 Welcome to Ancestral Health Today. Evolutionary insights into modern health. Welcome to Ancestral Health Today. I'm Todd Becker. We're talking today with Professor Pedro Carrera Bastos. And Dr. Bastos is a dietitian and researcher affiliated with the European University of Madrid in Spain and Lund University in Sweden. At Lund he studied and collaborated with Stefan Lindberg, the principal investigator of the famous Katava study. Pedro lectures extensively on health-related topics worldwide and has co-authored influential papers such as The Western Diet and Lifestyle in Diseases of Civilization and Chronic Inflammation in the Ideology of Disease Across the Lifespan, which was the most cited recent article in the influential journal Nature Medicine. Pedro has presented at the Ancestral Health Symposium most recently in 2022 he spoke on the Katava study, which we'll get into today. Today's discussion is going to be broad-ranging, covering the inflammation process itself, the role of inflammation in health and disease, what we can learn from studying traditional populations like the Katavans and Pedro's specific recommendations for how you could reduce the risk or the level of chronic inflammation through diet and lifestyle. And I hope our conversation will get you thinking. So, welcome to the podcast, Pedro. Thank you very much, Todd. It's a real pleasure to be here. So, Pedro, this term inflammation, it gets thrown around a lot in the popular media. So, maybe you could start by giving us a definition of how you see inflammation and how the inflammatory processes function in our bodies. Certainly, Todd. So, inflammation, I think it can be defined as a fundamental biological process initiated by the immune system in response to pathogens, tissue damage, toxins, and various other insults. So, this is a complex response that involves a series of biochemical and cellular events aimed at, first of all, eliminating the of an agent, such as virus and bacteria, for example, clearing out damaged structures and also, and very important in very often forgotten, establishing the necessary conditions for repair. So, typically, the inflammatory processing responds to an infection or an ankle sprain, for instance, is characterized by increased blood flow to the affected area, to increased permeability of blood vessels, and the migration of immune cells from the bloodstream into the site of injury or infection. In these immune cells, primarily white blood cells, such as neutrophils and monocytes, play a very important role in neutralizing pathogens, removing debris, which is basically garbage, and initiating the healing process. So, we know that inflammation is a very important response that not only heals, but can also enhance our tissue defenses. For instance, when faced with inflammation, certain tissues like those in the intestine and in the airways increase their mucus production to better protect us against invaders. Additionally, we know that inflammation can induce protective changes in tissues to prevent them from further damage or future damage. A good example is the inflammatory response to exercise, such as resistant strength, for instance. We know that inflammation adds in the growth and strength of muscle cells as a response to chronic exercise. And finally, information can also occur as a natural response to various environmental challenges that can threaten our survival, such as cold or starvation. And indeed, we know that various inflammatory molecules, such as cytokines, can increase thermogenesis, which is heat production, and lipolysis, which is fat breakdown. And this is crucial for managing a cold environment or a situation where you don't have anything to eat for a long time. So, I think that all of these responses that I mentioned can be considered normal physiological process. So, what you're describing, we would call short-term inflammation. Yeah. And you're describing its positive and necessary function in the body, which is very important because I think a lot of people misunderstand inflammation as a bad thing, right? And so, it's great in the short term in these processes that you just described of repair, defense. They're really beneficial to the body. But how can this go wrong? What happens if inflammation is extended? So, as you said, all of this is normal, provided this is brief and provided it's not disproportionate or excessive and is effectively resolved once the trigger of inflammation has been dealt with. But when there is a failure in the resolution phase of inflammation and when we are exposed to multiple stimuli, then in this case, we can have multiple metabolic, hormonal, nutritional changes that can lead to a state of chronic normally systemic and normally low-grade inflammation that although it is low-grade, it can still produce a lot of adverse effects. So, I think that there is a clear distinction between this normal physiological process that I described earlier on and this low-grade chronic systemic inflammatory state that can be one of the causes of various degenerative diseases, so-called diseases of civilization. So, the difference between short-term and chronic inflammation is this just a matter of time? Are we talking going from days to weeks and months? Or how do you make the distinction between the short-term beneficial inflammation and the longer-term chronic inflammation? What's the cut-off? So, it's not just time. Of course, time is an issue, but it's not just time. Because we are talking about something that is low-grade, which means subclinical. And oftentimes, it is not perceived by the person affected by it or by their physician. So, this means that most of the time we don't know that we have this state of low-grade chronic inflammation. Conversely, we can have a chronic inflammatory state that is perceived by the patient because it produces symptoms, which is typically what occurs in certain inflammatory diseases such as, for instance, rheumatoid arthritis, where you have a high-grade chronic inflammatory state that is often, if not always, perceived by the patient and by its physician. And this leads to the treatment of this inflammatory state. However, when we are talking about this subclinical inflammatory condition, in this case, often there is nothing that is done to ameliorate or even prevent it because simply no one knows that this is occurring. So, this is a big issue. How can we know that we have a low-grade chronic inflammatory state? There are, of course, a few biomarkers that we can discuss later on that can perhaps add us in this diagnosis. Nevertheless, they have certain limitations. But coming back to your... And we can discuss this later on. But coming back to your original question, which is, is this just a matter of time or is something else that is different between these two inflammatory states? And indeed, there are various differences. Not only the process is different, so there is activation of the same immune cells. In some cases, there are some other cells that are also activated, but the same immune cells that participate in the acute response can also participate in the chronic response. But the triggers, and here lies a big difference. The triggers are completely different. We are not talking about the toxin. We are not talking about tissue damage. We are not talking about often of an infectious agent. We can be talking about endogenous factors such as, for instance, molecules produced by our adipose tissue. When we have excessive adipose tissue, and especially when we have excessive visceral adipose tissue, this can lead to the activation of various inflammatory pathways that can lead to this low-grade chronic inflammatory state that we are mentioning. Then we can have various exogenous factors such as pollutants, smoking, psychological stress, sleep disruption, circadian rhythm disruptions. Various dietary nutritional factors can also lead to this. So this means that there are multiple stimuli that are not the cause of acute inflammatory reactions but can lead to this low-grade chronic inflammatory state that we are discussing. So the biggest difference is in the intensity. Typically, an acute inflammatory reaction is of high intensity. And also, of course, the time, because if we are talking about a chronic inflammatory state, the name suggests it is a persistent state and also the triggers. The triggers are very different. Triggers are different. Yeah, that's a really key point that you mentioned, the triggers. Although here's an interesting