Keto, Fasting, and Resilience | Dr. Dominic D’Agostino July 31, 2019 6 By William Morgan A good protocol which I think is, you knowSix six hours of eating and eighteen hours of fasting. So for me today is a dayI’m intermittent fasting. I will start eatingMaybe at about 3 p.m. And I will finish eating. I’ll have a nighttime snack at 9 p.mSadam how did you end up working with Navy SEALs?I came in from sort of the the back end port likethe office of Navy research they fundProjects under a particular program called the undersea medicine program and that’s for warfighterperformance and safety andI was an avid diver as a PhD student and my under my postdoctoral fellowship research was reallydeveloping technologies funded by the Department of Defense and the Navythat would allow us to study the problems that the Navy SEAL divers haveAnd and also deep-sea divers so that could be oxygen toxicity as it pertains to the pulmonary systemoxygen toxicity as it pertains to the brain which causes seizuresdecompression sickness nitrogen narcosis high pressure nervous syndromeso these are all things that I studied sort of intensely in my postdoctoral fellowship years andMy project was funded to really study fundamentallyoxygen toxicity seizures andWe 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 themsothat led me down a path to basically look into anti-seizure strategies and toYou 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 outthe military wants a deliverable so they want some little widget orDeliverable at the end of your study to say look, you knowThe guys can take this out to the field and it can apply to them or they can move itwhatever you develop into a large animal model like they study pigs for example, soSo my research initially really with the Navy SEALs and and office of Navy researchwas to do very fundamental science in their basic science program andTo develop an anti-seizure neuroprotective strategy, so I was mostly focused on drugs at the timebut I realized that the anti-seizure drugs are really not very good for people with epilepsy or other seizure disorders andIn the process of looking and the process actually helping a friend in the UK in 2008 or six seven and eightISuggested the ketogenic diet just by looking to see what two peopleDo who have drug refractory or drug-resistant epilepsy and I discovered the ketogenic dietWhich I thought I knew about Atkins and but I didn’t actually know the history of the ketogenic diet as a very powerfulmetabolic based program oryou know nutrition therapy that can prevent seizures and it was developed in the 1920s and Idecided to pitch this to the military as aneuroprotectivestrategy andIt took course it took about two yearsfrom you know initial thought andStudying and pitching it it took about two and a half years two years to get funding for thatSo right now, you know going back about ten years ago eight years agoThe initial funding was to develop to understand why oxygen toxicity occursBiomedical countermeasures that can prevent option toxicity and then the last, you know five years developingspecific things formulas that the warfighter can take by mouthThat will instantly produceTherapeutic ketosis to enhance theirProtection against oxygen toxicity cognitive performance physical performanceAnti-inflammatory effects because that’s a problem too. So we’re looking into a wide range of things on a particularYou know class of compounds and how that can be usedspecifically in the context of extreme environments so as it pertains to the undersea environmentBut now we’re working with NASA in the space environmentyou know Air Force AFRL, you know altitude soThat’s that’s kind of like the very very general picture and we have lots of research projects that are run byundergrads medical students PhD students postdoctoral fellows andThen we collaborate with people all over the United States and all over the worldActually, and we have a human study going on at Duke University right now looking at for examplenutritional ketosis inHumans to prevent oxygen toxicity. I do a lot of rat studies in the labBut we have actually got to the point now where we’re developing and moving some of these strategiesinto more like human factorsTraining or experimentationWell, I want to talk more specifically about what it is that how this came about that Navy SEALs getting seizuresI 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 oncentral nervous system oxygen toxicity or CNS oxygen toxicitywe know that oxygen toxicity of the CNS is a limitation ofHyperbaric oxygen therapy which has about 14 differentfda-approvedApplications so you have things like decompression sickness, right if you get the bends you got to put somebody in a chamberPress them and then bring them back upYou know to surface to prevent little bubbles from forming that’s called the bends or decompression sickness. That’s one applicationWound healing is probably the most popular most, you know used applicationIschemic wounds diabetic wounds radiation necrosis as it pertains to cancer treatmentcarbon monoxide poisoningSo if you can for example think of carbon monoxide poisoningSo 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 chamberPress them with the maximumPartial pressure of oxygen that you can you can use right but that a limitation of how high you can getthe oxygen level would beoxygen toxicity seizures so you can really only go up to about 3 atmospheres ofoxygenSo we’re right nowI’m breathing air, which is0.20 80 a of oxygenIt’s 20% oxygen when you’re breathing100% 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 hyperbaricenvironment soThe 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 veryOxygen as a drug. It’s a very powerful drug and itAt a certain level it becomes toxic to humans. Soso oxygen soNavy SEAL divers are kind of unique and that they use a closed-circuit rebreather andMeaning 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 unitsIt’s a hundred percent oxygen. So if they go down to just fifty feet of seawaterThey have the potential to have an oxygen seizure within 10 to 12 minutesSo that’s not a lot of time right at just 50 feet of sea waterTypically, they dive pretty shallowBut in the event that the water is very clear and you have people looking for you overhead or you’re taking fireOr you got to dive down to a ship or a bridge and plan a mine. You got to go deeper than that occasionally, soto enhance the safety and performance and success of the mission youKnow we want to be able toto ensure that the that these units can be used without the potential of oxygen toxicity seizures theseclosed circuit rebreathers andWe don’t know how real to predict it. So if you could wear a little widget that could for exampledetect heart rate variability or EEG activity oryou know respiratory rhythm generation or you know, we know thatthere arePerturbations in respiratory control that precede a seizure, you know from animal data. So we’re working on littleStrategies to predict the seizures, but most importantly we’re working on strategies that canGive more bottom timeTo the guys out in the field using this type of equipment and making it safer for themand the development of these technologies thesethesecountermeasures against oxygen toxicity haveutility for hyperbaric oxygen therapy making it safer andMaking