Dr. Dominic D'Agostino: Using metabolic Therapies to Prevent & Manage CANCER

These are really important things that an oncologist is never going to tell the patient to do. Hyperglycemia and hyperinsulinemia is associated with much greater, sometimes two to three to four-fold higher incidence of cancer. But if we had a drug that did this, it would be a blockbuster for sure.

Yeah, I am glad to discuss this topic. It's a topic that got put on my radar by someone I think you know very well. You've had on the podcast, Dr. Thomas Seyfried, who published an article in 2008 on a calorie-restricted ketogenic diet in an animal model of brain cancer, and that caught my attention because I was looking at anti-seizure effects of the diet and also was doing some work at Moffitt Cancer Center at the time and really appreciated that cancer at the time in 2008 had a metabolic component that was grossly kind of underestimated and not really appreciated from the standpoint of targeting as metabolic therapy. So there are various imaging technologies like FDG PET scan that was used to image the aggressiveness and the location of tumor, and that's a metabolic phenotype, but that was not being used to actually target the cancer. So that sent me down a path to understanding cancer as a metabolic disease. And I would say I was not swept away by what Tom Seyfried was putting out there initially, but when I started fact-checking him and actually reading all the literature, I realized that this is a path I think I wanted to go down. And I had a student at the time, a PhD student, a fresh PhD student in the lab, Dr. Angela Poff, and she nudged me to go down that direction because she wanted to do her PhD dissertation on this topic. So that was, you know, I got to look at the calendar here, that was 15 years ago. So that sent my trajectory down looking at the ketogenic diet and metabolic interventions as an adjuvant to cancer therapies. But also the more we delved into it, we realized that this was a potential preventative strategy, and now we've, you know, partnered with different people who are kind of advancing that front too.

So I know Dr. Seyfried probably went into this ad nauseam, but when I lecture to the medical students or just kind of give like a summary of my research to like faculty who are unfamiliar with it, I start from a very basic kind of understanding, is that we, the mainstream understanding is that cancer is a genetic disease, and then alterations at the level of the nuclear genome, alterations in DNA function, and now we know epigenetic regulation and various mutations can trigger the activation of oncogenes at the level of the nuclear genome. And the nuclear genome, I guess stated another way, the fidelity of the nuclear genome in regard to DNA repair is intimately linked to the bioenergetic state of the cell. And what that simply means is the cell produces energy in the form of ATP. And when ATP levels, like when we're young and healthy and our mitochondria are very robust, we make sufficient amounts of ATP and all the corresponding signaling pathways associated with robust mitochondrial ATP production are up to par. But when ATP levels fall, that signals a mitochondrial dysfunction. And there's a retrograde response at the level of the nuclear genome that senses an energetic crisis right from impaired mitochondrial function. And this could be due to oxidative stress, aging, inflammation, a wide variety of environmental toxins can do this. And it's a failure of the mitochondria and an overproduction of oxidative stress that then triggers the activation of oncogenes, which could essentially be the carcinogenic response, right, the transition of a normal healthy cell to a cancerous cell. And but it starts, the important thing to appreciate and acknowledge and to further test and validate this theory is that it kind of starts at the level of the mitochondria. And I'm just speaking, I'm making it very simple and speaking at the level of the mitochondria making energy. But the mitochondria is an organelle that does so many different things. And our lab actually studies the redox control and how the mitochondria control redox levels, and the mitochondria are a source of neurotransmitters. So as a neuroscientist I study, you know, for example, monoamine oxidase, you know, is produced in the mitochondria and a wide variety of neurotransmitter systems. But when we're talking, if we get to the essence of the metabolic theory of cancer, it dates back to Otto Warburg, where he posited a theory that disregulated mitochondrial function, stated as insufficient respiration, leads to compensatory fermentation. So respiration, we're not talking about breathing, we're talking about oxidative phosphorylation. When that process is impaired at the level of the mitochondria, there are compensatory mechanisms that are very robust in cancer cells. This observation was made where the cancer cells default to an energetic pathway to derive energy from fermentation or substrate-level phosphorylation is a kind of scientific term for that, and that would be the metabolism of glucose and glutamine to preserve the energetic state of the cell simply because, and this is what the metabolic theory says, simply because the mitochondria are altered in a way, the metabolic theory says they are dysfunctional and they are, you know, lacking.

Mainstream, and it's important to acknowledge this, that mainstream cancer biologists would say the Warburg effect causes a shift in the mitochondrial function to endow the cell with the capacity for biosynthetic production. So various intermediates are then shifted to biosynthetic pathways, for example, to make lipid membranes and things like that. So the Warburg is an advantageous effect for the survival of the cell, where the metabolic theory is like the initial hit to the mitochondria alters the retrograde response and then that kicks on the oncogene. So the mitochondrial function becomes the driver for cancer, and stated another way, and Tom Seyfried kind of coined this term, you know, healthy mitochondria are the ultimate tumor suppressor. So, and I think that's a theory that still needs to be studied, that if we have healthy robust mitochondria, is it possible for a normal cell to transition to a cancer cell, a cancer cell that has all the hallmarks of cancer? So that's a very provocative question and we don't have an answer to that yet.

