cns602 -- front page -- diseases of affluence thomas ...€¦ · cns602 -- front page -- diseases...

CNS602:DiseasesofAffluenceT.ColinCampbellCenterforNutritionStudies

Forindividualstudentuseonly:pleasedonotcopyordistribute.©2018Allrightsreserved.Allothercopyrights,trademarks,tradenames,andlogosarethesolepropertyoftheirrespectiveowners.

CNS602 -- Front Page -- Diseases of Affluence Thomas Campbell, MD Over the next two weeks, let's go a little deeper into the science behind optimal nutrition, a whole food plant-based diet. And specifically, let's talk about the diseases of affluence. These are the major burdens on our society from a medical and healthcare point of view, cancer, heart disease, diabetes, and obesity. When my dad and I wrote the China Study we went to a publisher and, at one point, it was kind of a tough sell, selling the book. And at one point the publisher said, maybe you could talk about each different disease state and suggest a different diet to combat each different disease state. And of course we couldn't do that. Because as the science has shown and the science that you'll see suggests, the same foods tend to be good across a wide range of our diseases. Getting a sense of the depth and breadth of the evidence across these different diseases is really going to build upon the fundamentals that you have learned about in the first two weeks. CNS602 -- 1.4 -- The Cancer Atlas & The China Project T. Colin Campbell, PhD We don't consume nutrients as independent nutrients. Usually we don't at least, at least when we're consuming food. And that relationship between food and health, and food and disease formation is much more complex. It involves more than a single nutrient. And what really came out of that work as far as I was concerned is that, although we learned a great deal about the distinction between animal and plant based protein material on one hand, it was really important to get a feel for the larger context. And we got just that opportunity in the early 1980s when a visitor from China, a very senior scientist from China by the name of Dr. Chih-Chang Chu came to Cornell University to work in my laboratory. While he was at Cornell working with us, we learned of a major study that the Chinese had done some two to three years before on discovering how much cancer occurred across China as a whole. Basically in the middle 1970s, at the instigation of the late premier Zhou Enlai who was dying of cancer at the time, the Chinese undertook a major survey of how much cancer occurred for about 12 different kinds of cancer, for a total of 2,400 Chinese counties around the country. And this survey involved most of the counties in China and also included about 880 million of their people, which was about 96% of their total citizens at that time. It was a mammoth study. It was easily a world record study in terms of number of people involved. It was said that it involved something like 650,000 workers around the country as they collected this information on analyzing different kinds of cancer in these different counties were concerned. It really was the most ambitious biomedical research project that had ever been undertaken in the history of science.



And what they were showing in the early 1980s when we first became aware of it was that cancer tended to occur in certain places and not in others. This was easily seen in the beautiful color coded maps that they were producing. The map that is shown here, for example, is a map showing how much breast cancer occurs in different parts of the country. And you can see from the color coded scheme that from the red to the slightly less red to the orange to the green. You can see that there are certain counties in China where breast cancer tends to be quite common and others cases where it is not. And incidentally the counties where you don't see it as much as the cancer, these counties often times can be almost next door, so to speak. So it was clear that for this cancer and as I said for about a dozen other cancers forward which are also these colored coded maps, it was clear that cancer was a geographically localized disease. In those days, that was a very exciting proposition. We knew, in fact, prior to that, that cancer tended to be more common, obviously, in some countries than in others. But it could always be argued that perhaps this has something to do with genetics, or some other characteristics. Whereas in China, where most of the people presumably are the same ethnic group and that might be argued that are somewhat reasonably similar, insofar as their genes are concerned compared to other countries, here we see in China this remarkable geographic localization of these different cancers. And so this came to our attention and we wanted to do a study to see what were the major factors that were responsible for these different rates. I should point out that for the different cancers that we use to selected counties, we discovered in fact that the rates of cancer from the highest rate counties to the lowest rate counties were really remarkable. I mean it was several dozen fold from the highest to lowest for men and women for these different cancers. And this is very different from what we see in the United States and other western countries. In the United States, for example, if we see about a twofold difference from one part of the country to another, we've seen about all that we're going to see as far as the range is concerned. Whereas in China, we're not talking about a one and a half twofold difference. We're talking about a several dozen fold in some cases even more than a hundredfold difference between these different rates of cancer. So just the idea that cancer was geographically localized suggested of course that diet and environment probably had something to do with this, rather than genes. And at that particular point in time, based on other kinds of studies, comparing different countries, it was already being concluded by those who were looking at this kind of information that cancer was, in fact, an environmentally determined disease. And, in particular, a dietary determined disease. We wanted to go to China and see what, in fact, were these factors. And of course at the same time as far as my own work was concerned, with respect to protein. I was particularly interested in measuring as many things as we possibly could. In order to try to see, if we could see some patterns of disease production, on the one hand, and patterns of dietary environmental conditions, on the other. As these patterns might relate, one to another. Now, before I get into talking about the study design itself for this study in China, let me point out that at that time there had been publications of data showing that for these different cancers, for several different cancers, the rates of cancer in the different countries were very different. And the accompanying chart that we have is the one for breast cancer. The same cancer that we have for the China Project. When we look at the relationship of breast cancer between different countries, we see very different rates of cancer. And in the chart, we see that, in fact, as breast cancer goes up, so does dietary fat intake as well. And we see this remarkable relationship between dietary fat intake and breast cancer for different countries. On the one hand, there are some countries in the world



where breast cancer is almost nonexistent. Other countries, such as the United States, have a lot of breast cancer. And of course, the higher the fat intake, the higher the breast cancer rates. One of the things that came out of those studies that were published in the '60s and 1970s, prior to the China Project, was the fact that when people move from one risk area to another risk area. Let's say they move from Japan to the United States or other studies, for example from Poland to Australia or from Africa to the United States. As people move from one country to another where the risk of disease is very much different. What had been noted at that point in time was that when they moved from one risk area to another risk area they kept their genes the same. They took on the risk of cancer or the risk of disease of the country to which they moved as they changed their dietary and lifestyle conditions. At the time the China Project started, we really already had, at that time, a lot of impressions that cancer was an environmental disease. And it did have, in fact, some important dietary links. And that people could in fact manage to prevent cancer, in theory at least, if in fact they knew what kind of diet to consume. So the China Project really was ideal. Where we had such remarkable differences in disease rates for the different parts of the country. And also, we had the opportunity, well, at least we thought, we could go there and select some counties and study rather comprehensively the relationship of diet and environment with these different cancers just to see really what caused these different rates. CNS602 -- 1.5 -- Fat & Fiber Intake T. Colin Campbell, PhD So let's turn our attention then to average fat intake. As I said before, the fat intake ranged from a low of 6% of calories to a high of 24%, these are main numbers for various counties. There is one small group of people in the far North of China, and we did have one county there, too, who actually consume much more fat than this. They're a Muslim minority group who live in the far North, just south of the Russian provinces, just south of Siberia, and they consume much more meat. And they were really an outlier. So this 6% to 24% actually represents most of the Chinese, not counting the Muslim community in the far North. So they're between 6% and 24%, our range is somewhere around 25% to 55%. In other words, their high is near our low. And, of course, it again points out how distinctive is this population compared to those of us here in the West. And incidentally most of the studies that have been done on diet and disease have been done on Western subjects. And so again, it really points out how unique is this particular population in China, and how unique was the opportunity of studying various relationships. It's worth pointing out how we have been, in many ways, misled by this question concerning fat intake. We talk about low-fat diets in this country, oftentimes, or low-fat foods, and we usually refer to something like 25 to 30% of calories. I don't consider that to be low-fat. That is simply not low-fat. It's advertised that way, oftentimes, even scientists talk about low-fat diets that way. To me that is simply not a low-fat diet because you can see from these ranges, a truly low-fat diet gets down much below 25% down to as low as 5 to 10% or so. We call milk, for example, has 2% fat, we call it low-fat milk. Still 35% of the calories in that milk comes from fat. So, low-fat milk is containing 35% fat when it's expressed as percent of calories. And that's the way we should do it. So there's a bit of sleight of hand as far as our information's concerned, particularly in the advertising of these foods. Even 1% so-called low fat milk, still 21% of the total calories in that milk is from fat. And so, this kind of points out how we've been using our language in a rather inappropriate way as far as fat intake is concerned.



Incidentally, in the China Project as we got into the information and started looking at it, there are all kinds of examples like this where it tended to point out the misassumptions that we often have in our thinking in working with subjects, never really having had an opportunity before of looking at a population quite like this. So we have a China diet that is, as I said, much lower in fat, much higher in fiber, much lower in animal foods. And as I pointed out before, one of the things that I was particularly interested in was to look at big patterns of effects. I think looking at patterns of effects, dietary patterns, and looking at patterns of diseases that may be related to each other and may share causes, this gives us a sense of what the really big picture really is. And this is something we should understand before we start looking at some of the more detailed kind of relationships. Because I think it's the big relationships that really matter when we talk about the occurrence of the diseases that we experience in the West. Now let's take a look at dietary fiber. Dietary fiber is a constituent only found in plant material and was one of the first nutrients that had been discussed some decades ago in reference to its relationship with cancer, particularly with large bowel cancers such as colon cancer and rectal cancer. The late Denis Burkitt gained a lot of fame for drawing attention to the relationship between high fiber intake and low rates of large bowel cancer in his studies in Africa for a number of years. We measured dietary fiber in many different ways in our study in China, 14 different ways to be precise. Dietary fiber is a very complex carbohydrate, and these different fiber fractions, these different fiber entities have somewhat different properties. And we don't know a lot about the distinctions between one kind of fiber and another kind of fiber. We do know a few things, but those distinctions are probably not terribly important as far as this question's concerned. High fiber diets are generally associated with lower rates of colon and rectal cancer, and that was known at the time that we conducted the China Project. It turned out that in China the fiber intake was significantly higher than in the West, on average about 3 times higher. And as we explored the relationship in China between these different fiber intakes and colon cancer, what we found was that consistently the higher the total fiber intake, the lower the rates of colon and rectal cancer. So once again, we're getting this indication that plant based diets, essentially almost going the whole way, if you will, that's what it suggests to me. Plant-based diets were beneficial in so many different ways as far as the nutrient composition was concerned. CNS602 -- 1.6 -- Hormone Levels in Females T. Colin Campbell, PhD Let's turn our attention now to the hormone levels that we measured in the Chinese women and in this particular case, we measured several different hormones. We measured estrogen and prolactin and testosterone, we measured the protein that carries hormones around in the blood. In other words, we looked at the hormone activity in many women from different perspectives. At that time, there was some indication that the hormone levels in the blood might be related to breast cancer in women, for example, or perhaps even prostate cancer in men. We wanted to look at the hormone levels fairly carefully, the best we could. It also turns out that the hormone levels within a woman's menstrual cycle tend to go up and down, of course, and so it was not easy to do because we had women who were at various stages of their menstrual cycle. As we say in research, there was some noise in the system. But in spite of the noise in the system, we still saw some rather remarkable results.



And incidentally, in this case, the people who determine these hormone concentrations were scientists at the University of Oxford who had already been doing a very significant study on British women, in the Guernsey Islands, known as The Guernsey Islands Study. So, the same analysts using the same methodology in London and Oxford determined our blood samples for hormone levels. As far as methodology is concerned, as far as analysts are concerned, we had the exactly the same people, same analyses, the same methodologies. That was important because we were worried about this variation of estrogen levels that occur over a woman's cycle. We got good data out of it and the group that, in fact, did this work on estrogen concentrations is a group that is best known in the world for understanding the relationship between estrogen and breast cancer. What we learned in this was that for estrogen, the estrogen levels amongst the British women was about 50% higher than it was amongst Chinese women. British women, of course, being rather similar to American women by all accounts. So British women were having estrogen levels about 50% higher than rural Chinese women. At the same time, we also measured the age of menarche, which is the period during which the woman's menstrual period first begins. We measured the age of menarche in the Chinese women. We also noted the age of menopause in most Chinese women and it turned out that amongst the Chinese women, the average age at menarche was 17 years. The range was from 15 years to 19 years. Here was a situation where these young girls in China, consuming a mostly plant-based diet, were starting their menstrual periods much, much later than what women do in the West. They're starting their menstrual periods much later and that's the time when estrogen levels really surge and rise and stay high during the reproductive years and then decline when menopause comes. So the Chinese are starting their reproductive years quite a bit later than what we do in the west and in turn, ending the reproductive years about two to three years earlier than what women do in the West. When you take that into consideration, the total time during which estrogen levels are remaining high during those reproductive years, and you also take into consideration that the fact that the British and American women, that the concentration of estrogen is about 50% higher. You take both of those factors in consideration. It turns out the the total estrogen exposure amongst Western women, according to the data that we have here, was about three to fourfold higher in Western women that what it is amongst the women in rural China. This is a remarkable difference. And because of the fact the higher estrogen levels have been associated with breast cancer and because of the fact that age of menarche also has been, in several studies, shown to be related to breast cancer. That is the early the age of menarche, the higher the breast cancer risk. That combination of observations and the fact that the estrogen levels or total estrogen exposure of most Western women was so much higher than it was in rural China. It turns out that that fact, estrogen exposure itself per se, especially when you take into consideration the amount of so called free estrogen, as opposed to the stuff that's down and not available. You take all these factors into consideration; I'm of the very strong opinion that the cause of breast cancer in Western women is largely related to the circulating levels of estrogen. And the circulating levels of estrogen incidentally are strongly influenced by diet. That is to say, animal foods tend to elevate estrogen levels. Plant foods tend to decrease estrogen levels. It has been shown in several studies in the West and it's very consistent with this particular relationship here. Animal foods, in fact, cause a woman to start their menstrual periods earlier in life. Animal foods also cause estrogen levels to be higher and animal foods are associated with higher breast cancer levels. I think where we've been wringing our hands on what causes breast cancer in our Western studies, almost no one



has, to my knowledge, except for a couple of the individuals that were involved in this study, almost no one is drawing attention to the fact that this total exposure of estrogen that really accounts probably for breast cancer. And that in turn, all of a sudden, provides a bridge for understanding how diet works in the case of breast cancer. Plant-based diets, of course, being beneficial in reducing breast cancer risk. CNS602 -- 1.8 -- Cancer Stages & Development Over Time T. Colin Campbell, PhD Cancer is a disease that is often dreaded, an emotion that need not be actually if we were to better understand how this disease begins and how it progresses. And in fact this is a matter of exchanging fear for hope which arises when we have reliable knowledge. A lack of knowledge encourages fear, an emotion that seems to permeate at every level what now has become a cancer industry. In this first of a series of three lectures, we will begin by considering what many believe is the chief cause of cancer, the chemicals that pollute our environment, especially those that arise from the harvesting, packaging, and processing of our food. Many of these cancer causing chemicals, or carcinogens as we generally call them, are those that are manmade. That is, they are not normally found in nature. We begin with this topic on cancer causing chemicals because they have dominated the discussion on cancer for at least four to five decades. We spend large amounts of money testing chemicals for their cancer causing properties. Then we spend excessive amounts of time and emotions debating how they should be regulated and how they should be controlled. Although much has been learned, especially about the biological and biochemical properties of cancer, there also has been what I consider to be some serious misunderstandings, some of which will be considered here and some in the next lectures. I want to point out that researchers who investigate the nature of cancer traditionally divide the development of cancer into stages, admittedly, for the convenience of their own thought processes. Although the lines dividing these stages are somewhat arbitrary, each stage, nonetheless is considered to have certain unique characteristics that help us to identify events that may help us to treat, even cure, this disease. Although these stages have unique characteristics, they also have some common features as we shall see. In this slide, we see that there are three stages of cancer, occurring in order, initiation, promotion, and progression. Initiation, as the name implies, begins the process. Promotion pushes it along. And progression describes the more serious stages of cancer as it begins to spread from its primary site into other tissue sites. In this slide, we're gonna begin by considering initiation. This is the initial stage where chemicals are primarily thought to act, at least that's the way it's been through the recent years. Chemicals capable of causing cancer, as we said before, are called carcinogens. Following consumption, and after passing into the intestinal tract, they are then absorbed into the bloodstream. Because most of these chemicals are soluble in fat, they tend to seek storage in our body fat. However, the body also likes to rid itself of these chemicals, thus needs to, through enzymes, convert them mostly in the liver to water-soluble metabolites that are much more readily excreted from the body. Unfortunately, during this enzymatic conversion of these chemicals into water-soluble and, of course, less toxic metabolites, a small amount also may escape the process and be converted into intermediate



metabolites that are, chemically speaking, highly reactive. These intermediate products are so reactive that they can non-enzymatically attack crucially important molecules, like DNA, RNA, and protein. Attacking DNA to form what we call covalent chemical bonds is especially troublesome because DNA is the stuff of genes. Although the cell has a highly efficient process of repairing most of this damaged DNA within their genes, small amounts may escape repair. If the damaged DNA remains unrepaired and remains permanently changed for future cell generations, it is considered to be what we call a mutation. In this slide, we show that if the cells containing this damaged DNA divide or replicate, as we say, into a new generation of cells before they're repaired, the damaged mutated DNA will be retained in the genes of these new cells. These mutations are rarely, if ever, reversed, thus fix the destiny of these new cells and their progeny, some of which may give rise to cancer. This slide describes how promotion begins with the replication of initiated or, as we said before, mutated cells into clones of these cells. These new clones will continue to multiple or replicate as the years pass if the conditions are right. These new cells eventually cluster together to form so called foci cells that can be seen under a relatively low power microscope. Promotion may be a years-long process, but most importantly this stage of cancer development may be reversible under certain conditions. In this slide we see how these early clusters or foci of so-called pre-cancer cells gradually grow into small then ever larger tumors, eventually to be diagnosed as cancer itself. Tumors may stay at their site of origin, and they may remain benign and relatively harmless in many cases. Or they may begin to invade neighboring tissues, some of which may be elsewhere in the body. This property of invasiveness is called metastasis. Malignancy describes the property of cancer cells of becoming independent, aggressive, and relatively resistant to their destruction. Rugged individualism might be a good phrase to describe this property. Here we see how schematically summarizes the three stages of cancer development. Although these stages are arbitrarily divided in this chart, note the gradual color change that conveys the idea, at least it's meant to convey the idea, that these stages also share some common features. They gradually change in degree, but also the time dimension for these stages. Initiation, at least from the perspective of a single cell, occurs within a very short period of time, merely including the time required for the body's absorption and transport of the carcinogen into the cell, where it is metabolized to a form that tightly bounds to DNA, now called a DNA adduct. Promotion, in contrast, may take years from the time that they initiated, mutated cell first replicates itself until the time that it grows into a troublesome tissue mass. One of the most important features of promotion is its reversibility, as we said before. This implies a push-pull kind of process that is controlled by the relative amounts and activities of so-called promoters and anti-promoters. When promoters are more active, the process goes forward toward cancer. When anti-promoters are more active and prominent, the process regresses. This concept can not be overstated, because it suggests that if the identities of these promoters and these anti-promoters are known and they can be controlled, of course, then the cancer process can be kept in a stable state of regression, even if and when mutated cells remain in the tissue.



