Robb Wolf – Darwinian Medicine



so yeah ken ken reached out to me about home in six months ago right before I embarked on writing my second book and while we were at the very beginning of starting a six-month long three-month house remodel and he asked me if I would like to do oh and I have two children under the age of four also and I said yeah that sounds like a great idea and then as this thing kind of progressed longer and longer I started thinking this seems like more and more of a horrible idea because I wasn't sure if the house was actually going to finish in time to be able to get out here it's my wife's Italian and if I had abandoned her with the kids the house the goats the chickens and the whole ball of wax to come to Florida and hang out for three days with Ken if I came back home the next time that I woke up if I did parts of my anatomy would be inside my mouth so luckily we wrapped all that stuff up she was a loving woman but she she has the the wrath of her her Italian people down pretty well so huge honor to be here like Ken mentioned I've got a decent background in nutritional biochemistry I was a cancer and autoimmunity researcher way way way back in the day I was also a former California State powerlifting champion so I've always had a really powerful interest in human performance and health in medicine I've tended to drive my boat much more in a direction headed towards health and wellness I guess like I still am very interested in elite level performance I work within the the Naval Special Warfare community in some athletic scenes but my heart is really in helping people who are facing life shortening or life-ending diseases and trying to help them understand if they have some alternatives and that that's really what what you know fires my process so I'm gonna start this off I'm doing this a little differently so you guys are kind of an experiment of one so we'll see if this see if this goes well so how many of the you folks in the audience have a smartphone on your person currently virtually everybody okay so cool coal now it's that smartphone better than what it was ten years ago yeah like amazingly better is it cheaper relative to the way that you could have bought that same type of phone ten years ago yeah so it's gotten cheaper and it's gotten better does anybody know what that process is things getting cheaper things getting better there was there was this Moore's law yeah I heard somebody say at Moore's law it's kind of like who's buried in Grant's Tomb say who's more he was a computer scientist in the early to mid 1960s and he observed that computer micro processors tended to get faster and better twice as fast half as cheap about every 18 months and we've been on this kind of exponential process it'll probably flatten out at some point but in general we see that process moving along and it's interesting this Moore's Law story goes across a ton of different fields particularly as we're able to bring information processing to bear on different situations the human genome project there was a time when when sequencing one mega base of DNA costs more than a million dollars and now it's like a few pennies it's incredibly inexpensive so we know more about genetics and biochemistry and type 2 diabetes so here's another another little diversion along this how many that so I put into a the United States website the the PubMed the National Institutes of Health website where you can search about different health topics and in that search I put in type 2 diabetes and I put a filter for the last five years so now English language primarily last five years type-2 diabetes how many peer-reviewed citations do you think there were hundred and ten thousand but still how many of you have the time to read a hundred and ten thousand research papers I mean it's so so it could couldn't we argue that you know and there's some back and forth on whether or not science is being particularly well done these days I don't know if you guys have had stayed up on some of that but I would argue that we probably know more about type-2 diabetes Parkinson's Alzheimer's dementia than we've ever known in history does anybody know what the rates of these diseases are if we were to to graph them are they flat are they going down they're going up can anybody describe the type of up that they're doing it has a exponential growth Exponential's don't do well in biological systems they end up causing really nasty repercussions and for us there's a very interesting paper done by the Congressional Budget Office a very nonpartisan missionary style kind of governmental organization that is pretty non-controversial and it puts a number at about 2050 that we will be spending about 300 percent of GDP on diabesity related issues alone now that's three hundred three times all of our projected productivity to deal with that one problem that will not fill one pot he'll pothole educate one child or deal with one other issue now my question to you is how on earth can we know more about everything that you would care to know about but yet we have these problems that are literally going to the moon how could that possibly be the law the longer life is is not it it's a it's a it's a good thing to think about but they are not expensive generally people don't the the expense and this is an interesting piece within the Congressional Budget Office and I have those numbers and different talk so if the if the geeks want to check that out we can grab some wine and check that out after the main talk but in general this increased cost is related to diabetes diabetes and in the obesity related to that I'm gonna go out on a limb and say that the reason why we have these problems is medicine is approaching the problem the wrong way period now if we were tackling this like an engineering problem engineers don't get in squabbling matches about whether you should use a triangle versus a hexagon rebar versus balsa wood it's been very very narrowed down and and and figured out medicine and this is somewhat opinion based but I've got some pretty good facts to back this up when medicine discovered antibiotics it was a golden age these antibiotics changed everything people used to die in the millions from simple infectious disease and this was magic people were saved in the millions but it was so powerful that it oriented medicine towards a single cause or single etiology and a single cure and that is simply not the case with the modern Western degenerative diseases cancer Parkinson's Alzheimer's senile dementia these are chronic issues and they do not lend themselves to an acute phase solution and I am an absolute nutcase optimist but I'm also very very knowledgeable about the complexities of biology and you will not fix complex solutions like this with a single pill or a package of pills what you will do is bankrupt our country in the process of trying to chase that process so what I'm gonna sell you guys on if I do an effective job of it is this idea of Darwinian medicine we need to get some some evolutionary biology some evolutionary perspective into our medical systems into our healthcare systems and this approach does not provide answers what it does is it Orient's questions currently we are not even asking the right questions to get a right answer that's how far away we are from so what this methodology can do if we implement it properly it will orient our scientific investigations in a way that we can start asking the right questions and then move towards the correct answers so I'm gonna kind of move this thing forward a little bit wait what does anybody who clearly if you answer this question it indicates you have no social life and don't get out a lot but what are the foundational tenets of physics Newtonian mechanics quantum mechanics statistical mechanics those types of things yeah it's not a lot of controversy around that most people know that what are the guiding tenets of biology evolution via natural selection theodosius dobzhansky observed that nothing in biology makes sense except via the light of evolution medicine is a sub-branch or I would argue is the application of biology but yet there is virtually no evolution training no orienting no epistemological framework that's offered with that kind of evolutionary biology couching for most physicians and I just