New science of ketones for cancer, brain health, and insulin | Dr. Dominic D'Agostino

I like magnesium glycinate, MCT, creatine monohydrate, D-beta hydroxybutyrate, 10 g of BHB, melatonin occasionally.

Neuroprotection and general brain energy stability. Also, it reduces systemic inflammation and neuroinflammation. It reduces insulin and that increases fat oxidation, helps sort of train your metabolism to burn fat more efficiently, enhances mitochondrial function. They have more mitochondria, more efficient mitochondria. And then there's like epigenetic effects that we can go into, things on like visceral adipose tissue. Probably mentioned more than five there.

Great to be back on again. Thank you for having me.

Yeah, thanks. That was a great introduction. It covers a lot and we can dig into some little side things too that, you know, we study.

Yeah, I think the benefits of dietary ketosis, we do like to use the term ketone metabolic therapy because we do use it for the metabolic management of different disease processes. And more recently, we've been sort of proposing to do a larger project on sort of prevention, you know, using it as a longevity kind of protocol for an NIH project that we're working on. So I think, you know, from a... I use a ketogenic diet. I mean, just... I'm not managing any type of disease process, but over the years, about 20 years ago, I started studying it and I wanted to be in a state of ketosis to understand what individuals have to do to achieve and maintain therapeutic ketosis, that's defined by an elevation of ketones and sustained. And my background was studying seizures. So for seizure disorders, for neuroprotection and general brain energy stability, and I think really that's the common theme. And probably the most credible information and evidence behind being in ketosis would be undisputedly it's that when ketones are elevated in your blood, you can also measure them in your breath and in your urine. When ketones are available physiologically, they cross the blood-brain barrier easily and they supply an alternative fuel for the brain and that can positively impact brain energy metabolism, also the neuropharmacology of your brain, and also it reduces systemic inflammation and neuroinflammation. And neuroinflammation can be the root cause of different brain disorders and that could be seizures, that could be migraines, that could be psychiatric disorders. So, you know, this is relatively new information over the last five years, maybe about 10 years ago it was key. So I would say brain energy, neuroinflammation, it reduces the insulin, and many people, about 50 to 60% of people over 60 have elevated insulin, have insulin resistance. So suppressing the hormone insulin and that increases fat oxidation from your own fat stores and also dietary fat stores that you're eating. It helps sort of train your metabolism to burn fat more efficiently. There's an increase in mitochondrial... it puts a stress on your mitochondria when you initiate a ketogenic diet. And then that mitochondrial stress is like a hormetic stress that enhances mitochondrial function. And ultimately in animal models it takes about a month or more to get increased mitochondrial biogenesis. And I think in the human studies too, in athletes that are adapted to ketogenic diets, they have more mitochondria, more efficient mitochondria. There's a reduction of oxidative stress. We are looking at different inflammatory markers that are really important, linked to autoimmune diseases. We have a recent clinical trial at the Moffitt Cancer Center. It's a National Cancer Institute center, one of the bigger ones, one of the biggest ones I think in Florida. And we have a clinical trial using exogenous ketones that we call pharmacological ketone metabolic therapy to augment what's called immune therapy checkpoint inhibitors, specifically in lung cancer. So we're starting that up to basically do a feasibility study to use this as like an adjuvant. And then there's like epigenetic effects that we can go into, or, you know, things on like visceral adipose tissue and things like that. I probably mentioned more than five there. But I think I covered like, you know, the main sort of the main reasons why we do. And also I know you've had Dr. Thomas Seyfried on. So when you're in a state of therapeutic ketosis, defined, his definition is a glucose ketone index. So the ratio of glucose over ketones and achieving, you know, 1:4, I think he likes the 1:2 range. But I think in one to four you're getting a lot of benefits and that can be effective for reducing cancer growth and also making what we study is like standard of care or immune-based therapies work better and the patients get less side effects and they get a better response to treatment. You know, and it limits glucose availability and also reduces sort of insulin and various hormones that can influence cancer growth, that suppresses them in a way that sort of suppresses tumor growth in the large majority of cancers that are out there.

Yeah. So in the United States we tend to measure glucose by milligrams per deciliter. So, you know, so like, you know, 100 milligrams per deciliter would be about 5, you know, 5.5 millimolar. So there's a device that, oh actually I have here on my desk, the Keto-Mojo device which we use in our research. So I have...

