Ketogenic Metabolic Therapy for Health and Disease

Angela Poff, Ph.D

Hi am great. How are you?

Sanjeev Goel, MD, FCFP (PC), CAFCI

Thank you so much. I’m really looking forward to today’s talk. So, maybe just take me through before we get into more detail about your research, how did you actually get involved into this field of ketogenic medicine or therapy?

Angela Poff, Ph.D

Yeah, so I, I’d always planned on being a scientist. I wanted to be involved in research and I did my undergraduate work in biochemistry in molecular biology. And I graduated and started looking for PhD programs. I landed on the University of South Florida here in Tampa and moved down here and started that program. And that’s when I met Dr. Dominic D’Agostino and he was starting up his lab at that time. He was a junior faculty member. And he was looking for his first PhD student. And, he was funded by the Office of Naval Research to look at mitigation strategies for oxygen toxicity seizures. And he had a big interest in nutrition and specifically ketogenic nutrition at that time, but he was interested in expanding his research into cancer. 

And there was a little bit of data at that time looking at ketogenic diet as a potential therapy for cancer and in particular brain cancer. And I remember, my first conversation with Dom kind of on this topic, it was really just incredibly eye-opening to me. I’d never thought about nutrition as being a powerful tool in the face of something, very serious like cancer. And my father had brain tumors when he was young. And then again, when I was young and, he thankfully went through therapy and responded to them but he had some lifelong consequences from the radiation therapy that he was given. 

It saved his life, but it also, had some long-term problems. And I just remember thinking like, “Wow, what a cool idea that we might be able to contribute to finding some therapies that can impact cancer in a way without some of these classic side effects that can come along with standard of care therapies.” And, so I just really got kind of enthralled by this idea. And I ended up joining Dom’s lab and I did my PhD research based on ketogenic diet and hyperbaric oxygen as a potential non-toxic metabolic targeted therapy for cancer. And then I’ve stayed on and worked with Dominic ever since then. And we continue to do a lot of research on the topic of ketogenic therapies in cancer but also in various neurological diseases as well.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Well, so now, are you, run your own lab or you still work with Dr. D’Agostino?

Angela Poff, Ph.D

So, I still work with Dominic, yeah. I’m a research associate which is like a research faculty position, but I work within Dominic’s lab. And we have a variety of students and some postdocs that do a lot of the work that’s going on.

Sanjeev Goel, MD, FCFP (PC), CAFCI

So, we had a, we just had a guest talking about hyperbaric and we’re actually gonna be opening a center here in Toronto for that as well. So, I’m curious about what did the results of the initial, your PhD show? What was that?

Angela Poff, Ph.D

Yeah, so that was really interesting. We found in the mouse model system that we were using which was a brain tumor derived model of metastatic cancer. We found that the ketogenic diet alone and we use two different formulations, was able to slow tumor growth and prolong survival in that model. We found that on its own hyperbaric oxygen did not result in a significant slowing of tumor growth or extension of survival. But, when we combined it with ketogenic therapy both the diet and then actually also exogenous ketones, we found a really nice synergy there. And so the results were actually greater than the additive results individually. And so there was some kind of synergy happening between ketosis and hyperbaric oxygen in that mouse model that we studied it in.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Oh wow. Okay, I’d like, there’s couple of things I definitely wanna talk about. Maybe before we even get into ketosis, what are your thoughts about just, so hyperbaric oxygen on its own, how would you, what are, what are the effects on brain health? Like, I’m just curious.

Angela Poff, Ph.D

Yeah, so it’s interesting, hyperbaric oxygen has a long history of research. I’m most familiar with the literature surrounding its potential use in cancer. So of course, with hyperbaric oxygen, you’re breathing 100% oxygen at elevated barometric pressure and this allows more oxygen to become saturated into the plasma of the blood and allows for greater diffusion of the oxygen into the tissues. Now, this is very helpful in conditions where oxygen diffusion or oxygen carrying capacity is limited. So it’s used clinically for things like carbon monoxide poisoning. It’s also used for diabetic foot ulcers in chronic wounds or radionecrosis. 