Okay. It does it through a number of ways, and the optimal diet for cancer prevention may not be the ketogenic diet for some people, in particular people who are obese, type two diabetic, overweight. It's a very effective way to get insulin under control. And when we suppress the hormone insulin, that activates metabolic machinery to increase our fat oxidation capacity and our ability to make ketones, and actually limits or marginalizes glucose as a fuel source. So it makes us more metabolically flexible. And the standard American diet, eating multiple, you know, high carbohydrate meals throughout the day, day in and day out, largely suppressed metabolic flexibility where, you know, in the past, of course, you know, we had limited food availability and we did not have access to the amount of carbohydrates we have now. So we were metabolically flexible in the past. And it's debatable, but maybe that's why we didn't have the high rates of cancer way back in the day. Or of course, we didn't have the diagnosis and imaging technology to diagnose this. So people just died for unknown reasons. But I think even epidemiologists agree that, you know, cancer is a disease that is far more common today than it was in the past. Right? So I think that's important to appreciate. A ketogenic diet kind of brings us back to our evolutionary past in that by eating a ketogenic diet macronutrient ratio that's high in fat, sufficient and moderate in protein, not high in protein, and the carbohydrate source is largely fiber, fibrous carbs from vegetables. So you have fat, adequate protein and fiber, and this diet suppresses the hormone insulin, which is a really important component in regard to cancer outcomes. And it also reduces blood glucose levels to some extent, not too much baseline glucose, but it does highly, it reduces the glycemic variability. So, or spikes, and actually those spikes in glucose are triggers for other pathways, other growth factor pathways, like when you could have a normal baseline glucose, but if you have a spike, periodic spikes in glucose, it's releasing insulin, and that relative change in glucose then is the driver for releasing insulin, which can then augment and change IGF-1, mTOR, and other pathways associated with cancer growth. So a ketogenic diet really takes the foot off the gas pedal of cancer growth if you have it, and actually produces an environment that makes it less likely that cancer would grow or even initiate. That's what we believe, you know, and I think if you go back to the calorie restriction studies, you know, this was seen. And I think an important thing to acknowledge too, that if you have any diet and you reduce calories or you do it intermittently and you control insulin, you control glucose, and you keep insulin or you keep inflammation low, those three things, I think it would be very similar to the cancer suppressive effect of a ketogenic diet. So you could do that with any diet. The advantage of a ketogenic diet is that it likely makes it easier to adhere to caloric restriction, which can be very helpful for many patients. Also limiting that glycemic variability, reducing insulin a little bit more, and then you have the production of ketones. So the liver produces ketones but can't use ketones as an energy source, lacking succinyl-CoA transferase, unless you have like liver cancer. So the liver is almost like an endocrine organ that's releasing this, you know, fuel that the body is using, this endogenous metabolite that is not only providing energy, but it has its own receptor, GPR109A receptor, you know, as an example, and that can trigger a reduction in inflammation. It has epigenetic effects through histone deacetylase inhibitor enzymes. It directly interacts with the histone via beta-hydroxybutyration, which is a whole pathway a graduate student of mine is studying right now. So not only is it energetic fuel that can increase ATP production per unit of oxygen, perhaps even 20% higher ATP production. We know that's the case with the heart. No one has validated that in the brain or muscle, but cardiac muscle they have. So you have a fuel that is more bioenergetically favorable when it's metabolized. It produces less reactive oxygen species. And then it also functions in a way that can increase our antioxidant capacity. It has favorable epigenetic effects and it changes various signaling pathways that would favor a suppression of cancer growth. So that's the advantage of the ketogenic diet. But, you know, taking a big step back, if we just focus on our body composition, if we, you know, keep a healthy weight, if we stay active, exercise, maintain strength and vitality with any diet, that's probably the most important thing. But the ketogenic diet is kind of like the icing on the cake. And when we talk about a ketogenic diet that puts your glucose ketone index within the range of like one to three, then that is what I call a prescription ketogenic diet. There's like the internet ketogenic diet, right? And then there's the prescription strength ketogenic diet. And that's a highly calculated ketogenic diet that needs to be managed that keeps your glucose ketone index, which is the ratio of your glucose over ketones in millimolar concentration, that ratio between one to three. And that in and of itself has incredible anti-seizure neuroprotective effects, but will have tremendous tumor suppressive effects and would further augment the therapeutic efficacy of standard of care therapies, including radiation, chemo, and immune-based therapies like checkpoint inhibitors, PD-1 inhibitors, for example, would be augmented by that metabolic state.

