in ketosis.

So doesn’t that mean it’s unhealthy? So, I know this is an incredibly broad topic without a clear question I’m even asking, but like how do you see this whole concept of evolution was, is ketosis evolutionarily healthy and necessary? And how do we relate that to our modern day society, which is nothing like the lifestyle and the societies that we evolved in?

Isabella: 
Yeah, we’ve got a cohort of research that’s in nutritional and therapeutic ketosis. Now, the reasons for this clearly is because we are looking at properly diseased cohorts. Then suddenly, we start to see the need for being in therapeutic levels. So there’s very high levels of ketones versus people who don’t have disease, never have disease.

How necessary is it to be in nutritional and therapeutic levels of ketosis? It’s definitely arguable, in actual fact, because there’s not a lot that has to be fixed, you could say. Additionally, to that fact, when we look at the Inuit, and certainly we’re going to see regional areas where we have adaptations to our environment.

So with the Inuit, we have to go back to where the Inuit are obviously not interacting so much with the West and trading goods, and then therefore, eating Western foods. So, if we go back to them, they sort of, if we go back to the Stefansson sort of studies and things like that, the Inuit were essentially eating pemmican for about six months of the year. About three months of the year then it was fish.

And then, the remainder was anything between. Actually, they had one month of the year that was eggs. And this wasn’t mixed up food. It was like that’s all you had for that period of time, and then some blubber. We could argue this is a very ketogenic diet in a lot of people.

So, why wouldn’t the Inuit producing high levels of ketones? Now, first of all, they’re not producing no ketones. Although, you just ask why, how can I substantiate that because they wouldn’t have been testing it back then? It wouldn’t have the capacity the way that we have to test it. One of the things we know is that in pregnancy, the inability to produce ketones is fatal for the developing fetus.

They actually, they require ketones. There’s a level at which we are producing ketones that we don’t detect on a home meter, that’s for certain. And the fact that the brain order to produce the cholesterol, it actually doesn’t draw the cholesterol from the bloodstream,. it takes in the ketones and turns this into cholesterol.

And so, it’s argued the Inuit we’re producing ketones, just not at this therapeutic level. And your liver as well uses ketones. We always hear the liver doesn’t use ketones. It doesn’t use ketones for energy, but it does use ketones as the process of cholesterol synthesis. Quite often, again, you may not be seeing it in your bloodstream. Again, another thing to take into account is what you measure in your bloodstream is not necessarily your actual ketone level production, per se. You can have someone who’s an amazing ketone user, then you’re not going to see it inside of the bloodstream.

So, we’ve yet to actually tease that out. It might be that they’re producing the ketones, but they’re using them up prolifically. So, we don’t actually know in that regards. Then there’s another argument, which is if you are superb at producing ketones, and you can’t use them.

What are you going to do with them? You are going to pee them out. You’re going to pee them out and breathe them out. That’s actually highly inefficient. In actual fact, now if you have disease, it makes sense because you want to get all the epigenetic signaling of that huge flood of ketones plus all the antioxidant effects that ketones will have to detox, to improve mitochondrial function.

There’s a huge argument. Plus, you’re working to drive down the growth factors, which are basically coming with the elevated insulin. And so, the ketones act as a proxy marker that you’re getting the insulin down with the growth factors down, and that you’re getting blood glucose going down as well.

Blood glucose down with the presence of the high level of ketones. Of course, not a low blood glucose with no ketones, which wouldn’t be safe. So, you know, again, the context of the desire to be in therapeutic ketosis and high levels should be health conditions-specific in actual fact. So when we look at subsets of populations like the Inuit, are they actually producing a lot of ketones?

How do we determine that? Are they consuming what they’re producing so efficiently that we can’t measure in the bloodstream? Are they also preserving so as not to overproduce the ketones because they need to store more, it’s better for them? Maybe they don’t have access to certain foods as much?

We’re studying a modern population these days when it comes to being able to use biochemical methods of testing. So, we’re not really studying old school, old fashioned indigenous Inuit either. So, it’s hard to really be able to make absolute claims. So, we need to put it into an evolutionary context really.

Bret: 
Yeah, so it’s clear when we talk about evolution and try and relate it to modern day society, there are so many different steps and so many things to consider. But, I think maybe a, just a simple way to phrase it is, we’re talking about ketosis and longevity, and is it safe? Is there any evidence or any concern that it isn’t?