The final stage of progression is often considered to be foreboding and relatively short. Perhaps also a time when the process can be only prevented by harsh treatments, hopefully treatments that selectively target destruction of cancer cells without damaging normal neighboring cells. But there's little reason, or essentially little or no reason to believe that the reversible process occurring during promotion does not also operate during progression, a very exciting concept indeed. CNS602 -- 1.9 -- The Causes of Cancer T. Colin Campbell, PhD Here summarizes many different kinds of cancer causes, some of which are unequivocally proven and some of which are a little more speculative, as we say. But first, I need to define what I mean by the word cause. Namely, I consider any factor or any condition that favors cancer development at any of its stages as a cause. Chemicals and certain viruses have been shown to initiate cancer. Many of these agents also promote cancer. Family history implies the presence at birth of cells already initiated, that is the genes have been mutated. Thus, implicating genetics as a cause of cancer. Excessive radiation, either from sunlight or from radioactive substances may act both to initiate and to promote cancer. Stress is a more speculative cause, although it is widely thought to be significant. The biochemical and physiological bases of stress, of course are very complex. Nonetheless, most word searches would agree that stress compromises in some way, the very complex immune system that, otherwise, keeps under control the development of cancer. Stress incidentally may act during any of these pre-stages of cancer development. Nutritional imbalances are the most significant causes of cancer. Many nutrients consumed above or below their optimal levels have been experimentally shown to promote cancer. In contrast, returning to optimum levels of consumption of these nutrients will halt, perhaps even reverse promotion. Perhaps all the way back to, but not including the initiation stage. Keep in mind, of course, that reverse of initiation in theory requires a vac notation, a rare event. Nutritional control of cancer during its promotion stage may also act during the progression stage, although the supporting evidence is much less developed. Incidentally, nutritional control of cancer should be considered within the context of food not as supplements of individual nutrients. And of course, with food, the nutritional effect will be mostly dependent on the integrated activities of a very large number of highly active nutrient, light substances in food. This summarizes a few of the more important points made so far. During the past five to six decades, most people and this includes researchers and the public alike, by the way, have assumed that cancer is caused by chemicals found in our food, water and our environment. Furthermore, researchers have assumed that these chemicals primarily act during the initiation stage. Thus, being considered as initiators. As a result, there has long been considerable public pressure to identify which of the many environmental synthetic chemicals might, in fact, cause cancer. This very public concern and pressure led to a government led research program to test these chemicals for such activity. Thus, to regulate how much, if any of these substances might be allowed in our environment.



This shows that the primary regulation for testing and controlling these chemicals was a 1958 amendment added to the Food and Drug Regulations. An amendment called the Delaney Amendment, named after Congressman James Delaney of New York. Although this amendment was rescinded in 1996, its underlined presumption continues to this day. It is for this reason that we need to understand how the carcinogenicity of chemicals has been experimentally determined. This shows the actual wording of this amendment. It left no doubt that these chemicals should not be added to food in any amount. This necessity of there being none has been referred to as a zero tolerance. This begins our consideration of the limitations of this regulation and there were many. Most importantly, the number of environmental chemicals to which we are being exposed is far more than can be reasonably tested. Early estimates during the 1960s and 1970s, not long after the Delaney Amendment was passed, quickly demonstrated that testing a single chemical would cost a few hundred thousand dollars. More of the time required for these tests and for evaluation of the results was prohibitively long, perhaps three to four years per chemical. It thus was clear from a very practical perspective that this regulation made little or no sense. There are also other concerns that emerged, that continue to linger in the public mindset even today. Most importantly, the focus on chemicals as the main causes of cancer diverted attention away from other possible causes, especially those concerning nutrient imbalances. Also, the experimental requirements to do these tests turned out to be seriously flawed. CNS602 -- 1.10 -- Carcinogenicity, Testing & Predicting Human Response T. Colin Campbell, PhD Testing these chemicals in humans was clearly not allowed. Thus, experimental animals, specifically rats and mice for the most part, were required. The slide shows that there are several important features or criteria of testing chemical carcinogens. First, multiple groups of animals. One group used as a control, and three to four groups used as treatment groups had to be included in order to determine whether there was a so-called “dose-response relationship” for those chemicals that were shown to cause cancer. That is, when it chemically experimentally causes cancer there should be increasing numbers of tumors with increasing doses of the chemical. As an aside, if the number of tumors observed in the treatment groups is not related to dose then the results are to be seriously doubted. Second, the results are more convincing if the observed tumors are the same type because specific chemicals being tested usually don't cause a variety of tumors. Third, there is a need to have enough animals per group in order to statistically detect relatively small but statistically significant increases in tumor development. And fourth and lastly, the length of the study is about 2 years, the normal lifetime of the animals. This, of course, is considered to be equivalent to seven years of lifetime for humans. This presents a graph which illustrates schematically a typical tumor response where increasing chemical doses are associated with increase in tumor responses. Note, also that the doses chosen for study are intentionally set very high in order to maximize the detection. Statistical detection, I should say, of a potential response.



And finally, the doses also span a very wide range, perhaps two to three orders of magnitude as shown by the logarithmic nature of the doses in this chart and the 1, 10 and 100 scale has been used. This schematically illustrates two serious problems with this types of testing, namely the experimental doses are usually far higher than the practical doses normally experienced by humans in everyday life. Therefore, it is necessary to know what is the so-called dose-response relationship for humans. This requires knowing how to extend the line at the high experimental doses to the much lower, practical doses. An exercise called interpolation. Does, for example, that slope of the line observed at the upper doses extend in the same linear manner all the way down to the zero dose? Or does it slope downwards to indicate a dose below which no cancer might be expected? This uncertainty has led to a serious and acrimonious debate in science for many years, mostly with little consensus. Thus, regulatory authorities politically and playing it safe, so to speak, have assumed that linear line extending to zero, but others have objected. Specifically when it became known that certain chemicals when tested in this way, using this methodology, are already present in nature. This adds a new dimension of difficulty. In addition to the difficulty of knowing how to interpolate high dose response to low dose response, as we have already discussed, there also is the additional problem of knowing how to extrapolate the response from one species, for example, in rodents to another for example humans. Again, this is a highly arbitrary exercise as illustrated by the fact that even for closely related rat and mouse species, there is only a 50% correspondence. That is of the chemicals causing cancer in rats only about 50% is likely to cause cancer in mice. It's anyone's guess what the correspondence might be when extrapolating from rodents to humans. This summarizes the evolution of some of the main ideas that have occurred since the adoption of the zero tolerance of the Delaney Amendment in 1958. With these concerns and with the other difficulties mentioned earlier, the original Delaney Amendment eventually was abolished in 1996. However, keep in mind that although these regulations may have gradually changed, the focus on single chemicals as primary causes of cancer still remains with us. This slide summarizes a couple of the main points that we've been making during this lecture. First, cancer development is typically considered as an ordered sequence of three stages, initiation, promotion, and progression. Secondly, chemical carcinogens, mostly but not always, have been considered as initiators, thus conditions that promote, for example, nutrient imbalances, have been under emphasized and even ignored as causes of cancer. CNS602 -- 1.11 -- Initiation vs. Promotion T. Colin Campbell, PhD This lecture is focused on a specific question, namely, if in fact nutritional imbalances are important in the cancer process. The question that we raised in my research group was, is there a difference in this effect on initiation as opposed to promotion, for example? And so, I want to spend this lecture here talking about a comparison of the features of initiation and the features of promotion. And particularly the role of a particular nutrient on the activity of those two stages. This is a repeat of the slide seen in the previous lecture simply showing the different stages of cancer. Initiation stage, the promotion stage, which of course is reversible and that's the thought to keep in mind as we go through this, and of course the final stage, the progression.



This, the third slide, is somewhat repetitive of what we generally talked about in the first lecture but showing a little bit more detail, which is important as we get into this question concerning the comparison of initiation and promotion. This is the stage of initiation showing how when a chemical that causes cancer comes into the body and then eventually goes to cells and how it gets metabolized to eventually cause damaged DNA or a damaged gene. These chemicals that can cause cancer are very toxic and it's natural for the body to want to get rid of them. These chemicals also tend to be lipid-soluble, that is to say that they are more soluble in fatty tissue than in aqueous or water tissue. And so, when the chemical comes into the body it is metabolized by a very complex enzyme system called the mixed-function oxidase enzyme system or MFO system. And that enzyme, primarily located in the liver but also in few other tissues, it's responsible for converting the chemical to less toxic metabolites. And in that process it's converting a fat soluble chemical into a more water soluble chemical with the additional enzyme steps incidentally, to eventually produce metabolites, that are less toxic, that then can be excreted. But, in that enzymatic process that we studied extensively in considerable detail, it's a very complex system, in that process, it turns out that that enzyme, as it converts the carcinogen to less toxic metabolites, also produces a very small amount of an intermediate, what referred to as an epoxide. And that epoxide only has just a fraction, a minute fraction of a lifetime, it's actually extremely reactive. It's so reactive, for the chemist who may be listening to this, it's electrophilic in nature, it is so reactive that it can bind to, as an electrophile it can bind to so called nucleophilic substance, once of the most important being the DNA component of the gene. So once that material forms it very quickly binds chemically in a very tight bond, called a covalent bond, to the DNA to actually lead to what we consider to be a damaged gene. This, the fourth slide, shows what eventually becomes of this so-called damaged DNA or this, we call it also a carcinogen DNA adduct. What becomes of these damaged genetic components as they progress on into the promotion stage. Most of the damaged DNA is repaired, some estimates in the neighborhood of 99, maybe 99.9% of it actually gets repaired. But if in fact the cell actually divides into daughter cells before some of this damaged DNA is repaired, then in a sense the damage DNA gets fixated into the so-called daughter cells of the progeny of the parent cell. And once it's fixed into the DNA then it's going to remain there for all subsequent generations of cells coming from that original cell and that is considered to be the process of mutation. In other words, it's the carcinogen coming into the cell, getting enzymatic metabolized to cause a reactor product that then binds to the DNA, alters the DNA permanently, to give rise to a mutation. And that mutated cell, or damaged cell, which is a clone of the original cells, eventually grows into clusters of little cells, which will eventually become larger and larger, eventually to form tumors and of course, that's the process of promotion. So, now the question is, since we know a little bit about initiation, something about promotion, the question is, how do they compare in terms of actually producing the ultimate tumor? CNS602 -- 2.2 – Dietary Protein & Liver Cancer T. Colin Campbell, PhD In this slide I'm simply drawing our attention to the idea that henceforth with the remaining slides I want to talk about some experimental results that we obtained over a number of years showing the effect of nutrition on the development of cancer. And as I say in the process we learned a great deal about the relative importance of nutrition affecting promotion on one hand and initiation on the other. I'm basically outlining some ideas that lead to this area of research. The initial observation arose in the Philippines when I was there helping to coordinate a nationwide program in feeding malnourished children. And it was widely assumed in those days and of course



assumed by myself and my senior colleague, that these children most of all needed to be consuming more protein. Somewhat like what we would be doing here in the West. They said to be consumed a very low protein diets and that was certainly true. They were also consuming protein that was not so-called “high quality.” Which is the term that's often used in describing animal protein. In any case, one of our efforts in the Philippines was to make sure that these children got enough protein. However, it turned out that rather in a happenstance manner, I learned that there were a few children in the Philippines, very few but some children in the Philippines, very young in age, four years of age and younger, who were actually getting primary liver cancer. And that could have been just a bit of an anomalous observation I guess, except for the fact that when I started inquiring about who these children really were and inquiring about their families, it turned out that the families of these children were the ones who were in fact already consuming the higher levels of protein. Like, what we were attempting to provide to the rest of the children. And so this idea arose that somehow, higher protein diets like what we might be consuming here in the West are more likely to create a condition where the children are more susceptible to primary liver cancer. So this remaining research then was focused on the question concerning how did protein relate to primary liver cancer? Here I'm showing some interesting results that were published from India by some researchers in India that varied on the question concerning the higher protein intake in primary liver cancer in the children. Of course, the observation of higher protein diets would tend to promote liver cancer, for example, was obviously somewhat provocative and somewhat anomalous until I saw this report that came from India, in which case these researchers were studying the effect of regular protein diets compared with low protein diets on the ability of these two different levels of protein to affect the development of liver tumors in rats. And incidentally, the liver tumors in rats that were being observed were actually caused or initiated, if you will, by a chemical carcinogen that was being widely studied at the time including some work in our own lab. A chemical called aflatoxin which is a metabolite of a mold that grows on peanuts and corn, in particular. In any event, these researchers divided their animals into two groups, those fed regular levels of protein, that is to say, 20% of total energy, or another group fed 5% which is considered to be an inadequate level of protein. And they thought in fact, initially, that the animals fed the higher levels of their regular levels to good levels of protein would help to repress the development of liver tumors that might be caused by this chemical carcinogen. And, in actual fact, what they learned was that the animals given the regular levels of protein were the ones that produced the tumors. And the ones given the lower level proteins did not. And you can see in the results here, that the difference between the 20% protein diets and the 5% protein diets in terms of their ability to affect tumor development was really substantial. It was essentially a 100% in one case of the animals fed the regular levels of protein. And only 0% in the case the animals fed to 5% protein. So this was consistent with what in fact I thought I was seeing with the children. Here I am simply listing two objectives that we set for ourselves in a long series of experiments that were to be continued over the next 25 to 30 years in my laboratory, research that was primarily funded by the National Institutes of Health and a bit by the American Cancer Society and the American Institute for Cancer Research. In any event, we set for ourselves two objectives at the beginning of this research. First, was to simply confirm these unusual findings from the laboratory animal experiments that were conducted in India. We simply wanted to know, is it really true that



animals fed higher protein diets promoted tumor development in those animals exposed to aflatoxin. And secondly, since this observation was quite different from what one would otherwise expect, we wanted to learn how the protein worked. And we do in science want to know how things work because once we get an understanding of how they work It gives us a lot more confidence in the original observations that we make. Here I'm showing just one sample of findings that we obtained over the next many years looking at this question concerning the effect of protein on tumor development, initiated by this chemical carcinogen called aflatoxin, or AF, as it's abbreviated here. And in this slide, I’m simply showing the effect of protein feeding on the development of early precancerous foci; recall I talked about clusters of cells that would emerge early on during promotion eventually to lead to tumor development. So, what I'm showing here is simply a display of results comparing the effect of 20% protein diets with 5% protein diets, on the development of these early pre-cancerous clusters, or as I refer to them here, as foci. Now, if we look at the dotted line as shown there over the first 12 weeks of this early tumor development, you can see that the animals fed the 20% protein diets, these early foci began to increase and continue to increase over that 12 week period if in fact the animals are fed the 20% protein diets. In contrast, if we went back then, and decided to switch the diets from 20% to 5% and back to 20% and back to 5% again, in other words, do a so-called “dietary intervention study.” We got some really interesting results. Animals, for the first three weeks fed the 20% protein diets, that's the regular levels, they would grow the full size they expected them as you can see with the dotted line. In contrast, animals then, if they were switched to a low protein diet, the development of those early foci were turned off. That was for the next 3 weeks. And of course you can see for the following 3 weeks going up to 9 weeks, if the animals were put back on the 20% protein diet, these cells continued to grow, were turned on again. What we in fact learned, with this kind of study, was that we could virtually turn on and turn off tumor development as expressed here by these early pre-cancer foci. I really probably shouldn't say tumors, but they're pre-cancerous foci, they were indicative of tumor development. We can essentially turn on and turn off the development of these early, foci, over the first 12 weeks of the experiment, simply by feeding them the 20% protein diets or the 5% protein diets. CNS602 -- 2.3 -- Effects of Protein Feeding on Viral Carcinogenesis T. Colin Campbell, PhD Okay, here is an extension of what we looked at with respect to early foci development. What we were doing here was to look at the effective protein intake or protein consumption on the development of tumors over the lifetime of the animal. Not just early foci formation, but instead on full tumor growths during that period. And this experiment was designed in a way in which these animals, of course, were exposed to a chemical carcinogen in the beginning that could cause liver cancer, but then were fed two different levels of protein again, the 5% and 20%. And we measured to see what kind of tumors actually formed after 100 weeks or about two years, which is the normal lifetime of the animals. And you can see that with the animals fed the 20% protein diets, they got a very large amount of tumor activity, we refer to it as tumor severity, which means, it takes into consideration mostly the percent incidence, as the number of animals actually getting the tumors as well as the tumor weight. In any event, you can see with that tumor severity index, that the animal given the 20% protein diet



got lots and lot of tumor activity. The animals given the 5% protein diets had virtually almost no tumor activity. But what was really interesting about this study was that when the animals were given the 5% protein, they were all living at 100 weeks, were very thrifty, alive, well, had sleek hair coats, very energetic and active in jumping around the cage. As if, in fact, they were still reasonably young with no tumors, no absorbable tumors. In contrast, the animals fed the 20% protein diets, they were all dead at 100 weeks with liver tumors. A really remarkable difference that was consistent with what, in fact, the Indian workers had reported. So we achieved the objective number one, that was to show in fact that animals fed the regular levels of protein did indeed grow tumors far more dramatically than did animals fed the lower levels of protein. What we just saw in the previous slide was the effect of protein feeding on the development of tumors initiated by a chemical. The next question we wanted to ask, and we were able to ask the question because some research had been done in other laboratories on this in part, we wanted to ask the question whether the protein feeding might have an effect on the development of liver tumors in animals that were initiated not by a chemical, but by a virus. And so we're asking a question about what was the effect of protein feeding on viral carcinogenesis? In the case of the chemical in the previous studies, it was aflatoxin that obviously we already know gets metabolized, attacks genes, and initiates the liver cancer, and that's in rats. In the case of the study on the virus, what we were doing there was to take advantage of some work that had been done by others, showing that when animals were exposed to Hepatitis B virus, this virus comprised of DNA, incidentally, was capable of inserting a portion of its DNA or its gene into the liver DNA, in this case of mice. And that was the means by which the virus started or initiated the development of liver cancer in these animals. So the question then we wanted to know was whether or not the protein feeding could affect the subsequent development of the tumors that would emerge from this Hepatitis B virus initiation. CNS602 -- 2.4 -- Carcinogenicity & Explanatory Mechanisms T. Colin Campbell, PhD Here are some results from the feeding of different levels of protein on the development of liver tumors in the mice that have been exposed to the hepatitis B virus gene, just a word by way of background on what this picture is really showing. These are four we refer to them as sections. They're four tissues that have been prepared from, essentially a biopsy of the livers of these mice to see what we see. And just a word of caution, you'll see that two of these pictures have big white holes in them ignore that. It means nothing, it's just a cross section of a vessel passing through the tissue. What I wanna draw your attention to is the idea that animals that were so to speak transfected with the virus, they are considered to be transgenic. That animals that are transfected with a virus and then fed different levels of protein, the effect of protein on the development of these lesions and these animals was really substantial and we can see that in the slide or the section in the upper right quadrant. If one looks at this, you can see some dark stained areas and it's the dark staining that really matters here. That's what's indicative of the emergence and development of tumor material in these animals, you can see a lot of it in animals fed 20% protein. And in contrast, the panel that's on the lower left, animals fed 12% protein. That's quite a bit less. It's just enough to satisfy development of growth and a little more at that. You can see that there is somewhat less tumor activity in these