case, viruses, right? That would fall into the category of an acute trigger. But can you also have a chronic viral infection? Maybe this is like the long COVID that people are getting. Does that go over into chronic inflammation or is it just a extended acute inflammation? How would you categorize that? Indeed, as you mentioned it very well. Infections can be both a trigger of acute inflammation and also a promoter of chronic low-grade inflammation. We are talking about a chronic infection. And indeed, there are multiple theories about long COVID. And one of those is that there's simply some, at least some viral material that is constantly stimulating immune cells and producing this inflammatory response. Another possibility is that the infection has led to another immune reaction that can contribute to these symptoms that are categorized in this label called long COVID. And there are also other theories, but I'm not an expert on this, so I won't go into this. So I won't go further down the rabbit hole on this. But indeed, infections can also be a promoter of this chronic low-grade inflammatory state. Great. So you alluded briefly to measures of inflammation. And this can be useful because, as you said, sometimes this goes undetected. It's subclinical. One of the common measures of inflammation would be something like high sensitivity C-reactive protein. There's others like cytokines. What measures do you think are the most useful and what are some of their limitations? So every one of these measures has limitations, especially when they are used in isolation. As you mentioned, we have C-reactive protein, which levels increase in response to inflammation. And when we have high levels, this can indicate acute or a chronic inflammatory state. Then we have very cytokines, the ones that are more commonly used in various studies and also in clinical practice are interleukin-6, interleukin-1-beta, and tumor necrosis factor alpha. But there are others that can also be used. Then we have other proteins such as C-reactive proteins called acute phase proteins. One of those is fibrinogen, and the other one is ferritin. And ferritin, while primarily it is a marker of iron storage, so of our iron status, we know that this protein can also increase in response to inflammation. Then we have another marker that is commonly used in clinical practice, which is erythrocyte sedimentation rate. And this basically measures the rate at which red blood cells sediment in a period of one hour. And a faster rate can indicate inflammation, although this is a non-specific test and many other conditions can lead to an increase in erythrocyte sedimentation rate. And also if we have, for instance, iron overload, this can lead to an increase in ferritin. And there are various other conditions that can lead to an increase, for instance, in fibrinogen. Moreover, we know that the levels of these markers can change rapidly over time, especially the levels of cytokines, which means that a single measurement, and this is also true for C-reactive protein, which is the most commonly used biomarker, especially in clinical practice. So a single measurement may not accurately reflect the state of information over a longer period. So to solve this, it would be better to do regular measurements. And finally, we know that there are biomarkers that may not be sensitive enough to detect these low-grade stage information. And one example is C-reactive protein. You alluded to this in your question when you mentioned high sensitivity C-reactive protein. So we know that C-reactive protein is measured in serum or plasma, and the typical method used to measure it detects levels of 3 to 5 milligrams per liter. We are talking about the lower cut-offs. And this is suitable for monitoring, for instance, the acute high-grade information that occurs when we have an infection or after a surgery, for instance, where the CRP levels typically are above 10 milligrams per liter. However, this sensitivity is insufficient for detecting these low-grade chronic inflammatory states where CRP levels might be below 3 to 5 milligrams per liter. So to use CRP as a biomarker for these low-grade chronic inflammatory states, we needed to use high sensitivity methods capable of detecting very low levels. So this is termed high sensitivity C-reactive protein, which have a detection limit down to 0.1 milligrams per liter. And just to be clear, the optimal CRP levels are below 1 milligram per liter. This is a very useful background. Now, these measures can be used by people doing research, right, who have access to a huge portfolio of these inflammatory markers. How about the individual patient, you or me, going into their doctor, either something we can do ourselves or with our annual checkup? Is this useful for us to get, say, an annual HSCRP measurement just to see how we're doing from an inflammation standpoint or do you find that that's not useful? I think it is useful to measure high sensitivity CRP along with various other biomarkers in order to better grasp what this level may mean. For instance, when it is higher than expected. However, I don't think that just measuring this once a year will be the best approach. I think that measuring this regularly, for instance, once every three months would be a better way to use this as a biomarker for this low-grade chronic inflammatory state. Great. Well, I do actually get this measured myself and it is quite low, so should that give me a false sense of confidence is that should I be looking at other signs and symptoms of inflammation? Well, you should be looking at various other biomarkers in order to know how your kidney function is, your liver function needs, your cardiovascular risk, etc. So although inflammation, in my view, and I'm biased, of course, because I've given a long time to the study of this topic, so I'm biased. Nevertheless, I recognize that this is only one mechanism behind various chronic diseases. So just measuring a biomarker of inflammation should not be used for you to have this sense of confidence that everything is okay. How we'd use many other biomarkers and other measurements that could be used in order for us to assess our health and our physical capacities, such as VO2 max for instance and other ones, in order for you to know that you're on the right track in terms of your diet and exercise and other lifestyle interventions that you are applying to yourselves. That's right. It's not just blood biomarkers. I mean, you mentioned VO2 max. You can look at functional things like how many push-ups you can do or how fast you can walk. There are many different measures of your overall health. And your blood pressure and blood pressure. You really have to look at the whole picture, right? Exactly. So before we get into some of your research, which I think is very interesting, one other concept that's sometimes thrown out there and is confused with inflammation oxidative stress, right? They're sometimes lumped together, but they're different. You know, reactive oxygen species can cause damage. They have a positive and a negative potential in the body in terms of some of the similar processes. How would you distinguish oxidative stress and inflammation? Where are they similar and how are they different? So first of all, they are different and there are different blood biomarkers to assess each one. However, having said this, we know that oxidative stress can be both a cause or a consequence of inflammation. So we know that oxidative stress can activate inflammatory pathways that can lead to, when oxidative stress is chronic, it can lead to a chronic state of inflammation. Moreover, we know that inflammation means the activation of immune cells. And when certain immune cells are activated, these cells can also produce various reactive oxygen and nitrogen species that can lead to oxidative stress. So it is common to lump them together. Although they are different, indeed they can coexist and they can affect each other. And oxidative stress in the short term can be beneficial, right? After exercise, we get a burst of this. This is useful in, for example, building muscle and exercise. You don't necessarily want to shut it down. So is it, and yet if it's too prolonged, it can be detrimental. Would you agree with that? I do. And indeed it is the same more or less as inflammation. We know that when we exercise, what we are doing is hurting ourselves. Let's say it's like this. So exercise can be seen as an insult. Nevertheless, it is, if it is well done, it is a