Like why is the burden of proof to say that it is safe? If it is something that we’ve been in and out of through evolution, like why do we have to prove that? Where’s the concern or the evidence that it’s not safe to be in ketosis long term? 

Isabella: 
Yeah, it’s true. I think that probably stemmed more than anything else from when we started measuring and understanding ketones, it was in the presence of type 1 diabetic ketoacidosis.

And it’s very unfortunate because, still to this day, we see papers where they’ll be talking about ketoacidosis with a elevated glucose, which is in the six and seven range, which is, it definitely is hypoglycemia, but it’s not in the diabetic type 1 range, and then the presence of ketones.

So, they’ll be like, oh, your blood glucose is 5.9 or 6.5, and you’ve got ketones at 1. So, you have ketoacidosis, which is not true. Ketoacidosis is three factors. And the third factor is a triad. The third factor is bicarb of the blood, the buffering, the bicarb of the blood, and that to be below 18.

So, if you’re seeing it trending at 20, then you know, you start to pay attention to it. So, diabetic ketoacidosis is not just elevated glucose and ketones. And, also again, diabetic ketoacidosis is when the ketones are in double digits, so is the glucose. But because of that, because the medical world understood ketones under the ketoacidosis context, it was viewed as pathological.

So, therefore, everything thereafter with regards to ketones and ketosis is therefore pathological, unfortunately. And It made it so that if we hear anything about ketogenic diet, being in ketosis, you have to prove that it’s safe. And of course, we’ve got the other paradigm, which is that saturated fat and fat is bad for you.

And so, therein lies the problem that a ketogenic diet is inherently high in fat, isn’t it? And so that’s another battle. And there are studies, animal studies, but there are studies that are showing, putting animals into ketosis and these animals have resulted in cancer.

And then people will go with, see, you get cancer in these animals because they were in ketosis. You have to always consider every single study with regards to ketosis or anything else as well. Is it a species-appropriate diet? So, when you see with rat studies and animal studies that they get cancer when they’re in ketosis, then you have to investigate. What was the fat that they used?

What was the protein they used? Was this appropriate for this animal? if you’re going to feed a bunch of mice canola oil, soybean oil, soybean protein isolate, are these species-appropriate foods? No, so this is why I always say to people, it’s not just ketones that begets health. What those ketones are made from, the molecules that make up your body, they really do matter.

So, if you’re drinking soybean oil and canola oil and eating pea protein isolate and soybean protein isolate, I don’t actually think, no matter how high your ketones are, I don’t think it’s going to turn out into a health outcome.

Bret: 
Yeah, that is such an important perspective. That it’s just not black and white ketosis or not, but how you get there. And really points out the difficulty of taking rodent studies, animal studies and extrapolating the findings to humans. And that’s why we have to do the human studies, like you said, species-appropriate diet.

And you started this whole conversation talking about caloric restriction in animals. And I think that’s such an interesting topic because it’s an animal in a cage. It’s only going to eat what you give it. It can’t go down to the 7-11 and buy a bag of chips. It can’t DoorDash food.

It is not the same environment. We have to consider that environment. So, when people calorie restrict, some people can do it very well. And some people are going to be hungry and miserable and have cravings and binge and have the opposite effect. So, I guess this ties into a conversation we had offline where you said you really do like to do these trials and people who self-select rather than forcing something upon them.

So, tell us about your rationale for that because I think it’s so important. With how we interpret the gold standard randomized control trial or the non-randomized trial, how does this fit into what we know about science and how it relates to us as human beings? 

Isabella: 
Yeah, it’s funny because with drug trials, and not just drug trials, but in general medical practice when drugs are prescribed, a doctor will often say, adherence matters. So, if the patient doesn’t adhere, of course, it’s not going to work, and that’s going to be exactly the same as lifestyle. Adherence matters. So, what governs adherence tolerability?

Of course, it’s very obvious. So, you know just as much as if you take someone who enjoys a vegan high carb diet and you put them on a carnivore high fat diet, they’re probably going to be miserable. Equally. If you particularly like Indian cuisine, and I force you to go on a Mediterranean Italian cuisine, you might be miserable, too.