So the type of necrotic tissue damage that can occur following perhaps radiation treatment for cancer. And, but it has, oxygen, we in the field of hyperbaric medicine kind of describe oxygen as a drug. So it has drug like effects in the brain. And we, interestingly our lab kind of is very involved in hyperbaric medicine research from kind of the alternate perspective of when too much hyperbaric oxygen could be dangerous to the brain because too much, can result in a central nervous system oxygen toxicity, which has a lot of signs and symptoms but the most concerning of which is seizure. 

And we are funded by the Navy to look at mitigation strategies for that condition because of course a seizure underwater, can be fatal. And so this really greatly limits the amount of time that a Naval war-fighter can spend on a mission. And so, but interestingly, within the kind of realms of a more therapeutic range of hyperbaric oxygen, you do see, changes going on in the tissues, obviously more oxygen getting delivered to the tissues and changes in excitability of the brain. And so it is being studied as a therapy in a few different conditions related to neurological damage. 

And then, from my perspective it was interesting because it was historically viewed as a potential radiosensitizer for cancer because tumors have hypoxic areas that actually drive tumor growth and drive resistance to both chemotherapy and radiation. And so, restoring oxygen levels in the tumor is thought to maybe inhibit some of those beneficial effects that the tumor is receiving from the hypoxia. So, there’s a whole lot to do in the hyperbaric medicine. It’s very fascinating, ’cause it’s really impacting the tissue on a very cellular level. The hypoxic response within the cell is pleiotropic, influencing hundreds of genes simultaneously. So there’s a lot going on.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Well, yeah, that’s I guess a whole other topic, but I guess it seems like it’s not so, it’s not so straightforward, it’s what we see in the answers, yeah.

Angela Poff, Ph.D

Yeah I would say so.

Sanjeev Goel, MD, FCFP (PC), CAFCI

So let’s, a little bit, then let’s start moving into then, so you started getting involved looking at ketosis and how that can have a treatment in cancer. And then, you’re also working on its effect on metabolic dysfunction, chronic disease, and neurological disease as well. So if you wanna tell me, how did you pivot to that and why did you decide that? To do that?

Angela Poff, Ph.D

Yeah. I mean it’s, so it’s been fascinating to see the field of ketogenic therapy research over the past decade. It’s really exploded, within the public conversation even, which is coming off the heels of really, some pretty amazing advancements in our understanding both molecularly and clinically in terms of what’s happening in a physiological state of ketosis. And, we’ve seen just this explosion of interest and ketosis is really now being studied kind of across the board in terms of metabolic disorders or some of the more obvious potential applications things like obesity or diabetes. But also for things like neurological diseases, neurodegenerative diseases in particular, is a very fascinating area of research. 

And we have a strong interest in the brain. As I mentioned, our lab is very strongly footed in, and neurological research with our, we have a strong interest in seizure disorders, of varying ideologies and, and so it was kind of a natural transition or continuation really to continue this kind of work in neurological conditions. There’s been a lot of research looking at how in, especially neurodegenerative diseases, so things like Alzheimer’s disease or Parkinson’s or multiple sclerosis, you see kind of these common threads, when you start looking at the tissue level of what’s going on in those cells, you see some of these things like neuroinflammation is a very common theme, high levels of oxidative stress. 

And then things like aberrant energy metabolism, so like glycolysis or glucose hypometabolism and insulin resistance. And all of these areas are things that there’s data to show ketosis might be able to target therapeutically. So it’s really fascinating, even just within the past year, there’s been research. A lot of it is preclinical, but a lot of research has come out looking at ketosis as a potential therapy for things like spinal cord injury, autism even, it’s very fascinating. Mental illness, so depression, depression, anxiety, even schizophrenia. So there are kind of these common themes that we’re seeing in these chronic diseases that might be targeted by ketosis. So it’s a really hot area of research.

Sanjeev Goel, MD, FCFP (PC), CAFCI

So maybe let’s, I know that not all the viewers may completely understand like what’s happening during ketosis. So maybe if you don’t mind doing, to kind of explaining that piece in a, kind of a short manner. And then I’d love to talk more about Parkinson’s and Alzheimer’s, specifically how does this, how do we think this is happening? At least what is your understanding so far from the research of how it’s impacting those

Angela Poff, Ph.D

Absolutely. So, I would say ketosis is first and foremost, a natural metabolic state. So this is, in my kind of view, just a very normal part of our physiology that is initiated when glucose and insulin are suppressed. Now, if you think about it, our ancestors were not eating three times a day, every day. And they weren’t always eating these very high carbohydrate load meals. So the carb, they had some carbohydrate in their diet but they were often, came with a big load of fiber along with it, right. Like natural sources of carbohydrate. These very processed carbohydrates that have basically stripped all fiber from them is very new in terms of human evolution. And so, our ancestors were regularly going in and out of ketosis. And ketosis is just–

Sanjeev Goel, MD, FCFP (PC), CAFCI

Can you just give an example of what is, what would be a way, what would be a food now that we could eat that would be similar for like a high fiber carb? What would that look like?