it possible to allow people to get a much higher concentration of oxygen to to treat variousmaladies ortoxic exposures for example like carbon dioxideAnd to be able to do that in a much more safer way, you know or if someone’s prone to seizuresPerhaps they have a brain tumor and we’ve explored the use of hyperbaric oxygen therapy for cancerBut if you have a brain tumor you may be already susceptible to having a seizure but being in a state of therapeutic ketosisMay give you much more leverage and decrease your potential for having a seizure so you could potentiallyutilize a therapy that would otherwise beYou knowcounterindicated or contraindicated for that soSo we work in a lot of different areas nowmy main thing was studying high pressure oxygen the negative effects of it andPreventing that and now we actually have studies where we’re looking at hyperbaric oxygen therapyfor different applicationsRight now they aremore or lessYou know off-label use things like hyperbaric oxygenFor cancer, but unless you’ve had radiation therapy. So it is fda-approved for radiation necrosisbut we think thathigh pressure oxygen can hyper oxygenate tumor tissuereverse tumor hypoxia and shut off some of the gene drivers like if one alpha veg F and various factors thatContribute to cancer growth in proliferation also by hyper oxygenating the tumor tissueIt increases reactive oxygen species to the point where you can overwhelmThe cancers antioxidant capacity and it sensitizes that cancer tissue to other forms of therapyRight and radiation kind of works the same way radiation kills cancer cells through reactive oxygen species hyperbaric oxygen therapyJust does it more gentle in a more gentle fashion. So we’re exploring the use ofSo out of my military funded research came the observationBecause we have hyperbaric atomic force microscopy hyperbaric laser scanning confocal microscopyWe have unique technologies that no one else really has in the world. It allowed us to to look atCancer cells for example, and we do human dermal fiberglass and different type different types of cellsWe observed that in cancer cells they over produce oxygen free radicalsUnder graded levels of oxygen and that oxygenwasWould kill those cancer cells whereas normal healthy cells wereResilient against a similarlevel of oxygen so that led us down a path which was kind of getting off track in some ways, butLed us down a whole path of exploringhyperbaric oxygen and othermodalities forCancer treatment as an adjuvant to different therapies. We’re exploringright now so a little bit off topic, but that now I can saywe have about a third tomaybe half of the lab is studying cancer and different projects related to cancer andusing hyperbaric oxygen in combination with other thingsso that could be a whole nother podcast, but for him, but that was that project evolved out ofResearch and an observation from equipment that was funded by the Department of Defense with what’s called a Durov grant itallows us to buy andDevelop and use that equipment for very novelSomewhat esoteric projects, you know, you know looking at you knowCNS oxygen toxicity or the mitochondria of neuronsDuring a po2 equivalent of a Navy SEAL dive operation sort of scenarioWell done, you are you’re blowing my mind. You’re all over. There’s so many amazing thingsI didn’t mean to go off in different different areas, butWhat 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 todayyou know GPS other things really evolved out ofMilitary funded researchAbsolutely. YeahMy graduate work before I was in the Navy was a study of people with a disease called spinal muscular atrophyAnd it was it was Department of Defense funded and you know, people don’t always make those connectionsBut it’s amazing how how it does play into so many so many different fields of research as wellYeah, and and while I was there also, my principal investigator was dr. Darryl DeVivo. Hevivos disease or glue blunt aboutAbsolutely. I know dr. DeVivo. Yeah, yeahYeah, we’re actually funded by the glucose transporter type one deficiency syndrome foundationSo we have glut Wendie mice where we don’t we just published a paper lastTwo weeks ago looking at the effects of anesthesia on the glut1 mice so I know drclapper who sort of may be his protege andYeah, I’ve met with dr. Diva because I present at the glut1 deficiency Foundation conferencesAnd yeah, very cool that yeah, you know him small world. Yeah, maybe we’ve crossed paths before thenYeah in working with him and on gluten deficiency syndromeThere was talk of the ketogenic diet epitaph. Yes. It was new to me. I just saw these amazingslides where you’d see achild who was having seizures that weredebilitating and then all of a sudden I’d say then the child did the the ketogenic diet and who the child walking upright andhealthy and alert and and things can you explain how there’s in aHistory of this ketogenic diet that it’s not just a new trend in 2018 and it’s something that’s been around for a whileYeah, yeah, it’s been aroundwell, I meanfasting ketosis we could say has been used for millennia dating back to the times of Hippocrates likeyou know 400 BC or more and it was observed that fasting could quote-unquote cure seizures andActually would work for some time after even after initiating food againBut fasting in that context was really not sustainableRight because you you have to eat again and then it takes you out of fasting ketosisso a lot of the benefits were derived fromthe the metabolicphysiological state of fasting which is a suppression of the hormone insulin and also adecrease in some extent of glucose levels and also in elevation of ketone bodies andaMetabolic based therapy was developed at the Mayo Clinic’s in in the early 1920sand this was the ketogenic diet whichincorporated a macronutrient ratio, that was very high in fat about 90 percent fat andIt had adequate amount of protein to prevent protein malnutritionWith the least amount of carbohydrates possible, you know 0 to maybe 5% if that and consuming this diet producedaMetabolic physiology that was in many ways mimicked the state of fasting in a you caloric dietMeaning that you were getting the calories that you needed to sustainYou know growth and repair and your weight maintenance and that this this nutritional ketosisWas a means to induceTherapeutic ketosis and then that had in and of itself just through a dietary means an ability to metabolically manageseizure disordersIndependent of the etiology so which is interesting because you know, whether you have temporal lobe epilepsyglucose transporter deficiency syndrome now, we know Angelman syndrome orabsence seizures even different types of seizures the ketogenic diet tends to work and and now even you know acentury laterit tends to work better than theDrugs in most cases when drugs fail they people are put on a ketogenic dietespecially for kids it’s abouttwo-thirds of the kids respond favorably even after multiple drugs failso the question could be like why wouldn’t kids use this first because many of theAnti-seizure drugs do cause developmental delays that may not be reversible in kids. So if you load a child up withYou know phenobarbital or different types of anti-seizure drugsIt can actually impact theirDevelopment 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 maybeFor different