gotta ask and I get this a lot are humans exempt from evolution and it's really it's a it's a funny it seems funny but in in polls and this stuff gets really contentious like I can get chased out of town depending on where I am when I talk about this stuff but people are much more comfortable talking about the evolution of ants and elephants and they are people and so sometimes you kinda have to do a little bit of a circuitous route towards getting in on this I will say this up front though somewhat like a superior operating system this evolutionary medicine this ancestral health model is out there and it's working and it's changing ideas it's changing the way that things are happening it's how many people remember the old boss interface on a computer how much better is an Apple product or even a standard PC today these are technological innovations these are essentially operating systems which drive innovation and drive the ability for people to interface with a process in this evolutionary medicine ancestral health model is changing medicine now it's not necessarily going to be a top-down activity this is largely a grassroots activity it's very driven by social media but it's Stanford Harvard the Cleveland Clinic are all now certifying their doctors in evolutionary medicine and or functional medicine which functional medicine is kind of a trumped up term for evolutionary medicine so it's a very exciting time 15 years ago is when I got into this around 1998 and none of this existed having a talk like this could have never occurred so it's really a fascinating time for me and very very exciting but you know my my case with a lot of this stuff if we look at the early human timeline and there's there's contention on the the timeline with with these things but we had a huge amount of time that was spent as pre-human eventually proto-human and then we start getting into our actual genus of Homo and we have homo sapien and Homo erectus neanderthalensis living in a pretty brief period of time relative to the total genomic history of humanity and then it that one of my mentors Loren Cordain he has a really interesting analogy which is that if you were to take a football field one one goal line to the other goal line and you started at one goal line being the beginning of human history and it's somewhat arbitrary how far back you want to go with that but you know we'll pick something that kind of makes sense and you move all the way forward how close do you think that we get to the other goal line such that it represents a period of time remaining that represents the last ten thousand years since agriculture is come into being yeah like an inch yeah almost nothing so now part of it the you know what the implications are there is that we might we might have a set of genetics and an expectation about food and exercise and socialization that we are wired one way and we're experiencing something that is completely different and there may be problems associated with that that is the crazy used-car salesmen pitch of evolutionary biologists and it's called the discordance model you may be wired for one set of circumstances you may be living in another set of circumstances and it's the discontinuity in that communication between your environment and your genes that may be causing a whole host of problems so there's some interesting anthropological observations and again these are observations but it's a fascinating place to start with and one of my Bugaboos about the current state of skepticism and evidence-based medicine is that observation is the beginning point of all scientific inquiry we cannot just throw that stuff out we also can't run pell-mell and throw our arms around it and accept it as fact but carl sagan had a line that was something to the effect that if we're exposed to a new idea we should be just just incredibly skeptical of this new idea but we should be so excited about the possibility of discovering what the story is one way or the other that we just tackle it and investigate it and what I find today is that skepticism is merely a Wikipedia search a way to see what the consensus is and that's the end of the story and for me that's pretty frustrating so anyway we have anthropological data survey shion's and these observations were that contemporary hunter-gatherers who lived what we would consider an ancestral life way we're largely free of modern Western diseases now what does what does this mean we've had people living in and around hunter-gatherers and non westernized populations since the mid 1800s in the since the 1900s forward we've had people living among hunter-gatherers horticulturalists transitional agriculturalists and doing biometric testing which i'm going to show you some of that stuff doing autopsies so this isn't just a deal where some scientists walked down the forest paths looked over and they said I guess those folks look healthy like they actually it lived in and among these people and they were largely free of most of the cron degenerative diseases that we see dental malformations cancers obesity tuberculosis they stop very very low rates of tuberculosis among these people I thought there might be something going on with the way that their immune system functioned there was another observation though that a transition to an agrarian life way tended to cause a significant amount of problems for these people the more refined the foods that these folks started consuming the greater the problems they had and what's really fascinating you can go to any anthropology department at any University ask some folks hey did hunter-gatherers kind of suffer some deterioration in their general health well-being infant mortality rates by shifting agriculture and the Anthropology folks will be like yeah that's pretty well-established did that further increase in severity as we industrialized our food system oh yeah without a doubt now you go over to the nutritional science department and you ask that same question and the people look at you wanting to know if you want to go talk to the anthropology department and that's about as far as the interface goes so it's interesting this this foundational understanding like if you were an alien traveling from another world landed here and looked at an organism what would you want to know about it what does it eat how does it sleep what's its reproductive status is it does it live in a group like those things are really important right but yet from a medical perspective we essentially forget all of that basic ecological steeping that makes humans humans and I think that that's created a huge blind alley for the way that we can approach things so I have this this quip called the the Russian literature paradox people will freely comment about what their thoughts are on the anthropological observations related to to human health with absolutely no background on the topic but imagine that we were in here talking about mid 18th century Russian literature and I pointed somebody out of the crowd and I said young lady could you please comment on the syntactical change of mid 18th century Russian literature and give your your thoughts on it then why not so so an honest and honest statement there would be I'm not actually well-versed on that topic and what's fascinating though is that when you start proposing this particular I do this talk frequently within medical systems and the the kind of pushback is rather fascinating then I can use the Russian literature paradox it's okay not to know something about something it is not ok to comment in a highly certain with much certitude when you don't know about a certain topic but I kind of like that thing but really here again is my greasy used car salesman pitch that kind of ties this whole thing through wind changes relative to the ancestral environment cause pathogenic epigenetic signaling in us and epigenetics is the way that our food and our environment turn our genes on and off yeah I mean it is that a crazy supposition now we need to go out and maybe find some information that starts fleshing this out and and what this means is just that we're born with a certain set of genetics but our genetics are not our destiny the way that we turn these genes on and off is what more determines in our destiny how we sleep how and when and what we eat the