animals given the 12% protein, as indicated by the dark staining. And of course, the animals at 6% protein. There was essentially no staining. So what this is telling us is 20% animals really was actively growing early tumors, the 6% animals were not and the 12% protein animals were somewhat intermediate. These three panels can be compared with the one on the upper left-hand side. This is a section, this is a normal liver section in an animal that has not been transfected, but has been fed 20% protein and you can see that there is no tumor activity in that animal that was not transfected with the hepatitis B virus. I'll come back to this. This will all really mean a lot a little bit later on when I'm talking about the results that we got in the China study. Here, I've simply summarized some of the so-called explanatory mechanisms that we learned about as the protein affected the development of the tumors. You recall that we satisfied objective number one, simply showing that a higher protein diet has turned on tumor development far more so than the low protein diets and the second question that we wanted to concern ourselves with was how does it work? And this is just a very brief summary of some of the so-called mechanisms that we examined and you'll see that both during the initiation stage, and during the promotion stage that the level of protein actually affected the development of these early tumors. And subsequently, the later tumors in a number of different ways both during Initiation and during promotion. It was almost as if every time we looked for a so-called explanatory mechanism, we found one. And that was an observation that I first found was somewhat frustrating and troubling, because it was hard to know which one really mattered. But then eventually, it became quite clear that the protein was acting in such a way on both of these stages, the dietary protein was acting in such a way that it seemed to cause the emergence of a whole host of different kinds of mechanisms that were very likely to be highly integrated as a produced the final response. Again, I wanna come back to this point a little bit later on and I'm talking about mechanism and the way in which nutrients work as they affect development of cancer. And in this process, we were learning, of course, that the effect on promotion was apparently much greater than the effect on initiation and we'll see it in subsequent findings how that really works. CNS602 -- 2.5 -- Casein: The Importance of Casein T. Colin Campbell, PhD Here I'm simply making a statement summarizing a very provocative part of our research, when we asked the question concerning the kind of protein that we're actually using in these animal studies. Throughout these studies we had been using Casein, which represents about 87% of cow's milk protein. And that was really quite a remarkable thing to realize, that something so commonly consumed and so regarded as being so important was capable of better access of what is actually needed could have this rather remarkable effect on tumor development. And what really made it more remarkable was the fact that when we tested soy protein, and wheat protein, at also 20% of the total diet calories, we did not see tumors being developed at all, with those soy and wheat proteins, two plant proteins. It only happened when we were using casein, an animal-based protein. Here, I want to just point out a couple more features about the way in which protein works that we need to bear in mind. In this slide, I'm simply showing the effect of the percent of dietary protein on



the development of these early cancer cells. And you can see that, as we explored this relationship, it turned out that when casein represented anywhere from 4 to 10% of the total dietary protein, essentially, there was no effect on the development of this early full side. However, when the level of protein exceeded a level of 10% in the diet. There was a fairly sharp dose-response relationship going from 10 up to 20% protein. And, of course, you could see the two figures on there of 20%, and a 4 to 6% at the bottom to see these remarkable differences. And so, what really was interesting about this particular finding was the fact that about 10% protein is the amount that's required for maximizing growth rates in these young animals. In fact, they can actually do with less than 10% as they become older. But in any case, 10% is the amount that is actually needed for this very important nutrient. In contrast, it was actually the amount that's consumed in excess of the amount needed that actually causes cancer's response. And to put this in the context of human nutrition, I should point out that the amount of protein required by humans is approximately the same as is the case for rodents. We also need about 10% protein, more or less, in fact even less, possibly. On the other hand, it turns out that most humans, in fact almost all humans, are consuming diets that are in excess of the ten percent of the amount that we actually need. This, if it's related to humans, is a very important observation. Here, I'm showing yet another feature effect of this protein effect that's really quite interesting. In fact, I could show a lot of effects of protein on various and sundry activities and I'm only showing here just a couple that are particularly significant. In this case, what we're looking at is the effect of protein feeding comparing 20% dietary protein with 5% dietary protein on the principle enzyme that's responsible for metabolizing that initiating chemical procedure called aflatoxin and that enzyme is very, very important, it has all kinds of activities. But what was really interesting about this is that we saw essentially a twofold difference in that enzyme activity within one day, after feeding the protein meals. There was, from other studies, an indication that this enzyme activity can change very rapidly even after a meal of consuming high or low protein. And it continued to, as you can see from this presentation here, it continued to become very, very different over a four day period as one tends to feed a 20% versus a 5% protein diet. Of course, from my perspective, I think that's an extremely rapid response that reflects the ability of a food that we consume to alter important activities that may in fact bare our relationships on cancer development and it can cause this effect in a very short period of time. I want to pause just for a moment and summarize what we've observed so far, just pointing out three observations that many would regard then and still do today as virtual heresy. Principally because it does involve a very, very important protein that people think is healthy. Namely protein, or, obviously in this case casein, fed higher than the amount that's actually required, promotes cancer. Secondly, a reasonable shift in the level of dietary protein going from, let's say, 5% to 20% or let's say from 10% to 15%. These are the kind of levels that people will shift around from day to day or between individuals. A reasonable shift in level of dietary protein consumed turns cancer on and off, even at relatively advanced stages of the disease. That's a provocative thought if one stops and thinks about it a bit. And finally, protein feeding, as it causes these changes, can act very swiftly, within perhaps just hours after consuming the meal.



I want to just draw our attention to one more observation that many would regard as heresy, but I don't. I think we establish this information very carefully and for many different perspectives, only a part of the data of which is shown here. In any event, if we were to observe the traditional regulatory criteria as to what is a chemical carcinogen, and what is not, according to the Delaney Amendment that we talked about in the first lecture, if we observe these very traditional sort of rules of the day, we'd have to conclude that casein is the most significant chemical carcinogen ever discovered. That, of course, in the minds of most people would be considered absolutely heretical. But we did it very carefully and for multiple different perspectives and published the results in the very best cancer research journals.CNS602 -- 2.6 -- Activity: Is Casein a Carcinogen? T. Colin Campbell, PhD Casein is a chemical carcinogen. Some chemicals in our environment qualify as carcinogens, that is, they cause cancer based on testing them and experimental animal studies, according to criteria set forth by our government. Such a study has one control group, that's no chemical. Then two or three treatment groups, each with increasing amounts of chemical, usually far above the amount we as humans might experience. In order to be sure that it does not cause cancer, take a look at the graph. A cancer-causing response shown here as dependent on level of chemical consumed is then used to estimate which levels of carcinogen exposure might be of concern for humans, shown in the small green box on the lower left. But estimating likely human response is virtually impossible because the rat carcinogen levels are usually orders of magnitude higher than typical human experience. In our experiments, over 25+ years, and published extensively, we showed that casein increased experimental cancer at levels within the range of human experience, that is the green box. We have no need to estimate low-level response in humans from high level response in rats, and we also know how it works. This suggests that casein, and likely most other animal proteins, is a far more relevant carcinogen than any pesticide, herbicide, food additive, or other noxious chemical ever tested. What would you conclude? CNS602 -- 2.8 -- Nutrition & Gene Expression in Cancer Development T. Colin Campbell, PhD Here is another observation that subsequently turned out to be very, very important in my view, that was illustrated by the studies that we just talked about. Namely, nutrition controls the expression of genes that are involved in the development of cancer. In other words, if we have genes that can give rise to cancer, we can in fact use nutrition to control the expression of these genes. And this was demonstrated in the information that I provided here, both for genes that are altered by carcinogens, that's chemical carcinogens, as well as genes altered by the effect of viruses. In that sense, the effect is somewhat broad, but it brings into focus the idea that it's not necessarily the question of what kind of genes we may have. Rather it's the ability of nutrition and the food we consume that becomes important in terms of controlling the expression of these genes. Here I'm simply summarizing very quickly the effects of some other nutrients on perhaps other kinds of cancers that we also studied in our laboratory. In addition to the work that we did, of course there was research actually being done by others in other laboratories that really expanded the scope of what we were beginning to understand about the role of nutrition in the development of experimental cancer. In our laboratory, for example, diets that were higher in fat tended to increase the development of early pancreatic cancer clusters, or lesions. And, we also know from larger human studies that high



fat diets are associated with a higher risk for pancreatic cancer. We also studied the effect of a very low intake of so called carotenoids, things like beta carotene for example, the colored components of vegetables. As the intake of those carotenoids, those plant-based antioxidants was decreased, the liver cancer that evolved from that was increased. So that was a nutritional imbalance in a sense that stimulated tumor development. And finally we also studied the effect of diets high in fat on transplanted mammary tumors. Similarly, high fat diets increased the abilities of these mammary tumors, once they were transplanted into animals, to take hold and to grow. This summary here, therefore, together with the earlier work that I discussed, addresses this whole concept of nutritional imbalance. In some cases it is related to an inadequate intake of nutrients, in other cases it's related to an excessive intake of some nutrients and these comparisons divided along plant versus animal-based nutrients. Animal-based nutrients, when they were fed in excess, tended to stimulate cancer, plant based nutrients, in contrast, tended to decrease tumor development. And the effects that we saw in these experimental studies were really substantial. Here I am summarizing schematically what we've talked about during this lecture, especially in regards to the question that I posed at the beginning, and that was which is more important as far as the effect of nutrition is concerned? Is it more important during the process of promotion, or is it more important during the process of initiation? Or, I could even simplify the question still further, which is the more important process, is it promotion or is it initiation? In this slide, I'm simply showing schematically how normal cells all shown in blue at the top, when initiated, either with a high dose of Carcinogen, that's a high C or a low dose of Carcinogen. We get different amounts of cells that have been converted to cancer cells, we get more cancer cells through the high dose of carcinogen than we do with the low dose of carcinogen, as indicated by the red cells in that cluster. And if we continue on this course, that is to say the only difference between these two groups is the level of carcinogen that being consumed, or administered, and we continue all the way to the end of this study the animals that are given the high dose of carcinogen, they of course have more initiation, they have more so-called DNA adducts, more mutagenesis, and in effect more initiation. And this, in turn, then grows out to give rise to more clusters or foci and eventually to more tumors. In contrast, if we look on the right hand pathway the animals given a lower level of carcinogen, less DNA adducts, less mutations, of course less initiation, less clusters, and less tumors. So the amount of tumors that we get at the end of the experiment is strictly a function of how much carcinogen we get exposed to. And, this goes back to the concept of talking about the dose-response relationship between chemical carcinogens that initiate, and the ultimate tumor response we see at the end. We've done something here that really is quite remarkable, namely, we have the two groups of animals given either a high dose of carcinogen or a low dose of carcinogen. And instead of continuing the same diet, we put the animals that had more preneoplastic cells in the beginning because of a high dose of carcinogen and put them on a low protein diet, which I call an optimum diet, shown in green, and in effect we get less foci, less tumors. And in contrast, if we take the animals that are given only a low dose of carcinogen much less initiation, but then in turn give them a diet that is considered to be excessive is high in protein, we've got more foci and more tumors. This only shows schematically this effect, but the results that we got were really remarkable in this regard. That is to say, it didn't really make any difference as to the level of carcinogen that we got exposed to in the beginning, or that we were using these experiments that don't, those of course that



have made no difference if in fact we subsequently fed diets that had different levels of protein, and thus diets that could affect the growth of these tumors after they were present. I mean, the animals that had the highest amount of initiation were the ones that gave little or no tumors. The animals that gave the lowest level of carcinogen when given the high protein diet, they in fact got more foci, more tumors. This really does show very dramatically that the effect of promotion supersedes that that goes on during initiation. And more particularly, it shows too, that simply altering diet during the promotion stage can have really a dramatic effect on whether or not tumors really grow, regardless of the carcinogen dose in the beginning. Here, I am just simply summarizing the points I just made, and I need not dwell on this, except to point out that these two observations, in my view, really summarizes a lot of research only a small portion of which has been shown here. But it shows primarily that nutrition, especially in the form of protein intake, but also in the form of intake of other nutrients as well, play a very important role in the development of cancer. And the role that is played is primarily during promotion rather than during initiation. I should point out however, and I didn't show the results of that here. High protein diets actually increase initiation, increase the activation of the carcinogen, for example, increases the formation of the DNA adducts and so the high protein diet actually increases initiation activity as well as during promotion activity. But the effect of protein on promotion activity supersedes whatever may have occurred during initiation. CNS602 -- 2.10 – What is Angiogenesis? William W. Li, MD So angiogenesis is the process by which our bodies grow blood vessels. It's a fundamental process that is critical for developing a network that we call the circulation. That is much bigger and broader than anyone previously thought. Blood vessels literally service every cell and every organ and every tissue in the body. And in fact, if you were to pull out all the blood vessels in the body and line them up end-to-end, you would have a line that will be 60,000 miles long. In other words, you'd actually have a string that would encircle the Earth twice. So this network, this extensive network of circulation made of blood vessels, we used to think only carried oxygen and delivered nutrients to parts of the body. But we now know, using contemporary research findings, that the cells that comprise the circulation, we call this the endothelial cell, has a profound other function. Not only does it line blood vessels, but these endothelial cells are factories that produce a whole host of other paracrine survival and even regenerative factors that act on the cells and the tissues next door to where the blood vessel cells are, and help them function in a healthy way. Understanding angiogenesis is really about understanding balance. And when one speaks about or learns about angiogenesis, often you think about either too much blood vessel growth, excessive angiogenesis, or insufficient angiogenesis, or not enough blood vessel growth, as it relates to disease. But actually, a modern way of understanding angiogenesis is that it's a defense system in the body. Just like the immune system, the blood clotting system, the inflammatory system. And because it's a defense system, it has to function in a balanced way. And that means that you can't have too much angiogenesis or too little angiogenesis, but rather you have to have just the right amount. Now we've actually been reconceptualizing this kind of function, which also applies to the immune system, as the Goldilocks zone. So just like the fairy tale where you didn’t want to to have porridge that was too hot or too cold but looking for the just right, this Goldilocks principle is now beginning to



enter biology with angiogenesis and the immune system. And it's also entering cosmology where we're discovering new planets and looking for which planets are at the right distance, not too far or not too close to the sun. So this is really a modern concept that we think can be very powerful for understanding vascular health in angiogenesis. So when angiogenesis is healthy and we have just the right number blood vessels, our organs are healthy, we are healthy and everything is in balance, including all the other systems in our body that are tethered to the blood supply, including the heart, the lungs, the brain, our nerves, and also the functioning of all of our organs. Now, when angiogenesis is disrupted from this Goldilocks zone, this physiological zone and insufficient angiogenesis occurs, that's when you can have problems. For example, in ischemic heart disease or in heart failure, where the body is unable to support enough angiogenesis to stay within that Goldilocks zone. If you can't stay within the healthy zone, and you don't have enough blood vessels, you wind up having problems. Now, the flip side of that, is that there are certain diseases like cancer but also other diseases. For example, in the eye like diabetic retinopathy, or age-related macular degeneration, where the pathology is such that the Goldilocks zone is upset in the other direction. So beyond the physiological required amount of blood vessels, there is excessive, inappropriate, and usually abnormal blood vessels that grow above the Goldilocks zone. Way too many blood vessels that aren't functioning normally. And that's where you have blood vessels that are not in balance and feeding disease and driving them along. So the big picture is that angiogenesis is a bodily defense system that has to be kept in balance. And when it is not in balance, the goal, therapeutically, is to put it back into the state of balance. Back in the 1990s, when I was involved with the early days developing assay systems, test systems in the laboratory to study angiogenesis, we were developing these test systems with the goal of developing biotechnologies, sort of targeted new drugs that would actually be able to knock out bad blood vessels on one hand or grow them where we needed to restore them into balance. These are angiogenesis inhibitors which wound up leading to dramatic breakthroughs for cancer treatment. Or angiogenesis stimulators which actually have been very helpful for transforming the work of surgeons for wound healing. The key is really that these test systems that allowed us to look at drugs really relied on using cells and animals' systems, and even genetics systems to be able to test candidate interventions. I began to wonder whether or not the same system could actually be used to test foods. After all, foods are the chemotherapy that we take three times a day, and here we were developing cancer drugs. And so, what we did, along with some other pioneering folks and groups around the world, was to begin taking a look at what bioactives are in foods. How do we extract them? How do we think about them in a meaningful way that would relate to what they do in the body once we ate those foods? And then what, and this is the key, what impact would the foods actually have on bodily function itself? Could we study this using these assay systems in an angiogenesis system? And when we actually tested foods finally, we were not at all surprised to find that many foods inhibit angiogenesis. And in fact, this is supported by the hundreds of scientific publications that have emerged showing that specific bioactive natural chemicals that are found in foods, found in fruits, vegetables, herbs, spices, are actually angiogenesis mediators, and most of them are angiogenesis inhibitors.