subsets of people. So so the dye has been around for a long timeIt’s use was marginalized in the nineteen late 1950s 60s and 70s and even 80sWhen drugs came online and then Jim Abrams of the Charlie foundation the Hollywood producer his son CharlieWas stricken with seizures was not controlled by multipledrugs andhe was really upset that his son was not offered this as a therapy andthey initiated the diet at Johns Hopkins andHe became very vocal about the ketogenic diet for epilepsyHe was on Dateline NBC in the mid to late 90s and then Meryl Streep came on and did a movie about the ketogenic dietMost people don’t know a Meryl Streep did a movie about the ketogenic diet and that was called firstYou know harm and that brought more publicity to the ketogenic dietFor 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 treatmentBut it works for glucose transporter deficiency syndrome where there’s essentiallyHypoglycemia in the cerebrospinal fluid because you can’t transport glucose across the blood-brain barrieran elevation of ketones in the blood will readily cross the blood-brain barrier andRestore brain energy metabolism and even neurotransmitter production like in kids and adults that have glut1 deficiencySo it is really a life-saving therapy for that disorder and many other even metabolic disorders pdhDeficiency, I mean there’s all different types of disorders. It’s used forAnd now we explore its application for you knowA lot of other things we’re looking at kabuki syndrome right now, and we’re starting a new projectkabuki syndrome is essentially a balance betweenGene repression and gene expression and in elevation of beta-hydroxybutyrateFunctions as something called a histone deacetylase inhibitorWhich can actually turn on the expression of genes that are otherwise silenced with this genetic disorderso even in the presence of a persistent molecular pathologythe ketogenic diet by virtue of elevating beta-hydroxybutyrate which is a class 1 class 2 h dag inhibitor canepigeneticallyenhance andrestore normal brain function in the Kabuki mouse model it actuallyIt’s it saves the dentate gyrus neurons and rescues them from being degradedSo we are doing work on that now in the lab and just starting that up and the idea is to rapidly move that intoahuman therapy with kids andElevating that endogenous metabolite that we know functions as an h-back inhibitorThere’s an experimental drug called AR 42, but it’s not available yet for kids that have thisBut beta hydroxy butyrate works just as good or better than AR 42, which is not yet availableSo our lab is actually workingtologistically right now set up everything that’s necessary to do a preclinical animal model study that will hopefullyparlay that into ahuman clinical trial on something like kabuki syndromesoYou know basically using ketones as an epigenetic regulator to basically alter gene function to restoreSome sort of normalcy and people who have this genetic disorder and for those who aren’t familiar with epigeneticsCould you kind of kind of explain because I think when people hear ketogenic diet or even if they know what bhp isThe idea of it functioning as a way that affects genetics is maybe new for a lot of folksyeah, yep, so think about yourYou know your your genome your normal genome we go to 23andme and we get our genome right and that’s kind of aWritten in stone. I guess you could say, you knowThat’s that’s kind of our genome. But or we used to think that right, but there are processes that happen in the bodythatAllow us to go in there with more or less a repair kit and and alterThe genes in a way or the expression of various genesTo alter those expressions to influence our genome and and we call thatepigenetics so epigenetic is it’s sort of a above the genome right uppy and it’s the process in whichThat our body has the ability to alter the expression of various genes and even to some extentchange our genome over time and that could beenvironmental factors that could be drugs do thisthat could beYou know metabolism fasting, you know now we’re realizing thatMetabolites just are not energy substrates that these metabolites like beta-hydroxybutyrate in particularHave a have a functions have the signaling functions in our body thatin some ways can impact the expression or repression of different genes andWe are just going down in that direction when I started this research in ten years agoWe only knew of ketones as an alternative energy fuelMostly for the brain but over the years we’ve discovered thatThey can influence gene expression that they can that there’s a toan receptor that they can inInfluence an inflammatory pathway that the drug companies are scrambling to design a drug to inhibitYou know that the beta-hydroxybutyrate can do that. So these are allThings that sort of have popped out of the data and published not all in our lab actually most of it ins published by othervery big high impactyou know journals and and labs that have really teased out the molecular pathways thathave a reallyBeen elucidated and and more needs to be sort of determined exactly how some of these pathways are influencedbut one of the most exciting one to us is being able toAlter our genes right through altering epigenetics, which is being able to edit in some waysor influence the expression of variousgene pathwaysAnd 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 NASAFor 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, likethis resource is right now at its infancy, sothe the use of the ketogenic diet as ameans toenhance resilience in an extreme environmentSo, you know, I’ve done enough experiments and rodent models to know that being in a state of therapeutic ketosisMakes the rat what we call, you know from our drug studies a super ratSo basically when you put a rat into a state of ketosis and elevate its ketonesTo the same level that would be achieved after me fasting seven daysThat rat is 600 percent more resilient against oxygen toxicity seizuresand we’ve never been able to achieve that with any drug even and even likeAnti-seizure compounds that are so powerful that are not on the market yet. They have, you know side effectsWe can’t even get that’s never protection from thatSo this has work done, you know about eight years agoso the question isHow do we leverage this technology? How do we develop it into a way that’s palatable. That’s tolerableThat is fda-approved. So we’re working on that wellwe’re working on the use of these compounds for different childhood disorders and thatMay set a precedent or a pathway for us to you know, get some of the more powerfulCompounds for use in Special Operations community things like thatSo we do know that the ketogenic diet has a macronutrient ratio. That’s mostly fat and ketones arethe fourth macronutrient I like to say because they are calorie containing substances when weconsume them if we ate nothing else andstudies on dogs have been done where you consume something like 1/3 butanediol and it can sustain performance on a treadmill forFor a long time and that compound is not ketones are not classified as a macronutrient yetSo 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 barrierSo the advantages to the warfighter or NASA, you know personnel would be the energy density is quite higherRight. So the key of junk diet if we’re just