Okay, so your listeners may be familiar or people watching this. So there are various devices out there that you can set the device to measure the millimolar concentration of glucose and the same device using a different stick or sensor or thing that you put into the meter itself will measure beta hydroxybutyrate. And it's important also to me to mention that it measures a particular enantiomer, it measures the D-beta hydroxybutyrate. And there are different forms of beta hydroxybutyrate. There's also acetoacetate and acetone. So it's not measuring them. And when you're in a state of ketosis, it could be elevated. You could have D, L-acetoacetate and acetone. And we call that total ketones. So we measure like total ketones too. So the ratio of glucose over ketones would be your glucose ketone index. And say for example if you were to achieve a low glucose level of 3 millimolar, which would be like 65 to 70 milligrams per deciliter, and 3 millimolar ketones, that would be a glucose ketone index of one. And that's for many people, you could achieve that through about three or three to five days of fasting. So that is difficult to achieve. In the lab and even in the clinic, we're working on ways to consume exogenous ketones with other protocols that could within 30 minutes, you could go from a glucose ketone index of 20 to a glucose ketone index of one and with various dosing protocols maintain that indefinitely and that could be, you know, you could quickly induce that therapeutic ketosis. So yeah, the glucose ketone index is simply the millimolar ratio of glucose over ketones and it becomes a really important single biomarker that is now used in registered clinical trials and we're using it for our research. And so it takes into account the glucose which is a driver for insulin and then the ketones obviously which signals that the insulin is low, but also the ketones have signaling properties that are really important for some of the work that we do.

Yeah, I think for, you know, daily activity, sort of your baseline metabolic physiology, if you could have a glucose ketone index of 5 to 10, that would be significantly better than the general population which is probably always over 20, for example, not really making any ketones. So if you could maintain a glucose ketone index of 5 to 10, which is achievable with just a low carb diet and maybe some, you know, MCT oil or like a little bit of ketone salts here and there, that'll give, you know, there's credible evidence to suggest that you could derive a lot of benefits from that, from your cardiometabolic biomarkers that we can go into too. So, and that's really like the big thing is that, you know, using a dietary nutritional ketosis and supplemental, we call that umbrella term ketone metabolic therapy, to shift the cardiometabolic biomarkers in a way that can confer sort of brain energy but also brain resilience and also have anti-cancer effects for longevity. But it also impacts various hormone systems and signaling mechanisms that can really help with the longevity profile that someone is seeking.

Yeah. Over. Yeah.

Yeah. So when I started research on the ketogenic diet and exogenous ketones, I think I kind of started for, I was curious of the, you know, the mental benefits. The body composition changes. I've never really had a lot of fat mass. I've always been kind of lean but at the same time sometimes I wanted to, you know, reduce my fat mass or just change my body composition periodically or situationally. So it was a very effective tool for that. And what I was always concerned about is that ketogenic diets would cause muscle loss and like, you know, rapid weight loss and muscle loss, but that was pretty much a consequence of like a lower protein ketogenic diet which is used clinically in the world of epilepsy. It's like, you know, 10 to 12% protein. So even the modified versions of the ketogenic diet that we advocate for have about 18 to 25% protein. And even we have a sort of an engineered rodent or animal ketogenic diet that doubles the protein. So historically, you know, in animal research they use about 8% protein to 10. So we doubled that and I think we have about 22% protein even in our cancer studies that we've run a half dozen cancer publications. We have many of them with Dr. Thomas Seyfried who you interviewed. So after following a ketogenic diet, you know, over the years I would always keep modifying it and adjusting it and personalizing it to me based on food preference and also based upon my blood work and my biomarkers and also subjectively based upon like my energy, muscle mass, my DEXA scans, things like that. And I did, you know, following a standard ketogenic diet and doing intermittent fasting, which about 10, 15 years ago I was doing that quite often. I lost a significant amount of lean body mass and that did not occur to me until I did like more comprehensive, you know, DEXA scans and things like that. However, I did not necessarily want to gain more muscle, but I wanted to, as you know, I started doing this in my early to mid-30s I guess and now I'm in my 50s. So as you get older, especially in your 40s to mid to late 40s and even like once I, you know, got turned to 50, it becomes increasingly harder to maintain your strength and your muscle mass. So I've had to sort of adjust the protein levels up a little bit. And that kind of kicks you out of ketosis or you're not achieving as high as ketones. So I've been relying more just on a low carb diet, a low carb Mediterranean type diet, if you want to use that term. And then adding things like MCT oil and also exogenous ketone electrolyte salts. Occasionally, I use, we do research on ketone esters too. So sometimes periodically I'll use them, a little bit less so now, but we've developed some new novel types of ketones that I've been experimenting with. So yeah, I probably just do it mostly for the brain benefits and the energy benefits because in academia you have to spend a lot of time at the desk writing, being able to focus, and it becomes really important to keep your energy and metabolism sort of stable and going. And if you have fluctuations in energy, especially in the mid part of the day, which was really common before I started the ketogenic diet, I always had that dip in the early to mid-afternoon. And I don't get that at all when I stay in ketosis.