Yeah. Yeah. So it's, we call this, it's multifaceted, pleiotropic effects, right? So, and that makes it very difficult to study too. You know, a lot of people ask, well, what's the difference between a ketogenic diet and just giving like exogenous ketones, which is another topic. It's like a hack really to lower your glucose ketone index, and similar to giving a fuel like exogenous ketones, when you alter metabolism and shift the metabolic machinery and also the fuel that it's using, you are changing so many different downstream pathways, and it's hard to disentangle and identify specifically what's, you know, what is favorably changing, and that might be different depending upon the person. You know, one person may have an insulin level of 20, right? And a ketogenic diet may bring it down to five or six, and that's beneficial. Another cancer patient may have a normal insulin of four or five, but they may be benefiting from, you know, the higher ketone levels and maybe the anti-inflammatory state of that. So it's hitting many different, if we had a drug that did all these different things, and I mean, the closest thing that we have is maybe metformin, and there are some side effects to that, right? But if we had a drug that did this, it would be a blockbuster for sure. And I think that's important to acknowledge that from the context of people asking, well, where are the human, you know, randomized clinical trials, which we do have for epilepsy, but where are the, you know, the RCTs for cancer? We have quite a few pilot studies show it's feasible and that it's efficacious under some conditions. But they still, I mean, doing nutrition research is incredibly hard. I was talking with Dr. Jeff Volek yesterday, who's like a pioneer in this, actually is doing quite a bit of cancer research. So it's just hard to do this kind of research. But if you go to clinicaltrials.gov, and people listening to this can just go to clinicaltrials.gov and type in ketogenic diet and cancer, and you'll find at least three to four dozen clinical trials for cancer, and ten years ago there may have been two. So it's very reassuring that this has been put on the radar. There's even some federal funding supporting it. But it is not purely a non-toxic metabolic therapy. So what institutions are doing or pharmaceutical companies are doing are actually using the diet to further enhance and augment specific drug therapies. That could be the case for metabolic drugs too, like PI3 kinase inhibitors, for example. So I think Dr. Lewis Cantley kind of spearheaded this class of drug, which on paper, I mean, these seem to be remarkably promising, the idea of a PI3 kinase inhibitor, but when you administer these drugs, there's a counter-regulatory effect that causes your insulin to surge. So the elevation of insulin associated with PI3 kinase inhibitor drugs then negates the effect of the drug by itself because insulin can enhance cancer growth by increasing glycolysis and other growth factor pathways. But in the context of a ketogenic diet, a PI3 kinase inhibitor, then you sort of unleash the beneficial effects of a PI3 kinase inhibitor in the context of insulin suppression through a ketogenic diet. And, you know, a lot of high-level investigators that are publishing papers on ketogenic diets, and they don't even put it in the title. They'll say like insulin suppression therapy plus drug X, you know, improves cancer outcomes. And you look at like, what's the insulin suppression therapy? And I'm not going to mention names here, but it could be, you know, in one case metformin, but insulin suppression therapy is a ketogenic diet, you know, but as cancer researchers, federally funded, there's a stigma to the diet, and that actually prevents a lot of people from talking about it, I think. And I've never been shy to talk about it, but I was a neuroscientist, physiologist that kind of stepped into the world of cancer. So I viewed cancer as something that was very difficult to understand. I think it still is. But when you approach it from the context of like a physiologist and cell biologist, it started to make more sense from the perspective of a metabolic component. There's a lot that I don't understand from a genetic and epigenetic standpoint, but what I do know is that there's a grossly underappreciated metabolic component of cancer that has been utilized by an FDG PET scan, but that metabolic component has not been leveraged, or targeting it has not been leveraged from a therapeutic standpoint. So that was the case in 2009 or 2010 when I started studying it. It's still the case now, but it is actually ramping up to where now there's actually conferences on cancer metabolism focused on these pathways.

Yeah. Well, if we look at epidemiological data, and that's not always the most reliable data, especially in nutrition, but if we look at epidemiological data, it's very clear that higher blood glucose or hyperglycemia and hyperinsulinemia is associated with much greater, sometimes two to three to four-fold higher incidence of cancer. Right? And the hyperglycemia and hyperinsulinemia is associated with an elevation of even systemic inflammation like CRP or high-sensitivity CRP, C-reactive protein, or certain inflammatory cytokines, and that metabolic dysregulation creates fertile ground for a transformed cell from a healthy cell that has transformed into a precancerous cell to take root and then proliferate and grow. And then as that tumor grows, it becomes larger. And as a tumor grows, the core of the tumor, as a tumor grows, it outstrips its ability to supply blood and oxygen to it. So this is like the core of the tumor, and then the mass of cells that then become a tumor becomes even more genetically disregulated with more mutations occurring from the hypoxia at the core of the tumor, and the hypoxia further damages the cells of the tumor and it becomes more aggressive. Right? So, and then as it becomes more aggressive, then it starts meeting all the hallmarks of cancer, right? You have insufficiency of growth signals and immune evasion, and then most importantly invasion and metastasis, where clumps of tumors can come off, they get in circulation, and then they seed, for example, in the liver and the kidneys and the lungs, and then they become metastatic. So most people don't die of a tumor per se, unless it's maybe a brain tumor, but people die of metastatic cancer. So actually the model that we used is an excellent model of cancer because it's a highly aggressive model of metastatic cancer, and this was developed by Thomas Seyfried, and it's a very unique model, the VM-M3 model, because the primary tumor was a brain tumor, glioblastoma, but we use an inbred strain of animals, the VM mouse, and when we take these cells now, dissociate them, plate them, grow them, and implant them into the flank, then you have very rapid systemic metastatic cancer, and it becomes a very powerful model, and it also features cancer cachexia and muscle wasting, which is a term, cancer cachexia, that's a unique feature of the model, and one of my PhD students studied that. So that's, you know, that's the features of cancer that could be targeted by a protracted ketogenic diet. Not only a ketogenic diet, but a diet that's low in carbohydrates, a diet that moderates calories in a way that optimizes metabolic biomarkers and cardiometabolic biomarkers that produces a physiological state that would make it less likely for cancer to occur. I mean, that's the most we can do, right? I mean, some people are just unlucky. I have communicated with people who are elite-level athletes, people that had great metabolic health on the surface that got cancer. So this challenges in many ways the metabolic theory, but when you talk to them, they're like, oh, you know, well, I had Epstein-Barr virus or I had, you know, some kind of viral hit or I was exposed to some kind of toxin. And it's kind of unfortunate because they believe maybe there are some things that they did that caused the cancer. And that's, I think, kind of unfortunate. But I do think that some people are just unlucky, and they could have a pre-existing gene, a SNP, or an environmental hit or toxin that, you know, triggers an oncogenic shift and triggers tumor cells to grow that form a tumor. So, you know, and that's been the case with childhood cancers too, like they really haven't lived long enough to be metabolically disregulated, to have poor metabolic health, to get it. So there's a lot of, I could see there's a lot of ways we can challenge the metabolic theory of cancer. But I think what's important from my perspective is that a rapidly growing tumor is highly glycolytic and is fueled by high glucose and high insulin and glutamine. And we have tools that we can target that. And also from the perspective that, I mean, it's appreciated now, right? I wrote the foreword to Travis Christofferson's book, and I really kind of delved into Tripping Over the Truth, and he would be a great guest to have on if you haven't. So in Tripping Over the Truth, that foreword really just kind of delves into metabolic health, why it's important, and why a wide range of cancers are increasing due to poor metabolic health, and why we need to target that.