Angela Poff, Ph.D

Yeah, so, well, I guess kind of, yeah I mean, so natural sources of carbon. So like things like berries for example, berries are, they have carbohydrate, but the glycemic load is much lower than a lot of other fruits. And they come with a higher amount of fiber. So this is a more kind of natural form, I would say, of carbohydrate especially compared to like, cane sugar, like these processed added sugars that are now added into every food that’s on the supermarket shelf. So, when I view kind of carbohydrate choices, I tend to view in that regard. I am, from my perspective, I’m not scared of whole food kind of sources of carbohydrates, especially when they come with fiber and their other ways, nutrient dense type foods. 

But some of these processed forms of carbohydrate are quite new to human physiology. And so, historically speaking, our species was not constantly consuming food. You know, we might have a meal and then it might be, even days or a week before, we secured another large meal. And so, the human body is set up in a way that we have plenty of calories on board to, carry us through those times in between meals. So we store calories primarily in the form of fat. And when we don’t eat sufficient calories or we don’t eat a significant amount of carbohydrates, we start breaking down that stored fat. 

And fat is converted in part to ketone bodies. And the whole reason our bodies do this is actually to support the brain. So, most of your body can, is perfectly happy to run on fatty acids that come from the stored fat when it gets broken down. But, fatty acids are not sufficient fuels for the brain ’cause a lot of them can’t even get into the brain. They can’t cross the blood brain barrier and we need to be able to fuel our brain in these scenarios. And so ketone bodies are small like water-soluble fat molecules and they are indeed the only other molecule, energy molecule that our brain can really use to support its high energetic needs.

Sanjeev Goel, MD, FCFP (PC), CAFCI

And is there a different, different people have different ability to use ketone, ketones in their brain?

Angela Poff, Ph.D

Yeah.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Like do the nerve cells, is there, you know, people have different receptors or–

Angela Poff, Ph.D

That’s an interesting question. So the type of transporters that carry ketones into the cell are called mono-carboxylase transporters. They’re ubiquitously expressed because they’re all, they also carry some other very common molecules. So things like pyruvate and lactate, so other really common metabolites. And so, you have a baseline expression of ketones, regardless if an individual has ever been in a state of ketosis. And it’s possible that someone who, eats very regularly and perhaps eats a fairly high glycemic load diet has never, or barely ever been in even a mild state of nutritional ketosis. 

But, studies show that even in individuals that are not consuming a ketogenic diet, they can take up ketones into the brain. So Dr. Steven Koonin has done a lot of work looking at pet imaging, showing ketone uptake in the brain of adults with healthy brains, also mild cognitive impairment all the way up to Alzheimer’s disease. And it’s very fascinating because, individuals across the spectrum do, are able to take up ketones into their brain. Even in cases where perhaps glucose uptake is impaired such as in Alzheimer’s disease. And we can talk about that in a minute. 

But yeah, studies absolutely show that everyone for the most part, unless you have some kind of like very specific unique, maybe inborn error of metabolism type disease, you express these transporters and are able to take in ketones and utilize them. But as people are, adapt to a state of ketosis, you become more efficient at taking up ketones. And that’s why you see, sometimes people might be tracking their ketones with your urine strips or they might be measuring in their blood. And after a few weeks of being in ketosis, they see their levels start to drop. And they get worried that something’s wrong, but that’s normal ’cause your tissues have actually just become more adapted actually, taking up those molecules to use them. So you do see–

Sanjeev Goel, MD, FCFP (PC), CAFCI

Everywhere in the brain that can happen, is that’s what’s happening? I mean, everywhere in the body or just in the brain?

