Keto, Fasting, and Resilience | Dr. Dominic D’Agostino

A good protocol which I think is, you know Six six hours of eating and eighteen hours of fasting So for me today is a day I'm intermittent fasting

I will start eating Maybe at about 3 pm And I will finish eating I'll have a nighttime snack at 9 pm Sadam how did you end up working with Navy SEALs? I came in from sort of the the back end port like the office of Navy research they fund Projects under a particular program called the undersea medicine program and that's for warfighter performance and safety and I was an avid diver as a PhD student and my under my postdoctoral fellowship research was really developing technologies funded by the Department of Defense and the Navy that would allow us to study the problems that the Navy SEAL divers have And and also deep-sea divers so that could be oxygen toxicity as it pertains to the pulmonary system oxygen toxicity as it pertains to the brain which causes seizures decompression sickness nitrogen narcosis high pressure nervous syndrome so these are all things that I studied sort of intensely in my postdoctoral fellowship years and My project was funded to really study fundamentally oxygen toxicity seizures and We don't know why they occur and at the time we didn't know how to prevent them or how to predict them and prevent them so that led me down a path to basically look into anti-seizure strategies and to You know being funded by the Navy is a little different than funded by the National Institutes of Health where? You know, you're required to just published high-impact peer-reviewed papers and get papers out the military wants a deliverable so they want some little widget or Deliverable at the end of your study to say look, you know The guys can take this out to the field and it can apply to them or they can move it whatever you develop into a large animal model like they study pigs for example, so So my research initially really with the Navy SEALs and and office of Navy research was to do very fundamental science in their basic science program and To develop an anti-seizure neuroprotective strategy, so I was mostly focused on drugs at the time but I realized that the anti-seizure drugs are really not very good for people with epilepsy or other seizure disorders and In the process of looking and the process actually helping a friend in the UK in 2008 or six seven and eight I Suggested the ketogenic diet just by looking to see what two people Do who have drug refractory or drug-resistant epilepsy and I discovered the ketogenic diet Which I thought I knew about Atkins and but I didn't actually know the history of the ketogenic diet as a very powerful metabolic based program or you know nutrition therapy that can prevent seizures and it was developed in the 1920s and I decided to pitch this to the military as a neuroprotective strategy and It took course it took about two years from you know initial thought and Studying and pitching it it took about two and a half years two years to get funding for that So right now, you know going back about ten years ago eight years ago The initial funding was to develop to understand why oxygen toxicity occurs Biomedical countermeasures that can prevent option toxicity and then the last, you know five years developing specific things formulas that the warfighter can take by mouth That will instantly produce Therapeutic ketosis to enhance their Protection against oxygen toxicity cognitive performance physical performance Anti-inflammatory effects because that's a problem too

So we're looking into a wide range of things on a particular You know class of compounds and how that can be used specifically in the context of extreme environments so as it pertains to the undersea environment But now we're working with NASA in the space environment you know Air Force AFRL, you know altitude so That's that's kind of like the very very general picture and we have lots of research projects that are run by undergrads medical students PhD students postdoctoral fellows and Then we collaborate with people all over the United States and all over the world Actually, and we have a human study going on at Duke University right now looking at for example nutritional ketosis in Humans to prevent oxygen toxicity I do a lot of rat studies in the lab But we have actually got to the point now where we're developing and moving some of these strategies into more like human factors Training or experimentation Well, I want to talk more specifically about what it is that how this came about that Navy SEALs getting seizures I don't think people necessarily make that connection with diving Could you explain these guys having having seizures? How does that work? What could be going on there? Yeah, absolutely So if you just, you know do a search on central nervous system oxygen toxicity or CNS oxygen toxicity we know that oxygen toxicity of the CNS is a limitation of Hyperbaric oxygen therapy which has about 14 different fda-approved Applications so you have things like decompression sickness, right if you get the bends you got to put somebody in a chamber Press them and then bring them back up You know to surface to prevent little bubbles from forming that's called the bends or decompression sickness That's one application Wound healing is probably the most popular most, you know used application Ischemic wounds diabetic wounds radiation necrosis as it pertains to cancer treatment carbon monoxide poisoning So if you can for example think of carbon monoxide poisoning So the carbon dioxide attaches to the hemoglobin molecule and it's starving your body of oxygen, right? So how do you get that molecule? It binds very tightly

You got to put the person inside a hyperbaric chamber Press them with the maximum Partial pressure of oxygen that you can you can use right but that a limitation of how high you can get the oxygen level would be oxygen toxicity seizures so you can really only go up to about 3 atmospheres of oxygen So we're right now I'm breathing air, which is 020 80 a of oxygen It's 20% oxygen when you're breathing 100% oxygen that's actually five times higher the level of oxygen that you're breathing and it's not toxic unless you're in a hyperbaric environment so The partial pressure of oxygen is a function of the barometric pressure and the concentration, right? so you factor those together and that's that's hyperbaric oxygen therapy and it's a very Oxygen as a drug It's a very powerful drug and it At a certain level it becomes toxic to humans So so oxygen so Navy SEAL divers are kind of unique and that they use a closed-circuit rebreather and Meaning that the advantage is a stealth component They can be underwater and there's no bubbles coming up, right? The disadvantage is that the oxygen concentration is very high