Yeah, I do think that some cancer cells can use acetoacetate and maybe beta-hydroxybutyrate and ketones for biosynthetic production of lipids. And I think that's possible. I think more indolent cancers can maybe use fatty acids for fuel. So by indolent, I mean like kind of slower-growing tumors like prostate cancer or things like that. However, the more aggressive and the more metastatic a tumor is, the more glycolytic it is, and the more a fundamental feature of that cancer. If you were to cut out the tumor and do an electron microscopy, the structure of the mitochondria would not look normal at all. The cristae would be almost absent or just right. The mitochondria may look like hollow little shells without the inner mitochondrial membrane. So structure dictates function, and the more aggressive and glycolytic a tumor is, the less likely the mitochondria are serving in the capacity of ATP production, but that does not mean they may have other functions and could be biosynthetic processes and there's other functions associated with it, but it's less likely that they would be using fuels associated with oxidative phosphorylation, which are ketone bodies and fatty acids for fuels. And that's pretty much, I don't know too many people that would even challenge that. They may challenge the idea that cancer, you know, many still do believe, and I think in the lab and in various model systems, the mitochondria have normal oxygen consumption, and in some cases, in some cancer cell lines, maybe normal ATP production to some extent, but that's more likely an artifact of the model. But if you, for example, to do biopsies of, you know, aggressive metastatic tumors, for example, glioblastoma, this has already been done, you'll find that there's a significant decrease in the number of mitochondria and a tremendous change in the structure of the mitochondria, especially the inner mitochondrial membrane. So that would challenge the idea that cancer is using fatty acids and ketones as a major fuel source. So they need to essentially default to fuels that are fermentable, and that includes glucose, of course, but also some amino acids, including glutamine, maybe alanine too, but glutamine for sure.

Do everything possible to improve your cardiometabolic health. So you will be doing yourself a very big favor by incorporating a dietary intervention, a stress reduction intervention, and maybe even most important, and I haven't talked about it, you know, an exercise, an aerobic exercise and strength training intervention. And when it comes to, you know, when people who have advanced metastatic disease, they generally succumb to muscle wasting and cancer cachexia, and a big factor is the wasting of muscle, which limits their ability to, their mobility, and then things go downhill very fast from there. So it's really important to build metabolic currency and also muscle as metabolic currency. So the first thing that I would do is, you know, talk to your doctor, talk to your oncologist. Ideally, an open-minded oncologist who has an appreciation that the food that you eat and your nutritional status have profound implications on the outcome of this disease. So that's first and foremost. You need to have an oncologist who acknowledges that, appreciates that, and is going to support you. Because if you have an oncologist saying don't do this approach, even if you're giving him papers, then that's going to create a lot of doubt in your mind. And what I've observed in just communicating with cancer patients over ten years is that when certain patients, I mean, when they believe that the metabolic-based theory is working for them, that has a profound effect on the outcomes. And whereas, you know, maybe other patients, and they may not be following through with all the different components of a comprehensive metabolic, you know, based therapeutic approach, the outcomes are less favorable. So it's super important to, so I would say that upfront, and then, you know, as you, you know, eliminate all processed carbohydrates, stick to whole foods, reduce glycemic variability, do standard CBC, CMP blood work, get your insulin measured so you know that. And if you're overweight, if your BMI is, you know, twenty-eight, twenty-nine, thirty, if it's up there and it's not muscle, of course, and you have some fat to lose, it's important to follow an approach where you create an energy deficit, a caloric deficit. So that caloric deficit is further going to suppress insulin, glycemic variability, and also reduce many of the metabolic drivers for cancer. Whenever you have surplus calories, those surplus calories are going to end up feeding the tumor. However, if you create an energy deficit and a caloric restriction, then that's just going to marginalize the fuel to the cancer. What's really important when you create a caloric deficit is to do some kind of strength training and ensure that your protein is adequate, ideally one point five to one point seven grams per kilogram to preserve lean body mass, and if you can build strength and muscle while you're doing it. And these are really important things that, you know, an oncologist is never going to tell the patient to do, at least the way that I'm talking about it in giving specific, you know, guidelines in regards to that. But I think another important aspect is to work with, you know, the next thing to do is actually to seek out a trained diet consultant and to seek out information. It could be Miriam Kalamian's book, you know, A Ketogenic Diet for Cancer. It could be different nutrition oncologists that I've worked with in the past. Beth Zupec-Kania is very good. Denise Potter. You can look these people up, and they have been sort of the go-to people that have helped a number of patients, and there's an emerging amount of registered dietitians and consultants that work on this. And then to work closely with a consultant, or if you're educated enough to follow strict guidelines and to buy various monitoring off-the-shelf, commercially available in Walmart. I saw it the other day. Amazon, you get a Keto-Mojo device. If you want to be fancy and get a continuous glucose monitor, but you want to be able to measure your glucose and your ketones and seek to get a glucose ketone index between one and three, and that may be hard to do in the beginning. I mean, the standard American probably has a glucose ketone index of like twenty-five to fifty. A low-carb diet may push you down to like a glucose, you know, low-carb meaning one hundred grams to one hundred and fifty grams of carbs a day, maybe a glucose ketone index of ten. But when you get your carbohydrates down to fifty grams or lower, then you start to approach a glucose ketone index of five. And then you can tweak things with a dietitian to maintain that therapeutic range. And there's very good data in animal model systems and emerging data in human outcome trials to suggest that a GKI of one to three is highly therapeutic, and not just for epilepsy, which is kind of my wheelhouse, but also for cancer.