Angela Poff, Ph.D

So everything, so there are only a very small amount of tissues that don’t take in or utilize ketones. The liver is one. So the liver is where you make ketones. And because of that, it lacks enzymes that are required to actually utilize ketones, which makes sense, you wouldn’t want, the area that’s making them to just turn around and use them immediately. So the liver makes them and ships them out to circulation to be used by, almost all of the rest of the body. I mean, just a few kind of tissue types that are thought to maybe not be able to, for example, like red blood cells to mature, overthrow sites, they don’t contain mitochondria. And, ketone metabolism happens exclusively in mitochondria. So those cells can’t use ketones. But, yeah, most tissues in the body can and do very efficiently.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Do you mean by the, people who are more like, their bodies are used to being ketosis, are you saying that they become more efficient and is this because of the receptor? Or how are they becoming more efficient at this?

Angela Poff, Ph.D

Yeah, so I think largely you see like an up regulation of receptor expression and transport. There might be other things at play but that’s kind of generally speaking the thought process.

Sanjeev Goel, MD, FCFP (PC), CAFCI

So we can train our bodies to become better at this?

Angela Poff, Ph.D

Yeah, I would say so, yeah.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Okay. That’s really interesting. So then yeah, tell us about the, about what’s happening in Alzheimer’s and Parkinson’s or other neurodegenerative diseases?

Angela Poff, Ph.D

Yeah, so this is a very fascinating area of work. There’s been, it’s been known for quite a while that a very consistent hallmark characteristic of Alzheimer’s disease is reduced glucose uptake. So you can actually look even in individuals who are at high risk for developing Alzheimer’s and end up developing it decades down the line. Even very early on, so before there’s even any symptoms of cognitive impairment, these individuals will show reduced glucose uptake in the brain. And Dr. Koonin and others have really shown that, as the dementia increases and mild cognitive impairment turns into Alzheimer’s disease, that becomes even more and more severe. 

And so by the time an individual has full blown Alzheimer’s disease, their glucose uptake capability is significantly reduced, compared to a normal, healthy individual. And so, being that ketones are the only other primary fuel for the brain, it’s kind of an obvious idea that well, potentially ketones could support brain energy metabolism in this condition. And there’s been research that shows very interestingly while glucose uptake is reduced in these individuals they still retain very normal ability to take in ketones. So, and it’s probably just because it’s a different type of transporter and kind of a different way that these molecules are metabolized. But for these reasons, ketosis is a very, at least from a theoretical standpoint, it makes a lot of sense to study this. 

And there has been both animal research and some preliminary human research to show that it does seem to be therapeutic in some cases. And so, there’s work in a variety of animal models of Alzheimer’s disease. And then some work in humans to support this. So, we need larger trials before it can be, proven that this is therapeutic and there might be some, some subset of the population that doesn’t respond. That’s pretty typical for almost any therapy. But the preliminary evidence that we do have is very encouraging.

Sanjeev Goel, MD, FCFP (PC), CAFCI

So let’s, so you’re saying that these patients who have early Alzheimer’s, or they have problems getting glucose into the cell, is that right, into the neurons?

Angela Poff, Ph.D

Yeah.

Sanjeev Goel, MD, FCFP (PC), CAFCI

So are you saying that then their basis, these cells are being starved, and so this is further progressing their illness?

Angela Poff, Ph.D

Yeah, that’s what we think, yeah essentially. So I mean, we have to keep in mind that the brain is, a very energetically, demanding organ. So it, uses about 20% of the energy that we consume and use on a daily basis but it only makes up 2% of our body weight. So, in neurological diseases, you very consistently see kind of an energetic crisis where the neurons are not getting adequate amounts of energy. And so, yeah, there’s thought processes that perhaps with chronic impairment or energy deficits over time, you start to see, cell death or just a reduction in the viability of these neurons that leads to this impairment.

Sanjeev Goel, MD, FCFP (PC), CAFCI

And so what, let’s say, if patient has diabetes or metabolic syndrome and, does this impact how fast Alzheimer’s is progressing? Or like this glucose uptake?