So it's like for a dragger rebreather in similar units It's a hundred percent oxygen So if they go down to just fifty feet of seawater They have the potential to have an oxygen seizure within 10 to 12 minutes So that's not a lot of time right at just 50 feet of sea water Typically, they dive pretty shallow But in the event that the water is very clear and you have people looking for you overhead or you're taking fire Or you got to dive down to a ship or a bridge and plan a mine You got to go deeper than that occasionally, so to enhance the safety and performance and success of the mission you Know we want to be able to to ensure that the that these units can be used without the potential of oxygen toxicity seizures these closed circuit rebreathers and We don't know how real to predict it So if you could wear a little widget that could for example detect heart rate variability or EEG activity or you know respiratory rhythm generation or you know, we know that there are Perturbations in respiratory control that precede a seizure, you know from animal data So we're working on little Strategies to predict the seizures, but most importantly we're working on strategies that can Give more bottom time To the guys out in the field using this type of equipment and making it safer for them and the development of these technologies these these countermeasures against oxygen toxicity have utility for hyperbaric oxygen therapy making it safer and Making it possible to allow people to get a much higher concentration of oxygen to to treat various maladies or toxic exposures for example like carbon dioxide And to be able to do that in a much more safer way, you know or if someone's prone to seizures Perhaps they have a brain tumor and we've explored the use of hyperbaric oxygen therapy for cancer But if you have a brain tumor you may be already susceptible to having a seizure but being in a state of therapeutic ketosis May give you much more leverage and decrease your potential for having a seizure so you could potentially utilize a therapy that would otherwise be You know counterindicated or contraindicated for that so So we work in a lot of different areas now my main thing was studying high pressure oxygen the negative effects of it and Preventing that and now we actually have studies where we're looking at hyperbaric oxygen therapy for different applications Right now they are more or less You know off-label use things like hyperbaric oxygen For cancer, but unless you've had radiation therapy

So it is fda-approved for radiation necrosis but we think that high pressure oxygen can hyper oxygenate tumor tissue reverse tumor hypoxia and shut off some of the gene drivers like if one alpha veg F and various factors that Contribute to cancer growth in proliferation also by hyper oxygenating the tumor tissue It increases reactive oxygen species to the point where you can overwhelm The cancers antioxidant capacity and it sensitizes that cancer tissue to other forms of therapy Right and radiation kind of works the same way radiation kills cancer cells through reactive oxygen species hyperbaric oxygen therapy Just does it more gentle in a more gentle fashion So we're exploring the use of So out of my military funded research came the observation Because we have hyperbaric atomic force microscopy hyperbaric laser scanning confocal microscopy We have unique technologies that no one else really has in the world It allowed us to to look at Cancer cells for example, and we do human dermal fiberglass and different type different types of cells We observed that in cancer cells they over produce oxygen free radicals Under graded levels of oxygen and that oxygen was Would kill those cancer cells whereas normal healthy cells were Resilient against a similar level of oxygen so that led us down a path which was kind of getting off track in some ways, but Led us down a whole path of exploring hyperbaric oxygen and other modalities for Cancer treatment as an adjuvant to different therapies We're exploring right now so a little bit off topic, but that now I can say we have about a third to maybe half of the lab is studying cancer and different projects related to cancer and using hyperbaric oxygen in combination with other things so that could be a whole nother podcast, but for him, but that was that project evolved out of Research and an observation from equipment that was funded by the Department of Defense with what's called a Durov grant it allows us to buy and Develop and use that equipment for very novel Somewhat esoteric projects, you know, you know looking at you know CNS oxygen toxicity or the mitochondria of neurons During a po2 equivalent of a Navy SEAL dive operation sort of scenario Well done, you are you're blowing my mind You're all over

There's so many amazing things I didn't mean to go off in different different areas, but What maybe you're you're people to know that? Military research, you know just like NASA research has very broad applications and a lot of the technologies that we use today you know GPS other things really evolved out of Military funded research Absolutely Yeah My graduate work before I was in the Navy was a study of people with a disease called spinal muscular atrophy And it was it was Department of Defense funded and you know, people don't always make those connections But it's amazing how how it does play into so many so many different fields of research as well Yeah, and and while I was there also, my principal investigator was dr Darryl DeVivo He vivos disease or glue blunt about Absolutely I know dr

DeVivo Yeah, yeah Yeah, we're actually funded by the glucose transporter type one deficiency syndrome foundation So we have glut Wendie mice where we don't we just published a paper last Two weeks ago looking at the effects of anesthesia on the glut1 mice so I know dr clapper who sort of may be his protege and Yeah, I've met with dr Diva because I present at the glut1 deficiency Foundation conferences And yeah, very cool that yeah, you know him small world Yeah, maybe we've crossed paths before then Yeah in working with him and on gluten deficiency syndrome There was talk of the ketogenic diet epitaph Yes