No, there are very powerful homeostatic mechanisms that maintain your blood glucose within a very tight range. Even after I fast for seven days, my glucose was like, you know, sixty-five, seventy. So that is important. When you fast, you're liberating triglyceride from adipose tissue. The glycerol backbone can then be converted to glucose. Gluconeogenic amino acids can be converted to glucose. So lactate, if you're, you know, exercising through the Cori cycle, gets converted back to glucose. So your glucose may fall from like, you know, one hundred and ten, one hundred and twenty down to half of that, to like sixty or seventy at the end of fast. But, you know, I'm a little bit hesitant to tell people to fast if they have a normal body weight, especially if their BMI is kind of low. However, if someone has fat to lose and a high body weight, which is a large majority of people who have these metabolically associated cancers do have quite a bit of weight to lose. And one thing that I see in many people that communicate with me, especially those that are overweight when they are diagnosed, when they go into remission or have like what's called no evidence of disease after the therapy, some of them, most of them that communicate with me are just doing, they're doing the standard of care, but they're coupling it with metabolic, and some of them are not. And like I was communicating with a glioblastoma patient that went over ten years when she was diagnosed. She was pregnant with her daughter, and she unfortunately just passed away a few months ago, but her daughter was eleven years old, you know, and she was pregnant with her daughter when she was diagnosed with a glioblastoma. She did not do debulking, she did not do chemo, she did not do radiation. She did a calorie-restricted...

restricted ketogenic diet, fasting and hyperbaric oxygen, and then some, you know, some plant-based compounds too, like, you know, green tea and various other things, I believe. So, but we stayed in contact and, you know, it was sad to see that she passed away. But, you know, it's important for people to look at the literature depending on what kind of cancer they have and to ask their doctor, show me the randomized control trials on this particular drug and the outcomes, not only extension of life but overall survival is going to be important, and to appreciate that outcomes can be highly influenced by the health and vitality and metabolic state of the patient. And I don't think that is actually, and I'm in contact with some of the top oncologists in the world and they don't approach nutrition like that. So nutrition is approached to mitigate side effects of chemo and radiation. So let's just keep calories, let's get calories in the patient and let's prevent as much weight loss as possible. So that's kind of like the approach, right? And also to prevent any kind of nutritional deficiencies. So some things may impact, you know, certain vitamin status, some things may dysregulate the gut microbiome. So there's like probiotics and things like that. But they don't approach it from the perspective of augmenting, further augmenting the therapeutic efficacy or targeting the tumor itself.

Yeah. I think the first person that I saw observed in the literature that was doing it was Dr. Adrienne Scheck and she was at Barrow Neurological Institute. She's a great friend and colleague of mine. She would be great on your show actually. She was doing radiation in a GL261 model of glioblastoma and showing that doing radiation therapy, temozolomide by itself, and then looking at tumor growth and then the death of the animal. And then she would do a ketogenic diet after the tumor implantation and the tumor growth and then couple that with radiation or chemo and seeing extension of survival. And then ultimately when she was, you know, she was tweaking the diet and settled on a dietary formula, she was able to cure cancer in this particular animal model that I don't think people have using chemotherapeutic drugs. When she coupled the ketogenic diet with radiation and chemo in some cases, she was able to basically put the animal into remission from this advanced high, you know. And Dr. Seyfried would argue with the efficacy of radiation therapy as a therapy that would increase the overall survival in patients, that he may argue that, which he rightly so, and he's written papers on this, that it damages the microenvironment in a way that can feed the tumor. And I'm not going to argue against that, but I think in some cases debulking especially can be very therapeutic and certain targeted radiation therapies can be advantageous for some patients, I think. But I think patients need to question their doctor. And then when we come to, and that's radiation in and of itself without a ketogenic diet. So when you couple radiation with a well-formulated ketogenic diet and you're working in the capacity of what's feasible with the patient with their metabolism. Sometimes there's dexamethasone involved and that can increase your glucose. But when you have a well-trained dietician who knows the art and the science of doing this, they're able to adjust the glucose ketone index within that one to three range. And that largely mitigates many of the side effects associated with radiation, including reduces the inflammation, reduces the associated necrosis, and gets insulin and glucose and inflammatory cytokines. It reduces these things in a way where side effects are dramatically reduced, where there's some patients that communicate with me that it's like they didn't have any side effects at all. Like even with the dexamethasone, they could keep a glucose level, you know, at 70 to 75 milligrams per deciliter or close to three to four millimolar, you know, and maintain that. And that would be the highest that it gets. I mean, these are, you know, not all patients can do that. But, you know, on the other hand, if they were not following a ketogenic diet and were just following the recommendations for nutrition, their glucose would be in the mid 100s, would be double that for sure. So that's having a tremendous effect on the outcome, but also the side effects. So the first thing we need to do is not eliminate the standard of care and just say just go, or I mean, at least from a research science point of view and getting this accepted into the mainstream oncology centers like the Moffitt Cancer Center, which, you know, we collaborate with MD Anderson and other cancer centers. It's true they do make their money off giving therapies, right? They do make their money off giving chemo, radiation, and many cutting-edge immune-based therapies. And I do think there's a lot of potential for PD-1 inhibitors and other checkpoint inhibitors to synergize with a ketogenic diet. And when I say synergize, that would enhance the efficacy, but also reduce the side effects.