Angela Poff, Ph.D

Oh, that’s a great question. I don’t know of any research specifically looking at that, I do know that we now know that, these are common comorbidities. So if an individual has diabetes, they have a much higher risk of also developing Alzheimer’s. So there is some sort of link, but honestly, I can’t think of many chronic diseases that are not also, your risk is increased if you have diabetes. This is a very, it’s like, to me it seems like a central hub, right, that this insulin resistance is playing this role and linking to the development of all of these chronic diseases that seem completely separate. You wouldn’t necessarily think that, something like Alzheimer’s disease might have anything to do with insulin resistance. But people are even now calling it type 3 diabetes. Insulin resistance of the brain. So, there’s clearly a link. And that’s why I think, there is so much research looking at ketosis in such a variety of areas because these common threads of insulin resistance, hyperglycemia, oxidative stress and inflammation are really seen in a lot of different disorders. And so, and we think that maybe ketosis can target these therapeutically.

Sanjeev Goel, MD, FCFP (PC), CAFCI

What about in patients who have APOE4 allele?

Angela Poff, Ph.D

Yeah.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Is there any studies looking at ketosis in those individuals, are there, does that any other risk,

Angela Poff, Ph.D

Yeah, so there is,

Sanjeev Goel, MD, FCFP (PC), CAFCI

Are they better?

Angela Poff, Ph.D

Yeah, so there is, right now I’ll say it’s unclear. So there’s definitely some research that may have suggested that they might not be as benefited by ketogenic metabolic therapies, but there’s actually also case reports of APOE4 individuals who responded very, very well. Now again, those are case reports, so take that as you will, but, you know, in a field like this, all of this is kind of informing the direction of the research next. So, I would say it’s hard to say but conflicting, I guess, ideas there.

Sanjeev Goel, MD, FCFP (PC), CAFCI

So, how does the ketogenesis, ketosis state change the insulin resistance? Just for our viewers to understand. How does that happen?

Angela Poff, Ph.D

Yeah so, really the biggest impact of ketosis on insulin resistance is just removing the primary substrate that is contributing to a high insulin levels. So ketogenic diet is a low carbohydrate diet. Carbohydrates are the macronutrient that most significantly contributes to your blood glucose levels. So about 100% of the carbohydrates you consume get converted into glucose in your blood. About 50% of the protein that you consume is made up of something called glucogenic amino acids that can then contribute to a rise in blood glucose. And fat is considered basically a negligible source of blood glucose. So, it makes sense when you consume a diet, that’s more based on fats and proteins and less on carbohydrate. 

You’re simply removing, reducing glucose levels. And so when glucose drops, insulin drops because insulin is produced by the pancreas in response to glucose. And this is a very interesting area of work. And there’s certainly been a lot of research in the past couple of years especially looking at low carbohydrate or perhaps ketogenic diets as a viable tool for diabetic patients, specifically type 2 diabetes. Although there’s interesting thought processes with type 1, but that is a very, very kind of special situation, because, and I’ll say, in all of these scenarios, people tend to kind of think about like, “Oh, it’s a diet change, it’s benign,” but from my perspective this is a medical intervention. 

So, if anyone is interested in a ketogenic diet or ketosis for a medical condition, it’s very important that they work alongside their physician on that, because you can have affects that you just, you don’t even think about as being, potentially something that needs to be considered. Cancer patients for example, I know a lot of people are interested in this, very important they work with their oncologist because, there could be specific interactions with chemotherapies that individuals are going on, weight loss in that scenario can be dangerous, for late stage cancer patients. There’s just a lot going on. It’s not just a simple, oh, just a diet change, when you’re talking about someone that has a medical condition. 

But regardless, there are a lot of clinical trials now kind of validating that this is a feasible, method of perhaps treating insulin resistance in people that have historically not been able to reverse this disease. I think type 2 diabetes has been viewed as a chronic progressive disorder that does not get better. And maybe you can slow its progression but you don’t see improvements. And Virta Health for example, has done an incredible job showing that, and published this data that their patients using these low carb ketogenic diets are able to reverse their symptoms of their type 2 diabetes and come off medications and reduce insulin requirements. And, so it’s been a fascinating kind of area I think of hope for a lot of people that maybe otherwise didn’t think that they had hope in certain situations.

Sanjeev Goel, MD, FCFP (PC), CAFCI

I wouldn’t mind if you could maybe just talk about the different types of ketogenic diets, like you know, I mean, is there also differences in type of fat that you’re using in the studies?

Angela Poff, Ph.D

Yeah, absolutely, there is.

Sanjeev Goel, MD, FCFP (PC), CAFCI

And what impact does that have?