So, it really matters that you do, food is important, not just as a nourishment and to indicate affect our health. It’s part of our cultures, part of our lifestyle. We get what’s called a motherland when we eat dishes that bring us back to our childhood. All of these sort of things.

So, it’s really important that each participant is able to incorporate the diet that suits their palate and lifestyle as a result. And so what with our trial, that’s what we looked at. We took women who already had been in ketosis for years, and they had figured out what works for them because, again ketosis trials, quite often it’s controlled.

You are all going to get a set amount of calories based on your body weight. We’re going to do it all isocalorically. We’re going to control the type of fat that you’re having, the type of protein that you’re having. A lot of things, or it’s just a shake, and then the problem is here.

It’s possible this person needs more protein. It’s possible this person is responsive to a different type of protein. It’s possible this person, cheese works really well for them. And this person, cheese doesn’t work well for them. We found this within our own participants that some could have yogurt and cheese and have high ketones and others, it just would flatten their ketones altogether.

I tell you, and the more interesting one was broccolini. Broccolini which occurs a lot in ketosis dishes. We had some participants where it would really halve if not more their ketones. So, in terms of a ketosis trial, you also need to understand that things have to be teased out that enable the individual person to produce a certain target level of ketones.

So, we’ve got a number of problems here because there’s a lot of keto trials that just consider reaching a threshold, but not anything above that. So, it’ll be, the cutoff will be above 0.3 or is above 0.5 for nutritional ketosis. Now, if we’re talking about something like cancer as a study, if everyone reaches 0.5, 0.6, 0.7, you’d consider it compliance.

Their in ketosis, but it’s arguable whether it’s going to be therapeutic enough to make a difference. Plus, if you’re measuring that in the morning, it’s got the highest rate of false positives because if you produce 0.7, 0.8 in the morning. Even quite often, type 2 diabetic, obese people will produce that because they’ve slept for eight hours, seven or eight hours, not eating their dinner two hours beforehand.

So, it’s essentially a 10 to 12 hour fast, and then they’re measuring this morning fasting ketones. So, studies that are only measuring morning fasting ketones are going to result in a fair amount of participants likely not in ketosis during the trial. And then you look at the final results and the data, and you wonder how come there’s not a strong statistical significant difference?

This is why in our trial we had all our participants measuring four times a day. When you wake up, before you go to sleep, before dinner, lunchtime and dinnertime, whether you have lunch or dinner or not. And roughly always three hours minimum after a meal so that you, the test is having as little interaction with the meal as possible.

And so, of course, sometimes if you have dinner late, you’re going to go to bed two hours after. We factored that in, but essentially, so each participant in our trial took 252 tests over the course of the trial. So, it’s a lot of tests. But that really lets you know compliance. That really lets you know if the day is supporting ketogenesis for the individual.

If you control the meals, some people can have fiber in their diet, still produce ketones. Other people, fiber in the diet, they cannot produce ketones. So, it’s really important for it to be teased out for the individual participant. And then, therefore, testing through the day, they can then also fine tune. And with women, their ketogenic, to be able to produce ketones are going to be affected by their monthly cycle as well.

So again, those things are going to have to be teased out and worked out for the individual participants. And this is why we covered all of these things. And why it was necessary inside of our trial in the hopes that future studies in disease cohorts, they look back at our study and go, okay, so we clearly need to do more testing through the day.

But if there’s a budget issue, which test would you do? You do them between 4 to 6:00 PM where it’s at least three hours after lunch and it’s before dinner because this one has the least chance of being the false positive of morning. Number one to assess compliance, but also because if you’ve got lunch, breakfast and lunch or any kind of drink in between or things like that.

And then the reading is more likely to drop if the lifestyle is not a properly supportive of ketogenesis. So, we’re going to get less of those false positives in studies, which is obviously much better. 

Bret: 
Yeah, that’s such a fascinating point. And it’s a question we get a lot here. Like, when should I check my ketones?

When should I check my ketones? And there are a number of ways to answer that. One is, what are you trying to measure? What, why do you want to be in ketosis and why is that important? And are you checking, do you want to know the impact your meal has on your ketones or is it about your whole day?

So, there are different things, but I love that answer. If there’s one time you have to check, that 4 to 6:00 PM because that does tell you like your whole day, which is really important. And this is where a continuous ketone monitor, or a CKM, could be incredibly beneficial.