Well, I mean, chemotherapy has systemic side effects and chemotherapy is a carcinogen, right? So, you're giving a poison to kill off ideally proportionately more cancer cells than healthy cells. But the problem with chemotherapy obviously is that when chemotherapeutic agents are delivered, they're, you know, toxic to your normal healthy cells, but that also includes your immune system. So your immune system has incredibly fast, rapidly dividing cells that maintain immune surveillance, right? And I think that's, you know, really important to appreciate that when you compromise your immune system, a big part of getting cancer is failure of the immune system to recognize. And there's various killer cells and a whole host of cells that identify certain surface markers and then the body can then neutralize and kill cancer. And that is largely abolished after you do several rounds of chemotherapy. And I think that's important to kind of acknowledge that that could be one of the main side effects. And so a lot of times you have patients. So cancer is a disease of aging. As we age we get more cancer and you have like a triple whammy when it comes to muscle and function too because you have age-related sarcopenia on top of chemotherapy-induced muscle wasting on top of cancer cachexia. So yeah, like three different things that are compromising your skeletal muscle mass, which is your metabolic sink and creates metabolic reserve, but most importantly creates your mobility and your ability to be independent. So all these things are kind of synergizing together to compromise the patient. So you have that going on and then your immune system. So it makes the patient very weak. And I've seen like normal healthy patients. I mean, I actually trained with a patient who was an elite-level athlete, you know, and that was very strong. I mean, we were doing almost the same weights and everything in the gym and he was smaller than me, lighter than me. And he went through chemotherapy and was like could barely pick himself up, you know. He had, you know, a very advanced cancer, the pancreatic cancer, and, you know, so that is difficult to deal with. Not everybody will experience side effects. So my recommendation would be for the patient to talk to the oncologist and say maybe appreciate the idea of giving less of a dose of chemotherapy and do more targeted radiation therapy and to look into various different metabolic drugs that are out there. Would be, you know, if they're open-minded about that. I mean, even things like metformin, I mean, obviously it's off-label, but if you go to clinicaltrials.gov, type in cancer metformin, I think you get like 200 clinical trials. So there's existing science and there's emerging science being done now to show that it could be a favorable adjuvant to different, you know, therapeutic approaches.

I think cinnamon's great. I'm like a cinnamon freak. I get like probably a teaspoon or tablespoon of cinnamon every day. I think berberine's very interesting and has a lot of potential behind it. I've experimented with dihydroberberine, which is in a product by Optimizers, and I used dihydroberberine and it's a formulation with a few other things and I took a dose of carbohydrates and had a CGM response before and after berberine and berberine knocked it down maybe 25%. I think berberine is great for people who are insulin resistant and have problems reducing their blood glucose. I'm also of the opinion like the less supplements and drugs you can use the better and use these things as tools first. You know, nail down your nutrition, nail down your exercise, nail down your stress can augment your immune system and metabolism. Get these three pillars under control and then add in various things one by one so you can fully understand and appreciate them helping you but also some of the negative effects. If you just do a shotgun approach then you don't know, like, you know, there may be some beneficial things if you start taking five things at once and you start getting side effects, you don't know what's giving you the side effects. And I think it's important to start with evidence-based supplements that you know, something like alpha-lipoic acid could be very beneficial, you know, that could reduce glucose excursions with carbohydrates if you're on a carbohydrate-based diet. Yeah, things like turmeric could be used for cancer prevention. I mean, these things have anti-inflammatory effects, maybe protective mitochondrial effects. So I think from the perspective of cancer prevention, there's a lot of, you know, plant-based compounds and supplements that could be used. But even things like, you know, the supplements that I use that could be beneficial like creatine monohydrate. If you go to examine.com, there's like a number of studies on creatine and cancer that, you know, you have favorable outcomes people using creatine. It's super safe. It's the most studied nutritional supplement in the world and it can increase your strength and preserve muscle strength and function, you know, throughout your therapy. So there's simple things like that that are cheap, that are safe. Cancer patients have no idea. You know, the cancer patients going to the major centers have no idea, never probably never heard about creatine monohydrate. And, you know, it's a simple supplement you can get anywhere that can have a noticeable effect on your strength and preserving muscle mass and cancer outcomes. There's research behind this.