And in many cases, the mechanisms that have been discovered is that these food bioactives inhibit a protein called vascular endothelial growth factor, or VEGF, sometimes called VEGF. And that VEGF itself is the target of a billion dollar effort to really develop drugs, in some cases, very successfully. So, here we have a target, VEGF, that's important for angiogenesis, that has been validated successfully in drug development, that we have now found that foods can actually also influence. And this is just the beginning. Beyond VEGF, there are many other effectors and mechanisms involved with angiogenesis in which the foodborne bioactives also can play an important role for restoring balance by essentially pruning away the excessive abnormal angiogenesis induced by these factors. CNS602 -- 2.11 – Angiogenesis and Cancer Treatment William W. Li, MD Many of the most important modern cancer treatments that have been developed in the last 10 or 15 years, actually target angiogenesis. There are now monoclonal antibodies and small molecule drugs that actually hit what we call tyrosine kinase pathways, or tyrosine kinase inhibitors that are all designed, rationally designed, to be smart bombs to target the abnormal angiogenesis feeding cancer. And, in fact, there are more than 18 of these new cancer treatments that are FDA approved. The FDA, in fact, has recognized targeting angiogenesis, or angiogenesis inhibition, as the fourth modality for cancer treatment after surgery, chemotherapy, radiation, and now angiogenesis inhibition, so one of the hallmarks of cancer. So if we can treat cancer patients by bringing them in and giving them prescriptions, and infusing them with agents that are designed to target angiogenesis, the question is are we able to utilize the same types of effectors that are present in food to add something more to the equation? So for example, the cancer patient with colon cancer or lung cancer or brain cancer or kidney cancer these are all examples of cancers that for which there are approved, FDA approved anti antigenic treatments. Can we now use our knowledge of what's present in food to be able to add something to the treatment three times a day? Not delivered by intravenous infusion, but delivered by diet. Can we use food as a carrier for mother nature's arsenal against cancer, that would also help to balance angiogenesis in the body? And the answer is yes, and that's really what our focus of research is on today. When we think about cancer, traditionally we think of a horrible disease. One day we're healthy, and then we go to the doctor, we get a scan, and we are diagnosed with a terrible disease. But in point of fact, we're all forming cancer. Everyone who is watching this video has cancer in their body. And the reason that that is, is that the human body we now know is composed of anywhere from 60 to 100 trillion cells that are all replicating to be able to keep us alive, and as they divide, all that has to happen is for one or two mistakes to happen in cell division. And instantaneously, we have a microscopic cancer, a harmless cancer, but still a cancer nonetheless, that has formed. And our bodies, from the time we're born until the time we die not from cancer, are battling constantly these little, microscopic, let's call them pimples that represent cancer. Fortunately, our body is really good at defending ourselves. Our immune system wipes this out and the cancer cells themselves are rather fragile. So what we're actually doing with anti-angiogenesis in diet is both to prevent those small cancers from growing up. So without a blood supply these tiny dormant microscopic cancers can't grow larger than about five millimeters. That's about the size of the head of a pin. Without a blood supply they can't grow up. So by intaking dietary factors that contain angiogenesis inhibitors, we are depriving the ability of these microscopic dormant cancers from being able to grow their own blood



supply. Now by the same token for people that have been diagnosed with cancer and obviously the big ones are colon, lung, breast, prostate, but there are many other cancers that all depend upon angiogenesis, if a patient has been diagnosed with a cancer, there is inevitably, either in clinical trial or approved, an angiogenesis inhibitor drug that is being looked at or is in use for treating that cancer. So, here is an opportunity to use dietary approaches to introduce into our bodies factors that can influence exact same targets that the drugs are actually being developed and are being used for. So we augment treatments for intervention. We're able to augment what the drugs are doing. So it's both prevention, as well as intervention, that is a concept of angioprevention of disease or angiogenesis inhibition of established diagnose cancer. For us to look at antiangiogenic therapy, using a dietary approach, we've really taken a comprehensive approach, everything from looking at cells in the lab and their pathways to animals that have actually been developing tumors, standard test systems that are used when drugs are developed. And we've also looked at human research, and in the human research we don't have to look very far to find some really well-designed, prospective clinical studies, including dietary studies, with biomarkers of certain foods that are known to contain dietary angiogenesis factors. And then we can take it beyond that, to look at public health studies, in which we're looking at thousands, tens of thousands, or even hundreds of thousands of patients, and which we're correlating the reported intake of dietary factors or dietary ingredients, foods at certain doses or certain frequency and correlating that with a clinical outcome. So, I think that when you're looking at dietary approaches to disease, there is no single test, no single assay that is able to conclusively demonstrate the value or effectiveness or the mechanism. But really it is compiling multiple tools that are now available to us in the modern medical research era to be able to make that case. At the Angiogenesis Foundation, the research that we are doing and coordinating around the world is to look at naturally occurring, bio-active substances, natural chemicals that are found in foods. Many of these natural chemicals have already been identified for their anti-inflammatory or antioxidant approach. And we're taking a look, a new look at some of these substances for what they can do to rebalance the body's angiogenesis system. Many of these bioactives would be familiar to viewers of this video, for example phytoestrogens or polyphenols or sulforaphanes or tocotrienols or lycopene or catechins or omega 3 fatty acids. What we're finding is that many of these bioactives are in fact very powerful mediators of healthy angiogenesis. And you find them in foods that we know are healthy like tomato and kale and berries, mustard greens, nuts, oils like olive oils, and fish, marine fish, and shellfish. So we're not really reinventing the wheel here, we're actually having a much deeper dive into understanding a mechanism by which foods that are already known to be healthy could be leveraged perhaps more precisely to be able to have a beneficial impact to boosting our body’s defense system. One of the questions that's often asked is are there any angiogenesis foods that are impacting foods, that are actually harmful? In other words, are there any foods that can stimulate angiogenesis in a way that causes cancer by growing blood vessels or are there any foods that can inhibit angiogenesis to the point where it actually causes problems with wound healing or for the heart? The answer is no. And part of the reason is because the dietary approach to balancing angiogenesis very much appears to actually follow the Goldilocks zone. So, for example, we are unable to block angiogenesis below the body's ability to maintain it. By the same token, we are unable to grow blood vessels above the ability for the body to be able to control it within that Goldilocks zone. Let me give you an example of a specific molecule that is not harmful, but in theory, one could ask the question, what is its potential? Arginine is an amino acid found in many different types of foods,



found in seafood, soy bean, nuts, but it doesn't cause cancer. Arginine actually acts as a natural component amino acid in many foods by increasing the body's ability to upregulate nitric oxide. Nitric oxide is a switching mechanism for creating vascular endothelial growth factor, which is important for keeping blood vessels within that healthy zone, and only within that healthy zone, so eating foods with arginine we don't actually drive cancer, but it actually keeps cells in a healthy way. And similarly, we think that the bio act is present in other foods. Also to function the same way, they defend, they are guardians of the Goldilocks zone, and they're unable to, let's say, topple the kingdom. Rather they are able to just keep things propped up in the right place at the right time. CNS602 -- 2.13 -- Prostate Cancer & Lifestyle Research Dean Ornish, MD From a research standpoint, we went from looking at heart disease, to men with early stage prostate cancer. I was struck by how the epidemiology, the animal studies, and others were very similar with prostate cancer as they've been with heart disease. But no one had really done an intervention. So we took men and who had documented, biopsy-proven prostate cancer, but who had elected, for reasons unrelated to our study, not to be treated conventionally. What we call watchful waiting or now call active surveillance. And then we can randomly divide them into two groups, and look at the effects of lifestyle changes alone without it being confounded by the usual chemo, and radiation and surgery. What we found after a year is that PSA, which is a marker for prostate cancer, went up or got worse in the randomized control group, went down or got better in the experimental group who was on our program, these differences were highly significant. We published this in the Journal of Urology, the leading peer-review urology journal. And again we found that the more closely people made these changes that we recommended across both groups, the lower their PSA came. But as many people know, PSA can be affected by things other than prostate cancer. So we sent some of their blood serum to Dr. Bill Aronson's lab at UCLA. And he added it to a standard line of prostate tumor cells growing to tissue culture and found that the tumor growth was inhibited 70% in the group that made these changes in the experimental group but only 9% of the control group. Remember the control group was also making lifestyle changes. We couldn't tell them not to. They all had prostate cancer. They're on the Internet. They're reading things. But they weren't changed to the same degree. And so, there was a huge difference. 70% versus a 9% inhibition of the prostate tumor growth. In addition, in a subset of these patients, what was done was a new test called MR spectroscopy, as well as MRIs which looked at not only the anatomy but the activity of the tumor. And we've found that the tumor activity diminished as well as the PSA coming down. And finally, none of the experiment group patients underwent surgery, or radiation, or chemo during the first year, but six of the control group patients did. So taken as a whole this was the first, and as far as I know, still the only randomized controlled trial showing that lifestyle changes alone may slow, stop, and even reverse the progression of men with early stage prostate cancer. And what's true for prostate cancer will likely be true for breast cancer in women as well, which I think is particularly notable. Just a week or two ago a major study came out showing that women with early stage breast cancer in what's called ductal carcinoma in situ (DCIS) who often get a mastectomy or even a double mastectomy or at minimum a lumpectomy show no improvement from the surgery compared to those who did nothing. And that doesn't even include those who made intensive lifestyle changes.



So, we wondered what might be causing the improvement in prostate cancer. And so we looked at their gene expression and we found that after just three months, over 500 genes were changed. In effect, upregulating or turning on the genes that are protective, down regulating or turning off the genes, particularly the genes that cause oxidative stress and inflammation, and also, they're what are called RAS Oncogenes that promote prostate, breast, and colon cancer, were just turned off over 453 of these genes were down regulated. 501 genes altogether were affected. It’s the, you know, when I was in medical school, we were told that and oftentimes I hear patients say things like, I've just got bad genes there's nothing I can do about it. Well, it turns out there's a lot you can do about it and a lot more quickly than we had once realized. Not to blame, but to empower. Cause if we're just a victim of our genes then what can you do? But if we can do something about it, that's a very powerful message to give people. Again not to blame them, but to empower them. Here's what you can do about that and how quickly these changes can occur. And we submitted that with Craig Venter to the proceedings of the national academy of sciences which published it. We then did a study with Elizabeth Blackburn, a professor here at UCSF who was awarded the Nobel Prize in medicine about five years ago for her pioneering work on telomerase and telomeres. Telomeres, as you may know, are the ends of our chromosomes that control aging, and they tend to get shorter over time. They're sometimes likened to the plastic tips on the ends of shoelaces that keep your shoelaces from unraveling, in a sense they keep our DNA from unraveling. And as we get older our telomeres tend to get shorter, and as our telomeres get shorter our lives tend to get shorter and the risk of premature death from any number of chronic diseases. From heart disease, most forms of cancer, dementia and so on, go up. We found that after just three months, telomerase, the enzyme that repairs and lengthens telomeres, increased by 30% in these patients. And we published that in the Lancet Oncology. We then followed these patients for five years and found that the telomeres themselves after five years got about 10% longer, whereas they got shorter (which is what usually happens) in the control group. And when the Lancet Oncology published that paper as well, they sent a press release and they called it reversing aging at a cellular level which in many ways it is. It's still the only control study that I'm aware of showing that lifestyle changes alone can actually lengthen telomeres rather than just slowing the rate in which they get shorter. We're about to publish the first study showing that these same lifestyle changes may affect angiogenesis. When tumors grow, Judah Folkman at Harvard found that they secrete substances, the tumor secretes substances like VEGF that attract blood vessels to grow and stimulate them to grow and feed the tumor. Because the tumors grow so quickly, they outstrip the blood supply and if you can do that with drugs like Avastin and Nexavar, you can inhibit the growth of a tumor and sometimes even kill it with less toxicity by disrupting the blood supply that's feeding it, than if you're trying to kill the tumor directly. We found that this same lifestyle changes that we've been talking about could downregulate VEGF and therefore inhibit angiogenesis to the same degree that these drugs can. But the drugs are about $100,000 a year per person and the only side effects of lifestyle changes are good ones. Now it's worth pointing out that with all this talk about personalized medicine and precision medicine and so on, and there are some you know things that are worth discussing. But it was the same lifestyle intervention for all of these studies. It wasn't like there was one set of lifestyle recommendations for reversing heart disease, a different one for prostate cancer, or your genes, or your telomeres, your angiogenesis. Or, for that matter, type II diabetes or getting blood pressure or cholesterol levels down or losing weight and keeping it off. It was the same lifestyle intervention for all of these.



It's almost as though if you give your body the right raw ingredients, and again not just the diet, but the stress management, the exercise and the social support or love and intimacy, that your body can begin to heal itself. And our bodies have a remarkable capacity, in many cases, to begin healing. And much more quickly than we had once realized, if we can address these fundamental causes, which, to a much larger degree than people had once realized, are lifestyle-related. CNS602 -- 2.15 -- Food Components and Cancer Research Rui Hau Liu, PhD, MD We started whole foods, using the whole food approach to study the cancer prevention, use the fruit, extract, use apple as the example. We have a animal model induce the breast cancer and in the rat is a mammary cancer equivalent to the human breast cancer. Then we gave the animal apple extract equivalent to human consumption, one apple a day, three apple a day, and six apple a day. It inhibited tumor formation in animal model in a very nice, dose dependent manner, and not only inhibited the tumor formation, but also, the tumor grow much slower in apple treated group, and the tumor grows slower, and the malignant, less malignant the tumor, compared to the untreated of the group. Not only one compound, or two compound. Many compound together. I think the bioactive compound from the fruit vegetable. Including the carotenoids, including the phenolic or phenolic acid flavonoids. And many other compounds. It's estimated from the fruits, vegetables, and whole grains in human diets are roughly more than around 8,000 bioactive compounds. So they worked as a team and provided the additive and synergistic effect with a different mechanism reaction for the cancer prevention. In terms of the mechanism, as I mentioned early, the bioactive compound from the whole food. For example, apples, and provided the different bioactive compound and the ways the different manganese reaction for cancer prevention. Some compound with high anti-oxide activity quenches the free radical and help the DNA repair and help prevent the initial agent of carcinogenesis. Some other bioactive compound like phenolic is phenolic acid, the flavonoids and other carotenoids. They may inhibit the proliferation of tumor cell, specifically targeted on the PCNA called the tumor proliferating cell nuclear antigen. And also inhibited the second in D1 and the CTK for regulating the cell cycle, and induce the cell T1 arrest. Some other bioactive compound, they specifically targeted on the signal transduction pathway. Some act on the --- pathway, PF3K pathway and the status pathway. We're working on several signal transduction pathway, and in regulating the cell proliferation and apoptosis. And some compound may regulate the apoptosis, and the induction, induce the apoptosis in tumor cells. And some regulated oxidative stress and prevented the oxidative stress in vivo and also in retrocell cultural models, and some of the compound inhibited the cell and the migration and the inhibited the metastasis of the tumor cell. So there's many different manganese reactions. And altogether, they have a powerful anti-cancer activity. We really need is a team of the bioactive compound targeted on the different for the manganese reaction for cancer prevention. Our research clearly show s and the bioactive compound from the whole food especially from fruits, the vegetables the whole grain and other plant-based food, has very high activity with the cell proliferation and inhibits the tumor growth. And clearly, all of the scientific evidence is suggesting right now, whole food approach is powerful to prevent, for cancer prevention and for the health promotion. As a dietary supplement, and you take one compound or another compound, maybe multiple compound, cannot mimic a natural combination of the bioactive compound in foods,



vegetable, and whole grain. And the one compound, high dose, I call that the mige dose may have negative effect, currently. And the literature suggested the single antioxidant, single bioactive compound approach is not working. For example, beta carotene, selenium, vitamin E and vitamin C alone to prevent the cancer is not as effective as a combination of the compound from the whole fruit. So I encourage consumers to eat wide variety of fruits, vegetables, and whole grain and other plant based food instead of using expensive dietary supplements. And the key thing to consumer is increased servings of fruits, vegetables, and whole grain, and other plant based foods in their diet. And the key thing is to increase the serving, so including the fresh, the processed, and cooked, and frozen, and dried, and the 100% juice, all considered as servings of fruits vegetable. So we encourage consumer to eat wider variety fruit, vegetable in different form under fresh, processed, canned, and frozen. Some of the bioactive compound may retain in the processed fruit, vegetable after the processed, you may have a higher bioavailability and, for example, process the tomato as a higher antioxidant activity. And the lycopene in the process of the tomato is more bioavailable. CNS602 -- 2.16 -- Module Wrap-Up: Cancer & Current Research Thomas Campbell, MD Over the first two modules of this course, you've seen a very brief overview, a sampling of evidence relating nutrition to cancer. You've looked at a brief overview of my dad's lifetime of work. From the China Project, to his experimental research linking nutrients to cancer promotion. And importantly, you've also seen more recent research from other scientists and clinicians who have linked nutrition to cancer in important ways. You've seen, in some of this research, that it's not about isolated nutrients, that's come up a couple times. It's more about the foods. And it's the apple extract, the whole apple extract. It's not the single antioxidant, for example. And it makes me think of principle one from the principles of nutrition and health that you've already heard. And that is that nutrition represents the countless activities of countless food substances, working together. The whole is greater than the sum of its parts. CNS602 -- 3.1 -- Module Introduction: The Cause and Pathology of Heart Disease Thomas Campbell, MD In 1948, Doctor Lawrence Ellis who is an assistant clinical professor of medicine at Harvard Medical School, wrote a review article for the Journal of Nursing. The review article was about the causes of heart disease. It talked about some of the infectious causes like rheumatic heart disease that were more prevalent at the time. He also talked about some of the linked factors that they knew were related to heart disease. High blood pressure, obesity, and some disorders possibly of cholesterol metabolism or at least the hypothesis of that at the time. And this was also linked to diabetes and hypothyroidism. But in summary he wrote about the prevalence of the unknown in this disease. He writes, coronary arteriosclerosis is a disease predominantly of men. It occurs at an earlier age and in greater frequency among men than women. Why? We don't know. It is a disease of civilization. It is commoner in this country than it used to be and seems to occur with a special frequency in groups of the population subjected to the high pressure, competitive form of life so far removed from the simplicity of living close to nature. Is this a penalty man pays for getting so far away from the environment for which he was intended by nature? If so, the factors leading to his vascular downfall are yet to be unraveled. One thing is known. Persons who have any evidence of coronary disease



should regulate their lives to avoid chronic fatigue and mental and physical strain. Otherwise the treatment is largely symptomatic and palliative. Since that time, our understanding of this disease has improved dramatically. And yet 65 years later, heart disease and its risk factors remain the most expensive, most common ailments in our society. In my own practice I see patients all the time with heart disease and its risk factors, high blood pressure, high cholesterol, obesity, diabetes and so on. All physicians, all primary care physicians can say the same. The goal of our conversation is to understand the early research on diet and heart disease. How did we go from not knowing much to knowing what we know now? And how did that understanding evolve? What does that tell us about what is the optimal diet? CNS602 -- 3.2 -- Studying Heart Disease - Large Populations Thomas Campbell, MD So if we're going to start to explore the question of what diet causes heart disease, we might want to start with what I call the alien approach. And the idea is this, if you were an alien that were plopped down from outer space onto Earth, and you had been tasked with the job of figuring out what caused heart disease, what would you start with? How would you begin your investigation? I think a logical place that many people would think of is to look at those people who have heart disease, see what they do in their life and then look at those people who don't have heart disease and see what they do in their life. And then begin to compare, are there differences in their lifestyles, their diets, etc., to figure out what might be related to heart disease. The early research on diet and heart disease was of the same vein. So back in the early 1950s, we had quite a lot of data. The World Health Organization had compiled mortality statistics for a wide variety of countries around the world and they call them the vital statistics. And the Food and Agricultural Organization had compiled what they called food balance sheets, which was looking at the food that was available in each of these countries. So researchers had a task at that point just to begin to look at who was dying from heart disease and what food was in their country. And that's exactly what was done particularly for men of middle aged, aged 55 to 59. And the first study I want to go over, the first article, is one by Joe Leafe, published in the Journal of Chronic Disease. Joe Leafe worked out of New York, and published this work from a project in New York City. The first graph I want to show is the relationship between saturated fat and coronary disease death rate in men aged 55 to 59. So if you look at this graph, each dot represents a separate country. So, you look at the country in the World Health Organization FAO, and you see what their death rate is. And then you look at how much of their diet comes from saturated fat, what percent of their total calories. And what we see here is that in these countries, as they had more saturated fat in their diet, so they had a higher rate of heart disease, at least for men of middle age. And the relationship is really quite strong. So each dot is a different country, and the line that goes through them is called the line of best fit. That sort of represents the overall relationship, the overall correlation between these two factors among these countries. But we can also look, not just at saturated fat, but we can look at the percent of calories from animal protein. And he did just that. So we see another graph looking at the percent of animal protein in these diets comparing them with mortality rates from coronary heart disease. And what we see is that as more animal protein is in the diet, so goes up the death rate from coronary disease. Again, quite a striking relationship.