looking at macronutrientProfile and I’ve had some of the engineers do calculations on a four to six man crew to Mars and back it ends up savingabout two large SUV’s full of weightso in foodIf it’s a two one half or two year missionso that that’s a significant amount of weight when because the energy density you have nine calories per gram as you know forFor fat and four calories per gram for carbohydrates and proteinSo there’s shifting the macronutrient ratio instead of 70% fat or carbohydrates you make that 70% fatLike right there, you are more than doubling sort of the energy density, right so may major logisticaladvantagesWhich the engineers love, you know, I’m interested in more the more of it as a bioSort of a biological countermeasure against those environments which could be the undersea environment as you knowhypoxia, or hypoSo there is a satiety factor to so when you’re adapted when your body is fat adapted and what we call keto adaptedtheyou don’t get hungry so you can in the absence of food or if you’re in austere conditions andyour blood glucose levels dropYou are going to brain fog and a pretty dramaticPredictable decrease in cognitive and physical performance if you are adapted to ketonesThe ketone levels when they’re elevated in your blood and you gohypoglycemics you’re asymptomatic forhypoglycemia, so you can even in subjects that were fasted for you know forty days and they injected them with insulin they couldyou know readily do cognitive, you know function tests and be fine so that in and of itself I think isIs a major advantage?Obviously a major advantages and there’s no other fuel that I know of that could really do thatyou know that that could make you asymptomatic forHypoglycemia, when there’s an absence of food availability our body’s kind of do that naturally when we fast, you knowBut being keto adapted allows you to do that very quicklyAnd once you’ve done the ketogenic diet and go back to a highcarbohydrate diet and then go back to a ketogenic diet you make ketones about twice as fast because you’veUpregulated a lot of the enzymatic pathways catalytic enzymes and transportersThat readily it’s almost like you activate a genetic programThat we call it we call it metabolic memoryYou 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 getBack up to that fight. So your metabolism, I think and this is stuff we’re looking at nowIt’s kind of the same way. Once you’ve acclimated your body to be keto adapted that you can readily go in and outWe’re starting to see that has not been studied. So what I’m saying here, I guess I’ll have to stay step speculationBut as a scientist, you know, I’ve done it on myself and we have some rat data, you knowHopefully we’ll publish that soon with it with our colleagues. So the satiety factor and ketones are anti catabolicThat’s their evolutionary function if we did not go into a state of ketosiswe would catabolize all ourGluconeogenic amino acids in our skeletal muscle and we’d waste away in about two weeks and die probably of cardiac failurebut because we have essentially an endless supply of body fat even a lean person has like twenty to thirty thousand calories aBody fat that body fats liberated converted to ketones and then those ketones are profoundly anti catabolicSo they prevent many of the proteolytic pathways and that they are very protein sparing we say so that’s their functionSo it’s a satiety factor the energy density the protein sparingAnd some of the stuff that we’re looking at now with NASA extreme environment Mission OperationsI was on a crew member for 22 which is working with astronauts in an undersea environment where weSort of are looking at a variety of different things and my wife will be on Nemo 23 and that’s coming upWe’re preparing for that. So I’ve noticed in myself that the requirement for sleep is less about slightly less maybe about 3030 minutes less and the percentage of deep sleep is higher. So instead of gettingYou know60 minutes of deep sleep each night or 70 minutes if I’m at Iquitos if I’m in ketosisI routinely get about 90 minutes of deep sleep to two hours of deep sleep 220 minutesMy sleep is very deep and my sleep architectureMy sleep timing is less and my sleep architecture is more and then I’ve seen a lot of sleep data from people out thereSuggesting something’s going on. So it needs to be kind of studied and also stress soAnd we’ve already have several publications on this and another one that we recently submittedShowing using an elevated plus maze which is used by pharmaceutical companies to evaluateAnti stress orEvaluate the fear response in in rodent models. We noticed early on thatIt was easier to handle rats and mice that were in a state of ketosis. They didn’t have this fear responseThey weren’t trying to bite youSo if you use in elevated plus maze where a rat kind of goes out on a catwalkAnd they don’t like Heights they don’t like thatthey can they can stay out in the open arm or they can go into the closed arm where it’s safe andrats have a natural tendency to explore that’s and humans have a natural tendency to explore so when they’re in the state ofNutritional ketosis they stay in the open armI think about 25 to 30 percent more and they explore their environmentThe novel environment whether so that’s the implication there for humans. It’s for people who have like PTSDMaybe like social anxiety and things like that. We think especially for PTSDWe think that being in a state of nutritional ketosis helpsBalance the neuropharmacology of the brain by it. Does this by elevating gaba to glutamate ratio by activating?glutamic acid decarboxylaseAG add65 and 67 enzymes so you don’t have to know all that but it changes the neuropharmacology of the brainTo make you more relaxed. It’s actually hitting things andReceptors that actually may be hit, you know in a more abrupt fashion with alcohol, but it’s doing it, you knowNaturally, it’s you know, more GABAergic activity is a more, you know brain stabilizing calming activityAnd we’re also looking at the adenosine receptor insert to nergic systemsbut the thing that jumps out and why it may have an anti seizure effect is that you areTaking a potentially hyper excitableNeurotransmitter that’s actually could beNeurotoxic in the context of traumatic brain injury PTSD and seizures. That would be glutamateSo glutamate is converted to gaba through an enzyme called glutamic acid decarboxylaseKetosis activates that enzyme so convert more of this stress, you know anxietyhyperactivityneurotransmitter to a more brain stabilizing calming neurotransmitterSo that’s firmly worked out and we’re working out the details as to you knowWhat exactly what receptors or overlap with certain area kadena synergic and all these other things?So we’re working out that pharmacologySo from a warfighter perspective from an astronaut perspective, you know the energy density, you knowTakes ten twenty thousand dollars per pound to get something up in spacesatiety factor anti catabolic factorSleep and stress and we’re also nowWe can’t really talk about it, but we are doing studies now looking at physical performance and cognitiveperformanceFrom my perspective i’m interested in physical and cognitive especially cognitive performance inThe context of extreme environments so you can do this taskAt one atmosphere of pressure right