Yeah. Well, if you're following the ketogenic diet, carnitine is a good one. I like to use acetyl-L-carnitine. It crosses the blood-brain barrier. That's a good one. Magnesium is excellent. Magnesium is involved in hundreds of different biochemical reactions. Most people are deficient in magnesium. So that's an important one. It's really important to keep your electrolytes up. And this took me a while to appreciate, but calcium, I used to take a calcium supplement and then, you know, there was some cardiovascular papers that came out to suggest that calcium may not be a good thing to supplement. But when you have calcium in your arteries, that's like more of a side effect of what your body is doing with the calcium. But what I've observed and when I went, you know, I've learned from the paleo community, but also in the farming community, is our soil is highly deficient in calcium. So very deficient. I mean, it's, you know, part of fertilizers and things like that. So calcium's super important. I would recommend that at nighttime, different forms of calcium, magnesium, and K. Actually, I use a ketone salt product, KetoStart. It's by Audacious Nutrition and it has beta-hydroxybutyrate that's spread out across the electrolytes. So you have sodium, which you really need to get sodium. Some of the carnivore people say 20 grams of sodium per day is, I don't know, you need, I sometimes I get that much because I'm in Florida and I sweat a lot. So sodium, KetoStart has beta-hydroxybutyrate ionically bound to sodium, potassium, calcium, and magnesium. So you get a balanced electrolyte. The electrolytes are really, really important. So calcium can also bind things like oxalates and help your body kind of eliminate them. But most importantly, I think calcium is a really good buffer in your blood and reduces acidity. So you have monovalent and divalent cations, ions are like super awesome buffers and they help eliminate some, you know, plant toxins if you are eating salads and things like that. So are beneficial. But so beta-hydroxybutyrate salts, KetoStart is the one that I use. MCT oil, I use a product called KetoBrains, which is alpha-GPC, MCT oil, theanine, and lion's mane. So I mean, I just like that product. Gives me a good buzz when I'm writing. But other than that, you know, vitamin D if you're not getting a lot of sun and K2. And then I eat a ton of fish, mackerel, sardines, and anchovies, which I stay low on the size of the fish to reduce heavy metals. I eat massive amounts of fish, pounds of fish per day prior to getting blood work and doing a hair analysis. And my heavy metals tested to be like in the low end of normal. So that was very reassuring that the type of fish that I'm eating has a very low toxin amount. So I looked at lead, I looked at everything and did several tests. And so if you're not eating sardines, mackerel, anchovies, or just salmon and fish in general, I think it's really important to supplement omega-3 fatty acids because these have been shown in clinical trials, a lot of animal work, to have an anti-catabolic effect, in some cases an anabolic effect. So they help not only reduce inflammation, actually they may have an anti-catabolic effect by reducing inflammation. So I add omega-3 to the list. I said I'm not a big fan of supplements, but, you know, sounds like I'm saying a lot of things, but I do think that that's kind of like, that's what I take personally. And then I think that patients should probably get a workup like Genova Diagnostics is a great company where you can get, you know, tests done to look at your nutritional status and then from there then you could decide what you need. So it's not actually, it's not a good idea to supplement high dose of B vitamins if you're not deficient in B vitamins because high doses of B vitamins could actually fuel cancer in some cases. That's a controversial theory, but and also vitamin B1 or thiamine may be deficient in some people. So that's another one, especially if you're taking some drugs that we've worked with in the past like dichloroacetate. It activates pyruvate dehydrogenase complex which then can make your body deficient in thiamine. You know, you want to take, if you do that, you want to take alpha-lipoic acid and thiamine to help, you know, fuel that reaction. So it's kind of depending upon the therapy that the person is taking, but I'm not a big fan at all at megadosing vitamins or certain supplements. So strategic implementation of things, ketone salts, calcium, sodium, magnesium, you know, these things are really important. And MCT oils, very, these things can help lower your, they kind of hack your GKI if you will. Now I get a lot of questions because most of our research has been published on ketone esters, right? Ketone esters are exogenous ketones that are very powerful and they have anti-seizure effects. They also have anti-cancer and anti-catabolic effects. So a lot of what we've published have been ketone esters simply because that was what was available back then. Also animals are hard to get into ketosis. So you have to use these very powerful ketone esters to really induce and sustain ketosis. I worry a little bit about administering a high dose of a ketone ester because it could potentially reduce your body's ability to make ketones and it's doing that by virtue of an elevation of insulin. So the ketone esters do this. So we work with 1,3-butanediol acetoacetate diester. We've worked with 1,3-butanediol beta-hydroxybutyrate monoester. We've worked with a glycerol triester of acetoacetate and beta-hydroxybutyrate. So you don't need to know the terms. Just understand that I'm of the opinion, even though I've published on it, I'm of the opinion that ketone esters are not ideal for the metabolic management of cancer. I think we still need to do research on them and I think they do have real side effects. We've killed animals administering ketone esters. That said, I do think they have incredible capacity when the safety studies are done to be used in cancer therapy under certain conditions. I would default to simple things that you can get in the health food store. MCT oil, MCT oil powder, and then you have ketone salts, which are beta-hydroxybutyrate you could administer as a salt. KetoStart is one. There's the free acid of beta-hydroxybutyrate. Although that's one of the first things we tested and I think there's some supplement companies came out with it, but really you want the salts because you like to get the acid-reducing buffering effect of the electrolytes and that can help out. So I get a lot of questions about exogenous ketones and I do think they are a very powerful way. I've seen people with a GKI of five or six do nothing but add exogenous ketones and then be able to maintain a GKI of two just by supplementing two or three times a day exogenous ketones. And if you look at their insulin levels, it's normal. I consume like the highest dose of, the highest tolerable dose of a ketone salt, like two packets of KetoStart, and then an hour later pricked my finger and measured insulin and there was nothing. And then I administered our ketone ester and then I measured insulin and I thought I saw that it popped up. It popped up only from like three to six, but that pulse of insulin could, you know, could activate cancer. You know, it's not doing you any good, I think, even though your ketones are high. And also, if you consume a ketone ester at a dose that elevates your ketones, whenever you get a delta of two millimolar or more, that's releasing insulin. So what happens is you consume the ketone ester, your ketone levels pop up to like three or four millimolar, and then two or three hours later your ketones are back down to baseline and maybe lower than baseline because the insulin is going to reduce your hepatic ketone output. But three hours later you're hypoketotic and hypoglycemic, and then that can trigger a headache. And if you see, there's a couple clinical trials that came out with like 1,3-butanediol. They're selling it as a ketone ester, but it's really not a ketone ester. If you esterify that to ketones, it's an ester. And I don't want to confuse people listening to this because it may sound highly technical, but I think the important thing is that I think ketone esters are powerful. They need, more safety work needs to be done in the context of cancer, and that there are significant advantages to using ketone electrolyte salts, and that people should not fear salt. They should not fear sodium. They should not fear calcium. They should not fear magnesium. These electrolytes are beneficial. They help buffer your blood and they have very favorable effects in general.