Angela Poff, Ph.D

Yeah, that, it almost certainly has a big impact. And it’s something that, I’m sorry to say, we don’t have enough research on and it’s something that complicates the field of ketogenic therapy research, because, if you’re talking about, a new pharmaceutical agent that’s being studied and you say, “Okay, give five mix per gig of this medicine.” Anytime that’s studied in any lab, you know you’re getting the exact same thing. But when you say, “Okay, they went on a ketogenic diet.” What does that mean? People set their standards all across the board. And for an individual, it can mean something completely different. 

So, for example, a sedentary older individual perhaps with a higher BMI, they might really require a much lower amount of carbohydrate to get into a state of ketosis, meaning where their blood ketones rise above this kind of threshold that we’ve agreed upon which is 0.5 millimolar. And that’s kind of considered state of ketosis. But, perhaps a younger, leaner, highly active athlete could probably eat a lot more carbohydrate and protein and still enter kind of this zone of ketosis. So it does matter. And we, and there are a few different kind of formal formulations of ketogenic diets. 

When I’m talking about the research that’s being done, as potential application for medical conditions, I’m almost always talking about the classic ketogenic diet, which is this therapeutic version, which is like a four to one ratio of fat protein and carbohydrates. That’s like 90 plus percent of your calories coming from fat that is not easy to do. That is not something that someone on the street, that just is, “Oh, I’m doing keto.” They’re not doing a four to one. You know, it’s almost, it’s very difficult to even get patients in, serious clinical trials to adhere to a four to one ratio of ketogenic diet, right. But that’s where most of the research is actually, that’s coming from, so that’s an interesting point. But, people will do three to one, two to one ratios. People will do forms called like, MCT supplemented ketogenic diet. So MCTs medium chain triglycerides are a type of fat that is ketogenic and will actually cause ketones to be produced regardless of carbohydrate content. 

And so people can use this in their diet to kind of up ketones, while maybe being able to be a little more liberal with their protein and carb content. There’s formulations used, where people just simply only eat low glycemic index carbohydrates. So foods that have a glycemic index of 50 or below. And that’s being used for example, in pediatric epilepsy. And it’s been shown that in some cases, it’s as effective as this very strict therapeutic ketogenic diet. So, and then that’s not even touching on the types of fats and the types of other food. You can almost certainly eat a very unhealthy ketogenic diet if you’re loading yourself up with really low quality fats and some of these processed oils and things like that. So, you know, it all matters, but we unfortunately are not in a place where we have really good tabs on kind of what all is going on and what are the best recommendations, in my opinion.

Sanjeev Goel, MD, FCFP (PC), CAFCI

That’s one of the biggest things that, people have this vision about, “Oh, I’m gonna go keto.” And then all of a sudden they’re going to like, McDonald’s or having ice cream and things like that. And I think that’s, made some of the criticisms.

Angela Poff, Ph.D

Absolutely.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Of people, of the ketogenic lifestyle. Is it possible to be, and you were kinda mentioning the kind of fit athletic person to be producing ketones and eating carbs? Like, I guess you’re saying that that is possible. Like some people are doing,

Angela Poff, Ph.D

Yeah, absolutely.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Some people, it’s not an all or nothing phenomenon. Like, do we,

Angela Poff, Ph.D

No, it’s not. And it really is very dependent on the individual and both from like probably some genetic component as well but also especially lifestyle. I mean, the more active you are, I would say the more carbohydrate and protein, you can consume, the larger amount of muscle mass you have, ’cause muscles really love ketones. They suck them up pretty quickly. And yeah, so I think, I think it’s totally dependent, and this is one of the cool things about the ketogenic diet though, you can actually test if you are in ketosis. So a lot of diets, or some of these, people like to supplement with all kinds of things, and you don’t actually know if you’re reaching whatever your goal is, right. But with ketosis, there’s actually, objective end points you can measure and you can say, “Oh, yeah, I’m in ketosis.” Either a breath meter or a blood meter or urine strips. So that’s a kind of cool part about ketogenic diet. That isn’t really something that a lot of other diets or supplements can relate like.

Sanjeev Goel, MD, FCFP (PC), CAFCI

And so you mentioned at the beginning that you also added some exogenous ketones in your study, I’d love to hear your thoughts on that. What are the different types of ketones. I’m having my prove it base right now.