social connectivity that we have the gut biome that we carry within us our own feelings of love affection connectivity those are massively influencing in the way that our genetics are expressed and this is one of the big problems that I have with some of the genetic testing and I'll talk about this a little bit later when they tell someone you have BR a c1 gene the breast cancer gene I'm of the opinion that enormous number of these genetic diseases are only a disease if the proper epigenetic or environmental triggers are flipped and virtually no money and very little education goes into that fact and another fact that is completely missed and I will talk about that later that frequently people with these deleterious gene defects actually show evolutionary advantage they tend to be helped earlier in life they have more kids they fight off other infections and it just happens that some of this benefit may become problematic later in life if we don't do certain things correctly but the whole way that this thing is couched is of doom and gloom and and oblique understandings and I really think that this evolutionary framework can can help shed some light on stuff so historically we hunted and we gathered and there's very little controversy around that we were incredibly active pretty conservative estimates but that most humans walked at least about 6 to 10 miles a day just in their general activities and they lifted and sprinted and climbed and did all number of other activities but it was a pretty active life way today we literally and I I work from home like it can get bad I can sit in my underwear type on my computer order food to my door if I want to get crazy and go like the colostomy bag thing I can really save some time but you know I mean and instead of walking miles a day I can literally walk hundreds of steps and it is crystal clear now that sedentism is is as significant an issue with regards to health as smoking and this is really an amazing paper by Frank booth in his lab it's called exercise and gene expression physiological regulation of the human genome through physical activity it said they start off by asking the question what is the normal human phenotype what are we normally supposed to look like and when we dig around in pre-agricultural societies and in folks that live closer the earth and they're very active in the whole unprocessed foods they look kind of like professional athletes we are supposed to be essentially professional athletes tend to be lean strong good cardio nothing super crazy by modern performance standards but nothing really to laugh at either and this was the norm this is assumed to be the norm this is the norm of every other active animal on the planet we don't have bears and cheetahs and lions that look portly they look lean and athletic the only other animals on the planet that look portly are our pets so here's what's going on with this they make a model in which physical inactivity silences certain genes that are supposed to be favourable heightens other genes which may be negative and we get an inhibition in what we would consider favorable expressions of proteins and this is a genome-wide thing and I'll talk about that in just second but it reaches a threshold of negative signaling that eventually leads to pathology and it's a I used to do gene microarrays it was super boring work but they're kind of cool you basically can map every protein that's being expressed within a tissue or the body and what's really fascinating is you exercising you if we did a map of all the proteins that you make basically the genes that are turned on and off and then we did a map of sedentary you you are literally a different person you are not the same organism at all and the the basic argument that these guys make is that we just we hit some threshold and some people have better thresholds with this than others we all know someone you know like an uncle Fred they drank a bottle of gin a day and smoked and chaste women till he was 90 that's not me I would be dead in my 30s I came from the shallow end of the gene pool in that regard I would not handle that well so there's differences with everybody but there's a basic trend here that there is some basal need for activity that helps keep us healthy it's just woven into our genes it's baked into the cake now it in the I'll back up a little bit the exercise piece when we talk about this evolutionary biology ancestral health hunter-gatherer type thing even within medical circles is very uncontroversial we're like yeah ok I totally get it when we talk about what they actually hunted and gathered all hell breaks loose so I love this thing so yeah this is just so incredibly contentious and controversial and it's really pretty crazy here are the basic principles of a paleo or ancestral diet in general and I'm glad to fill in some details here in general it was Green legume and dairy-free not a hundred percent there's you know it they will find oh the Sun Bushmen were using a type of bean okay fine you know but this is the general deal they weren't getting the bulk of their calories from that they got the bulk of their calories from seasonal local fruits vegetables roots and tubers lean wild meat fish fowl and seafood nuts and seeds macronutrients varied with the seasonal locality if you live in a far northern climate in the winter you're not eating bagel type stuff there is no Begley type stuff around you're eating protein in fact because that's all that's there at that point so the the macronutrients protein carbs fat cycled with season cycled with location and it all had to follow this thing called optimum foraging strategy which you never want to talk about optimum foraging strategy in a state that receives funding for bio ethanol because it's the same story you got to get more energy out of the system than what you put into it or it fails and so optimum foraging strategy is basically the story of living as a hunter-gatherer which a guy about my size would have burned about 4500 calories a day being a hunter-gatherer and females are right in there it's its body weight match but we were very active we had to get our total caloric load from meat and vegetables nuts and seeds some fruit little starch no sugar and so there's some implications there about what the ancestral diet looked like and we understand that our ancestors were as robust as they were because of skeletal analysis we can see the the bone structure and particularly the muscle insertions are huge these people were built like professional athletes they were very very very active interesting Neanderthals and Homo erectus were way more robustly built than we are we started developing more culture in using our brains which allowed us to expend less physical energy to be able to do things but we were still no slouch our immediate ancestors were quite robust they ate a lot of food and these were the general things that they obtained that from and this is a great paper from Loren Cordain plant-animal subsistence ratios macronutrient energy estimations and worldwide hunter-gatherers and if you guys are interested in all the references for this I can put them all together and pin him to Kin and then he can email them out to you so super easy list so here's what I'd like to propose this kind of a way that we can move forward and it's the way that my research group has been tackling different different topics and something that I would encourage everybody to to use as a way of looking at things I'd really like to start this story from this anthropological observation when we have a problem let's start from anthropology and history and see if we can find any any insights into it and then we can start moving forward in epidemiology the study of populations is the next bridge to that where we can start asking some questions of that ancestral kind of story see if we can find some epidemiological support we can move that into clinical work both animal and human models and then we should be able to get some sort of a mechanistic validation of the process but we start this again with that anthropological observation we use this evolutionary medicine to ask the why then we start plugging it into our really powerful robust question and answer process of of modern medicine but I I'm arguing and I hope I'm not redundant but