It was new to me I just saw these amazing slides where you'd see a child who was having seizures that were debilitating and then all of a sudden I'd say then the child did the the ketogenic diet and who the child walking upright and healthy and alert and and things can you explain how there's in a History of this ketogenic diet that it's not just a new trend in 2018 and it's something that's been around for a while Yeah, yeah, it's been around well, I mean fasting ketosis we could say has been used for millennia dating back to the times of Hippocrates like you know 400 BC or more and it was observed that fasting could quote-unquote cure seizures and Actually would work for some time after even after initiating food again But fasting in that context was really not sustainable Right because you you have to eat again and then it takes you out of fasting ketosis so a lot of the benefits were derived from the the metabolic physiological state of fasting which is a suppression of the hormone insulin and also a decrease in some extent of glucose levels and also in elevation of ketone bodies and a Metabolic based therapy was developed at the Mayo Clinic's in in the early 1920s and this was the ketogenic diet which incorporated a macronutrient ratio, that was very high in fat about 90 percent fat and It had adequate amount of protein to prevent protein malnutrition With the least amount of carbohydrates possible, you know 0 to maybe 5% if that and consuming this diet produced a Metabolic physiology that was in many ways mimicked the state of fasting in a you caloric diet Meaning that you were getting the calories that you needed to sustain You know growth and repair and your weight maintenance and that this this nutritional ketosis Was a means to induce Therapeutic ketosis and then that had in and of itself just through a dietary means an ability to metabolically manage seizure disorders Independent of the etiology so which is interesting because you know, whether you have temporal lobe epilepsy glucose transporter deficiency syndrome now, we know Angelman syndrome or absence seizures even different types of seizures the ketogenic diet tends to work and and now even you know a century later it tends to work better than the Drugs in most cases when drugs fail they people are put on a ketogenic diet especially for kids it's about two-thirds of the kids respond favorably even after multiple drugs fail so the question could be like why wouldn't kids use this first because many of the Anti-seizure drugs do cause developmental delays that may not be reversible in kids So if you load a child up with You know phenobarbital or different types of anti-seizure drugs It can actually impact their Development their brain development and then you don't you don't get that back it can you know impact their IQ and things? What with the ketogenic diet that doesn't happen I mean it may actually have some cognitive enhancing properties maybe For different subsets of people So so the dye has been around for a long time It's use was marginalized in the nineteen late 1950s 60s and 70s and even 80s When drugs came online and then Jim Abrams of the Charlie foundation the Hollywood producer his son Charlie Was stricken with seizures was not controlled by multiple drugs and he was really upset that his son was not offered this as a therapy and they initiated the diet at Johns Hopkins and He became very vocal about the ketogenic diet for epilepsy He was on Dateline NBC in the mid to late 90s and then Meryl Streep came on and did a movie about the ketogenic diet Most people don't know a Meryl Streep did a movie about the ketogenic diet and that was called first You know harm and that brought more publicity to the ketogenic diet For its use in Neurology and it still remains the standard of care in Neurology for drug-resistant epilepsy

It's not the first line of treatment But it works for glucose transporter deficiency syndrome where there's essentially Hypoglycemia in the cerebrospinal fluid because you can't transport glucose across the blood-brain barrier an elevation of ketones in the blood will readily cross the blood-brain barrier and Restore brain energy metabolism and even neurotransmitter production like in kids and adults that have glut1 deficiency So it is really a life-saving therapy for that disorder and many other even metabolic disorders pdh Deficiency, I mean there's all different types of disorders It's used for And now we explore its application for you know A lot of other things we're looking at kabuki syndrome right now, and we're starting a new project kabuki syndrome is essentially a balance between Gene repression and gene expression and in elevation of beta-hydroxybutyrate Functions as something called a histone deacetylase inhibitor Which can actually turn on the expression of genes that are otherwise silenced with this genetic disorder so even in the presence of a persistent molecular pathology the ketogenic diet by virtue of elevating beta-hydroxybutyrate which is a class 1 class 2 h dag inhibitor can epigenetically enhance and restore normal brain function in the Kabuki mouse model it actually It's it saves the dentate gyrus neurons and rescues them from being degraded So we are doing work on that now in the lab and just starting that up and the idea is to rapidly move that into a human therapy with kids and Elevating that endogenous metabolite that we know functions as an h-back inhibitor There's an experimental drug called AR 42, but it's not available yet for kids that have this But beta hydroxy butyrate works just as good or better than AR 42, which is not yet available So our lab is actually working to logistically right now set up everything that's necessary to do a preclinical animal model study that will hopefully parlay that into a human clinical trial on something like kabuki syndrome so You know basically using ketones as an epigenetic regulator to basically alter gene function to restore Some sort of normalcy and people who have this genetic disorder and for those who aren't familiar with epigenetics Could you kind of kind of explain because I think when people hear ketogenic diet or even if they know what bhp is The idea of it functioning as a way that affects genetics is maybe new for a lot of folks yeah, yep, so think about your You know your your genome your normal genome we go to 23andme and we get our genome right and that's kind of a Written in stone I guess you could say, you know That's that's kind of our genome But or we used to think that right, but there are processes that happen in the body that Allow us to go in there with more or less a repair kit and and alter The genes in a way or the expression of various genes To alter those expressions to influence our genome and and we call that epigenetics so epigenetic is it's sort of a above the genome right uppy and it's the process in which That our body has the ability to alter the expression of various genes and even to some extent change our genome over time and that could be environmental factors that could be drugs do this that could be You know metabolism fasting, you know now we're realizing that Metabolites just are not energy substrates that these metabolites like beta-hydroxybutyrate in particular Have a have a functions have the signaling functions in our body that in some ways can impact the expression or repression of different genes and We are just going down in that direction when I started this research in ten years ago We only knew of ketones as an alternative energy fuel Mostly for the brain but over the years we've discovered that They can influence gene expression that they can that there's a toan receptor that they can in Influence an inflammatory pathway that the drug companies are scrambling to design a drug to inhibit You know that the beta-hydroxybutyrate can do that So these are all Things that sort of have popped out of the data and published not all in our lab actually most of it ins published by other very big high impact you know journals and and labs that have really teased out the molecular pathways that have a really Been elucidated and and more needs to be sort of determined exactly how some of these pathways are influenced but one of the most exciting one to us is being able to Alter our genes right through altering epigenetics, which is being able to edit in some ways or influence the expression of various gene pathways And so for people who want all these benefits of this diet, what would are what are other other benefits? I've heard you talk about things with austere environments your own work with NASA For athletes, how does this this change in your diet? Translate to so many of these things and what are those things that people could look for? sure, like this resource is right now at its infancy, so the the use of the ketogenic diet as a means to enhance resilience in an extreme environment So, you know, I've done enough experiments and rodent models to know that being in a state of therapeutic ketosis Makes the rat what we call, you know from our drug studies a super rat So basically when you put a rat into a state of ketosis and elevate its ketones To the same level that would be achieved after me fasting seven days That rat is 600 percent more resilient against oxygen toxicity seizures and we've never been able to achieve that with any drug even and even like Anti-seizure compounds that are so powerful that are not on the market yet