Angela Poff, Ph.D

Yeah.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Like soup base, but I’d love to hear your thoughts on this.

Angela Poff, Ph.D

Yeah, I think it’s a very, I view exogenous ketones as another tool in the ketogenic therapies tool belt, right. So I am very aware that there are, you know from my perspective, I’m almost always kind of thinking of like clinical potential applications of ketosis. And I recognize that there are always going to be some part of the population that is not able or interested in consuming a ketogenic diet. And, exogenous ketones might provide an outlet in those situations to open up this line of therapies, to those people that otherwise wouldn’t have had that opportunity. And just even thinking, sometimes kids with epilepsy also have other, sensory processing issues. So epilepsy and autism for example, are often found together. And it can be really hard for families to get their children to stick to a very strict diet, understandably. 

So there’s this thought process like, “Wow, maybe exogenous ketones could supplement, a low carb diet.” Or even in some cases, might be good enough and, to kind of get the job done. And this comes from a lot of research showing that, the beneficial effects of ketosis are at least in part thanks to direct roles of the ketone molecules themselves. Ketones are far more than just an energy metabolite. They have very potent signaling properties, that we’re only now really being able to understand, they can influence gene expression. They have dedicated receptors that they bind to and initiate cell signaling cascades. And they intersect with our immune cells to modulate inflammation. All of these behaviors at least those that are coming from the role of the ketones themselves is not necessarily dependent on carbohydrate restriction, as long as ketones are present in the blood. I mean, even the example of Alzheimer’s disease, if this idea is just simply to get ketones to the brain, which there’s definitely research to show that might be the major, impetus there. That might be a situation where exogenous ketones are gonna be a great fit. 

So, it’s been really cool to see exogenous ketones and you have like a whole host of them, things like ketone salts, ketogenic fats like these medium chain triglycerides, I can consider them a form of exogenous ketones, ’cause you just consume them and then you have a mild elevation in blood ketones. And then ketone esters, which are the most potent. And these are synthetic molecules that either are ketones themselves or they release ketones or they’re converted by the liver into ketones. And they can really, at least the preclinical research suggests they can kind of elicit a dose dependent elevation in your blood ketones. And so maybe in conditions where kind of a higher level of ketosis is needed to elicit the desired outcome. You know, ketone esters might be kind of the most promising tool there. But yeah, that’s how I view it. Exogenous ketones are just something that might work in certain cases for certain people. And more options is better in my opinion.

Sanjeev Goel, MD, FCFP (PC), CAFCI

So are all ketone esters the same? Like some–

Angela Poff, Ph.D

No, I mean, there are different ones that are available. And a lot of them are only, there’s not a lot that’s commercially available. There are some. There are others that are in development or in preclinical testing largely. They’re not all exactly the same. Some specifically only produce beta hydroxybutyrate. Some produce both beta hydroxybutyrate and acetol acetate. Those are the two primary ketones. And there might be specific scenarios where one is more desirable than the other. So, you know, these are synthetic molecules, so they can kind of be designed to fit your needs which is pretty cool.

Sanjeev Goel, MD, FCFP (PC), CAFCI

And isn’t there like ketone salts? Or is it same, that’s same as, that’s,

Angela Poff, Ph.D

So they are different. Yeah, ketone esters are different than ketone salts just in like the composition of the molecules. So ketone salts are a more simple molecule. They’re pretty much just beta hydroxy butyrate, with an eye on attach, like sodium for example. Sodium or potassium or magnesium or calcium, beta hydroxybutyrate. And that’s why they’re called salts because of the type of bond that they have with those ions. And yeah, it’s pretty much just like consuming straight ketone molecules with some of these other minerals.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Okay, that was perfect. Where do you think, like, where do you see the field going? I mean, in the next year or so. Like what’s the next big questions that you’re looking at or you think is worth investigating?

Angela Poff, Ph.D

Yeah, I think it’s really incredible to kind of think back on where we’ve come from in the past. Well actually a hundred years. So this year is the hundred year anniversary of the ketogenic diet, which a lot of people would be totally shocked to know that, because I think, because of the public conversation around this diet, it kind of gets viewed as this like fad diet. No, but it was developed at Mayo Clinic in 1921 as a therapy for epilepsy. And it’s been used clinically, essentially ever since then. So it’s not just the fad diet, there’s a hundred years of science behind it. But in the past decade, there’s been this huge resurgence and interest and people are really just seeing it go kind of all over the place. I’m probably most excited about the research being done in neurological diseases. So things like Alzheimer’s, as our population ages, we have a lot of people that are thinking about, “What can I do now to keep my brain healthy as I age.” And I think ketosis is a very promising tool in that regard. So I would say, you know, that’s where I’m most optimistic about seeing the most progress being made.