And those are in their infancy. They’re not nearly as widespread as CGMs. But hopefully, that will come out soon and be more widely available, at least for research, because that’s where it could be so important for a research study so you don’t have to prick your finger four times a day. But that’s impressive that you got your subjects to do it four times a day.

That’s really good, 99 plus percent compliance. That’s amazing. That’s amazing. And like you said, self-selected, very motivated population. Yeah. 

Isabella: 
Completely. Now if you think about it in a trial, if you have people self-selecting into a ketogenic, supportive lifestyle, but you also have people who are self-selecting into non-ketogenic support lifestyle, that therefore equalized the self-selection.

In that respect, you are still getting the correct representation when people say, oh yeah, but how come? it’s just because they like the, it’s a bias to that group. It’s like the other one’s biased to that group, too. So, it can work perfectly fine. 

Bret: 
Yeah, interesting, You brought up another fascinating point I want to circle back to, which is women in their menstrual cycle. Because so much of the studies, if it’s done in men or women over age 60, you exclude this whole very important physiologic phenomenon. And some women say, I just feel terrible at certain points of my cycle when I’m in ketosis.

So, I do want to eat more carbs. Some women don’t have that finding. So, I’m curious, since you have been studying this age group of women, what do you find most impactful about the menstrual cycle and how it changes either ketosis or someone’s need for carbs or cravings for carbs or what have you found around that?

Isabella: 
Yeah, so we have data that we haven’t analyzed in these sort of things. So, everything I say on this has obviously not been statistically analyzed, but it was very interesting. So, the commentary of when they were out of ketosis was, I think that it was, I wanted to eat everything but the kitchen sink. And which kind of makes sense in terms of, if you are already eating carbohydrates, this is obviously going to affect leptin resistance, satiety, these things. But also, because we had in our study, we measured GLP-1 as well, and GLP-1 is related to gastric emptying. So, as well as the fact that a GLP-1 signals the GLP-1 receptor, and this receptor is also sensitive to osteocalcin.

Osteocalcin also regulates GLP-1. There’s all these interactions which are really interesting and like GLP-1 is always studied in the context of wanting to, it’s been triggered because of carbohydrate, right? it’s a bolus trigger.

But in actual fact, you can see in our study that being in ketosis significantly increased GLP-1 levels. And so for satiety, this is very important. If your background or the markers that indicate better satiety, so one of them will be gastric emptying. Of course, if your tummy’s full, you are less likely to feel hungry, aren’t you?

And so if you have a slowing down of gastric emptying, then that’s going to affect satiety. We know this with the current drugs that’s GLP-1 agonist. Now the difference is, you know what, if you are having slowing of gastric emptying is probably going to matter what’s in your stomach, if it’s staying right for a long time. And so, therein lies the difference is you consider a ketogenic diet that is more slanted towards low fiber as well.

Then, we’re really talking about protein and fat at this point. And so protein and fat, they’re going to be worked on in the lower part of the stomach. You do want the many more hours of it broken down, small amounts to be released at a strong stomach pH level. Whereas, if you think if you have a high fiber diet, then it’s still being held in the stomach.

Small amounts are being released, but because it’s high fiber, the pH is going much higher. So, it’s not an alkaline value. It’s an acid value, but it’s going to be somewhere the way between pH 3.5 to. 5.5. Now, this is going to affect cholecystokinin. Cholecystokinin in the small intestines is regulating biosynthesis, which means also the emptying of the spleen, synthesis of taurine put into the bile. And then the gallbladder to release this bile into the intestines to maximize the uptake of the fat soluble vitamins and essential fatty acids as well as stimulate the cholecystokinin.

Stimulate the pancreas as well to release all the pancreatic enzymes, which are going to be working on digesting the proteins so you can absorb them as well as both of these, the bile and the pancreatic enzymes subsequently changing the pH of the small intestines so that the enzymes are working at their optimum as well as the correct microbiome is then going to reside in that location. So you can see how they all work together. So, something with regards to slowing gastric emptying, this evolutionary would be beneficial as well because why?

We didn’t used to have three meals a day. Refrigeration is quite a young, new technology for really, and we wouldn’t have three meals a day. We could even, could potentially go for days without food. In fact, and what food you would have, you would want to maximally absorb as much of the nutrients as possible in actual fact.