controlled and purposed insult, which will lead to adaptations. And those adaptations in the long term are very beneficial. And part of those adaptations are mediated by inflammation and by oxidative stress. So there are multiple studies showing that when you blunt inflammatory response with, for instance, non-steroidal anti-inflammatory drugs, you can shut down or decrease the process of hypertrophy when you do resistance training. But this is different depending on your basal state of inflammation. So for instance, in young people, with no sign of low-grade chronic inflammation, this appears to be true and consistent. But in the elderly individuals, in older individuals that have a low-grade chronic inflammatory state, and we know that aging is associated with this, not everyone that reaches an old age will have information, but the probability of finding low-grade chronic inflammation in an older individual is higher than in a younger individual. And we know that chronic inflammation can lead to anabolic resistance. So your sensitivity to an anabolic stimuli such as resistance training can decrease. And in those cases, an anti-inflammatory drug can be beneficial in terms of the adaptation to exercise. So all of this is very complicated because it depends on your basal state and on various other factors. Host factors and also nutritional factors, lifestyle, etc. Nevertheless, we can say that blending the inflammatory response may inhibit at least partially some of the adaptations to resistance training. Moreover, we know that giving antioxidants such as vitamin C and vitamin E to people who do endurance exercise such as running can blend some of the adaptations, such as, for instance, the increased number of mitochondria, so mitochondrial biogenesis. It is dependent also on reactive oxygen species, and it can even blend influence sensitivity that increases with exercise. There are already intervention studies in humans showing this. And also we know that when you exercise, because you induce oxidative stress, one of the adaptations is an up-regulation of your own antioxidant proteins. And we know that blending the production or neutralizing the reactive oxygen species that are produced during exercise can in fact lead to a decrease in this up-regulation of the endogenous antioxidant response. So if you want to use antioxidants and anti-inflammatory interventions, in my view, but of course I'm just giving you my perspective, and you are someone who regularly exercises and doesn't have a low-grade chronic inflammatory state, doesn't have any underlying condition, in my view, you should use this. For instance, if you compete for the competition day, but not for training days, because what you want on training days is to induce adaptation. When you compete, what you want is not to have any pain at all, and to be able to fulfill your goal, which is to gain a metal. And that's a very different ballgame compared to the training sessions, where you want to induce adaptation, so you don't want to blunt these mediators, such as reactive oxygen species and various inflammatory molecule. This is a really key observation. It sounds like you would be cautious in use of anti-inflammatory and antioxidant compounds as normal supplements every day, but maybe they should be used more selectively. Is that what you would say? Completely, that's exactly what I'm saying, yes. Very good. I'm going into some of the very interesting work you've published that connects inflammation, particularly systemic chronic inflammation, with a range of different diseases. And I'm going to your Nature Medicine paper, where you connected to a pretty wide range of diseases, everything from cardiovascular disease to cancer, diabetes, osteoporosis, autoimmune disorders. It's a pretty wide range of diseases, so maybe you could break it down into a few categories for us. What's the evidence or what's the connection between these chronic inflammatory processes? And for example, let's just take some of the metabolic syndrome conditions like type 2 diabetes or cardiovascular disease. What's the connection there? I would say that we have already compelling evidence suggesting that indeed a chronic inflammatory state can contribute to the metabolic syndrome and type 2 diabetes. And also to cardiovascular disease. We have, first of all, animal studies. We have acute human intervention studies, where you induce an inflammatory reaction. And you observe, for instance, I'm remembering one, where you induce in healthy units an inflammatory reaction and you measure their insulin sensitivity in the 24 or 48 hours after I don't remember exactly. And you see a very significant decrease in insulin sensitivity after this inflammatory response is activated. Also we have observational studies associating various inflammatory biomarkers such as high sensitivity CRP or specific cytokines with various health outcomes such as cardiovascular disease incidence and mortality and also type 2 diabetes and the metabolic syndrome. And more importantly, we already have randomized controlled trials, typically with drugs targeting different inflammatory pathways that have led to increased insulin sensitivity and even improved cardiovascular outcomes, for instance, in high risk patients that had had in the past an adverse cardiovascular event such as a myocardial infarction, where they are put on a specific drug targeting certain inflammatory pathway and you see improved cardiovascular outcomes in those patients. And these are studies that have been published in very high ranked journals such as the Lancet and the New England Journal of Medicine. Oh, that's great. These are really good evidence from interventional studies. So it's not just observational, right? You make a change and you see this. How about the connection with autoimmune disorders like arthritis or multiple sclerosis or things like this? So we know that arthritis such as, for instance, rheumatoid arthritis, which it is a condition that has provided deep insights into the broad and the very most often, seemingly unrelated effects of chronic inflammation that we discussed earlier. And we know that rheumatoid arthritis, which is an autoimmune condition because it arises when the immune system erroneously attacks, in this case, joint tissues leading to inflammation. This inflammation is a result of the autoimmune activity, but it is also a critical driver of the disease's progression. And it is what causes the typical symptoms such as pain. And beyond local damage, we know that in various autoimmune diseases and specifically rheumatoid arthritis, persistent inflammation, which is normally systemic, has widespread effects and can increase the risk for cardiovascular disease type 2 diabetes, osteoporosis, depression, and much more. And this is something that has been observed in rheumatoid arthritis patients. And when you compare them to healthy controls, you see that the incidence and prevalence of these conditions is much higher in those patients. And furthermore, there is also evidence that chronic inflammation can actually facilitate an autoimmune reaction in susceptible individuals. So I think it is fair to say that inflammation can be both a cause and an effect of an autoimmune process. And it is clearly a key factor in both the localized and the systemic impacts of the disease. And indeed, the typical drugs that are used for many autoimmune diseases such as rheumatoid arthritis and other rheumatic autoimmune diseases are drugs that target the inflammatory pathways. So this demonstrates the key role played by inflammation in these diseases. How about the connection between inflammatory processes and cancers? That's a more tricky one. So indeed, we know that there is some evidence that chronic inflammation can be a player encounter. It can contribute to various stages of tumor development. It appears to do so by stimulating cell proliferation, survival and eugenesis and metastasis. And as a matter of fact, we know that the tumor microenvironment is rich in immune cells, and some of which produce and secrete various molecules that can be considered inflammatory molecules that interact with tumor cells, facilitating their growth, their evasion and also their resistance to therapy. And we have in the epidemiological and also some clinical evidence linking chronic inflammation to increase cancer risk. And there has been already some trials with inflammatory drugs suggesting that they can reduce the risk of certain cancers. However, having said this, I