Yeah. And I think it will have a much bigger effect in people that have some form of a deficit. And that deficit can be due to, you know, as we age, we have general cognitive decline as we age, but also in people that are younger that are experiencing stress, lack of sleep. You know, we study extreme environments. That could be hypoxia, sleep deprivation, what we call different, a term that's used like in military and space research is allostatic load where you're trying to like, you know, you have a whole bunch of tasks, you're trying to juggle a bunch of tasks at one time. That's your allostatic load. And also another term is like team cognition which if you're working with a group that your mood and your behavior is such that you're working very cohesively within the group and you don't have fluctuations in mood and energy that could sort of disrupt the team cognition. So these are like some of the terms, my wife is more familiar with them as a behavioral neuroscientist. But I think the real benefits are that, you know, if you're eating a standard American diet and we use that as an example, you're eating primarily a carbohydrate-based diet and when you eat it, postprandially your glucose will come up and then for many people glucose goes up in the blood and then your body releases insulin and two to three hours later depending upon the meal, the level of protein in the meal, fiber, even fat, if those are not sufficient and balanced, you could oversecrete insulin and then you'll have two to four hours later you get a postprandial dip in your glucose which is very, which I was experiencing, and that dip in blood glucose would be sort of subjective hypoglycemia for many people and that can lead to brain fog, that can lead to hunger cravings, that could lead to a headache, and then...

Yeah. So for example, if someone has, you know, I'll use it in the context of type two diabetes because, you know, working, so if someone with type two diabetes that has like a high level of glucose. So if we look at the NHANES data of people over 60, 50% of them have pre-diabetes or overt type two diabetes. So their glucose could be running 130, 140, 150. If their glucose goes down to 100 or even 90 in millimolar concentrations, that would be like four, that would be normal, they are experiencing subjective hypoglycemia and a lack of brain energy, right? Because so, and the lack in brain energy can lead to brain fog, fatigue and things like that. So it's subjective meaning that you can feel it.

And what's happening is that if your body releases insulin, it's facilitating glucose disposal into peripheral tissues like your muscle and other organs. And then you have a lack of optimal brain glucose. So it's limiting the brain glucose availability to your brain. If your body oversecretes insulin or if you get that dip in blood glucose, and especially from a circadian rhythm point of view like in the mid part of the day, when you know, you're experiencing the morning, a lot of people can wake up and feel, I have a pretty strong cortisol response in the morning and then it goes down during the day, but if you're not getting sufficient sleep and stuff, many people report over 50% that they get like postprandial sort of fatigue after lunch. This is very common and it could be due in part to just not getting optimal sleep. But I also sort of attribute it to blood glucose fluctuations going low. So that's subjective. And when you're in a state of ketosis, even if your ketones are moderately elevated to 1 millimolar, and that's like moderate ketosis, one millimolar glucose or ketone in circulation will contribute to a 10% increase in available energy to the brain. So all these, a very elaborate sort of metabolic physiology was done at Harvard Medical School by George Cahill and Oliver Owen and they looked at the AV difference of brain use of glucose and ketones and really nicely established that about, you know, if your ketone levels are four to five millimolar, that represents 40 to 50% available increase in brain energy to that. So that would require your brain needing less glucose to maintain normal energy. So the practical, you know, real world advantage is that if your ketones are elevated and you experience mild hypoglycemia, you're asymptomatic for hypoglycemia and that's not triggering the fatigue, the craving, and the cascade of things that happen during that subjective. And a lot of people don't know that and I think that's like important. And there's actually research going on right now in diabetes and type two diabetes using ketones as sort of like an insurance against hypoglycemic shock and low glucose. So I think that's, and I've experienced that when I started experimenting with ketones, and experimenting, I won't mention how I did it, but I was able to bring my glucose down to where the glucose meter would not even read the level of glucose and as long as my ketones were elevated, and I did that with exogenous ketones, I was at a glucose level where I should not even be living. I experienced, you know, I was asymptomatic for hypoglycemia and I was experiencing fatal level of hypoglycemia according to like, you know, what I teach at the medical school. But because my ketones were elevated, I was perfectly normal and fine. And that kind of replicated the work that George Cahill did at Harvard 1967 where he injected subjects with 20 IUs of insulin, put them into what would be fatal hypoglycemia, but because their ketones were elevated, those subjects who fasted 40 days were asymptomatic for hypoglycemia. And reading those early papers, these types of experiments can't be done today, but reading those early papers got me very, very motivated to figure out ways how we could achieve that same level of ketosis independent of having to fast for 40 days or independent of a very restrictive ketogenic diet. So that sort of, I pivoted my research away from pharmacology research to more ketogenic molecules, ketogenic diets and exogenous ketones, you know, about 15, 20 to 15 years ago because of some of these seminal work.