And I wanted just make a quick point about the idea of correlation at this point. The correlation is a word thrown around but just to define it, it's really the relationship between two variables. Do they fluctuate together? So, do they occur in the same groups at the same time, going in the same direction? If one variable goes up, does the other variable go up? Or, we can also ask if one variable goes up, does the other variable go down? Are they linked in some way? That's really all a correlation is. So Dr. Yud Ken was at the University of London and he looked at similar data in the early 1950s and published his article in the Lancet. And we see largely the same thing, if you look at countries around the world where good data is available, again, as animal protein increases in the diet so does the death rate from coronary heart disease. Also one more thing, as sugar increases in the diet in countries around the world, so does the death rate from coronary heart disease. So now we have saturated fat, animal protein, now sugar, not shown but also in these studies, is total calorie intake. As total calorie intake goes up, so does the death rate from heart disease. Total fat intake, as that goes up, so does the death rate from heart disease. And this was all done in the early 19, this is all data from the early 1950s and published shortly thereafter. But this has been found since that time. I mean, this is a consistent finding over the past 50 years. In 1993, in the journal's circulation, a study was published using data from the 1970s, again, looking at World Health Organization and FAO, Food and Agriculture Organization, food balance sheets and correlating the diets with the death rates from heart disease. And what was found is that there were a group of foods that were positively correlated with heart disease and a group of foods that were negatively correlated with heart disease. What do I mean by that? A perfect correlation is a number represented by, is one. So, a correlation of negative one means that as one variable goes up, the other variable goes down in exact same proportion. Very tightly linked. If the correlation is positive one, the correlations move in the same direction together. Again, a negative one means that they move in opposite directions. So, back to our study in 1993 in the journal's circulation, the positive correlations with coronary heart disease and the dietary factors were these factors: milk calcium, butterfat, calories from animal food, saturated fat, milk protein, milk, cholesterol, meat fat and meat protein. All of these were very strongly, positively correlated with death rate from heart disease. As death rate goes up, so do these factors. Or as these factors are higher in the diet, the death rate from heart disease is higher. If you look at the negative correlations with heart disease, we see that there are calories from vegetable foods, iron, starch and total carbohydrate. So again, negative correlation means that as the diets contained more calories from vegetable foods for example, the death rate from heart disease was lower. So one goes up, the other goes down. And again, these numbers are really quite striking. In looking at some of these early correlations, we begin to see a sample of some of these findings on broad investigations, looking at international diets, and heart disease death rates in different countries. CNS602 -- 3.4 -- Studying Populations with Lower Rates of Heart Disease Thomas Campbell, MD So, we have looked at a large range of international data with very broad measures of diet and heart disease, but I want to draw your attention to something that is kind of an interesting idea. In this particular chart, the correlation between percent animal protein and the death rate from heart



disease. When we look at that line of best fit, that diagonal line, we see that if we extend it down it goes through the origin just about. So the lower the animal protein, is it possible, again just a conjecture, is it possible that the lower the animal protein you get down to zero death rate from heart disease? Well, in this particular study we only see countries with low but not zero rates of heart disease. So, which are these countries, and as you might guess the countries that have very low rates of heart disease. In these studies were some of the Mediterranean countries and some of the Asian countries. So, Japan, France, Yugoslavia, Ceylon, which is now Sri Lanka, all had significantly lower rates of heart disease death. But there have been some specific populations with very little or no premature death from heart disease. They got down to zero, they include the Papua New Guinea Highlanders. Now the Papua New Guinea Highlanders are an indigenous people that live in the highlands of this island nation and they rely very, very heavily on sweet potatoes, one food. In fact, when scientists went in to measure their diet, they found that up to 90% of their total calorie intake was from that one food, from sweet potatoes. They had almost no meat intake and they had almost no heart disease by the researcher's measures. Another research group looked at Papua New Guinea seaside islanders. Now this is a large island, island country, and this is quite a different population. But again, this indigenous traditional culture subsisted largely on one food again, tubers, sweet potatoes. Again with 50 to 70% of their total energy from this one food. Now, near the sea, they did have some fish, they had some coconut, and they had some fruit. One thing they didn't have, two things they didn't have, were added oils and added sugars, almost none of those refined foods. A third culture I want to mention is the rural Chinese. If you look at the mortality data of the 1970s or early 1980s, you can actually find some counties in China with hundreds of thousands of people. And not one recorded cardiovascular death recorded in anyone before age 65. Now that's an amazing, amazing statement. What do they eat? They ate rice, vegetables they had small amounts of animal foods about just 5% on their diet. And again in this culture they had almost little to no added oil and almost little to no sugar. So, let's look at our fourth culture: the Okinawans. The Okinawans are traditionally known for having a very long life span. I'm sure you've heard of the Okinawan diet and that number of centenarians that live on Okinawa. They, of course, as you might expect also have very low rates of heart disease. So what's their diet? Well their diet is relatively low calorie, you might have heard of the saying eat to 80% fullness which they follow. And they rely very heavily on whole unrefined plants. In fact, again in this culture almost 70% of total calories is from one food, again a sweet potato. They eat essentially no meat, eggs, dairy, no sugar, no oil, they did have very small amounts of fish. So now we've seen data from an international sample of whole countries and also data from some individual small cultures around the world. Is there a trend? Can we begin to see a trend in this small set of data? We might say yes, that we do begin to see a commonality in the research we've seen so far. And that is this, populations with low or nonexistent heart disease death consumed very high whole plant diets. These diets have lots of plant foods, but also very little refined sugar and oil. CNS602 -- 3.6 -- Studying Heart Disease - Migrant Studies Thomas Campbell, MD



Let's go back to our original question, what causes heart disease? In many of the graphs that we've seen, we've seen that different countries around the world have traditionally had dramatically different rates of heart disease death. So if we look at our earlier graph, comparing saturated fat in the diet to death rate, we see that one of the countries with the lower death rate is Japan. The country with the highest death rate at the time was the United States. So why are there these differences? Can we say it's just saturated fat, animal proteins, some of the other dietary differences? Perhaps as Dr. Ella said in the original quote I mentioned was, is this just related to civilization, or is it possible that it's genetic? Is it possible that there are just different gene pools in each of these countries with different genetic predispositions to heart disease? I'm sure you, like I, have heard many people talk about heart disease as running in their family or high cholesterol or high blood pressure. Certainly it seems like there is a significant genetic component, perhaps that's all that we're measuring here. There's an interesting study done by Robertson, Kato, and Rhoads, and in it they looked at three different sets of Japanese men. So they went in 1960 and they looked at men of Japanese ancestry residing in Hiroshima and Nagasaki. They look at a group of Japanese men residing in Oahu, Hawaii. And they looked at Japanese men residing in San Francisco Bay Area, California. Now the people living in Hawaii and California were first or second generation immigrants and when they looked at the records they actually found that many of these people had immigrated from Hiroshima. So this was kind of a perfect example of a group of people that all came from the same area of the world. They all had the same gene pool but they were changing their lifestyle. What did they find? They found that the age adjusted rate of heart attack or cardiac death in Japan was 1.4 per 1,000 years per person. The age of heart attack or death in Hawaii was 2.8 or 3, so the heart attack deaths had doubled in the group of men residing in Hawaii. And the Japanese men living in California had a rate of heart attack or cardiac death of 4.3. So here we see the same genetic gene pool. Same men of the same genetic gene pool in three different areas that have dramatically different rates of heart disease. This is what we call a migrant study. And there's a whole slew of research under this classification of migrant studies. And this result, along with many others, suggests that it isn't genes. We aren't just seeing the effects of different genetic predispositions. Of course we know that Hawaiian culture is influenced significantly by Japanese culture. And San Francisco is even more fully American. So it's kind of interesting that we see a doubling of heart disease rates from Japan to Hawaii, and then again a 50% rise from Hawaii to California. So, it's something in the environment. And what do I mean by that? I mean it's something about the lifestyles. It's something about the way people are living, it's not the genes. Maybe it's the dietary differences that we have already seen, but at this point let's be cautious. Let's keep an open mind. CNS602 -- 3.7 -- Drawing Conclusions on Cause Thomas Campbell, MD So at this point, we're still asking what can we really say about the cause of heart disease? What is the specific factor that causes heart disease when we see these large changes in heart disease death rates. Is it saturated fat? Is it cholesterol? Perhaps, as we've seen, it's animal protein which has a strong correlation. Perhaps it's milk, perhaps it's meat fat, perhaps it's sugar. One of the core principles of this research we've seen so far that we need to step back and remember is that correlation does not equal causation. I'm sure many of you have heard that before.



Let's look at an example of this. If we correlate the amount of telephones in a country with the amount of deaths from heart disease as we've done for other factors, we actually see a pretty strong correlation. As there are more telephone, countries with more telephone poles in them, have higher rates of heart disease. You can also look at the early 1900s in the United Kingdom and look at the amount of radio and TV licenses. The amount of people with radios and TVs, and correlate that with death rate from heart disease and you see that as more people have radios and TVs there is more heart disease. So does this mean that telephone poles, radios and TVs cause heart disease? Of course it doesn't. That is what I mean by correlation does not equal causation. These are simply factors that are linked in some way. One way to begin to disentangle these correlations and disentangle these observations, is to look at the biological plausibility or the biological connection between these different factors. Is it biologically possible that telephone poles cause heart disease? I don't really think so. What about dietary factors? Well one way to do that is with animal experiments. You can control the environment to a very high degree, and you're able to study the pathologic changes that result in great detail. The model that came to be the atherosclerosis or heart disease model was the rabbit, and it was found that the rabbit actually develops atherosclerosis, this blood vessel disease and heart disease, in very much the same way that humans do. Now reaching back through time, over 100 years ago, in 1908, it was actually found that protein, meat, animal protein, causes atherosclerosis in the rabbit model. This was a very early experiment, very crude but, what followed was decades of research. From researchers around the world much of it involving casein but, not all of it, looking at the effect of protein on atherosclerosis and blood cholesterol levels. And what was generally found was that more protein or particularly animal protein more atherosclerosis, more heart disease. And one of my favorite charts, this is a summary of many, many different research trials in the rabbit model looking at the effect of different proteins on blood cholesterol levels. They studied egg yolks, skim milk, turkey, lactalbumin, casein, whole egg, fish, beef, chicken, raw egg white, rapeseed flour, wheat, peanut, cottonseed, sesame, soy, sunflower, pea, fava bean. All of these proteins were studied in the rabbit model to see how the rabbits cholesterol responded and what they found was absolutely dramatic. The animal proteins all clustered together here on the left side of this graph. Animal proteins raise cholesterol as a group much more significantly than plant proteins. Plant proteins did not raise cholesterol to nearly the same degree and the plant proteins acted similarly to each other, the animal proteins acted similarly to each other. It's a very interesting and important observation. But this was just a rabbit model. So what does this really mean? Does this mean anything for us? Well, as it turns out, this question of protein intake and type of protein intake certainly has been studied in humans. Sartori published a study in The Lancet, a well-done study, certainly a very prestigious journal, that looked at 20 people with high cholesterol. What he did was he put them in a metabolic ward at a hospital. And he tried two different diets. So they followed the diet for three weeks. So he split them in half- ten people in each group and he had one group follow a high animal protein, low fat, low cholesterol diet and they did this for three weeks. At the same time, the other group of ten people followed a zero cholesterol, very low animal protein diet, also, for three weeks at the same time. In fact, actually, the low animal protein diet had even a little bit more fat. So let's take a look at the results. In the first three weeks, the low fat diet did in fact drop the cholesterol level in these human subjects a little bit. But when they were on the low animal protein diet, the soybean diet, their cholesterol dropped dramatically in just three weeks. Then, he took the same people and he switched them to the different diet. And the second set of data reaffirmed the first set. In the



second three weeks the soybean group saw their cholesterol drop precipitously. And the low-fat diet, their cholesterol actually went up on the high animal protein, lower fat diet. Of course there are similar bodies of research regarding different types of fats, polyunsaturated, saturated, monounsaturated, and there are similar bodies of research on cholesterol. In addition to the dietary data, we've also heard and learned a lot over the past 50 years about different risk factors. So the cholesterol question, whether it matters or doesn't matter. We know that high blood pressure and high cholesterol are linked, as well as smoking and obesity. But regarding diet, we have focused an awful lot on saturated fat and cholesterol. In fact, that's pretty much all we've heard. But you could make a case, as you've seen just from the very small sliver of evidence I've shown you that the evidence is just as strong or stronger for animal protein causing heart disease or atherosclerosis. That's if you insist on targeting a single nutrient culprit. Let's talk a little bit more about whole foods and get beyond the single nutrient concept. But right now we've seen quite a depth of research that's largely unfortunately been ignored. CNS602 -- 3.8 -- Studying Heart Disease - Recent Observational Research Thomas Campbell, MD More recent observational research has accumulated findings that are similar to what we've already seen. We've seen in recent research that vegetarians have lower death rates from atherosclerotic heart disease, in particular in studies in North America and Europe. Vegetarians have been observed to have lower body weight, lower rates of blood pressure, higher blood pressure, high cholesterol, and diabetes. Which all of course are risk factors for heart disease. But I don't want to get too hung up on the words vegetarian or even vegan at this point, though. And the reason is because vegetarians and vegans, at least in our modern society, actually have a fair number of similarities to health conscious meat eaters. When you look at the nutrient intake. For example, in some studies vegetarians and vegans consume just as much fat with lots of added oil. They consume plenty of sugar and refined flours and refined foods. And when we compare modern-day vegetarians and vegans to the traditional diets of 60, 70 years ago, we see that modern-day vegetarian or vegan diets don't have as much fiber as some of these traditional plant based diets. And I don't wanna diminish the opportunities, or possibilities of vegetarian, or vegan diets. I simply want to highlight that we have really discussed at this point dietary patterns of whole foods. When we step back we're looking at the dietary patterns of plants versus animals and really we're focused on the whole foods. Through this early research and through the research of many other scientists in many other areas we've had a dramatic evolution in our understanding of heart disease over the past 50 to 60 years. In fact we really have made remarkable strides in reducing our age-standardized mortality from cardiovascular disease. In this graph we see that in the mid-1900s we peaked at a very high rate of heart disease death. And then since that time we've had a dramatic decrease, in fact by more than 50% we have reduced our death rate. How is this possible? We've heard of course that we've had increasing rates of obesity, diabetes, some other risk factors for heart disease, but what we've done really well, is some of our medical treatments. When you hit the emergency room with an acute heart attack, you are getting definitive treatment faster and better than ever before. Certainly better than happened 50-60 years ago. We've also had some reduction in risk factors. So 50-60 years ago, there were more than 40% of adults who smoked. And now there is about 20% of adults who smoke. We have better control of high blood pressure, high cholesterol. And once you have these risk factors or you have heart disease, we have medications that do help prevent or certainly delay further heart disease deaths. Taken all together, we've made enormous strides.



And heart disease and its risk factors do remain among the most problematic, expensive, and persistent problems in our society. As I said before, I deal with it every day when I see patients. And worldwide, it's no different. The diet and lifestyle transitions that have been taking place in developing countries over the past several decades are really a harbinger for just a tidal wave of problems with cardiovascular disease and its risk factors. Dr Ellis, who I quoted earlier in this discussion, said is this a penalty man pays for getting so far away from the environment for which he was intended by nature? If so, the factors leading to his vascular downfall are yet to be unravelled. We now have a much better understanding of heart disease than we did in 1948. And we have seen, just from the small sliver of evidence so far, how diet and lifestyle is likely to play a key, or perhaps even the major role. Taking this big picture view will strengthen our understanding of heart disease even when we go at it with a more clinical individual perspective. And taken together, looking at the individual data, clinical data, along with this big picture observational studies we're really beginning to see, as Dr. Ellis said, what environment or what diet may have been intended by nature. What environment we have gotten away from and even what environment may prevent heart disease. CNS602 -- 3.10 -- Treating Heart Disease Today Caldwell B. Esselstyn, Jr., MD Greetings, my name is Caldwell B Esselstyn, Jr., and it's my opportunity to share with you my research and some of my clinical strategies in the prevention and reversal of coronary artery heart disease. I'd like to start this with a story of a patient whose name we'll say is Art. And at age 32, Art developed type 2 diabetes. And that didn't seem to be much of a problem. But now, by the time he was age 43, Art now noticed that he'd began getting chest pain. And for this chest pain, he went to a local community hospital. And he ended up having a stent in the coronary artery that goes to his heart muscle. Everything was fine for about ten months, when he had more pain, went back to the same community hospital, and had to have another stent, second stent. At this point, he thought they had it conquered. He was okay for about six or eight months when more chest pain came. And so he decided this time that he would take himself to the hospital that is revered throughout the United States as number one in heart disease. And there between 2004 and 2010, he had six more stents. He had four angioplasties, which is a way of putting a balloon in a narrowing in the artery and blowing it up. And eventually he had what we call the coronary artery bypass operation. After the bypass operation he had some further stents into the bypass because it was narrowing. At this point, one morning, his bed was surrounded by doctors in white coats who had been treating him. And they said there was nothing further that they could do for him. At this point, he met with a fellow parishioner at this church, who interestingly enough gave him a copy of my book, Prevent and Reverse Heart Disease. On Memorial Day of 2010, Art and I got together. Over the next five months, he lost 45 pounds, his diabetes disappeared, all of his chest pains disappeared. And now we're closing in on four years since we met. He has had no more chest pain, no more diabetes, and he exercises freely. And all of his medications have been removed except, he does take a small dose of a cholesterol-lowering drug. Now I use that to point out, I think, the point where we're going in cardiology, to me, reminds me a great deal of where we were in general surgery 40 years ago. For 100 years, the radical mastectomy was sort of the standardized surgical error. And it took forever for courageous physicians, after 100 years of this brutal, mutilating, and painful operation, to



figure out that much smaller procedures would give us equivalent results. And my question is, where are we going today with cardiology? For instance, in the last 40 years, we have used many of these similar medications, stents, and bypasses. And really, we still haven't made a significant dent. And cardiovascular illness is still the number one killer of women and men in Western civilization. Now let me say at the outset that I have nothing but the greatest admiration and respect for my cardiovascular colleagues in cardiology. They are caring, they are compassionate, and they're brilliant. But what do we have to say about those who we consider to be the best? Can they be better? Remember that Edison once said that for progress, we have to have a dissent. So let's see if we can't add some new dimensions that perhaps can improve this. CNS602 -- 3.11 -- Who Gets Heart Disease? Caldwell B. Esselstyn, Jr., MD If you were a cardiovascular surgeon and you decided that you were gonna take your trade to rural China, the Papua Highlands in New Guinea, Central Africa, or the Tarahumara Indians in northern Mexico, forget it. You'd better plan on selling pencils. These nations and these cultures, by heritage and tradition, are plant-based. Cardiovascular disease is virtually non-existent in these areas. On the other hand, we know that when we autopsied our GIs who died in Korea, fully 80% of these 20 year olds already had gross evidence of coronary artery disease that you could see without a microscope. Not enough for their cardiac events yet, but there the disease was established. Now the interesting thing was that this same study was repeated in 1999 and reported in the Journal of the American Medical Association, this time looking at young women and men between the ages of 17 and 34 who had died of accidents, homicides, and suicides. And now, the disease is virtually ubiquitous. You graduate from high school in this country, you get a diploma, and you also get the foundation for coronary heart disease, probably not a good arrangement. Now interestingly enough, approximately five years ago, when I was moderating a panel in the west coast, one of the panel members was Lou Color. And Dr. Color is a professor of public health at the University of Pittsburgh School of Medicine. And on the basis of his ten year cardiovascular health study, on that panel that day, Lou Color made the following statement. All males who are 65 and all females who are 70, who have been exposed to the traditional western diet, have cardiovascular disease and should be treated as such. Now that is really quite a statement. CNS602 -- 3.12 -- Trending the Mortality of Coronary Disease Caldwell B. Esselstyn, Jr., MD Now historically there was a time when we really could have gotten the answer perhaps to this disease, but we as a profession perhaps blew it. Now this was in World War Two. When the axis powers of Germany overran the low countries of Holland and Belgium and they occupied Denmark and Norway, it was characteristic of the Germans to take away their livestock, their cattle, their sheep, their goats, their pigs, their chickens, and turkeys, gone. Now suddenly these European cultures and nations were plant-based. And it was really rather interesting that in 1951, Drs. Strom and Jensen, reporting in England's leading medical journal, The Lancet, described the experience in Norway in looking at the rate of heart attacks and deaths from stroke and cardiovascular disease. And lo and behold, they found as you perhaps see on the left here, in 1927 these deaths from heart attack and stroke are going up, between 1930 going up, 35 going up, 39. When suddenly, in come the Germans, 1940, 41, 42, 3, 4, 5. Who knew these