So, you’d want it to slow down, and you want to grab everything you possibly can as early as possible. So anyway, being in ketosis, we saw the higher levels of GLP-1. We saw the lower levels of leptin, and that corresponded to satiety for our female participants. And that changed when they were suppressing ketosis.

And one of the comments that they all made, they were actually not out of ketosis in the morning until six days into the intervention to suppress ketosis. And if they ever went longer than four hours of not eating three and a half, four hours, they were back into ketosis even in phase two. But one of the things that they all commented on was waking up in the morning with their stomach growling.

It was really interesting. The body was telling them, okay, I’m used to it now. I need to have some food. So, they felt that, and they definitely noticed, even out of ketosis, they still wanted to eat more at particular time of their cycle, but it was much less strong that signaled in that regard.

Of course, that’s very helpful. 

Bret: 
Yeah, I gotta take a breath after that explanation though. That was a tour de force of the inner relationship, how everything’s connected in the biochemistry of all those. That was fascinating, and really helpful that you’re studying this population because I think it is a very understudied age group.

So super helpful to understand all that. Now, one last point I want to touch on with you is you mentioned you have also some mental health data. Maybe that hasn’t also been evaluated as much, but I’m curious where you’ve seen the mental health signal in your studies and what you’ve looked at.

Isabella: 
Yeah, again, the caveat that this is a self-selecting population. They chose this lifestyle. And when they were suppressing ketosis, we basically had our participants do the WHO and the NHS mental health questionnaire because they were validated already. And then we did another questionnaire, which was not a validated questionnaire, but we asked everything we thought we could possibly ask that would be of interest. So, that we just collected this data.

And our participants, they’re super healthy so we didn’t expect to see hugely negative changes. So they were, their focus was just as good. They weren’t fatigued, none of these sort of things. But they just, there was a shift to the negative side on things. That’s what they really did see.

They saw a shift on slightly easier to be agitated, things like this. And so that was actually quite interesting, just that one there, it wasn’t like this huge, oh my God, they became really depressed because it’s, again, this cohort. It’s not reasonable, but you would think about it evolutionary.

We’re opportunistic. In the past, if we saw a bunch of delicious berries or honey availability, we would certainly eat it. And many of us historically evolved near the equator. So, there definitely were, yes, high fibrous fruits, but there were fruits. And so it doesn’t make sense evolutionary that we would have suddenly become so depressed and so Ill.

We did a season of autumn, of eating some fruits and having essentially suppressing ketosis as a result. But you could see inside of our data, there was this absolute shift towards not being in the best mood. Things like this, having a slightly shorter temper, less patience, these sort of things.

It was very interesting but we have to run on data. 

Bret: 
That is fascinating. I look forward to seeing that data. My goodness, this has been a wonderful discussion. So many details, but also bringing it back to the person, the patient. And again, you talked about how it’s so important for researchers to understand the individual and how this impacts people’s lives and how it impacts their families. And so I just want to say thank you for the work you’re doing and also for adding the human aspect to that. So, thank you very much. 

Isabella: 
No, my pleasure. My pleasure. We’re all trying to do our bit, right? It’s, I think that once you have this kind of level of knowledge or the capacity to learn this stuff, it puts us in a position where, I would say if you can, an obligation to try to make a difference, try to make a change.

Because none of us will not have a family member affected by any of these diseases. So, it’s really imperative that we get on top of it, and it’s not only our direct family members. It’s our society at large, So yeah, being involved with people, not just looking at papers and numbers, keeps it really real.

And we have to do that. 

Bret: 
I’m sure after this interview, because you’re such a fascinating individual, people are going to want to follow you and learn more about you. So, where can we direct them to go to learn more about you? 

Isabella: 
I have a website which is called Forever Young Group, and it’s my research group, who are amazing.

None of this research could happen without them. It’s a lot of work. And so that’s at foreveryounggroup.com. And on my publications would be my email as well. And on Twitter, it’s at I_mitochondria and Facebook is at ellamitochondria. Yeah. 

Bret: 
Wonderful. Wonderful. Thank you again for joining us and hopefully we’ll talk to you again soon.

Isabella: 
Brilliant. Thank you.

Bret: 
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