They have, you know side effects We can't even get that's never protection from that So this has work done, you know about eight years ago so the question is How do we leverage this technology? How do we develop it into a way that's palatable That's tolerable That is fda-approved So we're working on that well we're working on the use of these compounds for different childhood disorders and that May set a precedent or a pathway for us to you know, get some of the more powerful Compounds for use in Special Operations community things like that So we do know that the ketogenic diet has a macronutrient ratio That's mostly fat and ketones are the fourth macronutrient I like to say because they are calorie containing substances when we consume them if we ate nothing else and studies on dogs have been done where you consume something like 1/3 butanediol and it can sustain performance on a treadmill for For a long time and that compound is not ketones are not classified as a macronutrient yet So there are carbo hard carbohydrates proteins and fat, right? So they are I think of them as a water-soluble fat molecule that can readily cross the blood-brain barrier So the advantages to the warfighter or NASA, you know personnel would be the energy density is quite higher Right So the key of junk diet if we're just looking at macronutrient Profile and I've had some of the engineers do calculations on a four to six man crew to Mars and back it ends up saving about two large SUV's full of weight so in food If it's a two one half or two year mission so that that's a significant amount of weight when because the energy density you have nine calories per gram as you know for For fat and four calories per gram for carbohydrates and protein So there's shifting the macronutrient ratio instead of 70% fat or carbohydrates you make that 70% fat Like right there, you are more than doubling sort of the energy density, right so may major logistical advantages Which the engineers love, you know, I'm interested in more the more of it as a bio Sort of a biological countermeasure against those environments which could be the undersea environment as you know hypoxia, or hypo So there is a satiety factor to so when you're adapted when your body is fat adapted and what we call keto adapted the you don't get hungry so you can in the absence of food or if you're in austere conditions and your blood glucose levels drop You are going to brain fog and a pretty dramatic Predictable decrease in cognitive and physical performance if you are adapted to ketones The ketone levels when they're elevated in your blood and you go hypoglycemics you're asymptomatic for hypoglycemia, so you can even in subjects that were fasted for you know forty days and they injected them with insulin they could you know readily do cognitive, you know function tests and be fine so that in and of itself I think is Is a major advantage? Obviously a major advantages and there's no other fuel that I know of that could really do that you know that that could make you asymptomatic for Hypoglycemia, when there's an absence of food availability our body's kind of do that naturally when we fast, you know But being keto adapted allows you to do that very quickly And once you've done the ketogenic diet and go back to a high carbohydrate diet and then go back to a ketogenic diet you make ketones about twice as fast because you've Upregulated a lot of the enzymatic pathways catalytic enzymes and transporters That readily it's almost like you activate a genetic program That we call it we call it metabolic memory You know when you workout in the gym and you work up to you know? A 500 pound deadlift it might take you like, you know, ten years to do that, right? but then you stop for six months and you get back in the gym again and about six or seven eight weeks you could get Back up to that fight

So your metabolism, I think and this is stuff we're looking at now It's kind of the same way Once you've acclimated your body to be keto adapted that you can readily go in and out We're starting to see that has not been studied So what I'm saying here, I guess I'll have to stay step speculation But as a scientist, you know, I've done it on myself and we have some rat data, you know Hopefully we'll publish that soon with it with our colleagues So the satiety factor and ketones are anti catabolic That's their evolutionary function if we did not go into a state of ketosis we would catabolize all our Gluconeogenic amino acids in our skeletal muscle and we'd waste away in about two weeks and die probably of cardiac failure but because we have essentially an endless supply of body fat even a lean person has like twenty to thirty thousand calories a Body fat that body fats liberated converted to ketones and then those ketones are profoundly anti catabolic So they prevent many of the proteolytic pathways and that they are very protein sparing we say so that's their function So it's a satiety factor the energy density the protein sparing And some of the stuff that we're looking at now with NASA extreme environment Mission Operations I was on a crew member for 22 which is working with astronauts in an undersea environment where we Sort of are looking at a variety of different things and my wife will be on Nemo 23 and that's coming up We're preparing for that So I've noticed in myself that the requirement for sleep is less about slightly less maybe about 30 30 minutes less and the percentage of deep sleep is higher

So instead of getting You know 60 minutes of deep sleep each night or 70 minutes if I'm at Iquitos if I'm in ketosis I routinely get about 90 minutes of deep sleep to two hours of deep sleep 220 minutes My sleep is very deep and my sleep architecture My sleep timing is less and my sleep architecture is more and then I've seen a lot of sleep data from people out there Suggesting something's going on So it needs to be kind of studied and also stress so And we've already have several publications on this and another one that we recently submitted Showing using an elevated plus maze which is used by pharmaceutical companies to evaluate Anti stress or Evaluate the fear response in in rodent models We noticed early on that It was easier to handle rats and mice that were in a state of ketosis They didn't have this fear response They weren't trying to bite you So if you use in elevated plus maze where a rat kind of goes out on a catwalk And they don't like Heights they don't like that they can they can stay out in the open arm or they can go into the closed arm where it's safe and rats have a natural tendency to explore that's and humans have a natural tendency to explore so when they're in the state of Nutritional ketosis they stay in the open arm I think about 25 to 30 percent more and they explore their environment The novel environment whether so that's the implication there for humans It's for people who have like PTSD Maybe like social anxiety and things like that