I also hope I'm clear on this that we generally are most of our research in my opinion we aren't even asking the right question we haven't even set the right stage to be able to get the types of answers that we need so I'm gonna walk you through how we can use this process to delineate some of the diseases of modernity mainly dis lipedema metabolic derangement and also autoimmune disease I'm going to show you how we can deconstruct that using this type of model so we're going to go from clinical observations to molecular mechanisms we're gonna start with the Kitab ins the gentlemen on your left is a hundred-year-old Katahdin they live near Papua New Guinea they're hunter-gatherers transitioning into horticulturalist but they live effectively without modern conveniences for the most part the the other guy is being measured by Stefan Linda Berg who's an MD PhD at the University of London in Sweden he and his family have lived in and among the Kitab ins for off and on for about 20 years he brings his whole family down there and they run these studies on them and this is where he has actually done autopsies on some of the Kitab uns so they had some really amazing data on these folks and he did this thing called the Catawba diet not surprisingly and I love the Catawba and story because it pisses everybody off I in one drop I'm able to make everybody in the room mad because the diet just annoys everyone so the traditional diet is yams taro bananas fish pork and coconut the macronutrients are about 60% carb 15 to 25% protein and then the remainder is fact the primary fat was saturated fat so I love this so if you're one of the low carb jihadis and you think the carbs are going to give you diabetes overnight then you're you you are horrified at a 60% carbohydrate diet if you are out of the t : Campbell Forks Over knives fantasy then these guys should have cancer out the wazoo and then if you buy into the American Heart Association idea of saturated fat being being you know Satan itself they should have cardiovascular disease late like you cannot believe and we see none of that they are completely free of Western degenerative diseases until they start eating modern food now what's really interesting about this is that the macronutrients didn't change the amounts of protein carbs and fat didn't change but the qualitative nature did now probably the last 50 years the United States in particular has been in this thing called the macronutrient Wars is it a high carb diet is it a low carb diet which one's better and I think that that has been one of the largest red herrings that we've ever had because if we're eating a largely whole unprocessed what we would call ancestral diet I would say in general it just doesn't matter unless you are metabolically broken in which case I would argue that a lower carb diet is probably better but that's kind of a topic for a different different discussion but uh what they noticed was that there was no real change in caloric content no real change in macronutrient ratios but as they started eating westernized foods they started getting sick and so Stefan Lindberg formulated this idea he had an idea about what might be at hand in this problem and he thought that the change was a shift towards grains and grains had these anti predation chemicals on them that dissuade animals from eating them and they tend to cause a lot of irritation to the gut gluten is a pretty good example in wheat rice has a stuff called zine corn has a protein I would say corn and rice or much less problematic across board gluten being pretty problematic but he he basically asked this made a couple of statements and then asked a question made the statements foods are appropriate for any given species if they were regularly consumed during most of its prior evolution plants protect themselves with bioactive substances directly aimed at animals substances which may have untoward effects on long-term human health basically everything in biology has horns and thorns or teeth or poison to protect itself if it doesn't it's a snack and that that's all there is to it the Luther Burbank of our fruit and vegetable supply dramatically decrease the bitter toxic ins which used to be part of our fruits and vegetables we made them larger and sweeter and and now they're much more prone to pass interestingly so he asked this question agrarian diet and diseases of affluence to evolutionarily novel dietary lectins cause leptin resistance and make sure I've got all my if I can drag this up here I do have a few notes I like to pull off so yeah the lectins are interesting we'll talk about lectins and left and it's really unfortunate that they're almost the exact same word lectins our sugar binding proteins their cell surface identifier is like when we do a tissue train organ transplant and it gets rejected it's essentially lectin type molecules that alert the immune system that there's a problem they're used in some therapeutics situations banana lectin has been found effective in certain strains of HIV one but some are pathogenic ricin is a main constituent in nerve gas and that is derived from the castor bean so there are our Bruce Ames the father of modern toxicology makes the point that all of nature is toxic it's just dose and how well you're able to clear that dose now leptin is a adipose derived neurohormone it basically tells us when we're hungry it fluctuates in response to body fat levels if our body fat levels are very low then leptin should go up making us hungry and if body fat levels are high it should go down letting us know we're full it kind of operates over the long term but what happens when we chronically overeat when we get chronically inflamed from poor sleep and poor diet and also because of the biological activity of some of these lectins they can actually bind to the leptin receptor and make it not work so we could actually be full of food yet still hungry and that's a problem let's see here did I get all that stuff inhibits appetite regulates insulin sensitivity so leptin resistance tends to preclude insulin resistance so the way that they tested this hypothesis pretty pretty slick so they started off with an epidemiological study they had a hypothesis based off of anthropological observations and they tested 200 kitab uns and 200 swedes make sure my notes on that or right yeah and they discovered large differences in certain leptin levels between westernized and non westernized populations cassava study basically the the Kitab ins had super low leptin levels so low that no one representative lee was found to have the same type of levels in age and gender match population of swedish folks so the Swedes were already leptin resistant relative to the ticket ovens now begs the question why why why was there a difference there and the implication would be the population with the high leptin levels is probably leptin resistant and therefore prone to overeating type 2 diabetes and a host of other issues so the next one was a animal study and I was actually the review editor for this Paleolithic diet confers higher insulin sensitivity lower c-reactive protein and lower blood pressure than a serial based diet and domestic pigs so they basically fed meat fruit veggies roots shoots tubers to some pigs and then they fed what would be considered a pretty darn good Mediterranean type diet whole grains low fat milk sand protein sources and what they found was that the Paleo group had much lower c-reactive protein which is a sign of systemic inflammation they lost excuse-me significantly more weight they had better phase 2 insulin sensitivity which what that means is that the muscles themselves were insulin sensitive in this Paleo diet group and they were they were otherwise calorically matched so they're eating the same number of calories approximately the same amount of protein but there was something different there one group had grains and legumes the other one basically had meat fruit root shoots and vegetables and really of importance there was no pancreatic leukocyte infiltration leukocytes are a white blood cell when they infiltrate the pancreas that is oftentimes the beginning of type 1 diabetes and we're going to see how this process leads into autoimmune disease here just a little bit so further testing this hypothesis they did a Paleolithic