Yeah, I would not advise people to do what I did in early experimental. I did it under very methodical situations. I did it according to published literature. I did it with a lot of safety contingency plans if something was to go wrong. But there's things that I did 15, 20 years ago that I would not do now when I first started getting into this because when I was reading the literature I almost became very skeptical of this idea that our brain could just like quickly get into ketosis and my understanding was that you had to adapt slowly over time. But I had many conversations with the icons in the field and some of them were Dr. Richard Veech of the NIH, he was mentored by Hans Krebs of the Krebs cycle. So he was the first to really develop a ketone ester and that was being used or funded by DARPA in a warfighter optimization program. So that caught my attention and I was able to dig up some documentation that this research was being done and I wanted to sort of use that strategy for seizures and things like that. But I also talked to the late Dr. George Cahill, Dr. Theodore Van Itallie, Dr. Samy Cady. I don't think, none of them are alive today, but I had the opportunity, I was very fortunate and grateful to be able to talk to them and they convinced me that if you could acutely elevate ketosis or ketones that would give a major benefit to your brain, it could be neuroprotection and it had all these tremendous potential. So they did the foundational work and I just came in to basically, you know, continue what they were doing, develop, you know, some additional molecules and I think what we did is apply it to different circumstances. So that could be, you know, enhancing cognitive function, many different genetic disorders, Angelman syndrome, Kabuki syndrome, Pompe syndrome, glucose transporter type 1 deficiency. So there's a whole list of different, we have like these animal models of the disease and I would say that exogenous ketones have worked better than any drug that we have. And that would also hold true for seizure disorders. So oxygen toxicity seizures limit hyperbaric oxygen therapy. It also limits Navy SEAL diving. And when we administer this to animals, it works better than any anti-seizure drug. So the level of anti-seizure drug that would even come remotely, you know, similar would put the animal into like a coma. So we were giving an endogenous metabolite and that would prevent the seizures better than any drug that I had ever used. And that was early experiments. So that kind of set the stage for thinking, oh okay, I need to study this more and I need to expand the applications into things like cancer and other applications.