We think especially for PTSD We think that being in a state of nutritional ketosis helps Balance the neuropharmacology of the brain by it Does this by elevating gaba to glutamate ratio by activating? glutamic acid decarboxylase AG add 65 and 67 enzymes so you don't have to know all that but it changes the neuropharmacology of the brain To make you more relaxed It's actually hitting things and Receptors that actually may be hit, you know in a more abrupt fashion with alcohol, but it's doing it, you know Naturally, it's you know, more GABAergic activity is a more, you know brain stabilizing calming activity And we're also looking at the adenosine receptor insert to nergic systems but the thing that jumps out and why it may have an anti seizure effect is that you are Taking a potentially hyper excitable Neurotransmitter that's actually could be Neurotoxic in the context of traumatic brain injury PTSD and seizures That would be glutamate So glutamate is converted to gaba through an enzyme called glutamic acid decarboxylase Ketosis activates that enzyme so convert more of this stress, you know anxiety hyperactivity neurotransmitter to a more brain stabilizing calming neurotransmitter So that's firmly worked out and we're working out the details as to you know What exactly what receptors or overlap with certain area kadena synergic and all these other things? So we're working out that pharmacology So from a warfighter perspective from an astronaut perspective, you know the energy density, you know Takes ten twenty thousand dollars per pound to get something up in space satiety factor anti catabolic factor Sleep and stress and we're also now We can't really talk about it, but we are doing studies now looking at physical performance and cognitive performance From my perspective i'm interested in physical and cognitive especially cognitive performance in The context of extreme environments so you can do this task At one atmosphere of pressure right some you know reaction time or critical thinking Tasks and there's different tests that we use for that Can you go to? You know 18,000 feet and do the same task Or 20,000 feet or whatever hypoxic There's a very predictable You know impairment that will be you know, conferred upon the person or you know to following this cognitive function tasks Can we preserve that under under extreme environments under the in the undersea environment as it pertains to nitrogen narcosis? high pressure nervous system Activity things like that So that's kind of what we're doing now in rodent models I mean, we will look at the activity under ambient conditions But we also put them into these extreme Environments and see if we can preserve you know Make them more resilient in that environment and we're vetting out Various types of strategies to induce nutritional ketosis and finding out what can rapidly go to the field so as far as you know tolerability safety safety is probably the one and You know Is it something I can put in a container or put in a little 5-hour energy size? Thing and have a couple hundred calories where I can consume that and that will give my body A superior alternative form of energy that has a host of other Things and it's likely not going to be a single agent, but it's likely going to be a formula So now we're working with different formulas It's encouraging that a single agent can have a profound effect But we think that the real, you know, the greater effect can be when you start mixing these things together and adding some cofactors But we're very encouraged by just a single agent has outperformed all the drugs That we've you know that have ever been tried for anesthesia So we're you you were probably going to take that agent and combine it with various other things To make it more tolerable palatable and more efficacious yeah, the the Possibilities of the ketogenic diet in a pill or a shot or something like that are huge In I was skeptical

I was pretty skeptical in the beginning but the military actually Wanted something that can be consumed just prior to admission and you know And they're looking at they didn't want to do the high fat diet Now our views have changed of the high fat diet over the last ten years so that could be revisited But they really wanted to it wasn't my sort of decision on this They really wanted a Key, they wanted to induce therapeutic level ketosis independent of dietary restriction that Was that was what was told to me? And I was like, how am I gonna do that? So I saw that NIH was working that Oxford was working So I visited, you know those places and met with scientists one of them Dr Richard Veatch, he was the graduate student of Hans Krebs and so one of his best students He's at the NIH and was actually funded by DARPA with a lot of money to develop a ketone ester for warfighter performance So so we, you know tested that compound and instead of just focusing on one compound which most labs do you know we study everything and find out what works and we throw away what doesn't work and then we focus on developing novel compound you know testing what's already out there, but also Developing new compounds that are more powerful more dense and more Have greater ability to be consumed and tolerated So we're at that now some of the things are highly Palatable and tolerable but they tend to be the sort of You know less potent agents So the potency of a compound is almost inversely proportional to its Tolerability so as these ketone esters as you have like a mono ester Diester or try a stir and in different compounds they tend to get increasingly more Aversive in taste and tolerability so we are working on That's why formulating is very very important to us And we're doing that in rats now

And and also I test things on myself too sometimes so Anyone experiments you're famous Yeah, yeah So thinking from the perspective of your day to day guy in the Navy Who wants who sees all these potential benefits who sees the idea of you know? I'm going on the ship and I'd love to be able to You know if I have to go a while without food to maintain performance to get that deep sleep even if I'm not gonna get a lot of sleep all these things that you're talking about and now a Lot of the folks that I work with they fly in a particular aircraft that just got aerial refueling capabilities So now their missions go from four hours to eight hours in plane We have you know, no coffeemaker No microwave Nothing like that Yeah, how can a normal person? Take this kind of stuff that we have right now the technology we have right now Into a shipboard environment and you can get these benefits So I'll approach it first from the perspective of diet and from time restricted eating Protocol, right so intermittent fasting that's a big thing Right? I like to call it time restricted eating, right? So I talked about when you fast or do the ketogenic diet and then you go off the diet and then go back into fasting again you were you would adapt much quicker to Fasting you could preserve your cognitive and physical performance, you know, because your body starts making ketones faster so I would suggest that guys do not that's not the ketogenic diet, but do intermittent fasting a Good protocol, which I think is, you know, six six hours of eating in 18 hours of fasting So for me today is a day