Sanjeev Goel, MD, FCFP (PC), CAFCI

How do you think that we can help make these recommendations about how to incorporate ketogenic lifestyle or like more personalized? Like what can, what do you think can we be learning about our genetic makeup and such that could potentially give us more ideas on how to make this more suitable?

Angela Poff, Ph.D

That’s hard to say, I don’t think there’s a lot of understanding exactly about how, for example genetics plays in the potential application of ketosis for a specific individual. We certainly need more research in that regard. I mean, we just need more long-term clinical studies across the board. And that’s, probably the biggest and obviously the most valid kind of argument against ketogenic diet being used so ubiquitously, is that, we do want to see longer human trials really kind of like sussing out some of these nuances. But you know, it’s hard to do those kinds of trials. Diet trials are hard to design. They’re hard to get someone to stick to permanently. I mean, can you imagine, convincing a hundred people to follow a very regimented diet for 10 years, just so we can see what happens.

You know it’s very, it’s difficult. So we kind of have to take what we have and improve from there. But yeah, I mean, just without more research, we don’t really know exactly where and when and if these therapies or these lifestyles are gonna be the best option for all different kinds of people. And again, people are different, there’s probably people out there that won’t respond super favorably to a ketogenic diet. May have some wonky, blood lipids happen. I’ve definitely heard of that happening. So it’s all has to be individualized. And I think more than anything, I would love to see greater education in the medical community about nutritional therapies and nutrition in general. So I’m sure you probably, could speak to, however much nutrition education you got in medical school. I know my husband’s a physician and he got one, three hour lecture. And nutrition should be a pillar of health education and prevention of disease and maybe even treatment of disease. So we need more education for the healthcare community and for the individual.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Yeah, thank you so much. That’s amazing. I really appreciate your time Angela today. This is great. Where can our viewers go, if they wanna learn more information. I know that you run the Metabolic Health Summit but, any other, you want to tell them about that?

Angela Poff, Ph.D

That would be great, thank you. Yeah, we host an annual scientific conference called Metabolic Health Summit and it’s, the next one is gonna be May 5th through 8, 2022 in Santa Barbara, California. It’ll be in-person. So we’ll all be back together, which is awesome. And we have, a lot of research presented related to metabolic health in general. But we do have a strong kind of interest in ketogenic therapies. And we have about 30 presenters from around the world, both scientists and clinicians talking about the cutting edge research and implementation of these kind of ketogenic and other metabolic therapies, everything from neurological diseases, to cancer, to metabolic disorders, to just human optimization and aging and longevity. And it’s a really cool experience. 

We have lectures all day and then we have mixers and events. We have a big gala dinner one night to support MaxLove Project and Charlie Foundation. These are some really incredible nonprofits in this space. And so we also, aside from that, once a year, in-person event, throughout the year, we put out a lot of high quality education content. Our kind of heart’s desire is to be a platform for evidence-based education related to metabolic therapies like the ketogenic diet. And we constantly put out on our social channels @metabolichealthsummit, put out lots of information about new research and just cool stuff like that. We even recently put out a 2020 Year in Review ebook. It’s completely free. 

You can find it on our website, metabolichealthsummit.com on the videos tab. And it’s a overview of the metabolic therapies research that came out in the year 2020. And we’ve addressed and presented the key findings of over 100 research articles. And it’s all in one spot. So that’s a cool, cool asset, especially for healthcare providers, because I think, they wanna be able to know what’s happening without having to do these long, extensive pub med searches. And so that’s a cool, a cool asset, I would say. Go check that out if you’re interested but,

Sanjeev Goel, MD, FCFP (PC), CAFCI

Metabolichealthsummit.com, right?

Angela Poff, Ph.D

Right.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Just wanna make sure we got that right. Thank you so much. I really appreciate your time. It’s awesome.

Angela Poff, Ph.D​

Thank you. This is great.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Okay, thanks.