some you know reaction time or critical thinkingTasks and there’s different tests that we use for thatCan you go to?You know18,000 feet and do the same taskOr 20,000 feet or whateverhypoxicThere’s a very predictableYou know impairment that will be you know, conferred upon the person or you know to following thiscognitive function tasksCan we preserve that under under extreme environments under the in the undersea environment as it pertains to nitrogen narcosis?high pressure nervous systemActivity things like that. So that’s kind of what we’re doing now in rodent modelsI mean, we will look at the activity under ambient conditionsBut we also put them into these extremeEnvironments and see if we can preserve you knowMake them more resilient in that environment and we’re vetting outVarious types of strategies to induce nutritional ketosis and finding out what can rapidly go to the fieldso as far as you know tolerability safety safety is probably the one andYou knowIs 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 bodyA superior alternative form of energy that has a host of otherThings and it’s likely not going to be a single agent, but it’s likely going to be a formulaSo now we’re working with different formulasIt’s encouraging that a single agent can have a profound effectBut we think that the real, you know, the greater effect can be when you start mixing these things together and adding some cofactorsBut we’re very encouraged by just a single agent has outperformed all the drugsThat we’ve you know that have ever been tried for anesthesiaSo we’re you you were probably going to take that agent and combine it with various other thingsTo make it more tolerable palatable and more efficaciousyeah, the thePossibilities of the ketogenic diet in a pill or a shot or something like that are hugeIn I was skeptical. I was pretty skeptical in the beginning but the military actuallyWanted something that can be consumed just prior to admission and you knowAnd they’re looking at they didn’t want to do the high fat dietNow our views have changed of the high fat diet over the last ten years so that could be revisitedBut they really wanted to it wasn’t my sort of decision on this. They really wanted aKey, they wanted to induce therapeutic level ketosisindependent of dietary restriction thatWas 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 themDr. Richard Veatch, he was thegraduate student of Hans Krebs and so one of his best studentsHe’s at the NIH and was actually funded by DARPA with a lot of money to develop a ketone ester for warfighter performanceSo so we, you know tested that compound and instead of just focusing on one compound which most labsdo you know we study everything and find out what works and we throw away what doesn’t work and then we focus ondeveloping novel compoundyou know testing what’s already out there, but alsoDeveloping new compounds that are more powerful more dense and moreHave greater ability to be consumed and toleratedSo we’re at that now some of the things are highlyPalatable and tolerable but they tend to be thesort ofYou know less potent agents. So the potency of a compound is almost inversely proportional to itsTolerability so as these ketone esters as you have like a mono esterDiester or try a stir and in different compounds they tend to get increasingly moreAversive in taste and tolerability so we are working onThat’s why formulating is very very important to usAnd we’re doing that in rats now. And and also I test things on myself too sometimes soAnyone experiments you’re famousYeah, yeahSo thinking from the perspective of your day to day guy in the NavyWho 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 toYou know if I have to go a while without food to maintainperformanceto 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 aLot of the folks that I work with they fly in a particular aircraft that just got aerial refueling capabilitiesSo now their missions go from four hours to eight hours in plane. We have you know, no coffeemaker. No microwave. Nothing like thatYeah, how can a normal person?Take this kind of stuff that we have right now the technology we have right nowInto a shipboard environment and you can get these benefitsSo I’ll approach it first from the perspective ofdiet andfrom time restricted eatingProtocol, 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 intofasting again you were you would adapt much quicker toFasting you could preserve your cognitive and physical performance, you know, because your body starts making ketones fasterso I would suggest that guys do not that’s not the ketogenic diet, but do intermittent fasting aGood protocol, which I think is, you know, six six hours of eating in 18 hours of fastingSo for me today is a day. I’m intermittent fasting. I will start eatingMaybe at about 3 p.m. And I will finish eating. I’ll have a nighttime snack at 9 p.mRight, it will be my last meal and I basically just skip breakfast and I’ll skip lunch sometimes I start at like 1:00 p.mAnd finish at like 7 p.mAnd that’s six hours of eating and now typically maybe two meals and maybe a snack and then that 18 hours of fastingDoes put us in a mild state of ketosis, even if we’re not like, you know on a ketogenic dietbut if you do low-carb or if you eat ketogenicDuring that eating window, then you you’re kind of always getting some of the benefits of ketosis when you start eating againYou still maintain?You know a mild state of ketosis and then you get sort of the benefits of fastingSo that cokes is your body into being what we call fat and keto adaptedSo if you take that individual and you take away and you have limited food availability in an austereenvironment that individual will have better access toHer his brain will be his or her brain will be more resilient to hypoglycemiaAnd also have a greater capacity to liberateFatty acids from adipose to preserve their energy cognitive physical performanceUnder high energy demands so that that’s sort of the advantage right thereSo so that’s that’s like low tech right? That’s like, you knowYour macronutrient ratios and time restricted eating and then you have exogenous ketones supplementation, right?So this could be something that’s in like a little5-hour energy kind of thing and it’s a veryenergy dense formula perhaps of ketogenic fats andexogenous ketonemineral ketones which could be beta-hydroxybutyrateAttached to sodium potassium calcium magnesium, which is a saltSo it gives your body minerals and then there’s different esters that could beUtilized and there’s a whole toolbox of esters that we’re studying right now. The important thing is thatYou knowYou could drop guys off for five or six days into an area and let them do their mission and they could carry on theirbodiesYou know variousSmall vials of this stuff and be able to consume it and it could be formulated in a way to give themNot only a burst of energy but sustained energy overa fairly significantPeriod of time if they were to get a blast injury traumatic brain injury or if they were going to do an oxygen rebreather diveif they’re going to hypoxia, like they they would potentially have neuroprotection under all those different circumstances andMay be able to maintain cognitive resilience a little bit better – under those circumstancesSo these are things that we are