Yeah. So hyperbaric oxygen has a lot of advantages that we're just starting to learn about. So I would preface it by saying that my career as a postdoctoral fellow got started in 2004, got started by studying the negative effects of high pressure oxygen. So we call that oxygen toxicity. So oxygen toxicity can come, you can have central nervous system oxygen toxicity and also pulmonary oxygen toxicity. But we're talking about a level of oxygen that in our experimental model we use five atmospheres of oxygen and that will produce a seizure in a human in about 5 to 10 minutes. The upper range of oxygen level would be three atmospheres of oxygen, 100% oxygen. So we are breathing at, if we're at one atmosphere, 20% oxygen, you know, at one atmosphere, so that's a 0.2 ATA of oxygen absolute. So in hyperbaric oxygen therapy you saturate the chamber or you breathe 100% oxygen and then you increase the barometric pressure upwards two additional atmospheres, you know, and that would be upwards of, you know, you could go to two or three ATA optimal, you know, the maximum load. And what that does is independent of hemoglobin, it gets oxygen into the fluid component, the plasma. So that allows the brain to get hyperoxygenated. When the brain is hyperoxygenated, oxygen is a stimulant. So it can increase glutamate. It can increase neurotransmitters. Hyperbaric oxygen, when you use different protocols, and the Israelis have developed different protocols, it can also optimize stem cell production and the release of stem cells from various tissues including, you know, individual organs but also from the bone marrow. It releases stem cells into circulation. Many people don't know this, but this is work done by Dr. Stephen Thom. He was at University of Pennsylvania. I think he's at Maryland now. That it would correlate to a drug called Neupogen or GM-CSF. So that drug is used like in cancer patients to boost like stem cells to get the, you know, your stem cells up and running again. And hyperbaric oxygen like almost stimulates the same amount of stem cell release. So not only the production but also the release of these stem cells. So that underlies its application for the use of hyperbaric oxygen for enhancing wounds. And when you have an injury to the brain, even a seizure creates like a bit of an injury. So we think about hyperbaric oxygen as sort of enhancing the wound healing effects to the brain, but it also has pleiotropic effects. And in the context of something like cancer, it can site specifically augment, cancer thrives in a low oxygen environment and when you reverse tumor hypoxia and hyperoxygenate a solid tumor, it overproduces oxygen free radicals similar to a way that radiation and chemotherapy, they kill cancer through an oxidative stress mechanism. When you do it with hyperbaric oxygen, it's much more gentle to the system. You're actually getting, you know, benefits to your healthy tissue while you're stressing, in some cases killing like the tumor. And what it does is it sensitizes the efficacy of radiation therapy is proportional to the pO2 of the tumor and also the redox state of the tumor. So if you couple hyperbaric oxygen with radiation therapy or you do it in and around the same time, it can sensitize the tumor to radiation therapy but also chemotherapeutic agents that work through a redox mechanism. So these are just some of the, you know, things that we study in the lab, but generally speaking hyperbaric oxygen can enhance your physiology, it can enhance stem cell production, it can enhance brain energy. And we are right now, it's a double blind, it's a blinded controlled trial, but at University of South Florida we're doing the biggest hyperbaric oxygen study that has ever been done. So we on traumatic, or mostly traumatic brain injury with or without PTSD. So that study is in process and it's actually using a sham where we give a pulse of pressure in the beginning to make people think they're having hyperbaric oxygen therapy. But we're keeping it at one atmosphere and we have, you know, the treatment group. So these are veterans that experience traumatic brain injury and there's some of them, most of them don't have PTSD but some do. So it's with or without PTSD. So that's an ongoing project and I think it'll clarify the utility of this therapy for brain injury. And many of the patients get headaches, brain fog and have like symptoms similar to what you described too. And many of them, maybe they do have, we haven't checked, but many of them may have an infection and that could be bacterial like Lyme disease, that could be fungal, that could be viral, right? Epstein-Barr, CMV, HSV. So various viruses too can sort of affect the neuroinflammatory state of the brain and I think this is underappreciated and I think it's an emerging area of research that things like herpes simplex virus, you know, is a driver for Alzheimer's disease that's being studied. I think the chair at Harvard is sort of spearheading this idea. There was an NIH funded workshop, you know, discussing that. And hyperbaric oxygen has like a lot of utility for some of these.

Yeah. That's underappreciated too. So, you know, for wound healing, diabetic wounds, carbon monoxide poisoning, decompression sickness, we tend to go high because, you know, if you have carbon monoxide sickness, you know, the carbon monoxide is attached to the hemoglobin and you have to push it off with as much oxygen as possible. So you push the limits. So hyperbaric oxygen clinics tend to use the maximum tolerable dose whereas there's a lot of benefits and research to be done with these more mild doses that you're experiencing which can be achieved with a soft shell chamber and not necessarily like a big steel hard shell chamber which is very expensive and it would also be expensive to pay for that for the person wanting to get benefits. There are soft shell chambers available now that could be much more affordable to get the benefits of hyperbaric oxygen therapy.