I'm intermittent fasting I will start eating Maybe at about 3 pm And I will finish eating I'll have a nighttime snack at 9 p

m Right, it will be my last meal and I basically just skip breakfast and I'll skip lunch sometimes I start at like 1:00 pm And finish at like 7 pm And that's six hours of eating and now typically maybe two meals and maybe a snack and then that 18 hours of fasting Does put us in a mild state of ketosis, even if we're not like, you know on a ketogenic diet but if you do low-carb or if you eat ketogenic During that eating window, then you you're kind of always getting some of the benefits of ketosis when you start eating again You still maintain? You know a mild state of ketosis and then you get sort of the benefits of fasting So that cokes is your body into being what we call fat and keto adapted So if you take that individual and you take away and you have limited food availability in an austere environment that individual will have better access to Her his brain will be his or her brain will be more resilient to hypoglycemia And also have a greater capacity to liberate Fatty acids from adipose to preserve their energy cognitive physical performance Under high energy demands so that that's sort of the advantage right there So so that's that's like low tech right? That's like, you know Your macronutrient ratios and time restricted eating and then you have exogenous ketones supplementation, right? So this could be something that's in like a little 5-hour energy kind of thing and it's a very energy dense formula perhaps of ketogenic fats and exogenous ketone mineral ketones which could be beta-hydroxybutyrate Attached to sodium potassium calcium magnesium, which is a salt So it gives your body minerals and then there's different esters that could be Utilized and there's a whole toolbox of esters that we're studying right now The important thing is that You know You could drop guys off for five or six days into an area and let them do their mission and they could carry on their bodies You know various Small vials of this stuff and be able to consume it and it could be formulated in a way to give them Not only a burst of energy but sustained energy over a fairly significant Period of time if they were to get a blast injury traumatic brain injury or if they were going to do an oxygen rebreather dive if they're going to hypoxia, like they they would potentially have neuroprotection under all those different circumstances and May be able to maintain cognitive resilience a little bit better – under those circumstances So these are things that we are doing in animal models that we want to do in human studies So the trick with human studies is finding the optimal formula that they can tolerate the dosing the individual, you know and it takes You know rats you have an inbred strain a rat and they're all kind of the same And the data looks great and they have humans and this guy is eating, you know, basically I don't know monsters and and you know sugary drinks and Snickers bars and another guys already doing paleo as he you know He may respond differently So we really need to Get funding to be able to do this in a very controlled environment Because the payoff could be pretty big as far as warfighter performance It'll probably start in the Special Operations community and maybe work its way down With the idea, is that you have This as a tool in the toolbox, you know I'm not all about Replacing what the military is going to eat as far as their nutrition because that's not going to happen but to let them know that a key to jet or low carb eating strategy is a strategy that may have these benefits and And to make it available for those guys who want to do You know Knowing what we know now the rodent date is very compelling and the stuff that we're doing now is very compelling and it's already moved to human studies that are ongoing So I see a lot of potential there is using new troop nutrition as a Performance not only as a performance enhancer But something that can enhance the safety – that's the primary objective the safety but out of those safety studies Also led us down paths where we're looking at performance and performance resilience So there's different ways to do it

Like I could talk about, you know different types of formulas for exogenous ketone formulas But I think we're a little bit too early yet in describing the ingredients in those formulas, you know We're in the basic science concept of that but time restricted eating low carb ketogenic diet exogenous ketones maybe all in combination – right So maybe not to do one or the other but these things likely have either additive or synergistic effects when you use together yeah, so many tools in the toolbox like you said and For people who are in general Just trying to see what works for them And what doesn't you're you're famous for these nf1 experiments where you you're testing yourself you're pushing your limits and Now so many people are wearing monitoring devices They have access to lots of data What a nice would you have to people who want to experiment and to see what's? Optimal for them and maybe could you also tell the story of your seven-day fast and the deadlifting? Yeah that gets round Tim Ferriss Mitch, I didn't know he was going to mention that on the podcast But I guess Peter Atia told him told them about the story so Okay, so monitoring So right

So what what can the person out there listening right now do they can go to their local? CVS Walgreens drugstore Amazon and buy a glucose and ketone monitoring system Right and they can simply it would be good to know Their glucose response to a meal that's very important from a health perspective You don't want to be you don't want to have glucose excursions up to like 200 milligrams per now, you know You want to stay, you know under one? so I Would say try intermittent fasting perhaps the time restricted eating protocol with low carbohydrate diet Perhaps starting 100 grams or less per day and then working down to 50 and over a period of time you can check your blood ketone levels and once you're above 05 You are clinically in a state of ketosis and for a diabetic a type 1 diabetic Person who's not on occasion a diet that could be dangerous but for us that that's a good thing So diabetic ketoacidosis is very very different and then nutritional ketosis and my PhD student And ruku, t'nuk did a TEDx talk That you can look up which talks about that subject a type 1 diabetic using nutritional ketosis to manage his disorder So that's all say about that, but I get a lot of questions about type 1 diabetes So I just you know refer to Andrews TEDx talk So for nutritional ketosis you want to be 05 or above ideally around two one to two million more range Check your ketones Typically later in the day when you've had some some ketogenic meals in you or you're fasting and see how you feel and also maybe when you're not measuring See how you feel subjectively when you have the most energy when you have the most lucidity and mental mental Resilience I guess you could say I when I get into these phases I'll do a lot of writing or a lot of sort of tasks that require a lot of you know cognitive and I will Tend to check my my glucose and ketones and I typically find That my ketones are in like the one to two and maybe upwards to the three range and some people I know Actually get much higher there's people in the lab that are like running four or five and Other people that are on a strictly to genic diet and can barely even make it to that 1 millimolar range So everybody is going to be a little bit different so by a meter online They're relatively cheap under 50 bucks the strips If you search around you can get them for anywhere between $1 to $2 a strip and and get some some data on yourself Experimenting yourself and then from there you can start You eating other things? So I use an aura sleep ring and for sleep and the aura ring? Monitors a number of different factors most importantly for me It's a pretty good measurement of your sleep time and sleep architecture like how much you know Delta sleep