doing in animal models that we want to do in human studiesSo the trick with human studies is finding the optimal formula that they can tolerate the dosing the individual, you knowand it takesYou know rats you have an inbred strain a rat and they’re all kind of the sameAnd the data looks great and they have humans and this guy is eating, you know, basicallyI don’t know monsters and and you know sugary drinks and Snickers bars and another guys already doing paleo as he you knowHe may respond differently. So we really need toGet funding to be able to do this in a very controlled environmentBecause the payoff could be pretty big as far as warfighter performanceIt’ll probably start in the Special Operations community and maybe work its way downWith the idea, is that you haveThis as a tool in the toolbox, you knowI’m not all aboutReplacing what the military is going to eat as far as their nutrition because that’s not going to happenbut to let them know that a key to jet or low carb eating strategy is a strategy that may have these benefits andAnd to make it available for those guys who want to doYou knowKnowing what we know nowthe rodent date is very compelling and the stuff that we’re doing now is very compelling and it’s already moved tohuman studies that are ongoingSo I see a lot of potential there is using new troop nutrition as aPerformance not only as a performance enhancerBut something that can enhance the safety – that’s the primary objective the safety but out of those safety studiesAlso led us down paths where we’re looking at performance and performance resilienceSo there’s different ways to do it. Like I could talk about, you know different types of formulas for exogenous ketone formulasBut I think we’re a little bit too early yet in describing the ingredients in those formulas, you knowWe’re in the basic science concept of that but time restricted eating low carbketogenic diet exogenous ketones maybe all in combination – rightSo maybe not to do one or the other but these things likely have either additive or synergistic effects when you use togetheryeah, so many tools in the toolbox like you said andFor people who are in general. Just trying to see what works for them. And what doesn’tyou’re you’re famous for these nf1 experiments where you you’re testing yourself you’re pushing your limits andNow so many people are wearing monitoring devices. They have access to lots of dataWhat 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 roundTim Ferriss Mitch, I didn’t know he was going to mention that on the podcastBut I guess Peter Atia told him told them about the storysoOkay, so monitoring. So right. So what what can the person out there listening right now do they can go to their local?CVS Walgreens drugstoreAmazon and buy a glucose and ketone monitoring systemRight and they can simply it would be good to knowTheir glucose response to a meal that’s very important from a health perspectiveYou don’t want to be you don’t want to have glucose excursions up to like 200 milligrams per now, you knowYou want to stay, you know under one?so IWould say try intermittent fasting perhaps the time restricted eating protocol with low carbohydrate diet. Perhaps starting100 grams or less per day and then working down to 50 andover a period of time you can check your blood ketone levels and once you’re above0.5. You are clinically in a state of ketosis andfor a diabetic a type 1 diabeticPerson who’s not on occasion a diet that could be dangerous but for us that that’s a good thingSo diabetic ketoacidosis is very very different and then nutritional ketosis and my PhD studentAnd ruku, t’nuk did a TEDx talkThat you can look up which talks about that subject a type 1 diabetic using nutritional ketosis to manage his disorderSo that’s all say about that, but I get a lot of questions about type 1 diabetesSo I just you knowrefer to Andrews TEDx talkSo for nutritional ketosis you want to be 0.5 or above ideally around two one to two million more rangeCheck your ketonesTypically later in the day when you’ve had some some ketogenic meals in you or you’re fasting and see how you feeland also maybe when you’re not measuringSee how you feel subjectively when you have the most energy when you have the most lucidity and mental mentalResilience I guess you could say I when I get into these phasesI’ll do a lot of writing or a lot ofsort of tasks that require a lot of you know cognitive and I willTend to check my my glucose and ketones and I typically findThat my ketones are in like the one to two and maybe upwards to the three range and some people I knowActually get much higherthere’s people in the lab that are like running four or five andOther people that are on a strictly to genic diet and can barely even make it to that 1 millimolar rangeSo everybody is going to be a little bit differentso by a meter onlineThey’re relatively cheap under 50 bucks the stripsIf you search around you can get them for anywhere between $1 to $2 a strip and and get some some data on yourselfExperimenting yourself and then from there you can startYou 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 meIt’s a pretty good measurement of your sleep time and sleep architecture like how much you knowDelta sleep. You’re getting and REM sleep and things andAnd I we use this for our NASA extreme environment Mission Operations sort of mission to on the crew membersSo it’s a very Hardy technology. I mean you can train with it and it’d be hard to break it actuallySo monitoring your sleep with a Fitbit or an aura ring measuring your glucose and ketone levelsI think is a good place to start right and then we all have certain thingsLike I know my strengthsI keep a training Journal or used to keep you knowVery detailed records of training Journal and then you could whether you’re a runner or a cyclist or whatever, you knowStart monitoring this get your baselineinitiate the ketogenic diet orexogenous ketones or intermittent fasting whatever you want to do andMonitor your blood ketone levels and then assess thoseThings that you’re interested in, you knowYour performance times not just subjectively but objectivelyRight and monitor your sleep because your sleep will be a factor in those, you knowperformance to get general blood work CBC CMPYou know do get a lot of baseline data because it’s going to be important I think for meI never thought I would continue with the diet. I was just doing it from an intellectual perspective and that I wanted to understandwhat it felt like for my brain to run off a different energy source, so I became obsessed with this about 10 years ago andand I was very inspired by the work of George Cahill at Harvard Medical School where he fasted subjects for 40 days andand was able to add some conversations withDr. Cahill, he passed away in2012 and a lot of the icons are up in their 80s and 90s pushing a hundred Allen many of them are still alivethey did go on to to live extremely productive lives andcontributed massivelyTo metabolic physiology, which don’t have the metabolic physiologists nowadays that we had back in the dayBut I was really inspired by his work and actually wanted to fast for seven days not 40 daysSo I didQuite a lot of blood work before during and after and was able to get my blood glucose downTo a level that was significantly below my ketone