think it's important to note that some immune cells within the inflammatory response also possess anti-cancer properties. So I think that this duality underscores the complexity of cancer as a disease with varying tumor types responding very differently to similar stimuli. So I think cancer is a complicated beast with many phases. And I'm clearly not an expert in cancer, which is why I'm very cautious when discussing this topic, and especially when trying to pinpoint information as a major cause of cancer that can lead to the suggestion that perhaps using anti-inflammatory interventions could be effective in cancer. And I don't think we can say that at all. And in some cases, it can be even detrimental. So I think we should be cautious with this. I guess one more kind of topic around biochemistry and metabolism. Let's go down to the level of the cell. Your article in Nature tied systemic chronic inflammation to cellular aging or senescence. What is that connection between inflammation and aging on the cellular level? So on one hand, we know that as we age, so senescence is basically the aging of the cell, but it can occur in younger individuals also, not in every cell. That's why it doesn't show. But in some cells, you can already have some senescence. This occurs, for instance, in young individuals that have a chronic viral infection. You alluded to this earlier on on our discussion when you mentioned that infections can also lead to a chronic state of inflammation. And indeed we know that chronic infections can lead to the exhaustion and senescence of certain immune cells. An example of this is HIV. The HIV, it's a virus that can lead to this. So this can occur also in young individuals, in some cells, not in every cell at the same time. So we know that as we are chronically exposed to inflammatory stimuli, we can have senescence. So inflammation could be a cause of senescence. On the other hand, we know that when cells adopt these senescence phenotype, they can also start to produce various molecules such as the chemokines, cytokines, and others that are collectively called the senescence-associated secretory phenotype. The SASP, for those of you who are more curious about this and can check the literature, you can just google SASP and senescence or inflammation and you'll find numerous papers on this. In fact, one of the key researchers on this topic was Judith Campisi that unfortunately passed away like two weeks ago. And she was one of the key researchers that identified this and has led many others to finding that the SASP, this phenotype characterized by the secretion of various inflammatory molecules can contribute to systemic low-grade chronic inflammation and can adversely affect many other cells. So we can say that inflammation can be both a cause and a consequence of senescence, of the cellular aging process. So, you know, we've talked a lot about the biology of inflammation and some of the clinical evidence for it, but let's zoom out a little bit and talk on a population-wide level. And, you know, a lot of our listeners are interested in this concept of evolutionary mismatch, the idea that our modern lifestyles and diet put us at risk for diseases in ways that were traditional populations largely avoided. And you worked with the famous Swedish physician Stefan Lindbergh in studying the health of some of the traditional populations, well, specifically the horticulturalists on the island of Katava. So, tell us a little bit about how you came to collaborate with Lindbergh and the study that you did in Katava. So, I actually met Stefan Lindbergh in 2007 in London thanks to Lauren Cordain. So, I was already in contact with Lauren Cordain for some time and he gave a talk at a meeting in London and because I was on my way to the U.S. at the time I was working with and I was very interested in sports nutrition. However, I was already interested also in the evolutionary aspects of diet and lifestyle. So, that's why I was already in contact with Lauren Cordain and that most of you, if not all, know because of his work with the pre-healitic diets. So, I went to this meeting in London and after the meeting, Lauren invited me and some Portuguese friends of mine who were there to have dinner with him and along came also a friend of him who was also at this meeting which was Stefan Lindbergh and he's at the time doctoral student, Tommy Jonsson and so I met both of them at that dinner and basically we became friends and to cut a long story short. After a few years, Stefan invited me to collaborate with him and Tommy Jonsson in his group and I eventually ended up doing my PhD with him and Tommy Jonsson unfortunately, Stefan Lindbergh died in 2016 and Tommy Jonsson took over his role as my PhD supervisor so I continued to work with Tommy Jonsson but Stefan was indeed the principal investigator of a study that unfortunately, in my view it is virtually unknown to many biomedical researchers although it is quite famous among evolutionary scientists and enthusiasts such as us it is unknown to many other communities and I think this is unfortunate because this study offers various clues to better understand the causes of many non-communicable diseases the so-called Western disease or disease of civilization so I think this was indeed a remarkable study and if you would like I can discuss it a little more in detail the study you're referring to was one that he did in 1990 correct? exactly and then maybe you could just summarize what he found in terms of the health conditions and some of the relationship to disease and the incidence of disease among this population so Kitava just to give us some context here is a small island about 10 square miles belonging to an archipelago off the east coast of Papua New Guinea and in 1990 when Stefan was there studying this population it had a population of more than 2,000 individuals and they lived as traditional archiculturalists in villages or hamlets and no electricity, telephones or motor vehicles were available and except for a few things like smoking kerosene lamps religion and certain costumes such as soccer for instance in some sanitation there was minimal Western influence and Stefan spent there 7 weeks between November and December of 1990 in this island staying with a local family and eating and living like Kitavas and during this period he and his family that lived there collected blood and hair samples and his wife helped him collect some of the samples and he carefully observed the dietary habits of the natives and conducted interviews as well as various measurements blood pressure and topometrics etc and he even did an NGC in these individuals so what did he find? he found that first of all their daily physical activity was high was compared to a farmer or construction worker and they followed a traditional diet that was high in carbs but with negligible amounts of Western foods and we can discuss this dietary aspect later if you like but to keep to your question despite their high carb intake not a single individual was overweight or obese in a sample of Kitavan natives aged 40 to 60 years whereas in a Swedish sex and age match control population the prevalence of overweight obese and morbidly obese individuals was already high and very similar to what we can find in many other Western populations and in line with this Kitavans had a lower waist to height ratio compared to healthy Swedes and Kitavans didn't have because this is a common mis... a common counter argument to this is that okay they are lean because they experience famine and they have no nutrition but Stafan didn't find any evidence whatsoever of this so this cannot explain the absence of obesity and I believe that this study is another empirical evidence that carbohydrate intake per se is not the cause of obesity it doesn't mean that in certain individuals restricting carbohydrates cannot have beneficial effects but saying that carbohydrates are the cause of obesity I don't think that's true at all and the Kitavan study is an empirical evidence of this and in accordance with the apparent absence of visceral obesity that Kitavans have fasting blood glucose levels were lower in Kitavans and their insulin levels were also lower their leptin levels were also lower leptin levels typically occur when you have obesity and you have associated insulin resistance and additionally we know that they didn't have acne so Stafan reported an absence of acne including 300 adolescents and young adults and this sees in my view to be expected