Germans were the greatest public health educators on the planet? But look what happened. In 1945, with the death of Hitler, the cessation of hostilities in the European theater, back comes the meat, back comes the dairy. Back come the strokes, back come the heart attacks, but we didn't get it. CNS602 -- 3.13 -- Defining Coronary Artery Disease Caldwell B. Esselstyn, Jr., MD Now what we're seeing at this point are two vessels. One is obviously horribly diseased, with just a small opening remaining for blood to go through. And probably, some of you are suggesting that, gosh when that finally closes down, there will be a heart attack. Well interestingly enough, these old plaques that are so advanced really only account for about 10% of heart attacks. I think the focus should be on that normal vessel. And if you look carefully, you will see a tiny, tiny dark layer on the inner-most portion that is one layer thick. Now experts in this disease agree that that is the absolute life jacket and guardian of the health of our blood vessels and it has a name. That carpet we call the endothelium. And each endothelial carpet obviously is made up of individual endothelial cells. And it makes as you'll see shortly, an absolute magic molecule that protects us. On this next slide on the left. What happens when you eat a typical western diet? When you ingest a milkshake, when you ingest cheeseburgers, when you ingest pizza with rich, with cheese. One of the first things that happens is we develop what we called intercellular adhesion molecules. That's a fancy way for saying that those cellular elements which are in our circulation become sticky. Your blood is now no longer flowing like Teflon, it's flowing like Velcro. And with this stickiness, we'll go right to this next slide. And if we will focus on the left in the blue area where the blood is flowing. You'll see there are orange molecules, which the artist has designated as our bad LDL cholesterol. But as I've just said, now that you've had the pizza and the milkshake, they are sticky. And as they drop down and bump up against those purple single layer endothelial cells you see there, they now migrate. Into the subendothelial compartment. So now we have bad LDL cholesterol in the subendothelial compartment and if you will see, they're no longer orange. The artist has now painted them all yellow, why? Because they have been oxidized by the free radicals that are from our diet into these small hard dense LDL particles, which are yellow. Now the subendothelial compartment really doesn't like this at all and sends out a messenger we call Chemokine. And the messenger goes out back into the bloodstream and recruits our swat team, which are our white blood cells. Which Peter Libby from Harvard, who did this slide, has painted it blue in honor of Yale, which we appreciate. Anyway, now we have the white cells, as you can see, also going into the subendothelial compartment, behaving as a scavenger. This macrophage, which we now are gonna call this white cell and in the subendothelial compartment, has the task of working like Pac-Man, gobbling up all these nasty, nasty yellow LDL oxidized particles. Until as we gradually move over to right, the macrophage now is absolutely chock full of these oxidized LDL particles. We now change the name, as we often do in medicine, to the foam cell. The foam cell is truly the absolute Darth Vader of this sequence. The foam cell is a rascal.



As we see on this next slide again, on the left, what the foam cell does, it elaborates some very nasty enzymes that we call metalloproteinases. If you want names, there's things like myeloperoxidase, collagenase, elastase, stromelysin. And they progressively erode or thin out that cap over the plaque. And if you will notice there, the top of the cap, where it's very thin, now, that seminal event has occurred. The cap over the plaque has ruptured. And that is the key event. With rupture of that cap, we now have the extravasation, or shall we say the oozing out of, if you will, of plaque content into the flowing blood, which is highly thrombogenic. That is to say, it activates platelets and suddenly we now go to B, and we have this clot forming. And the clot is in and of itself self-propagating, so in a matter of minutes we have now over to C, a clot which is so massive that it has totally blocked the artery. Remember now, we started out with a blockage that was no more than 30, 35%. That's never gonna give you symptoms. You have to be at least 70 or 75% blocked before you get symptoms, but here we are with this innocuous 35% blocking plaque. Suddenly the cap is ruptured, the clot forms, and now we have a clot that is so large it is totally blocking blood flow. So now all the downstream heart muscle has lost all its nourishing oxygen and nutrients and it starts to die. And that's how 90% of heart attacks occur. But, if I do my job correctly today, you're gonna see that this can be absolutely a wonderful lesson. Because if I can get you to eat in a way that you change your internal biochemistry so that you end up strengthening the cap over your plaque. Once you have strengthened the cap over your plaque, you will have made yourself heart attack-proof. Now, there's more to this story. On this particular slide, look and focus our attention at the artery. You will see that half of the artery is blocked with the plaque. The other half is still open. And you can see in the half that's open, those well-defined inner layer endothelial cells. Now up until 1980, we used to think of the endothelial cells as just these sort of cute little red bricks that were lining these pipes. That all changed in 1980 when Dr. Furchgott in Brooklyn was doing a study looking at the largest blood vessel in the rat, the aorta. And he would take the aorta of the rat and do this sort of spiral staircase incision, which would go right through the endothelial cell. Then he would immerse it in saline and it would constrict. One day, no injury, no cut to the aorta. The endothelial cells were not injured. They immersed it in the saline and it didn't constrict, it dilated. And he did it again and it dilated. Now the race was on globally. What was this EDRF that Dr. Furchgott had discovered? The endothelial-derived relaxation factor. Thank heavens that term was with us only for eight years. At the end of eight years, Dr. Furchgott, Dr. Lou Ignarro, and Dr. Murad discovered that the EDRF was a gas, nitric oxide. And for that, those three gentlemen received in 1998 the Nobel Prize. Now, what are the functions of nitric oxide? They're really magical. Number one, nitric oxide prevents our intracellular elements floating in the bloodstream from becoming sticky. It prevents, that is to say, it preserves the capacity of our blood to flow like Teflon, rather than like velcro. Number two, nitric oxide is the strongest vasodilator in the body. When you climb stairs, the arteries to your heart dilate, the arteries to your legs dilate. That's nitric oxide. Number three, nitric oxide will prevent the wall of your artery from becoming stiffened, inflamed, thick. It prevents you from getting high blood pressure or hypertension. Number four, an adequate, safe amount of nitric oxide will prevent you from ever developing blockages or plaque. Number five, nitric oxide will prevent the migration of smooth muscle from the artery wall from migrating into the plaque. Number six, Nitric oxide can destroy Darth Vader, the foam cell.



Now here is an example of a brilliant move by a cardiologist from the University of Maryland. And that was Dr. Robert Vogel. Vogel did a very interesting thing. Probably right now some of you in the audience are saying to yourselves, I wonder what my level of nitric oxide is? How can I measure that? It's not quite in the office yet. But when we measure the level of nitric oxide, as a research tool, you take an ultrasound probe and place it over the brachial artery at your elbow. And there on the screen you have the readout of this diameter. Then for five minutes, you encircle the upper arm with a blood pressure cuff and you inflate it above systolic blood pressure. So that for five minutes your forearm and your hand have absolutely zero blood flow. Now I've had that done myself and I don't find it exactly habit-forming, but nevertheless. You then release the cuff and now, once again, take the ultrasound probe and measure the new diameter of the brachial artery. In the normal individual, it'll be 30% greater. And this is where Robert Vogel from the University of Maryland did a brilliant study. He took a group of healthy young subjects to a certain fast-food restaurant which is characterized by arches which are golden. Half of the group got cornflakes, and their brachial artery tourniquet test after their cornflake meal? Normal. The other half had hash browns and sausages. Within 120 minutes, the group that had the hashbrowns and sausage could not dilate the artery. That single meal had so savaged, it had so trashed, it had so injured the capacity of their endothelial cells to make nitric oxide, they couldn't dilate the artery. But as they were followed into the afternoon and the evening, they began to recover. But you and I know that the next morning for breakfast it's gonna be scrambled eggs and bacon. Lunchtime, maybe we'll have some mayonnaise, white bread, and cold cuts. And perhaps for supper, we'll have a baked potato with sour cream, lamb chops, vegetables soaked in butter, ranch dressing on a salad and ice cream. Here in America we just take those lovely little endothelial cells and boy we beat on them and we injure them and pound them all day long, so that by the time we're ready to leave high school we have the foundation for coronary disease. So what are these diets that injure the artery? If you look on the left, flow-mediated dilation, fancy for saying dilating the artery. We see that the diet that is the worst for this is the one that's called the Atkins diet. The next worst would be the South Beach diet, and then there's your champ, plant-based nutrition. CNS602 -- 3.14 -- Natural Defense Mechanisms Caldwell B. Esselstyn, Jr., MD Now, we've just discussed the endothelial cell, which is the first of four what I consider to be very powerful natural defense mechanisms that perhaps standard cardiovascular treatment is not addressing. The second of these four is this endothelial progenitor cell. This is kinda the new kid on the block. The endothelial progenitor cell arises from our bone marrow, and it replaces our senescent, injured, worn out endothelial cells. Now, if I were to have in front of me here, someone who was obese, someone who is a couch potato, who is a smoker, who is hypertensive, who is diabetic, if I draw blood and measure the endothelial progenitor cells in this individual, they're going to be quite low. However, if I take somebody who's just the antithesis of this, they're gonna be higher. But for my patients, I'm greedy. How do I get the endothelial progenitor cells to sparkle in my patients? We go to to the healthiest human being on the planet: an Okinawan woman between the ages of 17 and 34. And this study was done in the following manner. Half of the group were control, the other half were ingesting five different Okinawan green leafy vegetables five times a day. And lo and behold, when the study was



completed and they drew blood, the endothelial progenitor cells in the women who are eating the additional green leafy vegetables were strikingly higher. And I think you will see when we come for treatment how important that can be. Now the third of these defense mechanisms is our HDL cholesterol. Everybody has heard that our HDL cholesterol is our good cholesterol. And there's been a lot of fluctuation in how this was interpreted over the last ten years with a lot of confusion because of studies which revealed agents or drugs that would elevate HDL cholesterol, were actually hastening the demise of people. And I should share with you that in our very first small study that was started in 1985, we readily noticed that most of these were males. We readily noticed that the HDL cholesterol in all of these men fell. These are all men who had significant cardiovascular disease. Their HDL cholesterol fell below the level of normal for the American male. And yet at the same time, we found that they were losing weight, their symptoms were disappearing. And at the time that we carefully tested them, we found that their disease was reversing, all with a lower than normal HDL cholesterol, and this is in the era when it was very important. Everybody was saying you had to have a high HDL cholesterol. Well, finally, some data from a wonderful study by Doctor Dan Rader and his team of lipid chemists from the University of Pennsylvania published in the New England Journal of Medicine on the 13th of January of 2011 was fascinating and brought some light on this whole topic. They drew blood from 2,000 patients, and they measured carefully the level of HDL cholesterol. There were some that were high, some that were medium, and there were some that were low. Then they further measured the capacity of the HDL cholesterol which they had measured, to do its job, reverse cholesterol transport. Guess what, the measured blood level of HDL cholesterol, whether it's high, medium, or low, had absolutely no relationship whatsoever for its capacity to do its job. Now, this really kind of threw a little bit of confusion into this thing. But the very next month, in February of 2011, from UCLA, there was a study on the major protein that is found in all of our HDL cholesterol, which has the name apo A-1. And apo A-1, if you're eating the typical western diet, you will injure your apo A-1. Once you have injured, therefore, the major protein of your HDL cholesterol, it will no longer behave as an anti-inflammatory molecule trying to protect you. But it will now behave as a pro-inflammatory molecule trying to join with your LDL to injure you, not a good plan. For instance, suppose we were to look at the HDL cholesterol level of the Tarahumara Indians in Northern Mexico who never have heart disease. Remember, that 40 is the low level accepted as normal for males. The Tarahumara have a HDL cholesterol of 25, which will drive the unknowing physician apoplectic. But their 25 HDL is an absolute metabolic powerhouse. Dimethylarginine dimethylaminohydrolase, this is the last of four natural defense mechanisms I want to mention. Now, this slide may initially seem a little bit busy and confusing, but it isn't if we focus first on the left with the arrow where arginine, which is our semi-essential amino acid, is now being metabolized by nitric oxide synthase. That's the enzyme within our endothelial cells which converts the product and produces nitric oxide. It's really quite simple as it were, raw material, factory, end product. But now, we have to look at the right side. And we see ADMA with an arrow going up to nitric oxide synthase. ADMA, asymmetric dimethylarginine, is in all of us is a natural product of protein metabolism. And we just don't want to have too much of this accumulate because it interferes with the production of nitric oxide. Now, therefore, nature has devised two ways to get rid of this, one is through the urine, and the other is by it being metabolized away, by a powerful but delicate enzyme called dimethylarginine dimethylaminohydrolase.



Now, I think, for an example, if we look at patients who have renal failure, they can't make urine, they're on dialysis. There's a significantly higher rate of cardiovascular diseases, such as strokes and heart attacks in those groups because they can't get rid of their ADMAs efficiently. But what about the rest of us, those of us who have normal urinary function and renal function? Is there anything that we do that interferes and injures that strong but delicate enzyme DDAH, dimethylarginine dimethylaminohydrolase? Yes, high cholesterol injures DDAH. High homocysteine injures DDAH, so does high triglycerides and insulin resistance and diabetes and tobacco. Now, let's review, all of these powerful natural defense mechanisms that I've mentioned, the endothelial cell, the endothelial progenitor cell, HDL cholesterol, and dimethylarginine dimethylaminohydrolase, to optimize these, you don't have to have a single operation, a procedure. You don't have to take a single drug. All of these can be absolutely, maximally potentiated with plant-based nutrition with the exception of tobacco. CNS602 -- 4.1 -- Module Introduction: Prevent & Reverse Heart Disease Thomas Campbell, MD 50 years ago, there was absolutely no understanding that heart disease might actually be reversed, let alone that this reversal could come at the hands of simple dietary and lifestyle changes. So we now want to spend some time learning about this revolution in our understanding of heart disease, really the data behind it, and what is the diet that makes this possible. We've learned from the doctor who generated this groundbreaking research. And through this process we will focus on the specific components of a diet that can reverse heart disease and atherosclerosis and the changes in the arteries. And hear from a patient who has made the changes and reaped the benefits. CNS602 -- 4.2 -- Maintaining the Covenant of Trust Caldwell B. Esselstyn, Jr., MD We have to look at some of the medications that are used for heart disease. And the drug that hit the scene with a big splash, in the 1990s, were the statins. And everybody thought that since they interfered with cholesterol metabolism that this would perhaps be the great cure all. And there's no question that in secondary prevention, after somebody does have cardiovascular disease, that they can be of benefit. But the question is whether they should be put in a drinking water, so everybody gets them, and is there rock solid evidence that you should take these if you don't have heart disease yet? And that is really very meager and heavily contested among scholars. Let us just say that, as the years have gone by, that we have found that there are people who have rather strong reactions sometimes, to statins. Some will have rather severe neuromuscular pain, so much so that they can't even get up off the floor. Others will develop diabetes, and in some, there are cognition problems. So, we really have to continue to look at perhaps a better way to treat this disease. And I think that we will see as we move forward, that as much as I admire and respect my cardiovascular colleagues, have we departed and gotten away from what has been really a basic covenant of trust, since the days of Epocrates, namely, whenever possible, does the caregiver share with the patient what is the causation of the illness? And when that's done we really get our best results. Sadly today, this is not done in cardiovascular disease. The other thing we do beside all these drugs that we use, which have nothing to do with the causation of the disease. But we have drugs for blood pressure, and we have drugs that will slow down the heart and make it work less hard. And all these drugs have significant side effects,