levelsSo my ketones were at at the end stage about double what my blood glucose was and because ketones can readily cross the blood-brain barrierWe can say thatRoughly two-thirds of my brain energy was being run off ketones and during that timeI actually worked on a lot of grants and was very productive and actually getting got funding off one of the big grantsI worked on during that time. I was teaching and even at the end of itI went to the gym and tested my strength and found that like my strength did go down a little bitBut I didn’t push myself too hard because I knew you know, I was thinking I’m fragile. I just wanted to be kind ofcautious as toMoving weight under that kind of condition, but I did findWhich was really interesting to me that my strength did not take a big hitAnd I was semi keto adapted because for about a half a year to a year or soI had been tinkering with the ketogenic diet the clinical ketogenic diet and it really made fasting pretty easy the third dayI was kind of hurting but after seven days, I mean I was lucid enough to be sharp and give lectures andAnd had the energy to move, you know, five six plates on a deadlift, you knowI didn’t ever thought going into this. I would have never I thought, you know after four or five days you’d be so weakYou it’d be hard to stand upYou know thatYou’d have and I did have orthostatic hypotension in the beginning I’d stand so I had to get I would have soup brothBut no calories, you know, I’d have sodium and water and fluids and things like that stay hydratedBut I don’t know the static hypotension is that’s when you stand up real quick. And you feel dizzy just for the yeahThat 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 sodiumSo I think in the beginning I was drinking a lot of water but not getting the sodium that I needed and once I startedGetting the sodium in it’s like I started kind of waking out. My blood pressure came back up againAnd I remember kind of sodium loading before you knowI had to do a thinking task or work out or something like that, but I would go for like long walksYou know at the time just very easy walks and that my ketone levels would get up I come back and my glucosewould 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 evendetect it andAnd I tinkered with a few things to get my my glucose down really lowI 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 andand realized thatThis really does make you resilient your body feels kind of Numb in a way like but at the same time your senses are heightenedSo I would go for a walk and I could smell things or maybe even see things sharper than I could could otherwiseSo now I got the full understanding of when when people fast and they say it brings them to another levelAnd I think the more you do it the easier it gets and probably the more benefits you derive from it, tooSo, I mean you could tell like major things were happening in your body, you know major things are happening like otologyof course like you when you force your brain to go from glucose toKetones luckily at the brain is incredibly metabolically flexible and its fuel utilization and then it can make that switchNot 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 itAnd I think it can be a very I mean I did it for scientific sort of reasons, but it’s also sort of a personalJourney, too. So you learn about a lot about yourself what you can and can’t take you knowHow 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 knowI could I could get through it and not die after you know, two or three days of not eatingSo 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 peopleYeah, no, no, no medical official advice dispensed herebut yeah a general general thing and you talked about how there are these great scientists who inspire you who haveMade a huge contribution and you are someone who is also very active you were on this big journeyYou 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 meI mean seeing their passion for science and and looking back and thinkingyou know remembering how fascinated I was for example with the brain like I wasFascinated like what is a thought like what is that? So I would as a neuroscientistsAs a PhD, I did patch-clampElectrophysiology, which is kind of sort of a technique where you record directly from neurons and how they communicate to one anotherand you delve verymechanistically into all that soasking questions and being very curious andand I think some from some extent there’s asort of a selfish if you want to call it that I want to be able to learn and extract information fromthe body of knowledge that’s out there but also from my own experience that I could apply to myself and I get soenthusiastic and even giddy that I want other people around me tofollow 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 standpointWhere my emphasis was really on drugs in the beginning and it was kind of more and I’m still do drug research. But this ideathatAltering your metabolicPhysiology through changing your macro nutrient profile can change fuel utilizationIn your body and that can have this host from cognitivetoanti-inflammatory effects to potentially tumor suppressing effects to anti-seizure effects like that that you can do that that youhaveYou know you are empowered to be able to do that just byYou know the food that you eat or the different supplements to that that could potentially be usedSo I’m pretty motivated by that and I really feelNot necessarily the case for everybody but uh because I don’t I don’t think some of the pioneers in this areanecessarily fast it themselves or experimented on themselves, but a lot of them did and IFeel 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 enthusiasmto the point where you’re so excited it’s hard to fall asleep or you wake up and you’re likeKind 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 andPart of your envision contribution, right? So you want toAnd also guides my researchSo 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 knowVarious research projects that we have so every day I wake up and I’m excited. I don’t know what’s going to happenlike I’m usually testing something new on myself my students havetheir in the lab now, you know in the trenches doing research I get to come in and they haveYou know so much enthusiasm about what they doso that’s kind of what drives me on a day to day basis and being able to look forward and actuallymake contribute toThe scientific body of knowledge to use food as medicine and it doesn’t have to be a macron. It could be likeThere’s companies out there that are creating what I call engineered foodWhether it be a cookie or a brownie where they’re not only changing the macronutrient profilebut they’re incorporating different ingredients that make it like a functional food whether it be a prebiotic fiber or probiotics orAn alternative energy substrate. I mean one of the first things I use wasSaito Maxx when I rode my bike, it had alpha L poly lactate in itWhich was sort of that got me interested in alternative fuels and this is going back 15 years ago and creatine monohydrateyou know, I started using that in 1991 or 92 andAlways stayed up on the literature. So I think of ketones is kind of like the next creatine and but a much more versatileso it can be neuroprotective if it can make your