You're getting and REM sleep and things and And I we use this for our NASA extreme environment Mission Operations sort of mission to on the crew members So it's a very Hardy technology I mean you can train with it and it'd be hard to break it actually So monitoring your sleep with a Fitbit or an aura ring measuring your glucose and ketone levels I think is a good place to start right and then we all have certain things Like I know my strengths I keep a training Journal or used to keep you know Very detailed records of training Journal and then you could whether you're a runner or a cyclist or whatever, you know Start monitoring this get your baseline initiate the ketogenic diet or exogenous ketones or intermittent fasting whatever you want to do and Monitor your blood ketone levels and then assess those Things that you're interested in, you know Your performance times not just subjectively but objectively Right and monitor your sleep because your sleep will be a factor in those, you know performance to get general blood work CBC CMP You know do get a lot of baseline data because it's going to be important I think for me I never thought I would continue with the diet I was just doing it from an intellectual perspective and that I wanted to understand what it felt like for my brain to run off a different energy source, so I became obsessed with this about 10 years ago and and I was very inspired by the work of George Cahill at Harvard Medical School where he fasted subjects for 40 days and and was able to add some conversations with Dr Cahill, he passed away in 2012 and a lot of the icons are up in their 80s and 90s pushing a hundred Allen many of them are still alive they did go on to to live extremely productive lives and contributed massively To metabolic physiology, which don't have the metabolic physiologists nowadays that we had back in the day But I was really inspired by his work and actually wanted to fast for seven days not 40 days So I did Quite a lot of blood work before during and after and was able to get my blood glucose down To a level that was significantly below my ketone levels So my ketones were at at the end stage about double what my blood glucose was and because ketones can readily cross the blood-brain barrier We can say that Roughly two-thirds of my brain energy was being run off ketones and during that time I actually worked on a lot of grants and was very productive and actually getting got funding off one of the big grants I worked on during that time I was teaching and even at the end of it I went to the gym and tested my strength and found that like my strength did go down a little bit But I didn't push myself too hard because I knew you know, I was thinking I'm fragile

I just wanted to be kind of cautious as to Moving weight under that kind of condition, but I did find Which was really interesting to me that my strength did not take a big hit And I was semi keto adapted because for about a half a year to a year or so I had been tinkering with the ketogenic diet the clinical ketogenic diet and it really made fasting pretty easy the third day I was kind of hurting but after seven days, I mean I was lucid enough to be sharp and give lectures and And had the energy to move, you know, five six plates on a deadlift, you know I didn't ever thought going into this I would have never I thought, you know after four or five days you'd be so weak You it'd be hard to stand up You know that You'd have and I did have orthostatic hypotension in the beginning I'd stand so I had to get I would have soup broth But no calories, you know, I'd have sodium and water and fluids and things like that stay hydrated But I don't know the static hypotension is that's when you stand up real quick And you feel dizzy just for the yeah That that happened a lot with me in the beginning I get because – yeah, your insulin goes down, right? So insolence role is sodium reabsorption in the kidneys, right? So if your your insulin levels down you're dumping a lot of sodium So I think in the beginning I was drinking a lot of water but not getting the sodium that I needed and once I started Getting the sodium in it's like I started kind of waking out My blood pressure came back up again And I remember kind of sodium loading before you know I had to do a thinking task or work out or something like that, but I would go for like long walks You know at the time just very easy walks and that my ketone levels would get up I come back and my glucose would be in a range that the meter wouldn't even detect it would just say low I would just say low and it wouldn't even detect it and And I tinkered with a few things to get my my glucose down really low I don't know exactly how low I got it because the meter wouldn't wouldn't register it and then and my ketone is pretty high and and realized that This really does make you resilient your body feels kind of Numb in a way like but at the same time your senses are heightened So I would go for a walk and I could smell things or maybe even see things sharper than I could could otherwise So now I got the full understanding of when when people fast and they say it brings them to another level And I think the more you do it the easier it gets and probably the more benefits you derive from it, too So, I mean you could tell like major things were happening in your body, you know major things are happening like otology of course like you when you force your brain to go from glucose to Ketones luckily at the brain is incredibly metabolically flexible and its fuel utilization and then it can make that switch Not everybody Can I mean some people may have a harder time than others? But like I said, the more you do it these your gets and the more benefits you derive from it And I think it can be a very I mean I did it for scientific sort of reasons, but it's also sort of a personal Journey, too

So you learn about a lot about yourself what you can and can't take you know How resilient you really are and you think man if I was dropped off? It got lost or something and had limited food availability, you know, at least I know you know I could I could get through it and not die after you know, two or three days of not eating So that was I encourage people to do that, but I don't make the recommendation I'm not a medical doctor right so not some people Yeah, no, no, no medical official advice dispensed here but yeah a general general thing and you talked about how there are these great scientists who inspire you who have Made a huge contribution and you are someone who is also very active you were on this big journey You were making contributions left and right What is it that drives you to keep to keep pushing on all these fronts? I think there's a lot of things You know that drive me my students drive me I mean seeing their passion for science and and looking back and thinking you know remembering how fascinated I was for example with the brain like I was Fascinated like what is a thought like what is that? So I would as a neuroscientists As a PhD, I did patch-clamp Electrophysiology, which is kind of sort of a technique where you record directly from neurons and how they communicate to one another and you delve very mechanistically into all that so asking questions and being very curious and and I think some from some extent there's a sort of a selfish if you want to call it that I want to be able to learn and extract information from the body of knowledge that's out there but also from my own experience that I could apply to myself and I get so enthusiastic and even giddy that I want other people around me to follow it too and family members because you become so aware of the benefits of some of these things even from a new you know, especially from a nutritional standpoint Where my emphasis was really on drugs in the beginning and it was kind of more and I'm still do drug research But this idea that Altering your metabolic Physiology through changing your macro nutrient profile can change fuel utilization In your body and that can have this host from cognitive to anti-inflammatory effects to potentially tumor suppressing effects to anti-seizure effects like that that you can do that that you have You know you are empowered to be able to do that just by You know the food that you eat or the different supplements to that that could potentially be used So I'm pretty motivated by that and I really feel Not necessarily the case for everybody but uh because I don't I don't think some of the pioneers in this area necessarily fast it themselves or experimented on themselves, but a lot of them did and I Feel that you really have to immerse yourself into what you're doing and almost be part of what you're doing to really have that enthusiasm to the point where you're so excited it's hard to fall asleep or you wake up and you're like Kind of you know, what's gonna happen today? Like what will this blood work show what will this measurement? Like how will this day go? so to be so immersed in your research that it becomes sort of part of who you are and Part of your envision contribution, right? So you want to And also guides my research So a lot of the things that I do on myself or maybe see others do I get a lot of feedback from people too? That actually guides my research someone will email me about this or that and that has actually guided, you know Various research projects that we have so every day I wake up and I'm excited I don't know what's going to happen like I'm usually testing something new on myself my students have their in the lab now, you know in the trenches doing research I get to come in and they have You know so much enthusiasm about what they do so that's kind of what drives me on a day to day basis and being able to look forward and actually make contribute to The scientific body of knowledge to use food as medicine and it doesn't have to be a macron