diet in humans Paleo diet improves glucose tolerance more than the Mediterranean type diet and individuals with the scheme ik heart disease so these were people who had existing heart disease and or were already type 2 diabetics they put one group on a Mediterranean diet one one group on a paleo type diet the the black dots are the pre the white dots are the post this is the Mediterranean diet with about a 3% improvement in the oral glucose tolerance test barely statistically significant this is the Paleo group all the members of this group and there were only about 14 people in each side so not a huge sample size but the people in this group were effectively no longer type 2 diabetics and they were each allowed to free eat the diet so they were basically given a buffet type deal that they had to weigh and measure the food and track that but but they were essentially free eating folks but pretty powerful change and I would have assumed so you can order this stuff out I think it's very logical to order this out if you're eating a complete junk food diet and then you shift to something that looks even like not that great of a Mediterranean type diet but you know to kind of emulates it I would expect better results than that I was actually shocked by that just shifting towards Whole Foods but again it's pretty pretty interesting so here's where we are everybody still there anybody need coffee okay hang in together okay so we had a conspicuous lack of cardiovascular disease within this anthropological data we asked why we went into a epidemiological study the Swedish versus Katahdin study the Swedes had very high leptin levels which was interesting but still doesn't answer any questions so we started moving into some animal and human models and we still see some consistency we see some consistency that this Paleo diet that seems to be lower in immunogenic proteins lower in these proteins that plants use to defend themselves people seem to be doing better on this theory they're spontaneously eating less or they have less inflammation or a combination so we're into the animal and human model and now we start getting into some of the mechanistic testing this stuff might get a little bit thick but I'll try to uh to go go through it in a pretty reasonable way have you guys seen Eliseo Fasano he's been here multiple times amazing guy he he and his lab really elucidated the the mechanism behind silly AK disease which is an autoimmune disease triggered by the gluten or gliadin protein I won't go into super deep detail on this but essentially in in susceptible individuals the gluten protein interacts with epithelial cells causes a release of interleukin 15 and Sanyal in this opens up the tight junctions do you want your intestines opened up with poop all around it no you want to keep your poop or tits yeah that's bad stuff so what happens is large intact food molecules make their way into the into the interstitial area and we have a ton of the stuff called tissue transglutaminase it's in essentially every cell and it modifies just about every protein that is manufactured in every cell or tissue of our body okay it has a tendency to glom on to that gluten particle and when they stick together then our immune system recognizes as if for as a foreign invader and attacks it so now you've got immune system activity against a protein that is in every one of your cells and is critical in making just about every damned protein you can make could that potentially be a problem yes there's eight different isoforms of tissue transglutaminase regular medicine tends to test for one sometimes two but this is one of the absolutely heartbreaking elements of this silly AK non-celiac gluten sensitivity story is that it sounds like the person is crazy because everything from neurological symptoms to bowel function to bone issues is occurring but we have a really well-documented mechanism for why that is likely to be and you can easily dig up literature that tends to support this idea but this whole leaky gut process appears to be necessary for autoimmune diseases to occur there's other factors but this this is part of what is it has been but forward I just wanted to throw this out really quickly this is again so sometimes when people hear that someone has celiac or gluten intolerance they say oh it's kind of perceived as a weakness the reason why people react to gluten and and gluten like particles is because their guts are more on alert for infectious agents people who have celiac or are prone to celiac tend to get fewer gut infections so it's a trade off if you have really really strong immune response you may not get many infections you may not get cancer but you may very likely die due to autoimmune disease if you have a very dialed down immune response you might die from an infection you're never gonna get out of immune disease and you could develop cancer so it's a balancing act it's a trade-off but I I pulled this one up this is just a paper talking about the comparative evolutionary advantage of the celiac gene loci because it seems to confer selective advantage in situations where you're exposed to a lot of infectious disease and it seems to developed right when we started living in cities and doing agriculture so we went from being exposed to not a ton of other people and other animals to a whole lot of them okay not everybody gets silly AK disease but all greens have prole amines Broll amines are these protein rich proteins which are very difficult to digest all of them use of these proteins has storage agents all of them are very very difficult for the gut to digest we do have Prolia lindo peptidases but those are within our synapses they do not we don't have anything in our gut that really hydrolyzes these types of proteins very effectively so they can be very immunological a challenging and all kind of build a story forward on that I hate reading things off of these but there's a few of them that I'm gonna have to do it because they're kind of long dietary intake of wheat your greens and the roll and inflammation and this review we discuss evidence from in vitro and in vivo and human intervention studies that describe how the consumption of wheat but also other cereal grains can contribute to the manifestation of chronic inflammation and autoimmune disease by increasing intestinal permeability and initiating a pro-inflammatory immune response so the take-home from this we have great data suggesting that in just about everybody if they consume wheat or wheat like substances we can see increases in gut and systemic inflammation these folks not everybody reacts the way of celiac does not everybody has the same degree of problems but we can see some pretty good inflammation from from ingestion of these foods tight junctions intestinal burn permeability in autoimmunity this one is is really one of my favorite papers there is growing evidence that increased intestinal permeability this is when the gut gets damaged plays a pathological role in various autoimmune diseases including celiac disease and type 1 diabetes therefore we hypothesize that besides genetic excuse me and environmental factors loss of intestinal barrier function is necessary to develop autoimmune disease now just as an aside I don't want to give away the the punchline at the end of the story but we've had huge success within this Paleo diet community at addressing various types of autoimmune disease and its really the reason why it didn't go Atkins or zone or something like that and why we have a significant number of research institutes that are actually poking around this stuff the the gut an autoimmune story is really really powerful and what's interesting though when you start looking at cardiovascular disease it's kind of autoimmune when you look at neurodegenerative disease it's kind of autoimmune so we have a really interesting kind of dovetailing of a lot of different issues I'm just gonna common causes etiology of autoimmune disease infection geography folks that live at higher latitudes because of low vitamin D levels and it's not just the vitamin D it's the whole seco steroid cascade of manufacturing vitamin D that seems to modulate the immune response so you guys live in Florida I live in Reno we live there because of the Sun and we we benefit greatly from that physical