since a major cause of acne is insulin resistance combined with hyperinsulinia and Kitavans didn't appear to have this but they had perhaps because of their very high carb intake combined with the fairly high saturated fat intake they had fasting blood glucose that were not exactly optimal however Stafan concluded that there was an apparent absence of cardiovascular disease in Kitava and this sees in accordance with the observations done previously by European physicians that work in those islands and I think that it is worth mentioning that according to interviews conducted by Stafan and he was a very rigorous researcher and he conducted these interviews in more than 200 adult Kitavans they reported that they didn't know about chronic exertion related chest pain such as angina for instance paralysis of arms and legs sudden inability to speak such as the one that occurs when you have a stroke so they didn't know about this at all and only 3 cases of spontaneous sudden deaths in adults were known to these people in the last 100 years so the dominant causes of deaths in Kitava were infections primarily malaria in children accidents, pregnancy complications and old age but stroke or myocardial infarction those were not something that these people could recognize you mentioned old age what would be sort of typical old age for the Kitavans how many years so Stafan found out that there were 125 individuals that were age 60 to 96 years so they represent about 6% of the entire population and I think this is in line with the average model which is the common the more common measurements so the average model age of adult deaths for instance hunter-gatherers which is 68 to 78 years according to a previous review by the anthropologist Michael Gervern and Healer Kaplan that I think it's very interesting in Kitava that I didn't mention is that the majority of adult men and women smoked and this to me suggests that optimal health results from the combination of many variables and just because one of the variables is negative such as smoking that we know that has multiple adverse effects the net result may still be positive when the other variables are all defined let's say like this to promote optimal health I'm not suggesting that smoking should be even considered by people not at all eradicating or decreasing smoking has been a big public health benefit nevertheless I think it's fair to say that in Kitavans although they smoked they still apparently have better health than most individuals in industrialized countries so you alluded to some of the aspects of the diet and by the way I would recommend to any listeners listening to Pedro's 2022 talk that he gave at AHS there's a lot of detailed analysis there of the Kitava study but just for some highlights here can you just give us the gross macronutrient breakdown in terms of carbohydrate saturated fat some of the things that people look at but then beyond that some of the specific foods because sometimes you could just call it a carbohydrate but which specific carbohydrates which specific fats can you give us both the macros and maybe a couple specific elements of their diet so the macros were 69% carbohydrate 21% fat with saturated fat comprising 70% of total energy intake which is above what typically is recommended which is below 10% and only 10% protein which is something that is also very interesting considering that nowadays there are lots of multiple lines of evidence suggesting that higher protein intake might be beneficial to offset for instance muscle loss that occurs with aging for instance among other potential health benefits and in terms of the specifics of the foods that they ate so their diet was composed mainly of fish but only about 100 to 300 grams per person 3 to 4 times a week so not every day tubers that indeed was the first contributor to their diet more than 1 kilo per day we are talking about yams sweet potatoes, taro in yuca or cassava it's the same term for yuca also some coconut about 100 grams per day fruits about 400 grams per day so this is obviously an average estimation and we are talking about various fruits but the ones that they have they are available like bananas, papayas, pineapples, mangoes guavas, watermelon and others they also ate some other plant foods that amounted to about 200 grams per day so leaves okari which is the type of nut some some corn but only in certain in certain seasons not every year some beans lasted once a week they would eat chicken, eggs, snails, octopus, shellfish turtles, ferny foxes pork and also some other fruits some other nuts, some mushrooms so this was more or less their diet and something interesting is that their omega 3 fatty acid intake was not very high because they didn't eat that much fish and also the typical fish in the diet doesn't appear to have a lot of omega 3 fatty acids at least when compared with for instance sardines or wild salmon or mackerel but when the fatty acids in their serum cholesterol esters were analyzed omega 3 levels specifically the ones that we are interested in which are EPA and DHA levels were high and their omega 6 3 ratio was very low and I think this was most likely because they had a very low intake of linoleic acid which is an omega 6 fatty acid present in the oil of most seeds and nuts and also another interesting thing is that they drank clean water from the rain so that was their biggest source of clean drinking water they also drink coconut water of course and they would use some sea water some sea water salt water for cooking so their sodium intake ranged from about 2.3 to 3 grams per day and this is not as low as what it was found in other traditional populations with no access to salt they clearly had some access to salt because they could collect the sea water and they used some of it for cooking so Pedro is sticking with a diet for now and we'll talk about some of the lifestyle aspects but just sticking with the diet there's some things here that you've mentioned that would be in accord with what a lot of nutritionists think are beneficial and anti-inflammatory if you want to call it that but then there's some things that are not aligned with that right you mentioned the high saturated carbohydrate smoking very low omega 3 etc so how do you first of all what were their measures of inflammation to the extent that you know them and what can you hypothesize about the connection between their diet and their inflammatory status so we indeed measured their sea reactive protein levels we compared those actually this was part of my doctoral thesis so I did this after stuff and passed away unfortunately so we measured the reactive protein in Kitavans and in also age-adjusted matched Swedish population and we found that although the difference was not very high there was a significant statistically significant difference between Kitava and Swedish controls with Kitavans having a lower high sensitivity CRP level and this level was the medium the medium was lower than what is the the cutoff for low-grade chronic inflammation which is one milligram per liter so we can say that based on this measurement that they apparently do not suffer from low-grade chronic inflammation however there were of course a few Kitavans that had very high levels of C-reactive protein and they had it most likely because of infections so again maybe you don't know the answer but what would you hypothesize what aspects of their diet could be responsible for this low- chronic systemic inflammation it's hard to say of course I think it's a combination of diet and lifestyle I don't think it's just diet but in terms of diet perhaps it's not so much what it contains it is perhaps what it doesn't contain so it's typically a traditional diet it's not the typical hypercaloric Western diet this was not a hypercaloric diet they're also stuff and estimated their energy and their energy expenditure and he estimated that they didn't have positive energy balance so I think this is also important because positive energy balance can of course contribute to obesity and obesity because of inflammation and various other metabolic changes that can lead to the metabolic syndrome and type 2 diabetes for instance and at the same time we know that high energy intake can also promote inflammation and it can inhibit some of their mechanisms that can prevent or inhibit or decrease the inflammatory response so I think this is one factor the diet was not a hypercaloric diet then it was not a diet high in sugar refined grains alcohol ultra processed