Yeah, thanks for bringing up this topic. I think it's an important one. I'll quickly say that metabolic psychiatry or nutritional psychiatry is underappreciated and from a conventional lens, from the practitioner who's a psychiatrist, many of them don't even know about this and I think it's important to get...

the information out there, and many of them are not skilled in the science and the art of giving this therapy, and that's a gap that we have in our treatment. But also there's a gap in the science, but as you mentioned, it's an emerging sort of field that it makes sense, right? Food affects mood, that's, you know, everyone has to sort of agree with that. And then also our general metabolic health impacts food, so that's like a statement I think everyone knows and appreciates. What they don't know and appreciate is that the state of therapeutic ketosis has very specific effects on brain energy, and we have to credit Dr. Christopher Palmer from Harvard, who spearheaded his book Brain Energy, which I was fortunate enough to get an advanced copy and read it, and just was really inspired by the work. Also, Dr. Shabbani Sethi at Stanford has a metabolic oncology division or clinic, and I think she's spearheading this too, and there are well over a dozen sort of research scientists and practitioners, you know, and a lot of it is spearheaded by the Bazooki group, Jen and David Bazooki, you know, through philanthropy they're funding these efforts. But now, and I think this is important to mention too, there are registered clinical trials, and some of them the NIH is funding. And I had the stats here. I was just on clinicaltrials.gov, and I think for psychiatric disorders there are over 50 registered clinical trials, and that includes bipolar, major depression, anxiety, schizophrenia, anorexia nervosa. Dr. Guido Frank from University of San Diego has a couple large trials and publications that came out recently. So anorexia nervosa kills more people than any other psychiatric disorder. So that was interesting to listen to his research.

Yeah, this is an emerging area, and it's kind of counterintuitive too, because I have a colleague at University of South Florida that studies eating disorders. There's eating disorders and disordered eating, and they go into different buckets, but I think, rightly so, she was skeptical of the idea that a high-fat ketogenic diet, but then as the science emerges, now people that were skeptical are now accepting that this could be a viable therapy. So I would say that metabolic psychiatry is emerging, and I think at the very least it's considered as an adjuvant to drug therapy. And so what we do know, I teach the antipsychotics and I teach the different drugs. So we do know that the atypical antipsychotics are often the go-to drugs for people that have psychiatric disorders, and the atypical antipsychotics cause pretty profound metabolic consequences. So that would be weight gain, insulin resistance, elevated blood glucose. This is well known and established, and it's something that I've been teaching, you know, for I don't know, over 15 years. So a good application for ketogenic therapies is to reverse and prevent the side effects of some of these things, and that's like in conventional psychiatry, that's sort of like the barrier to entry. So how can we make the current standard of care work better, and how can we decrease the side effects? So there's one or two studies funded looking at that, but also the ketone metabolic therapy in and of itself as a therapy, and to basically help deprescribe some of these SSRIs and antipsychotic drugs that are quite problematic for people. And also, like people with psychiatric disorders, even PTSD, they tend to self-medicate, so they go to things like marijuana, they go to cannabis, they go to alcohol, they go to benzodiazepines, they go to opioid-type drugs, and that has been historically very problematic, like in the communities that I've been associated with, like the veterans community and things like that. So where I think these nutritional approaches have a lot of potential to help, even with substance use disorder, is in the bucket of psychiatric illnesses and diseases. So I think there's also registered clinical trials on the use of ketogenic diets, and now more recently we can talk about exogenous ketones too, because some of the diet studies have already been done, and those same researchers are pivoting to not using a diet therapy because that's hard to do for this particular demographic or patient population, where exogenous ketones can fulfill many of the benefits, probably not all the benefits of dietary therapy, but also they're not mutually exclusive. So you could use a diet therapy that is less restrictive and then combine that with exogenous ketones to further augment that diet therapy. So this is many people who have studied ketogenic diet therapy are pivoting to the idea of using exogenous ketones or coupling the ketones with diet therapy.