trauma like a crushing injury can also release a lot of proteins in the circulation which can stimulate autoimmune process but all of these things can be in place but absent intestinal permeability at some level and it appears that the individual will not develop autoimmune disease you need some sort of intestinal barrier breakdown in addition to these processes to get that to happen vaccinations are are interesting some of the adjuvant slike cool AHA is is a product that's used in root beer is an immune system stimulant some people really get weirded out that the idea that nightshades like tomatoes could potentially be immunogenic but alpha tomaten is used in certain vaccines as an immune system adjuvant so again we don't have button type perfect randomized double-blind gold-standard trials but from a mechanistic perspective could tomatoes cause an immuno genic effect well are they used in vaccines yes why to cause an immuno genic effect so we don't have a button up it's not perfect but it's at least worth looking at you wouldn't believe the anger that some people throw at this stuff even though there's a credible and maybe it's wrong maybe that's not the issue but maybe we you know it's worth turning that rock over and looking and it really wouldn't be that hard okay so dietary factors those are the folks that cited all that there's a huge list so I kind of gave up looking every autoimmune disease that I have looked at so far and looked for a intestinal permeability linkage I have found it now correlation doesn't mean causation but it starts getting really you know there's some pretty strong suggestion there so what we've been talking about thus far is the potential of the oolitic foods via immunogenic proteins leading to intestinal permeability and potentially autoimmune disease now we're going to kind of split a little bit and look at how Neolithic foods with immunogenic proteins could potentially leave the gut permeability in insulin resistance leptin resistance diabesity so it's it's a kind of a way that we can we can arrive at this same spot or different spots with the same input which again is very hard to pin down when you're doing that our standard type of medical research because it's one disease one problem and that's not always the case so we're gonna look at gut permeability and metabolic syndrome metabolic syndrome is defined as elevated triglycerides decreased decreased HDL cholesterol insulin resistance and hypertension elevated blood pressure Jerald reven kind of figured this stuff out in the the late 1980s he works with our clinic and reto really amazing guy but here's some interesting stuff walk you guys through this if you missed your hepatology vol 49 issue six I've got it right here increased intestinal permeability and tight Junction alterations in non-alcoholic fatty liver disease conclusions a results provide the first evidence that non-alcoholic fatty liver disease in humans is associated with increased gut permeability in that this abnormality is related to the increased prevalence of small intestinal bacterial overgrowth bacteria growing in the wrong place at the wrong time in these patients the increased permeability appears to be caused by a disruption of intracellular tight junctions that was the story with the gluten peptides and whatnot in the intestines and it may play an important role in the pathogenesis of hepatic fat deposition do you know what one of the fastest growing morbidity mortality z' among youth is currently non-alcoholic fatty liver disease necessay ting a liver transplant as kids are developing fatty livers and dying from it because there's inadequate transplant and this is completely dietary driven and will we should have some pretty good ideas about how to to address this so now there's this stuff called lipeh polysaccharide and this is gets a little technical but this is about as technical as we're going to get has anybody heard of when going into septic shock yeah so what happens are these things gram-negative bacteria and they release these these molecules some of them called LPS lipopolysaccharide and we don't know why but every vertebrate species on the planet if they get lip a polysaccharide in their circulation that organism freaks out it goes into hypovolemic shock blood glucose shoots up fatty acids are released it just goes crazy and it's a really consistently conserved process across all animals all vertebrates but what lip a polysaccharide does is it activates an innate immune system response in human adipose tissue it basically it so the take away from their results again our suggested results suggests that type 2 diabetes mellitus is associated with increased endotoxin iya basically they're saying if we look at type 2 diabetic individuals we see elevated levels of endotoxin via elevated levels of intestinal permeability elevated levels of LPS so again correlative not causative but let's build a mechanistic story for how that how elevated LPS could actually bring about that state of metabolic derangement sepsis induce changes in pancreatic hormone secretion extreme insulin resistance tempeh Phi's the septic patient septic patient and a poorly controlled type 2 diabetic if you have them side by side you really cannot tell them apart for most of lab work they look almost identical and the reason why is that the sepsis state is causing essentially an uncontrolled type 2 diabetics phenomena Journal of leukocyte biology insulin resistance characterizes the septic patient and seems that the balance between insulin and it's counter regulatory hormones cortisol glucagon and growth hormone is perturbed in the metabolic response to sepsis during type 2 diabetes typically we are overfed and we are awash in energy the person is usually overweight but yet they're hungry and without an insulin dose to bring the they're glucagon back down glucagon insulin tends to put nutrients into the liver and into ourselves glucagon causes a release of fats and glucose out of the liver and out of the body but in the type-2 diabetic they have tons of energy but the brain and the liver aren't communicating they think they're starving so the body ramps up the release of glucose out of liver and this is where blood glucose levels can get six seven eight hundred it's not from dietary sources it's from our own liver because the communication is broken and this is what's happening in the septic environment it seems that one of the metabolic problems during sepsis is an inability to use free fatty acids as a metabolic substrate this is very common in elevated insulin levels the livers function is a regulator of glycemia is also disturbed as a result of hepatic insulin resistance this results in increased hepatic glucose output what we just talked about where you can get a blood glucose level of 600 and not eat a thing because it comes out of your own your own liver initially as a result of glycogenolysis but later from gluconeogenesis the conversion of proteins into into sugar basically it's gonna be a little crude but have you noticed that folks that have type-2 diabetes they don't have much backside fact two diabetes is a wasting disease it's a wasting disease because during blood sugar lows the body looks for anything it can can tab allows anything it can eat to turn into glucose and what it does is catabolize as the muscle mass what do we usually store within our muscles glucose so as this diabetic that can't control their blood sugar loses their muscle mass they have less and less ability to store glucose and it gets worse and worse do y'all remember the video of the Tacoma Narrows Bridge old suspension bridge wind would blow over it would shake it hits a resin in some point and then everything breaks and this is where the wheels fall off the wagon muscles become insulin-resistant free fatty acids are released by the adipose tissue and this again is while everything is already really high we have tons of energy circulating we don't need any of this to be happening but this is what happens in both the septic State and in the uncontrolled type two diabetic State the liver perceives low blood sugar even though it's high because we're insulin resistant cortisol is released because if we're on low blood sugar then we were stressed so we release cortisol the cortisol releases the lipids and glucose