foods that combine sugar, fat, flour, salt and various additives which can promote through various mechanisms oxidative stress and inflammation also this this diet did not contain trans fat which can also have various adverse effects and can also contribute to inflammation and at the same time although this was not measured by Stafan because this was a study done more than 30 years ago and at the time nobody was really that interested in the microbiota specifically in the gut microbiota but I think that the diet that they have combined with their exposure to the elements and to various microbes that exist in their environment I think I'm inclined to say that most probably they have a very different gut microbiota compared to us and I would say that perhaps their gut microbiota can also be an explanation for their apparently healthier phenotype compared to their Swedish culture part so let's shift then from diet to the other aspects of their lifestyle you did mention energy balance so physical activity were they more physically active what about their sleep patterns stress social connection what other aspects of their lifestyle do you think were most important in explaining health problems and inflammation outcomes unfortunately at the time Stefan was very very interested in diet but he also recorded physical activity and indeed the physical activity that was estimated to be equivalent to about 1.7 times their basal metabolic rate this is more or less what farmers have a construction worker has higher than what you find in many many people who live in industrialized countries because we know that unfortunately a large proportion of individuals in our countries do not meet any of the minimal required physical activity recommendations and what we find in the Kitavans is what we find in many other traditional populations that still follow a pre-industrial lifestyle so we know that they have a much higher physical activity level so this is something that we know for sure what we don't know for sure but I think it's very probable is that they had at the time lower exposure to pollutants except smoking because smoking is also of course a source of various xenobiotics nevertheless their tobacco could be different than the one that we smokers in our countries use so that could be also a difference there I don't know because I'm not an expert in that and as far as I know Stefan or another one from my group that has given some thought to the Kitavan study has looked into this but that's a possibility another one that I think it's a real possibility is that these people experience more acute psychological stress and less chronic psychological stress and we have multiple lines of evidence suggesting that stress can have various adverse effects and we also have evidence from intervention studies saying that stress management techniques such as meditation might reduce cortisol blood pressure, heart rate and even some inflammatory markers then I think it's fair to say that these people because they live near the equator they didn't use a lot of closing they didn't use sunscreen that these people had regular sun exposure and when we expose ourselves to the sun not only we can produce vitamin D through ultraviolet B radiation but we also know that ultraviolet A radiation and also infrared radiation and perhaps even visible light can have various other physiological effects so I think that vitamin D is only the tip of the iceberg when it comes to the various physiological effects that sun exposure can have so this could be also another factor explaining their optimal health or near optimal health then I think it's fair to say that these people because they didn't have access to artificial light like we do that they had sleep patterns and circadian rhythms that were in sync with the daily variation in light exposure and I think this is very important because we already have various studies including experiments under controlled conditions showing that reducing the number of hours of sleep or inducing circadian disruption such as the one that shift workers experience or people who suffer jet lag because they travel to a different time zone that this can have multiple metabolic and adverse effects leading for instance to increased oxidative stress increased inflammatory markers increased blood pressure decreased insulin sensitivity and so on and so forth so I think that all of these factors along with diet could explain their optimal lifestyle the other factor that some could say is that they don't belong to these earths they are extraterrestrials yeah so I'm really glad you brought up the connection between stress sleep and inflammation right because people just think oh inflammation is all about diet but the psychological factors are important here but what is actually the mechanism of action is it through hormonal regulation you mentioned things like cortisol some of the circadian related hormones how do you get from stress to these very biochemical inflammation processes so on one hand as you said you have hormonal changes that can activate inflammatory pathways so that's one mechanism the other possible mechanism that I'm aware of is that stress can induce some changes at the cellular level that can lead for instance to an increased number of certain molecules named dumps, danger associated molecular patterns or alarm means because they sound an alarm that can activate for those of you who are more geeky about this and want to know the exact mechanism these molecules could activate the inflammasome and the inflammasome can app-regulate the inflammatory response because the inflammasome what it can do it is to convert certain proteins that are not yet bioactive inflammatory proteins such as cytokines such as pro interleukin 1-bit and pro-interleukin 18 and when the inflammasome is activated by these molecules it can convert these cytokines into bioactive cytokines that can then app-regulate inflammatory response these are two of the mechanisms that I'm aware of perhaps there could be others I'm not an expert on the role of stress in inflammation I've studied much more rigorously the effect of diet in inflammation and the various consequences of inflammation specifically at the more metabolic level but I know I recognize that there are many other factors that can affect inflammation and the mechanisms that I'm aware of regarding stress and inflammation are these two that I just mentioned this is fantastic everybody talks about mind-body connection but here for all of you geeks and nerds out there Pedro just gave you the pathways and this was something I didn't even prepare him for impressive Pedro you can just come up with that but let's now talk about what we can do in our lives we can't all move to Katoffen and live like the Katoffens they had a unique lifestyle we love our conveniences we live in the west so what kind of diets can we look toward or dietary practices and lifestyle practices can we look to to minimize the risk of chronic inflammation and I'm thinking maybe just start on a on a the diet side if you look at Mediterranean diets paleo, keto vegan diets, whole food diets are any of these favored in terms of minimizing inflammation or can you adapt any of these diets to a pattern that will lead you to the same outcome so in my view and I've changed over the years in the past I was very in favor of a paleolithic diet and before that I was very in favor of vegan diet for instance I went vegan for some time then I followed a paleolithic diet I followed low carb ketogenic diet and various other ones and nowadays after many years of experimentation and reading the scientific literature and also seen some patients I don't see a lot of patients but I see some as a a dietitian what I can say is this that the diet should be personalized so there isn't one size fits all dietary approach that's something that I completely abandoned over the years so nowadays what I try to do is to recommend a more personalized diet it's not easy to do it of course and it has to be refined over time as we find more evidence and we have better ways of assessing the effects of diet on the individual but the diet should be personalized having said that I would basically say this the diet should provide everything that you need so all the nutrients I think it should also provide phytochemicals because phytochemicals although they have in certain circles a bad rep because they are viewed as toxins and indeed plants do not produce phytochemicals to help us plants produce