especially those that have to do with anti-clotting. And so, there are also procedures that we do such as stents and bypass. Now, there's no question, let's be clear about this, that if I am in the middle of a heart attack, the person that I want next to me is a man or woman who has great expertise with stents. Not only they might save my life, but they'll certainly save a lot of my heart from significant damage. But what about the other 90% of stents that are being done so-called “electively”? Well the jury is now out on this. Elective stents, which really are done most frequently throughout the United States and the rest of the world, cannot prolong life and they cannot protect us from a future heart attack. Now, there are some downsides to stents. The worst one being death. But it's very low, 1%. How many are done? Roughly 1.2 million, so that's 12,000 deaths from stents. How many heart attacks with the stent? Not many, 4%. 4% of 1.2 million, 48,000 heart attacks. Well, what about bypass surgery? We don't do as many, 500,000. Mortality 3%, that's 15,000 deaths from bypass surgery. How many strokes while you're getting bypass surgery? Not many, again, 3%, another 15,000. Take it over a decade, that's 270,00 deaths, a little over a quarter million from these procedures. 480,000 heart attacks with stents, almost half a million. And a 150,000 strokes. Can we do better? What about the expense? Right now cardiology is responsible for about 45% of Medicare. And what is cardiology today? It's a lot of expensive imaging, expensive drugs, and expensive procedures. And if you just take a look at procedures, you get an idea of how silly this can sort of be, when You have your first stent, second stent, third, fourth, or fifth stent. I have seen a patient who had as many as 51 stents. So there's an enormous expense. 45% of Medicare is cardiology, and if you estimate, as doctors or as economists Topel and Murphy did from Chicago in 1999, they estimated that if we could get rid of heart disease we would save the nation $40 trillion. So it's pretty important. CNS602 -- 4.3 -- Preventing Coronary Artery Disease Caldwell B. Esselstyn, Jr., MD Now this is fascinating to get to look at what Walter Willett, who was a professor of public health at Harvard, has to say about this present state of affairs with cardiovascular disease. The current path leads to increasing adiposity, diabetes mellitus, cardiovascular disease, and disability, and an unfit, socially isolated population stuffed with pills and subjected to frequent palliative procedures. So, in 1985, I went to our Department of Cardiology, and I asked if I could have about 24 patients who had significant cardiovascular disease, because I was interested in treating them with plant-based nutrition. And with the background that we've just reviewed, it seemed logical to try to take these patients and offer them the same type of nutrition that was identical with those cultures, where the disease was virtually nonexistent. Now, in as much as I was still involved with my surgical responsibilities, I was limited to a small study, 24 patients who had severe triple vessel disease. Now these patients had either failed their first or second bypass, they had failed their first or second angioplasty. They were too sick for these procedures or they had refused. And five were told by the expert cardiologist they would not live out the year. I'm happy to say that five all made it beyond 20 years. Now, the absolute key here, was to not have any food item pass their lips, that was, in any way, known to injure the endothelial cell, because, after all, they had lost so much of this protective nitric oxide. They were not able to protect themselves from having these cardiovascular events, so we wanted to absolutely optimize the endothelial cells. And I should mention, that one of the most important things we feel we stopped was oil. Olive oil, corn oil, soybean oil, safflower oil, sunflower oil, corn oil, canola oil, palm oil, oil in a cracker, oil in bread, oil in a salad dressing. Oil injures endothelial cells, as does anything with a mother or a face,



meat, fish and fowl, chicken, turkey. And dairy, milk, cream, butter, cheese, ice cream and yogurt. And not listed here, sugar, yes. Maple syrup, molasses, honey, orange juice, apple juice. It's fine to eat an apple, fine to eat an orange. There, the fructose is bound with fiber, the obstruction is slow, not a problem. But when you make orange juice or apple juice, you now have this sugar which is free, goes into your gut, immediately absorbed, injures liver, glycates protein, and injures the endothelial cell. You'd also like to omit caffeine and coffee. Now, for those of you who have some concerns that I'm being a little too extreme or radical asking you to leave the oil. Here is a peer-reviewed scientific study. Let's look at it together. Olive, soybean, and palm oil intake have a similar, acute, detrimental effect over the endothelial function in healthy, young subjects. Now this maybe a little bit confusing at the start but bear with me for a moment. Obviously, all that you see on this slide are animal products, and it has been found that omnivores who are eating these regularly have a certain type of bacterial flora, or microbiota, if you will. And those bacterial flora, when they act upon these foods, are able to produce a compound, trimethylamine, which is then oxidized in our liver to trimethylamine oxide. And trimethylamine oxide has been found to be fairly potent for producing vascular disease, especially in rodents. When they looked at the serum of 4,000 patients who had been through a large midwestern clinic, they found that those individuals who had the highest rates of trimethylamine oxide, were the ones to have the greatest amounts of cardiac events. Now the fascinating thing about this is, if you will ask somebody who is strictly plant-based in their nutrition to ingest a piece of steak or a lamb chop, they do not make TMAO. Why? When you are plant-based, you do not have the bacterial flora that enable you to make TMAO. Here we see the schematic. You ingest the lecithin and carnitine and any of these animal products. And if you are an omnivore, you have the gut bacteria that produce trimethylamine oxide and hasten vascular disease. CNS602 -- 4.4 -- Eating for a Healthy Heart Caldwell B. Esselstyn, Jr., MD Now, we've heard about the foods that we don't want them to avoid. What are the foods we want them to eat? All these marvelous whole grains for your cereal, bread and pasta. 101 different types of legumes or beans. All these marvelous red, yellow, and green leafy vegetables and some fruit. Now, a moment here about green leafy vegetables, I think is in order. Earlier, we discussed the endothelial cell and the endothelial progenitor cell. We know from that study in Okinawa, that the endothelial progenitor cells can be really made to sparkle with especially something like green leafy vegetables. We also know that, if you could somehow get your head inside somebody's plaque, you would see that it's an absolute cauldron of oxidative inflammation. So what do we want for that? We want antioxidants. No. Don't go down to the health restore and buy a jug of antioxidants. Not only that does not work but it probably is gonna be harmful. We want the antioxidants to come from food. What food? Food that has a high ORAC value, oxygen radical absorbance capacity. This can be things like, raspberries, blueberries and strawberries, they're great. But the absolute champ are the green leafy vegetables. Now, if I've got somebody who is significant in cardiovascular disease, whether it's their legs, their carotid, their heart, we really wanna hasten this along. Now, you can see how mean I can be or as much of a task master, although I'm not as mean as I look. I want them to have a green leafy vegetable, six times a day. And how do we do that? I want it to be the size of your fist after it has been boiled in boiling water for five and a half to six minutes, until it's nice and tender. Then anoint it with some delightful balsamic vinegar, so you've got something that is tender and delicious. And I want this alongside your breakfast cereal, I want it mid-morning snack. I want it with your lunch and sandwich. Again, mid-afternoon. Obviously at dinnertime. God, and I adore it when you have that evening snack of kale.



What you are doing is you are bathing that cauldron of oxidation inflammation all day long with nature's powerful anti-oxidant. What are the vegetables? Bok choy, swiss chard, kale, collards, collard greens, beet greens, mustard greens, turnip greens, napa cabbage, brussels sprouts, broccoli, cauliflower, cilantro, parsley, spinach, arugula and asparagus. That's just a few, but enough to get you started. Now, there's one other wrinkle to this. By the age of 50, if you were to measure the nitric oxide production from the endothelial cells of somebody who's beautifully healthy, it'll now be approximately 50% of what it was at age 25. Now, does that mean that your old carcass is gonna let you down? No. There's another avenue that we can make nitric oxide. How's that? Through the gastrointestinal tract. How do you do that? If I can persuade you to chew nitrates, not smoothies, not juicing, always chew. If you will chew nitrates, I'll give you six right now: kale, swiss chard, spinach, arugula, beet greens and beets. When you chew those nitrates, they are going to mix in your mouth with the facultative anaerobic bacteria that reside in the grooves and grips of your tongue. Those bacteria will reduce the nitrates in your mouth to nitrites. When you swallow the nitrites, they are further reduced by your gastric acid to nitric oxide, which will join your nitric oxide pool. The nitrites in your stomach that are not converted, further downstream, reabsorbed into the circulation. Circulate back to your salivary glands where they will now be concentrated ten to 20 fold. So, that now as you chew additional food, your own saliva is contributing nitrites into your mouth which when swallowed would be further reduced by your gastric acid to nitric oxide. CNS602 -- 4.5 -- Reversing Coronary Artery Disease Caldwell B. Esselstyn, Jr., MD So, those are the foods that are so vital and helpful for optimal nutrition. But remember, no oil. Yes, when we get rid of the oil, it is so easy to get patients to begin losing weight, as many of our patients need. Now, at baseline, the average total cholesterol for this group, was 237. And over the next five years, and 12 years, they were able to maintain their cholesterol under 150. Notice that the HDL cholesterol, in what was mostly men, was under 40, which is the lower limit accepted for normal, for males, for HDL cholesterol. Yet, as we'll see, this in no way adversely impacted their outcome. And what I wanna show you next are some angiograms of these coronary arteries. These angiograms were reviewed in triplicate, in the Cleveland Clinic Angiography Core Laboratory, by senior medical technicians that do this all day long for national medical trials. So, when I give you a certain percentage of disease reversal, we know that it's accurate. Now, on this first one, this happens to be 67 year old pediatrician. You are looking at the left anterior descending coronary artery. And if you look at the arrow, this is as small an improvement as the naked eye can see. This is approximately 10%. It's a little easier to see in this next one, which is 58 year old factory worker, where the degree of improvement from the arrow on the left to the arrow on the right is 20%. On the next, we're now looking at the right coronary artery in a 54 year old retired security guard. And this improvement was described as 30%. This next is interesting. This happened to be a surgical colleague of mine at the Cleveland Clinic, and at age 46, Joe began having chest pain. He had no family history of heart disease, he was not obese, he exercised regularly, he was not a smoker, he was not diabetic, he would not have high



blood pressure. He had none of the standard risk factors. His cholesterol was 156. And yet, he began having these chest pains in 1996. And in October of '96, he had a full work up in the Department of Cardiology, which could really find not anything that was significantly wrong. Three weeks later, in November, he was operating. He finished his surgical schedule, he sat down to write postoperative orders. While he was writing postoperative orders, he then had this splitting headache, immediately followed by this crushing chest pain, an elephant sitting on his chest, pain in his left jaw, shoulder, arm. He was having a heart attack. He was whipped down to the catheterization lab, and as you can see here, the entire lower one third of his left anterior descending coronary artery, the main artery to the front of the heart, was thoroughly moth eaten and diseased over too long a segment to be stented, and too far down the artery to have a bypass. So, when Joe was discharged from the hospital approximately three days later, he was very depressed because he felt they could do nothing for him. So, my wife and I had Joe and his wife out for supper two weeks after his heart attack. Joe, come on, you've been eating this terrible Western diet, you've got this typical Western disease. We have 10 years of plant-based nutrition in this study of ours. Why don't you think about going plant-based? And he said, well, they really couldn't offer me anything else, so I think that I'll give it a shot. He said, but I'm not gonna take any of those statin drugs. I feel there that are too many side effects, much about them is unknown. I'm just gonna stick with the nutrition. I said that's fine, that's absolutely your call, no problem. Well, over the next two and a half years, he became the absolute personification of commitment to plant-based nutrition. And his bad cholesterol went from 98 to 38. And then, after two and a half years, he had another angiogram. And it just so happens that up in the surgical office area, our doors are three doors apart. And at noontime, on the day that I knew earlier that morning Joe had had his follow up angiogram, I found myself going over to his office, opening the door, letting myself in. There he was, sitting behind his desk. Joe, I understand you had the old follow up angiogram earlier this morning. Mind sharing with me, how did it go? And he got up from his desk, came around, put his arms around me. Had a few of these. And he said, I think we're doing pretty well. And I said, well, would there be any chance that I could see the follow up angiogram? He said sure. And you can see that the disease is literally vanished. And it's really quite profound and exciting what can happen in patients who were so totally committed to this. Especially those who have a plaque which is largely of inflammation, and cholesterol, and fat, and does not yet have a great deal of scarring and fibrosis and calcification, because those can be resistant. But at the same time, they can have a beneficial outcome as we can see. CNS602 -- 4.6 -- Following the 12-Year Study Caldwell B. Esselstyn, Jr., MD Now, despite my sparkling personality, there were 6 of our original group of 24, and I should say they were just awfully nice guys. But they just didn't get it, and I had absolutely no money for this research. So with their understanding, I released them full-time back to their expert cardiologist, usually after somewhere between two and four months. Nevertheless, they became sort of a quasi control group, if you will. I would peek in from time to time to see how they were doing. At the end of 12 years, of those six that had left, actually two eventually died, and the other four had to have coronary artery bypass surgery.



Now on the other hand, what about the 18 that stayed with us? We wanted to know in the eight years prior to coming into our study, while they were in the hands of expert cardiologist, how many cardiac events had they sustained with these experts? And as you can see here, there were 49 coronary events in these 18 patients, in the eight years prior to coming in our study, that are listed among the categories of worsening disease that you see listed here, ranging from increased angina, angiographic disease progression, a need for bypass surgery, heart attacks, strokes, angioplasty, or worsening stress test. Now, once they came into the study, 17 of these 18 over the next 12 years had no further cardiac events. We did have one little sheep who, shall we say, wandered from the flock after six years, got into the lamb chops, the glazed doughnuts, and the french fries. Angina came back, he needed a bypass, but now he's back with the flock. That proves the point that I'm trying to make today. CNS602 -- 4.7 -- Treating the Cause Caldwell B. Esselstyn, Jr., MD Now, it was very interesting to see the sort of reaction to our study, and although, for many people, it was rather exciting to see the patients survive. Many of these we followed up to beyond 12, almost to 20 years, and to see them reversing their disease. But I think many in the medical community felt that the study was quite small, and they felt that perhaps with a larger group there wouldn't be the same results and we wouldn't have the success and adherence. And what is exciting about this group of 200 is that, contrary to belief, that almost 90%, actually 89.3% of patients who were compliant were adherent up to 3.75 years. With 89.3% adherence and people are wondering, well, did they really have heart disease? Well, 180 had that proven by angiography. Another 74 had abnormal stress tests. And 44 already had had a heart attack. The other co-morbidities, hyperlipidemia, 161, hypertension, 60, diabetes, 23, and we've mentioned 44 had previous heart attack. How about the outcome for that? Well there were 144 that were improved, 39 of that group had disease reversal either by angiogram or by stress test, 15 were stable. Disease progression. There was one person who had a stroke, one person who had to have coronary bypass surgery, the other who had coronary bypass surgery was somebody who actually came to us with stents that had been placed just before coming to our program where the artery was dissected with a stent and surgery was required. Another person had stents that were going down within four weeks of starting our program and required a re-stenting. There were five deaths in this group, and three were from a malignancy. One was a pulmonary embolism and the other a pneumonia. Now, what about the 21 persons who are non-adherent? Eight of those remained stable, 13 were worse. Of the 13 who were worse, there were 11 who had the following procedures or events. Two had a stroke. Four had to have a stent. Three had bypass. One a peripheral endarterectomy for leg disease and a heart transplant. And there were two in that group who died, and they died of cardiac deaths. Those were the non-adherent group. Now if we summarize the percent of recurrent events in those who were adherent, it was 0.6%. In those that were non-adherent it was 62%, so, a pretty profound difference. I don't know if there is such a thing as a severity index, but we wanted to try to point out the degree of significance of their disease, and we felt that if we identify the fact that of those who really, the patients who were adherent, 119 had previous interventions such as bypass or stents. And it was also rather fascinating that 27 of the group who were told prior to coming to see us, that they would require a stent, or a bypass, actually, as a result of their adherence to the program, were able to forego those intended procedures. So we calculate that as a severity index of 82%.



What about the outcomes of the 177 adherent patients? What about those that had chest pain or angina baseline? Of the 112 who had angina baseline, it was improved in 104. That's 93%. And benefits for adherent pace participants continues. Disease reversal 22%, angina improve 93%, weight loss roughly about 8.5 kilograms, something close to 18 pounds, recurrent cardiac events 0.6%. Now, in a way I sort of apologize for the comparisons here, because we have no comparison group of our own approach. So we've taken very well-known cardiovascular studies, such as you see here, the Lyon Mediterranean Diet Study, and in four years the major cardiac events such as heart attack, stroke and death are at 25%. It's about 20.4% for the study called the Natural History of Cardiovascular Disease, and 19.4% for Bill Boden's well-known Courage study. So you see, we're somewhere around 21 or 22% of recurrent events, but when you look at TTC, which is our study, which is Treating The Cause, it's six tenths of a percent, that's approaching a 40-fold difference. And it's so profound and so exciting what can happen when you actually treat a causation of disease. CNS602 -- 4.8 -- Arrest and Reversal Caldwell B. Esselstyn, Jr., MD Now, it's interesting if we summarize the challenges that occur with standard cardiology in terms of morbidity and mortality and then look at the plant-based nutrition. There is no mortality with the diet. There is no morbidity from the diet. There is no added expense. Remember, we didn't talk about expense with standard cardiology but right now, 45% of Medicare is cardiology. And sadly today, cardiology is too often your first stent, your second stent, third stent, fourth stent, maybe fifth or sixth, sometimes even more. Then a bypass operation and some stents in the bypass. Eventually congestive heart failure and you die of what? A completely benign food-borne illness that really has had therapy but hasn't had its causation treated. And all that happens with plant-based nutrition is that the benefits improve with the passage of time. And perhaps the most important thing of all is that the patients are empowered by the knowledge that they are in control of this disease that was destroying their lives. Instead of just going out, wondering when the other shoe was about to fall, with the sword of Damocles over their head, nobody knows why they've had this disease or when they're gonna get another heart attack. Nonsense, treat the causation of the disease and let's end this illness. This disease can be annihilated. CNS602 -- 4.9 – Additional Evidence of Reversal Caldwell B. Esselstyn, Jr., MD What we're looking at here is a PET rubidium dipyridamole scan of the heart. And on the left, this is the image of a 58 year old school bus driver from Youngstown, Ohio, who came to us originally with a cholesterol of 261. And at that time, with this PET Rubidium dipyridamole scan, if it is orange or if it is yellow, that means that perfusion is good. And you can see here on the left it was okay on the sides. But in the middle of the heart it's green, poor perfusion. But he gets it. 10 days later his cholesterol is down to 126. And six weeks later when we repeat, his perfusion scan, it is now back to normal. What in the world is going on? Let's look at another. Here we see, on the left where, in a normal situation, this is supposed to be sort of like a doughnut. This is the scan of a 60 year old stockbroker from downtown Cleveland. Comes to us with a cholesterol of 248. And after 10 days of treatment, it's now down to 137. Now, not three weeks later, excuse me, not six weeks later, but actually three weeks later, we repeat it, and now it's back to normal. What has been going on with these scans? What is actually occurring is