Yeah, very good question. So we design all our experiments to test the question: is it carbohydrate restriction associated with the ketogenic diet, or is it the ketones themselves that actually have the therapeutic effect? And one of the first publications we published in American Physiology Journal was on what's called central nervous system oxygen toxicity, or CNS oxygen toxicity. And hyperbaric oxygen is something that I'd like to talk about too. But when you go inside a hyperbaric chamber, or let's use the context of a Navy SEAL using a closed-circuit rebreather. When he dives down to 50 feet on 100% oxygen and gets down to, you know, 2.5 atmospheres or below, then that oxygen can trigger a seizure, a grand mal seizure. And so we have a model system in the lab where we replicate this in rats. And I was highly skeptical that giving exogenous ketones could mitigate oxygen toxicity seizures. So work was done by the military to show that if you fast 24 or 36 hours, but for a rat that's like me fasting like three to five days, that increases the latency to seizure more than any anticonvulsant drug. So this really inspired me to go down that path. I was like, let's do the ketogenic diet. The military was like, no, we're not going to give a high-fat diet, but we'll fund like a ketone ester. We want the ketogenic diet in a pill. So I tested beta-hydroxybutyrate monoester. I tested 1,3-butanediol. It had no effect. And so I was thinking, okay, keto adaptation needs to happen before you get the anti-seizure effects. You know, you really need to suppress insulin. But then I worked with a chemist. His name is Patrick Arnold. You know, he's got a Wikipedia page. You can read about him. He's a brilliant chemist. But I couldn't get the molecule that I wanted to synthesize in academia. So I was able to get it synthesized and it was a molecule that elevated beta-hydroxybutyrate and acetoacetate more or less in a 1:1 ratio. And I was given the recipe by Dr. Henri Brunengraber, who ran the NIH metabolomics core at Case Western. So I got the recipe, we synthesized it, I gave the monoester of acetoacetate, and it's a 1,3-butanediol acetoacetate monoester, and then we made the diester, and this worked remarkably well. The animals were consuming a high-carbohydrate rat chow. We gavaged, which means we tube-fed them 30 minutes prior to five atmospheres of oxygen, which induces a seizure pretty quick, like five minutes. And then when we gave them the ketone ester, they were in, you know, they're in the chamber for like an hour. And actually, we went to 90 minutes, which then you start to get pulmonary oxygen toxicity. Like it's almost like we couldn't give them oxygen toxicity. It was actually energizing and stabilizing neurotransmission, and it had such a neuroprotective effect it was almost hard to induce oxygen toxicity seizures. So this made me realize that independent of macronutrient manipulation, we could administer a ketogenic agent, not all ketogenic agents, but this specific ketogenic agent, and it has, you know, an anti-seizure effect. So then, I mean, you're asking about the effects on cancer. So we actually formulated various diets, and one of the studies we published in the International Journal of Cancer, Angela Poff was the first author on that, and I think the title is Ketone Supplementation Decreases Metastatic Cancer in a Metastatic Cancer Model or something like that. So if you just Google ketone supplement, you know, metastatic cancer ketogenic, it would come up. And it's open, we pay for it to be open access. So when we integrated the ketogenic agents, in this case it was 1,3-butanediol, and we also did 1,3-butanediol acetoacetate diester, which had a little bit more of an anti-cancer effect, but they both did, and we fed that to the animal. Then they lived longer. It increased their, you know, the duration, it decreased tumor growth, and we had an enhanced survival. And then we also directly added ketones to the media of brain cancer cells that we were growing, and we looked at proliferation, and so we saw less proliferation, and we saw more cell death in the brain tumor cells that we grew in the presence of like two millimolar beta-hydroxybutyrate. And so beta-hydroxybutyrate by itself can decrease glycolysis. Beta-hydroxybutyrate has anti-inflammatory effects. Beta-hydroxybutyrate has epigenetic effects through class one and two histone deacetylase enzymes that could further boost endogenous antioxidant capacity and make our healthy cells more robust. And that can, it also, there's probably an antioxidant component to the redox status of the microenvironment of tumors. And then there's the epigenetic effects directly associated with beta-hydroxybutyrate. So I think it's multifactorial, and what we say, pleiotropic effects of ketones. So I think it's a number of different things working in synergy. And it may also be due to changing the energetic source of the mitochondria. So when the mitochondria are burning the ketones for energy or deriving ATP, you know, from them, they produce, the mitochondria produce proportionally less superoxide anion. So superoxide anion then gets converted to hydrogen peroxide, and then in the presence of like free iron, you can drive something called a Fenton reaction and produce hydroxyl radical, and then that creates an environment that can fuel cancer, you know, you can damage nucleic acids, membranes, and things like that. So you have, and you ask about ketones, what are ketones directly doing? And I think they're doing many different things. They're altering the redox state of the cell. They're changing the bioenergetic capacity. They have profound anti-inflammatory effects. So we published a paper in Nature Medicine, and that paper, Dr. Deep Dixit from Yale was the first author on that, and he had studied the NLRP3 inflammasome in the context of fasting, and then some of the data that came out of that study showed that beta-hydroxybutyrate was very high, and that correlated with the NLRP3 inflammasome suppression. So I actually gave him the supplement and generated the diet for a further study that got published ultimately in Nature Medicine in 2015, I think, that showed that simply feeding food with ketone supplementation suppressed the NLRP3 inflammasome to a similar extent that fasting did. And that NLRP3 inflammasome, when it's activated, sets off a cytokine storm of various, you know, IL-1 beta, for example, IL-6, TNF-alpha, and other things, but mostly IL-1 beta. And these things can drive the tumor microenvironment in a way to drive metastasis and invasion. And even if you don't have cancer, the NLRP3 inflammasome can drive the initiation of healthy cells to cancerous cells. And the NLRP3 inflammasome is tightly linked to radiation necrosis and downstream damage from radiation. So all these different things could be factoring in to the patient. Not only the lowering of glucose and suppression of insulin and associated signaling like IGF-1 and mTOR, but the elevation and sustained elevation of ketones has cellular protection effects and also anti-cancer effects.