phytochemicals to defend themselves because they cannot bite they cannot scratch and they cannot run so plants have to come up with a different way of defending themselves and phytochemicals are one of those ways and while we are in phytochemicals they do stimulate our endogenous antioxidant systems NRF too so at least at a low level not excessive they can stimulate our own defenses right exactly that's exactly what I was about to say thought I indeed and I completely agree so although the phytochemicals can indeed be toxic especially in high amounts I know that first of all the absorption rate is low and it is low because in high amounts it could damage us and so in low amounts it can induce as you say an adaptation such as exercise for instance exercise also works through similar mechanisms or through similar principles so we are talking about Hormizis where a certain can trigger a beneficial adaptation and one of those adaptations is as you said the activation of a transcription factor called NRF2 which in turn will increase the expression of genes that will up-regulate our antioxidant response so phytochemicals can indeed lead to a better antioxidant capacity at the same time we know that phytochemicals can also down-regulate the expression of genes involved in the inflammatory response so it can also have a role in inflammation and I think this could be very interesting especially for individuals who have chronic inflammation also I think that for people who have chronic inflammatory condition that an increase in the intake of omega-3 fatty acids especially EPA and DHA that work through multiple mechanisms to decrease or to induce the resolution of inflammation or induce the resolution phase of inflammation could be beneficial for those individuals and we have randomized controlled trials in rheumatoid arthritis stations for instance showing that omega-3 fatty acids indeed seem to have at the same time the diet should avoid should not contain the specific factors that could induce oxidative stress inflammation, insulin resistance and so on and so forth so basically we are talking about a diet that provides us with everything that we need in the amount that we need and the amounts that we need are different than the amounts that our neighbor needs and at the same time does it contain the various factors that can promote adverse health consequence so we are talking about for instance advanced glycation end product that are present in fried foods or foods that are heated in low humidity conditions and at very high temperatures then that we can also find those ages, advanced glycation end product that can be partially absorbed and can induce oxidative stress enhanced inflammation in processed and ultra-processed foods can also find oxidative lipids in foods that are fried or that are overly heated at very high temperatures then we also have excessive sugar, excessive salt especially if we have low potassium intake for instance that can also promote an inflammatory response we also have trans fatty acids and we have the typical combination of flour, sugar fats salt and various additives that can also through multiple mechanisms induce an inflammatory response so the diet should not contain any of this and in my view in order for the diet to supply everything that we need I think the diet should be omnivorous however I'm not someone who is gonna tell you that you cannot follow a vegan diet because you can it's possible to adapt the vegan diet in order to provide everything you need but in many cases you may need to supplement the diet with some specific supplement some specific nutrients such as B12 it sounds like what you're saying is don't focus so much on the name of the diet or the gross outlines of it but more on whether you're getting the specific components that you need and you're avoiding the problematic components and if you look at more it on a component basis you could craft a diet or adapted diet that's more personalized or more in line with your preferences so for example you said phytonutrients omega-3 fats some of the minerals are things we should include what about fiber? Fiber is something you didn't touch on here is that important? No I didn't touch on because I think that on one hand we have many interventional studies suggesting that indeed higher fiber intake especially soluble fiber can have various positive health outcomes we have also some intervention studies suggesting that however it is true that we also have various examples of individuals who follow low fiber diet because of some health conditions where a higher fiber intake might adversely affect their condition and those people do not seem to be that do not seem to be sick or do not seem to have do not seem to experience some adverse effects so I think that on one hand there is indeed evidence that fiber especially soluble fiber fiber can have multiple positive health outcomes and can affect the gut microbiota that's for sure nowadays there is another term that is being mentioned in the scientific literature more often which is mac microbiota accessible carbohydrates so instead of fiber or prebiotics what some researchers are suggesting is that we mention we talk about these microbiota accessible carbohydrates which is as the term suggests carbohydrates that we need ourselves do not digest do not absorb but that can be used by the microbes in our gut and perhaps this can lead to a more positive get microbiota but why am I being a bit cautious and skeptical about this because I don't think that we are there yet in terms of trying to say that if you have these gut microbiota you're going to be healthier than someone who has a different gut microbiota I think that we are still a long way from finding out what the optimal gut microbiota is and perhaps the gut microbiota can be an adaptation to a specific environment a specific diet, specific lifestyle and for some individuals that microbiota doesn't necessarily produce adverse effects although it is different from what some consider the optimal one ah ok so fiber and the interaction with gut microbiota that might be a more personal or individual aspect of the diet let's talk about on the avoidance side you did mention sugars processed foods trans fats and maybe high levels of omega 6 what about grains dairy and alcohol should these be avoided excessive alcohol for sure there is a lot of controversy around alcohol if low amounts of alcohol could also have these effects such as phytochemicals or exercise through hormonies which is to induce some beneficial adaptations I'm not completely sure about that I know that some traditional populations that seem to be doing well do include a little alcohol but there are also other populations that also seem to be doing very well that do not include any alcohol at all or very little alcohol so I don't think that the epidemiological evidence can be used to settle this issue and then it's of course very hard to do intervention studies to know the low term effects of this so I would say be cautious with alcohol so if you drink alcoholic beverages do so in very in low amounts then you talked about sugars I think it's fair to say that we don't need that in our diet so perhaps someone can say ok but I might try I do triathlon and I do ultramarathon running so I need to use sugars during the event that the ultramarathon or cycling or whatever I agree in those cases say ok if you do that it will be of course beneficial it will increase your performance but I'm talking about health I'm not talking about these extreme outliers because doing that it's something that would not be considered normal by our hominin ancestors they would view people who do that as ok these people are crazy I'm not saying that these people are not some to be praised by what they achieve and they have shown as the limits of human physiology nevertheless we are not talking about health we are talking about performance and it's different performance in health when it comes to health I don't think that healthy individuals need to include refined sugars in their diet and high amounts of refined sugars especially when combined with other lifestyle factors and especially hypercaloric diet can produce various adverse metabolic effects and it can also contribute to inflammation then I would say that refined grains following that almost in that same category so high intake of refined grains can also have adverse effects then we go through whole grains and here is where things get much more tricky because first