it enhances your body’s ATP production, but it hasA lot of advantages and a utility that something creatine doesn’t have but but mixing them two togetherWould be sort of one of the formulas that I’m working on now like, you know putting variousAlternative energy substrates together and cofactors which allow you to use use these things in a in a more enhanced fashionI would saysoThat’s what’s I mean, that’s an exciting thing and also cancer. I mean a lot of what we doI 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 andwe we kind of kind of think of my PhD students assort of soldiers warriors that are kind of attacking cancer cells with their the therapies that they’redeveloping together as a group andTesting in cells and tissues and animal models and we’re moving it to human clinical trialsso we’re sort of on a war against cancer in a veryTargeted fashion from a metabolic standpoint. Yeah, and and everyone knows someone affected by cancerSo it’s it’s such an absolute a universal cause and and it’s it’s great that we’ve got you on the teamAnd the people the students many of the people in the lab were motivated from a personal perspective and that’s why they choseYou know their particular projects to that’s often the case. Oh, yeah, I can get thatYep, don’t want to be respectful of your time before I ask my last question. Where can people find you onlineThe best place to find me is the website keto nutrition most importantly it’s dot o-r-gnot calm so keto Nutrition dot Oh ROG andI have a blog there I haveProducts that we’ve tested I have resources like doctors consultantsPodcastThat’s my kind of one-stop-shop forpeople who want more information about what we do great andTell my final question if you were talking to a military leader who wants to create a culture where people have thisIntellectual curiosity that you display this self experimentation this driveWhat suggestions you give them? I?Was talking to a military leader to embrace his cultureIWould ask that military leader and try to persuade them to do it themselves and to evaluateWhether they thought personally that this was a viable strategy, you knowSo I would do somethingas simple as time restricted eating if you have I was locked into a pattern of not only eating like five or six meals aDay, I would eat like seven or eight meals a dayWake up in the middle of the night and eat a protein bar or shake and go back because I thought I needed thatso I come from that mentality, butwhen you liberate your yourself from these frequent feedings, orfree yourself from it becomes very liberating right when you free yourself from that eating pattern so when it comes to nutrition maybeYou know, we do a lot of different thingsbut the most simplestLow-tech thing I can think of is to say hey if you haven’t tried it before itMaybe try time restricted eating. Don’t do it every dayMaybe just do it like twice a week and see how you feel and the more they do it the easierIt’ll get and then a lot of that great feeling that they have towards the end of the fast that’s actually due tobeta-hydroxybutyrate the ketone body that I study so and that’s conferring many of thehealth benefits like anti-inflammatory effects and you knowEpigenetic effects and things like that. So that’s good. That may be a gateway to get them intoexperimenting with an eating paradigm thatwithout question has major logisticalPractical advantages to guys in the field from a physical cognitive and maybe even anti-anxietyPerspective and we know you know if you’re edgy and you’re jacked up on caffeine and edgySo, you know I go to the range. I shoot quite often and I experiment on things, you knowI don’t I don’t talk about those things on podcast usually, but but not only the gymBut I’ll go to the range and I’ll evaluate what gets me better scores on my shooting testsRight, and I could tell you that the things that I talked about and things that I mentionedStart doing it and startif you go to the range start recording you were your scores and you’re gonna see that too and that’s you know something INever really talked about but I think from their perspective is a very practicalBenefit to that. So the worst thing to do for a soldier that hasA gun shooting is to be sleep deprived and jacked up on caffeineso and I’ve actually been in that situation where I haveevaluated my shooting ability under those conditions and I was all over the place butBeing on Jack jacked up on caffeine it gives you the confidenceYou actually think you’re shooting well until you actually it gives you like a false confidencebut but when you’re in a state of fasting ketosis or nutritional ketosis and you’ve maintained that Iguarantee not only physical cognitive performancebut things like things are very important your decision-making and shooting performance will will improveSo I would say give it a try but they kind of for me I can read all the studies in the worldBut I needed to actually experience it myselfTo have the belief and that belief through self experimentation led to a furtherEnthusiasm to pursue this path as my career. So over the last ten years. That’s why I’ve been doingDumb, thank you so much CategoryArticlesTagsand brendan carr dom d'agostino diet dom d'agostino intermittent fasting dom d'agostino interview dom d'agostino keto dom d'agostino keto diet dom d’agostino dom dagostino intermittent fasting for performance dom dagostino time restricted eating dominic d'agostino intermittent fasting intermittent fasting for performance keto fasting and resilience dr. dominic dagostino the time restricted eating you 6 Comments Andy Spark says: October 29, 2018 at 4:38 pm Nothing new for me, but i hope some other people got some knowledge from the interview.May i suggest some guests for next interviews ? Dr. Hyla Cass, one of the good Psychiatrists, she lives in California.Dr. Datis Kharrazian PhD, DHSc, DC, MS, MMSc, FACN, is a clinical research scientist, academic professor, and a functional medicine health care provider. Clinic is also somewhere in California. another guest will be a challengeHe does many podcast a week, sometimes up to 3 a day. He is a comedian, MMA enthusiast and has the most powerful spinning back kick in the world.Who could it be ?If you have him for an interview, then remind him that he isn't a host today, so the most questions will come from you not him. 😃 Reply I Car says: October 29, 2018 at 7:24 pm This is a wealth of knowledge. Clearly he knows what he is talking about. Is there a way you can post highlights/bullet points of this entire interview? Reply Brendan Carr says: October 29, 2018 at 7:47 pm Hey everybody! What was your favorite point from Dom? Leave it below with a timestamp so others can learn from it 😀 Reply MonteSanoMTBer says: November 29, 2018 at 11:17 pm Any insight into when I should be supplementing with BHB Salts during my fast? Should I have them in the morning? Smaller amounts through the day? Reply George Borges says: January 8, 2019 at 5:58 pm I need subtitles Reply Spencer Calvert says: February 14, 2019 at 11:04 pm Thank you for having Dr Dom on fabulous researcher able to explain to layman. Reply Leave a Reply Cancel reply Your email address will not be published. Required fields are marked *Comment Name * Email * Save my name, email, and website in this browser for the next time I comment.