It could be like There's companies out there that are creating what I call engineered food Whether it be a cookie or a brownie where they're not only changing the macronutrient profile but they're incorporating different ingredients that make it like a functional food whether it be a prebiotic fiber or probiotics or An alternative energy substrate I mean one of the first things I use was Saito Maxx when I rode my bike, it had alpha L poly lactate in it Which was sort of that got me interested in alternative fuels and this is going back 15 years ago and creatine monohydrate you know, I started using that in 1991 or 92 and Always stayed up on the literature So I think of ketones is kind of like the next creatine and but a much more versatile so it can be neuroprotective if it can make your it enhances your body's ATP production, but it has A lot of advantages and a utility that something creatine doesn't have but but mixing them two together Would be sort of one of the formulas that I'm working on now like, you know putting various Alternative energy substrates together and cofactors which allow you to use use these things in a in a more enhanced fashion I would say so That's what's I mean, that's an exciting thing and also cancer I mean a lot of what we do I didn't talk about it much what could be more exciting than killing cancer cells? you know our soldiers go out to war to kill the enemy to protect us and we we kind of kind of think of my PhD students as sort of soldiers warriors that are kind of attacking cancer cells with their the therapies that they're developing together as a group and Testing in cells and tissues and animal models and we're moving it to human clinical trials so we're sort of on a war against cancer in a very Targeted fashion from a metabolic standpoint Yeah, and and everyone knows someone affected by cancer So it's it's such an absolute a universal cause and and it's it's great that we've got you on the team And the people the students many of the people in the lab were motivated from a personal perspective and that's why they chose You know their particular projects to that's often the case

Oh, yeah, I can get that Yep, don't want to be respectful of your time before I ask my last question Where can people find you online The best place to find me is the website keto nutrition most importantly it's dot o-r-g not calm so keto Nutrition dot Oh ROG and I have a blog there I have Products that we've tested I have resources like doctors consultants Podcast That's my kind of one-stop-shop for people who want more information about what we do great and Tell my final question if you were talking to a military leader who wants to create a culture where people have this Intellectual curiosity that you display this self experimentation this drive What suggestions you give them? I? Was talking to a military leader to embrace his culture I Would ask that military leader and try to persuade them to do it themselves and to evaluate Whether they thought personally that this was a viable strategy, you know So I would do something as simple as time restricted eating if you have I was locked into a pattern of not only eating like five or six meals a Day, I would eat like seven or eight meals a day Wake up in the middle of the night and eat a protein bar or shake and go back because I thought I needed that so I come from that mentality, but when you liberate your yourself from these frequent feedings, or free yourself from it becomes very liberating right when you free yourself from that eating pattern so when it comes to nutrition maybe You know, we do a lot of different things but the most simplest Low-tech thing I can think of is to say hey if you haven't tried it before it Maybe try time restricted eating Don't do it every day Maybe just do it like twice a week and see how you feel and the more they do it the easier It'll get and then a lot of that great feeling that they have towards the end of the fast that's actually due to beta-hydroxybutyrate the ketone body that I study so and that's conferring many of the health benefits like anti-inflammatory effects and you know Epigenetic effects and things like that So that's good That may be a gateway to get them into experimenting with an eating paradigm that without question has major logistical Practical advantages to guys in the field from a physical cognitive and maybe even anti-anxiety Perspective and we know you know if you're edgy and you're jacked up on caffeine and edgy So, you know I go to the range

I shoot quite often and I experiment on things, you know I don't I don't talk about those things on podcast usually, but but not only the gym But I'll go to the range and I'll evaluate what gets me better scores on my shooting tests Right, and I could tell you that the things that I talked about and things that I mentioned Start doing it and start if you go to the range start recording you were your scores and you're gonna see that too and that's you know something I Never really talked about but I think from their perspective is a very practical Benefit to that So the worst thing to do for a soldier that has A gun shooting is to be sleep deprived and jacked up on caffeine so and I've actually been in that situation where I have evaluated my shooting ability under those conditions and I was all over the place but Being on Jack jacked up on caffeine it gives you the confidence You actually think you're shooting well until you actually it gives you like a false confidence but but when you're in a state of fasting ketosis or nutritional ketosis and you've maintained that I guarantee not only physical cognitive performance but things like things are very important your decision-making and shooting performance will will improve So I would say give it a try but they kind of for me I can read all the studies in the world But I needed to actually experience it myself To have the belief and that belief through self experimentation led to a further Enthusiasm to pursue this path as my career So over the last ten years That's why I've been doing Dumb, thank you so much

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