of all we have to differentiate the various types of grains so when people just lump all of them together and say whole grains and they include oats, rice buckwheat, wheat, rye etc I think that we cannot do that because those grains can have different effects and there are already some intervention studies suggesting that indeed they can have different effects secondly when we say that including whole grains in the diet is very beneficial normally what we are saying is when compared to other foods whole grains seem to be more beneficial but that is not the same as saying that we need to include the whole grains because there are examples such as the Kitavans that have low grain intake and they still do fairly well as we just mentioned so I think that observational studies have various limitations and intervention studies that compare for instance whole grains with refined grains or with other foods that are used to say automatically that including whole grains in the diet will elicit those same positive outcomes because what we are really saying is that those studies that simply compare whole grains with other foods have elicit some health outcomes and we are extrapolating those results to everyone in all context and I don't think that we should do that but having said this I think the jury is still out when it comes to whole grains I would like to see more intervention studies and not epidemiological studies what I want to see is more randomized controlled trials comparing specific different whole grains with different foods specifically for instance fruits tubers, legumes, etc and as far as I know there has been very little studies doing such comparisons How about dairy this is probably one of the most controversial within the ancestral or paleo community because there are traditional populations that consume fair bit of dairy but then a lot of individuals have big issues with dairy so how do you come down on dairy this is also a topic where I've refined and changed my opinion over the years I was in the past very I would say anti-dairy and now I'm not I think the devil is in the details I'm much more nuanced about dairy first of all if you look even at randomized controlled trials trying to see if milk and other dairy products induce oxidative stress and inflammation you don't find that at all so I cannot say that dairy per se is a trigger of inflammation and oxidative stress having said that there are individuals who have indeed hypersensitivity reaction which is a new reaction to certain milk proteins and in those individuals dairy can elicit indirectly but it can elicit a type of inflammatory reaction but those are individuals that have a surgeon predisposition for instance or certain factors that can decrease their tolerance to these proteins and there are many factors that can do that even for instance perturbations there get microbiota, vitamin deficiency, its possibility in various other micronutrient deficiencies and also other factors let's not go into that now but just to say that some individuals indeed could have hypersensitivity reaction to some dairy proteins milk proteins and in those individuals indeed dairy could be pro-inflammatory and can have adverse effects then we know that milk induces a very high insulin response and so it is theorized that in high amounts perhaps dairy especially milk could lead to insulin resistance the data on that is not very clear and there are very little intervention studies that have been conducted to study this but some of those I'm remembering only two have shown a tendency to more insulin resistance in the high milk group compared to the low milk group and nevertheless this is also affected in this case insulin sensitivity by exercise, by sleep and by various other dietary nutritional components so it's very hard to isolate all of those in studies so I don't think the jury is out on that and then when it comes to various other health outcomes we have various lines of evidence which are unfortunately very conflicting so I don't think that at this point I can say that you really need dairy in your diet or that you should completely eliminate dairy in your diet in order to be healthy and indeed I would say that dairy in certain individuals especially fermented dairy such as yogurt, kefir and even some cheese could be a way for you to increase your intake of various nutrients great well this has been a very comprehensive discussion covering inflammation, covering the evidence from traditional populations and also looking at a lot of the studies and what I'm taking away from it is there's some strong themes around what we should include or exclude but there's a lot of flexibility a lot of options here to keep inflammation in check and to promote health so thank you so much again a very nuanced study I appreciate your honesty about what you know and also what's not known here Pedro so can you tell us a little bit about your current research and lecturing activities what are you up to these days first of all thank you very much for your kind words Todd I'm just someone who is very curious about all of this and what I try to do is basically read the literature on various topics that I find interesting but I'm far from being an expert in any of these topics I'm just someone who enjoys knowing a little more about this and many more individuals that know much more than I do about this and regarding what you asked about my activities so indeed I lecture a lot that's how I make my living is through lecturing and teaching and so I teach and also I teach for undergraduates and also some in graduate students and I also lecture worldwide for physicians nutritionists and other health professionals I'm fortunate to be born where I was born because I'm not from an English speaking country so English is not my first not even my second language my mother is Spanish so I'm a half Portuguese half Spanish and by combining that Portuguese Spanish and also English because if you don't know English you won't be able to do anything at all especially in science I'm fortunate to be able to speak in these languages so this will of course open more doors for me in different countries so that's how I make my living and I lecture mostly about chronic inflammation about the lifestyle factors and dietary factors affecting chronic inflammation I also lecture about biomarkers to assess cardiometabolic health immune status and also micronutrient status vitamin in mineral so that's another topic that I like to lecture and then or in terms of research I do research but I do it part time because I focus much more on lecturing but I also do some research and so I work with two different groups one at Lund University my alma mater we Tommy Jonson and his group so they are very interested in paleolithic nutrition and so we do some research on that field and I also work with professor Alejandro Lucia from the European University of Madrid and they have a much a broader a broader interest they are very interested in various lifestyle factors affecting multiple health outcomes not only diet but also exercise professor Alejandro Lucia is one of the world experts on exercise on exercise in health so that's another area that he's interested in I'm not an expert but I'm also collaborating on a few studies on that area and also I'm very interested in various other lifestyle factors that can affect health so I'm interested although I don't know much at the time but I'm interested in sleep for instance is another area that I want to cover more deeply in the future so I'm starting to also collaborate on a project regarding sleep so I could say that I'm someone who enjoys knowing about everything but knows very little about each one of these things well it's evident that your curiosity is alive and well and taking you in more directions and adding to this this whole interest you have in health, diet and inflammation so thanks so much for the discussion today Pedro and we'll also have any links that you send us we'll put in the show notes so others can follow you and of course I mentioned the ancestral health symposium lecture you gave in 2022 which is a great source so thanks for talking to us today it's been a pleasure and good luck in your continued research thank you thank you it was a pleasure thank you very much thanks for joining us on this episode of ancestral health today we hope you enjoyed our discussion on how evolutionary insights can inform modern health practices be sure to subscribe to our podcast to catch future episodes