Yeah, it's good you bring that up, and that's sort of work that has been done by a number of different groups. And I think Dr. Stephen Cunnane was the first to show, using a glucose PET scan coupled with a ketone PET scan, showing that as brain glucose utilization drops as we age, brain ketone utilization is largely preserved, and that's suggestive of a bottleneck of energy production with glucose metabolism. So with glucose metabolism, there's a lot of different areas where the metabolism can be impaired. So that could be, you know, you could have vascular dementia, it could be a blood flow problem. And then the ketones increase, it increases cerebral blood flow, like even acutely about 10 to 20 to even one experiment, 30% when you get into ketosis, and that has to do with the vascular endothelium. So you have a hallmark characteristic of Alzheimer's that is now accepted is that there's glucose hypometabolism. So you mentioned that 10 years ago, if I said that, people would not agree with that, but now Alzheimer's centers will even agree, and people who study Alzheimer's will now agree that, it took a while, but they agree that glucose hypometabolism is a hallmark characteristic of Alzheimer's and even mild cognitive impairment and even things like Lewy body dementia and things like that. So you have with glucose metabolism, the bottleneck could be the glucose transporter, so not the GLUT1, but probably the GLUT3, so that's on neurons, and also an enzyme called pyruvate dehydrogenase complex, PDH, and they tend to be like, and if you have brain injury or Alzheimer's disease, the proteins, if we do like Western blots or something like that to measure the protein levels, the protein levels are always lower for like pyruvate dehydrogenase complex, the protein levels and the catalytic activity of that enzyme is well established that it's much lower, especially with advanced Alzheimer's. So we know that glucose metabolism is a bottleneck, whereas ketones can readily cross the blood-brain barrier, the cell membrane, and the mitochondrial membrane to quickly generate ATP or to generate the reduced intermediates that drive electron transport chain. So we know mechanistically how that works. So we know the rationale is very solid, the scientific rationale, but we have not put that into practice yet. So, and even, you know, I've talked to many people who study Alzheimer's, and the big drugs are the monoclonal antibodies that target the amyloid beta or the tau proteins. And it was very controversial 15 years ago to say that amyloid and tau accumulation is a consequence, a downstream epiphenomenon of neuroinflammation and other things. But we know that even over 10 to 15 years ago, if you inject LPS, lipopolysaccharide, which causes inflammation, into mice, they quickly accumulate amyloid in the brain. And generally speaking, if we have a higher state of systemic inflammation, that leads to neuroinflammation that rapidly causes amyloid and tau plaques to accumulate. And that inflammation can be triggered by a fungal disease, could be triggered by mycotoxin, by bacterial, a viral illness. So now we have research that's being funded. If you go to clinicaltrials.gov, I think there's well over a dozen clinical trials looking at ketone therapies, and the ketone therapies could be a ketogenic diet. There's a few with the ketogenic diet, there's several on medium-chain triglycerides, and also several on exogenous ketones. So ketone salts, ketone esters, and various ketone precursors. 10 years ago there was none. So now we have over a dozen registered clinical trials. So what happens is that these types of studies need to be done over a protracted time frame. If it's an NIH R01 grant, you're talking like, you know, 3 to 5 years. A U19 grant, you're talking like, you know, 7 years of research there for that research to be confirmed and then published in peer review for it to be accepted by the scientific community. So it's an emerging topic. The rationale is there, but it's not part of the tools that people who help people with Alzheimer's are using at this time.

Yeah. And I think we have to take a very nuanced approach to that too, because a ketogenic diet that's really high in fat, that is sort of the classical kind of dairy-based ketogenic diet that's used for epilepsy. Like I started following that initially, and my blood work indicated that, you know, my LDL cholesterol was like over 300 at one point, and my ApoB, which is probably a more accurate indicator, was also elevated into the mid-60s, above 160. And then my triglycerides started to creep up a little bit, but they were still pretty good. Everything else was good. You know, I could say like most of my cardio biomarkers were very good. Blood pressure was lower, you know, hemoglobin A1C was lower, triglycerides were creeping up if the diet was very high in fat or if I had surplus calories, if I was trying to maintain my weight or even gain weight. So what I've experienced is that I've shifted away from very high dairy to a minimal amount of dairy, maybe sour cream, some fermented dairy, but shifted more towards fish. I do get beef. We live on a farm. We got cows. We got, you know, all around. So I have access to like, you know, grass-fed beef, eggs, and then, you know, things like broccoli, greens, wild berries, some walnuts here and there. You know, and I have like kind of a mix and some fruit too. So every day I get, you know, a little bit of berries, I mentioned, and maybe like one small apple. Total carbohydrates for me is about 50 to 100 grams per day. And that diet, the diet that I just described, it's a little bit more mixed. I'd call it a modified ketogenic diet that's higher in protein, probably upwards of about 30% protein.