further elevating the problem inflammatory signaling ramps up so everything that leads to after school or on ecclesia –nz immune suppression is ramped up high levels of blood glucose free fatty acids and tissue insulin resistance ensue the liver becomes backlogged with glucose and glycogen non-alcoholic fatty liver disease synthesis of the LDLs increase these this leads into the small dense LDL lipoproteins that are very atherogenic they like I said the VLDL de pattern be cholesterol systemic inflammation increases appetite signaling is lost so during all this process people are awash in nutrients but yet they're still hungry ravenously hungry blood Sugar's swing from high to low fat cannot really be adequately accessed for fuel because we're so profoundly insulin resistant so a dis lipedema and inflammation and evolutionarily conserved mechanism mm-hmm inflammation leads to changes in lipid metabolism range at decreasing the toxicity of various harmful agents tissues repair and tissues repaired by redistributing nutrients to cells involve with host defense acute phase response is mediated by cytokines these are chemical messengers that all of our cells release preserves the host from acute injury when the inflammation becomes chronic it leads it might lead to chronic disorders such as atherosclerosis and metabolic syndromes so what this paper is talking about this is LPS this is that gnarly stuff that comes off of a gram-negative bacteria like e-coli when that gets into circulation it raises all kinds of problems but it's really interestingly ldl-cholesterol everybody's called LDL cholesterol the bad cholesterol it raised familiar with that LPS binding protein circulates an association with a PO B containing lipoproteins and enhances endotoxin the LDL LDL interaction let me show you this so if LPS enters the system and is able to connect itself to an immune cell then it creates a feed-forward cascade of inflammation that leads into non-alcoholic fatty liver disease and a whole host of problems it's really really nasty but if LPS binds to lipoprotein binding protein and then that's get gets taken up by either an HDL or also LDLs can play a role in this then the LPS is effectively neutralized and here's an interesting side note people with high cholesterol levels who develop infections or sepsis are much more likely to survive those events than people with low cholesterol now it begs the question what's what's the right range to have and there's a whole host of factors on that but I want to I want to throw one piece out here that is really interesting my clinic mainly does lipid ology I'm not a lipid ologist but I help them on some of the functional medicine stuff I think if you get a blood test and it just has HDL LDL total cholesterol and triglycerides it is almost worthless what it will do is confuse you and it will not answer a damn thing that is a value in my opinion it is a borderline negligence at this point okay so we have two people that could look identical we've got an LDL C LDL cholesterol of 100 L DL cholesterol of a hundred the cholesterol is a passenger the LDL particles are the vehicles that they drive around in okay so we could have an LDL C of a 100 ldlc of a hundred if we have large fluffy vehicles we can carry a ton of cholesterol but have very few vehicles on the road if we have small dense vehicles zipping around we could have the same cholesterol number numbers but the particle count here could be a thousand the particle count here could be three thousand okay now from are these are the things that circulate in our vascular debt now we'll do a little thought experiment if we were just driving Vespas around the closed loop and we had a hundred of them on the track or 3,000 of them on the track which situation might more accidents and chaos occur the gradient driven process and that's not the whole story but there are a ton of people that look like they have high cholesterol levels but they have low lipoprotein talent conversely and this is particularly true in police military and fire and shift workers these people will look like they have low normal cholesterol levels but they have the sky-high lipoprotein count these are the people that die from a heart attack at 35 or 40 this is the triathlete firefighter who's been doing shift work for eight years and dies of cardiac event and the standard blood work is failing these people in a simple lipoprotein count like what they do through LabCorp and and a few other people are doing can discover this immediately and we can do immediate intervention both dietary and pharmacological to to send that thing in a different direction so back to the endotoxin eeeh really quick has everybody heard of metformin it's a glucose lowering drug it's really interesting because not only does it lower glucose it also repairs the gut metformin prevents endotoxin induced liver injury after partial hepatectomy basically they remove part of the liver and gave these animals metformin and reduced the amount of inflammation that they would have received from the LPS exposure so metformin is really interesting in the it addresses elements that we would see in elevated blood glucose by sensitizing the muscles by lowering glucose output in the liver and it also heals the gut it minimises gut permeability so it's addressing multiple factors within the the mechanism of metabolic derangement let's see here we're getting close I promise so so what I was trying to drive at here is that certain proteins can have pharmacological activity within our bodies okay and the extracellular domain of human leptin receptor contains 20 glycosylation points 20 binding points that we found that mammalian cells exposed to concanavalin a or we German gluten in it it bound to the leptin receptor site so this is my long circuitous way of getting back to that question of Candy's and Neolithic foods these evolutionarily novel foods epidemiologically we seem to have some suggestion that they're a problem we have some interventions on both an animal model and a human model but then the question was well are these things even biologically active do they produce a pharmacological activity and they do I'll share one more with you gluten X orphan b5 stimulates prolactin secretion through opioid receptors located outside the blood-brain barrier gluten X orphan B fight is a food to ride opioid protein identified and digests of wheat we've recently shown that GE b5 stimulates prolactin secretion through opioid receptors outside the blood-brain barrier since opioid peptides do not exert the role on the prolactin secretion directly but we have reduced dopamine energic tone our data suggests that G eb-5 can modify brain neurotransmitter release without crossing the blood-brain barrier so it has pharmacological activity it has pharmacological activity both inside and outside the brain so this stuff can affect any organ any system and this kind of brings us back around we started with an observation we got into clinical observations work towards a mechanistic theory and I feel like we have a pretty solid mechanistic theory here but comparison with ancestral diets suggests dense a cellular a hydrate process carbohydrate promotes an inflammatory gut microbiota everything I just told you about lectins I think it's true but there's another layer to it which is that if and when we process our carbohydrates it causes the virtually same responses that we just looked at particularly on the small intestinal bacterial overgrowth not necessarily with some of the elements of specific proteins activating like the prolactin receptors and things like that but my point here is that asking these questions are great we can build our way forward but then we get slammed wet fish across the top of the head with something like like this paper that looks very very similar and very synergistic to what we're talking about but it's also pretty consistent with what Stephan Linda Berg's original contention was was that westernized diets were somehow problematic and it's that refining of the carbohydrate that is likely a big issue and one one quick final thing I just pulled this up there was there was a day in time when anybody doing any type of illogical research looking at gut permeability if you suggested gut permeability they were last out of town that's in this any computer you put it on you you get this pulled up that's it's the hottest area of immunological research anything else huge nope because ken is telling me I am out of time I'm gonna tell you really quick really really quick when I got to got to Reno Nevada I started working with a clinic they were right at the end of a two-year pilot study we had 33 participants the program cost $1,000 per purpose participant we found cops and firefighters at high risk for type 2 diabetes and cardiovascular disease gaddama Paleo diet modified their sleeve got them exercising it's best we could the program savings are estimated to be twenty two million dollars per rated over ten years not 20 with a very conservative 33 to 1 return on investment now I'm going to do a little whining bit here I spent five years trying to scale this thing and turn it into a company that was going to change healthcare but because of the structure of the Affordable Care Act it doesn't work and so I am pissed okay thank you all for coming ibis I have a story behind cows eat grass if you want to talk to me about that then we'll talk later okay thank you little over okay so question and answer I believe gentleman up here thank you it's been reported that 75% of sad or the standard American diet is Pro chronic inflammation many of us are trying to minimize that with probiotics the word is now they're pro bodies just don't escape the gastric juices and really ineffective but I see that your recommendations are what they call a pre probiotic we can talk about that please yeah and you know I I think that probiotics are probably still beneficial there's a couple of products like prescript assist that they use HS o s homeostatic soil organisms these are our organisms that actually make cysts and they live out in the soil and this is what we would have been eating normally and they've found a lot of these to be pretty beneficial for different gut issues by eating fermented foods a variety of non-digestible fibers like resistant starch and then rotating through probiotics I think is a fantastic way to to shore that up yeah hey Rob before we go to the next question as the talk ends we only have a few more questions we should head out the door up here where Alan is because we've got a lot going on back here right now and we'd all be sort of in the way so we should go out where Alan is standing up there it'll take us an extra minute to get out but it'll it'll help people back here we have one here during the break alright interruption I asked Rob I'm I'm currently getting metabolic panels and CBC levels tested what should we ask for from our primary physician for blood work and Rob suggested the LP PC and that was the lipoprotein particle count and that I'm not sure if my physician would know how to read it if I asked for it but I think we're hearing that we need to go back and ask for that to be part of our blood panel absolutely that should absolutely be part of your base blood panel and probably in five years it will be standard of care because the current bloodwork they're putting people on statins it shouldn't be and then there are people who should be getting intervention who are not and I think this gentleman right back here I've read I've read books and articles that claim depending upon your blood type it should determine what foods you eat does that have any basis in reality I'm gonna answer that indirectly with a weird observation that the palm reader in Chico California where we used to have our Jim it didn't matter whether it was an economic implosion or explosion she was always in business gentlemen back behind there right it's changed a lot it's changed a lot well I mean like the clinic that I'm on the board of directors of in Reno Nevada we do work with police military and fire all over the world we work with the local community and we are an evolutionary medicine clinic I mean that's what we do and so even and it was crazy I showed up in Reno Nevada like wait would I had no idea those guys were there we my wife and I were gonna stay in Reno for a year and then I got hooked up with them and I've been working on this project since then the Cleveland Clinic is now training all their doctors in in functional medicine which essentially the dietary protocol is an ancestral type diet which isn't necessarily high carb low carb but it's it's thinking about it potentially immunogenic foods that could cause problems and then match things to you appropriately and is the gentleman still here who asked about the the blood type deal or did I chase them off oh you're still here I didn't mean to totally brush that off but it there's not a lot of science behind it yeah yeah sorry yeah yeah and did I sew it so it's much better it's an entirely different environment and again you know it's really growing exponentially the biggest challenge I found after my book was a lack of practitioners and I spent a lot of money creating a website called the Paleo physicians Network just as a clearinghouse to try to get patients and practitioners together and and it was pretty good but now all that stuff has taken off one more question one more gentleman over there sorry sorry you're close I'll grab you as we go out there's overwhelming evidence that introducing newborns and infants to a wide variety of bacteria and bacterial toxins improves gut health and immune response can we not say the same about food there's certainly evidence that maybe we should be introducing a wide variety of foods earlier and again for the same reason yeah you know it's it's interesting so there's some suggestion the early exposure to wheat or wheat like products dairy or soy can mitigate the risk of allergies and and type 1 diabetes but there's also indications that avoiding exposure to these substances completely negate the likelihood of developing type 2 type 1 diabetes later this this childhood onset diabetes I have no idea what the story is with that there's so many moving parts we've got a genetic component the epigenetic component of the guy and then the epigenetic component of the actual food and I have no idea what to to make of that with my own daughters I've generally they've eaten pretty much paleo we do a little bit of gluten-free pizza here and there I've largely fed them gluten-free part of the reason is that if I get a gluten exposure whatever bathroom might hit is going to be bricked over decommissioned you'll need a priest like it's done it'll never be used again and so I don't want it in the house but when they've been out to eat with friends they've gotten some exposures here and there and it doesn't seem to bother them but it didn't bother me as a kid it really destroyed me after I caught Giardia and Central America and then it really turned on but I mean it's a great question and I don't think anybody has good answers yet on it at all ok I think that's it image thank you

12 comments

  1. Great talk!

    Although, I think Rob is mistaken about leptin here…
    Leptin is a satiety hormone that makes us full, so everything he says here is the opposite of the truth.

    Am I the only one that's picked up on this? Or am I wrong?

  2. I love the fact that Robb Wolf emphasizes the evolutionary paradigm as the ultimate model by which all assertions in biology should be measured. I wish this was something that was taught in more K-12 science classes. Unfortunately, religious literalists are the major road block to getting this seminal intellectual framework in place in our institutions of learning. Think about how many more future scientists, if they were taught to think about biology and human health from an evolutionary perspective at an early age, would come up with better treatments and cures for many of the maladies that afflict us. Thank you Robb for being a voice of reason in a desert of religiously inspired ignorance – ignorance that has dire consequences for humanity.

  3. This is all chicken and egg stuff. Which came first? I'm going with microbiome imbalance due to industrial diet being the origin or source that then manifests in multiple different ways that are all interrelated.

  4. Thanks.  If you are
    using ketogenic nutrition, and are weak and underweight, what is the best way
    to gain strength and weight?
    Love

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