that we know that we haven't washed out the blockage or the plaque. Well, then how does more blood get there? Because what I'm trying to point out right now is there are different degrees and types of reversal. We think what happens, really, within maybe 48 to 72 hours is that the health for the endothelial cell, in response to this plant-based nutrition, and avoiding those foods that are going to injure it, begin to revive. And as the endothelial cell revives, so does the level of nitric oxide. So, if you think back to the heart now, all those blood vessels in the heart that are not diseased, but are normal, now are once again given an adequate supply of nitric oxide. So, those normal vessels in the heart will dilate as well as the abnormal ones. And if you recall in physics, Poiseuille's law of flow through the hollow viscus is related to the fourth power of the radius. Translation, a tiny increase in diameter, and a huge increase in flow. Now, let's look at a clinical situation. This happens to be somebody who's now a good friend of mine, who when he first came to see us, a week or two earlier had been to a famous mid-western clinic where he was scheduled to have bypass surgery. Because he had, as you see here, a 75% blockage of the end of his left main coronary artery where it divides to the anterior descending artery where it goes to the front of the heart, and the circumflex artery that goes to the back of the heart. Now, he had been told, in September of 2005, that we would require bypass surgery. And they were sort of backed up, and they did not feel that he was an emergency, so he was scheduled for December. 10 days after he had been there in September, in October the 9th, he came to our program, and really took it hook, line, and sinker. So much so that his angina, which he could sense with a fast walk to the mailbox, had now begun to disappear after 10 days. And it got a little awkward because, at that moment, this large clinic had had an opening and he could fill a waiting list, he found in an earlier opening. But with the result he was getting, he was reticent to have the surgery, and thought he would wait at least until December, when he was originally scheduled to have the procedure, to make a decision. And he progressively found that he was getting less and less angina despite an increasing effort. Now, if this gentleman had been a shopkeeper, I would have had him cured in 10 days to two weeks, with relief of his angina. But this was a successful businessman who had a passion for doing triathlons at his age of 53, 54. And he was very good at this, but it took us another three and a half years to get him to the point where he could flat out on his bicycle uphill. He never had the surgery, and he, to this day, remains a close friend and continues in his triathlete endeavor. But the point that I want to make with this, is that in patients who have a plaque which is not made of soft cholesterol, inflammation, and fat, the likelihood of it going away is really, is markedly reduced, and many of those won't really budge. But here is somebody where a follow up angiogram did not significantly change, but what changed profoundly was the speed of his blood flow through this area, the fact that he could dilate this area once again as his level of nitric oxide increases. The fact that all the normal vessel, non-diseased vessels in his heart, were now again responding. And so now, this is a gentleman who is in his 60s, and on his vacations is able to climb mountains and go wherever he wants on this planet without restriction and without fear of any recurrent disease. CNS602 -- 4.10 -- A Patient's Perspective on a Plant-Based Diet Dick Dubois The results have been amazing. Within about, I think I had my first lipid profile about six weeks after. I started the diet and my cholesterol went from around 200 to 101. My LDL went down into the 40s, HDL into the 50s. But more than just numbers, I could start to feel change in my own body. I could start exercising a little more. The angina would start to be less, it would also go away after the first



few minutes of running, or I'd stop and let it go away. And that just, almost every time I went out, I could actually notice the difference in the reduction of discomfort I was feeling. And that was very empowering to me, to know that I was actually impacting the way I felt. And the other obvious change was that I was starting to lose weight quickly. I lost between 45 and 50 pounds in the first three months. And that's significant for somebody who was a very overweight child, somebody who had been heavy his whole life. I actually got down to a weight that I was in grade school and that was a first for me in 40, 50 years, so that was pretty empowering for me. You have to look at yourself and if you're willing to make this change. It's a significant change, but it's an absolute life-changing thing for your own health, you are empowering yourself to be in charge of your health. And I think that's very important, we often as people want to blame somebody else for everything we do. Or we want somebody else to help us but we have the control to be healthy individuals. And I think if you try to do this and if you learn how to cook the foods. And you enjoy cooking the foods there's a wide range, I probably eat a bigger variety of foods today than I did before I went on this diet. It's very doable and I think it's important that we're offered these options and for many people, they just don't know. Given the option, given some help to get started it can make a huge change in your life, and I highly recommend you take a strong look at it. CNS602 -- 4.11 -- Summarizing the State of Coronary Heart Disease Caldwell B. Esselstyn, Jr., MD There are four points to be made in summary. Present-day cardiovascular medicine as it's presently designed cannot cure patients. Present-day cardiovascular medicine really is never going to be able to end the epidemic. And present-day cardiovascular medicine, as it's designed, is even in the richest nation on the planet, financially unsustainable. Point number two. I think it's absolutely a mistaken belief to feel that patients will not make this type of significant lifestyle change. It's not that the message is wrong, it really is how the message is articulated. Point number three. I think it may be a little bit unfair of me to ask our cardiovascular colleagues to carry the burden of this lifestyle transition. They have very busy schedules, they like the passion for this. And certainly have not had an opportunity to have any training in nutrition, or perhaps in behavior modification. Rather, those of us in lifestyle medicine really cherish the opportunity to work, synergistically, in the spirit of cooperative endeavor. With our cardiovascular colleagues, to assist them in having their patients make this type of a significant lifestyle change, so that they can be empowered as the locus of control to halt their disease. Point number four, in my opinion it is absolutely unconscionable not to offer this option to patients. Thank you. CNS602 -- 4.12 -- Dean Ornish on Heart Disease & Lifestyle Dean Ornish, MD So, I began doing research in this area 38 years ago when I was a second year medical student at the Baylor College of Medicine in Houston, Texas. And I was learning how to do coronary bypass surgery with Michael DeBakey, the heart surgeon. And we cut people open, we bypassed their clogged arteries. He'd tell them they were cured and more often than not they'd go home and do all



the things that had caused the problem in the first place. Eat junk food, not manage stress, not exercise, not have much love and support in their lives. And all too often their bypasses would clog up and we'd cut them open again, sometimes multiple times. And so, for me, bypass surgery became a metaphor of an incomplete approach that we were literally bypassing the problem without also addressing the underlying causes. Sometimes when I lecture, I'll show a cartoon of doctors busily mopping up the floor around a sink that's overflowing, but nobody's turning off the faucet. It's kinda like when someone gets put on medications to treat heart disease, or their blood pressure, or their cholesterol or their diabetes, and the patient asks, how long do I have to take these medication? And the doctor usually says forever. It's like how long do I have to mop up the floor and the sink is overflowing, it's forever. Well, why don't we just turn off the faucet? And to a larger degree than we had once realized that the underlying causes, the faucet, are the lifestyle choices that we make each day. And what we found was that an intervention that included a whole-foods, plant-based diet, moderate exercise, namely walking half an hour a day, various stress management techniques for an hour a day, including yoga and meditation, and what we euphemistically called social support, which is really more love and intimacy in people's lives. Or eat well, move more, stress less, and love more. That these simple changes cause profound improvements, not only in helping prevent, but even to reverse so many chronic diseases, beginning with heart disease. But later we found it could cause improvements in so many other conditions. And so I did a pilot study. I took a year off between my second and third years of medical school to do a pilot study. Using these very high-tech, expensive, state-of-the-art scientific measures, to prove the power of these very ancient, and low-tech, and low-cost interventions. And, so, I started with, in 1977-78, did a 30-day study with ten men and women who had severe coronary heart disease and who had not undergone bypass surgery, which back then was actually pretty hard to find because almost everybody ended up getting bypass surgery in the late 70's. It was kind of the heyday of bypass surgery. But we found them, and we put them in a hotel for a month, put them on this program, and they got better in every way we can measure, and not only did they feel better, but they were better objectively in ways that we can measure. There was a 91% reduction in the frequency of angina. Their blood pressure. Their cholesterol. Their weight came down significantly. And we used what was then a new test called Exercise Thallium Scan Disintegrity, which measure blood flow to the heart. And we found that eight of the ten patients showed significant improvement in their myocardial perfusion or blood flow to their heart, that had never been shown before. In other words, the heart disease was actually reversing. Instead of getting worse, they got better. Now it's also my first and we published that in a journal called Clinical Research, it was also my first experience that when you're doing something that doesn't conform with conventional medical beliefs at the time, that it's often met with skepticism, if not scorn, and they would say, the doctors that I worked with would've said, well, how do you know they wouldn't have gotten better anyway? You didn't have a randomized control group for comparison. And I'd say, well, that's true, theoretically, but have you ever seen any patients show improvements in the blood flow to their heart? And they said no, but it's theoretically possible, or you didn't control for the time of day you tested your patients, that kind of thing. So, we published that in the journal Clinical Research, went back to medical school, finished my MD, and then took another year off to do, again, another one-month intervention. It was actually 24 days



because the hotel said we could use it for free for 24 days. That's how these great decisions in science sometimes get made. And this time, we did have a randomized control group and we used another test called radionuclide ventriculography, which measured how well the heart was pumping blood at rest and at peak exercise. And after 24 days we found that normally your blood flow, the injection fraction should increase as you exercise, from rest to peak exercise because your heart not only beats faster, but it beats harder. So the percentage of blood, or the ejection fraction, that's ejected each time your heart pumps blood goes up along with the fact that it's pumping faster because you have a greater need for blood. But in someone who has bad heart disease, it may not be able to keep up with the demand. And so your ejection fraction may actually fall paradoxically. And that's what we found in the patients in our study when they began, the ejection fractions fell during exercise. But after 24 days, they continued to fall in the control group, the randomized control group, but they actually increased in the experimental group. And so instead of getting worse, they got better. And these differences were highly significant and we published that in the journal of the American Medical Association in 1983. We first submitted to the New England Journal Medicine. They kept it for over a year. They asked for revisions two or three times, which normally means they're gonna publish it. And in the final analysis, they rejected it just because they thought it was going to generate too much controversy. So, we ended up publishing it in JAMA. Then I went to Boston to Harvard and Mass General to do my clinical fellowship and internal medicine residency. Moved to San Francisco in 1984 and became a professor at UCSF and began the lifestyle hard trial which was the most definitive of these three studies. This time we used quantitative arteriography which is the gold standard for measuring blockages or atherosclerosis in the arteries at the time. And cardiac PET scans, which is the gold standard for measuring blood flow to the heart. We actually ended up flying our patients to Texas for their cardiac PET scans, which is a lot of work and logistical effort as you can imagine. But, I always believe in working with the best people in the field, and the most credible, and at the time, the best PET scanner was in Texas. The original study was a one-year intervention, and based on those findings after one year which was we found that there was an improvement in blockages in the coronary arteries in the people in the experimental group, and went through our lifestyle program, they got less clogged over time. Where as they got more clogged, which is what usually happens, in the randomized control group. And based on those finding and we publish those one year findings in The Lancet, one of the premier international medical journals. Based on those findings, we received support from the National Heart Lung, and Blood Institute of NIH to extend the study for four additional years, a total of five years. And after five years, we found there was even more reversal in terms of less clogging in the arteries, less coronary atherosclerosis, in the experimental group who went through our lifestyle program. Whereas there was continued worsening in the randomized control group. So instead of getting worse and worse, they actually got better and better in the experimental group. And those differences were highly statistically significant after one year, and even more significant after five years, even greater improvement. In addition to the improvement in the blockages or the atherosclerosis in the coronary arteries, we found a 300% improvement on average in blood flow to the heart as measured by cardiac PET scans. Got better in the experimental group, worse in the control group. And those were all blindly assessed by independent observers who were actually pretty skeptical if not hostile to the idea when



we first began. But that way I figured, that way if we showed anything that it would have a lot of credibility. And we published the five-year findings of the atherosclerosis in JAMA in 1998 and the five year PET scan findings in JAMA in 1995. Now one of the interesting things about this study was that, in both studies, in all three studies, we found there was a direct dose response correlation between the degree of lifestyle change, in other words, adherence to our lifestyle intervention and changes in their coronary atherosclerosis. The more they changed, the more they improved, at any age. Which was different than I thought we'd find, I thought that the younger patients who had milder disease would be more likely to show improvement, but I was wrong. It turned out it wasn't how old or how sick people were, it was simply a function of how much they changed their lifestyle. Also, none of the patients in the experimental group was taking cholesterol-lowering drugs like Lipitor or other Statin drugs during the course of the study. But in the control group none of the patients was taking them at baseline. During the five-year period, about half of the control group patients were put on statin drugs. And they had less progression. They got worse at a slower rate than the patients who weren't put on cholesterol lowering drugs. So the drugs had benefit in slowing the rate of disease. But in the experimental group, none of the patients took these cholesterol lowering drugs for the five year without the drugs. You couldn't even do a study like this now. It would be considered unethical to have a control group that wasn't put on cholesterol-lowering drugs. So, it just added more emphasis to the validity of the findings. CNS602 -- 4.13 – Compare Heart Healthy Diets: Part 1 Thomas Campbell, MD So you've seen the data that's really changed lives, You've heard from the doctor who's done it. But how do you really take this away and navigate the information in the world at large? We know, and I've experienced, that when you go to the grocery store, when you open up the newspaper or go on the internet, you'll see claims for being heart healthy everywhere. Heart healthy is everywhere and there's enormous confusion. In particular, the American Heart Association diet and the Mediterranean diet is something that you'll hear over and over. You'll hear it from your doctor, you'll hear it on the Internet, you'll hear it in popular media, as the ultimate diets in heart health. But those are a little bit different from what we've just heard. So take some time now to understand what are those differences between these popular diets and the diet we've just discussed. What are the differences, not only in terms of what foods comprise them? But also what are the differences, importantly, what are differences in what are their outcomes? What is truly heart healthy and how healthy do you want to be? Is there a meaningful difference in all of this mix of diets? Use the information we've already discussed, but also spend some time looking outside of the information that we've talked about to fill in your understanding of this different information. CNS602 -- 5.2 -- Facts About Obesity Thomas Campbell, MD So we have covered some important ground with cancer and heart disease with some leading experts in those fields. And those two diseases of course, take a lot of our energy because they are our leading killers. But I want to talk now about something more prevalent, or at least as prevalent, and that's some of the risk factors for heart disease and cancer. That's obesity and, of course,



diabetes as well, which is linked to heart disease. Obesity and diabetes have received a lot of attention and a lot of press recently. We've seen the maps from the CDC going from 1985 up to 2010 that show that obesity has rapidly expanded, pun not intended, across the US. And now we have a situation where about a third of our population is obese and about 70% of our population is overweight or obese. So only about 30% of our population is a healthy weight. And the reason we care about this is because being overweight is one manifestation of a metabolic dysregulation or metabolic problems. It's not always, but it usually is. When you look at the data from the US in 2001, you see for example that a normal weight or healthy weight individual has a baseline risk of diabetes. And the heavier a participant is or a subject is in this study, the higher their risk of diabetes. So someone who is very obese with a BMI of over 40, they actually have more than seven times the risk of getting diabetes. You can see the same thing is true of high blood pressure. As more weight goes up, the higher the risk is for having high blood pressure, high cholesterol, asthma, and arthritis as people move up through healthy weight, to overweight, moderately obese, to very obese, the risk keeps going up. So, this is really a health discussion rather than something related to looks. Or whether people are good or bad or any of those emotionally charged aspects of this. I just want to very quickly review that studies have shown now, for decades actually, that vegetarians and vegans tend to be thinner than their meat eating counterparts. One recent review, it was actually about ten years ago from Dr. Barnard who we're gonna hear from later. Looked at 40 studies, and showed that 29 of them found that vegetarians weighed significantly less than non-vegetarians. And of the remaining 11 studies, 9 of them showed that vegetarians weighed less. But the results weren't, for whatever variety of reasons, weren't quite statistically significant. So that's 38 out of 40 studies finding that vegetarians, those people who don't eat animal foods, don't eat meat, actually weigh less. And, it's not just a little less, these are pretty big numbers. Females, on average, weighed between 6 to 24 pounds less. Males, anywhere from 10 to 28 pounds less, which are impressive numbers. And if you follow populations over time, you see that the more meat they consume, in some studies, the more weight gain they have. In the Epic Study in Europe, for every extra half a pound or 250 grams a day of meat that they consumed, participants gained on average about 4.5 pounds over 5 years. So that's a significant amount when you add up 10, 20, 30 years of dietary patterns. And this was true, importantly, this was true not only for things like hot dogs, or bacon, or burgers. This was also true for the so-called lean meats, the things that people often turn to when they're trying to adopt a healthier diet. So turning to chicken, in this particular study, was not beneficial for weight loss. And then of course if you have people who are trying to lose weight in intervention studies, you can lose weight in a whole huge variety of ways. You can successfully lose weight by severely restricting calories. You can lose weight by following a very strict low carbohydrate diet. And then a variety of non-dietary ways of course, amphetamines, stimulants, all sorts of goofy unhealthy ways you could lose weight. But rest assured that a plant-based diet does help people lose weight for those who choose that path. In one review, compared to control diets, participants or groups that follow vegetarian or vegan diets lost about 4.5 pounds over the course of a variety of interventions. If they want all the way vegan instead of just vegetarian they lost a little more, they lost about 5.5 pounds during the course of the intervention. And this variety of studies ranged in duration from about eight weeks or two months to two years. There are other reviews looking at vegan or vegetarian interventions and they show largely the same thing. That the same kind of numbers, 5 to 16 pounds of weight loss on average in vegan and vegetarian interventions.



And then just moving beyond the vegan or vegetarian diets and thinking more about a whole food plant-based diet. We can look to the studies of Dr. Dean Ornish and Dr. Caldwell Esselstyn, of course, who we've heard from. Dr. Dean Ornish showed in his heart disease patients, after one year they had lost on average about 22 pounds. And Dr. Esselstyn after about three and a half years of participants who adhere to his dietary prescription lost an average of about 18 to 19 pounds. So, that's impressive, these are pretty impressive, impressive numbers. And just to tie this back to my dad's research in looking at some of the how does this work, a little bit. Some of the research that they did looking at diet and cancer, they also looked at body weight and exercise. What they showed was that the rats in my dad's lab who were eating a lower protein diet, they actually gained less weight. And so they thought, well, why did they gain less weight? Were they eating fewer calories? They measured it, and they actually showed that these rats were consuming more calories, not less. How was that possible? Well, they measured their exercise activity and it turns out that the lower protein diet rats, they were voluntarily exercising more. Seeming perhaps to have more energy to run around that wheel and they had more thermogenesis, burning off the calories as heat. And, of course, the thing that we've talked about at length, they had less cancer in the end. So weight loss is a big, complicated topic. But rest assured, you can feel very comfortable that a plant-based diet is very healthy for weight maintenance and weight loss. CNS602 -- 5.4 -- Observational Research - Rates of Diabetes Thomas Campbell, MD So one of the ways I think about understanding diabetes is to take a big picture approach, and that's true actually of most diseases when I think about how does food relate to any particular disease or any particular condition? One way logically to think about starting your investigation would be just simply to look around and observe who has the disease, what are they doing, who doesn't have the disease, what are they doing? And then begin to form some hypotheses or some ideas about how different factors might relate to having the disease or not having the disease. And that was characterized, that type of research was done in particular by a gentleman by the name of Sir Harold Himsworth. He was a very prominent physician in London in the early 1900's, and he was actually credited with discovering, writing a paper that distinguished between type one diabetes and type two diabetes. So he was very accomplished and an intelligent man and what he, started doing was looking at different populations around the world, looking at their diets and looking at their rates of diabetes. And what he found in the chart, this was data from the 1920s and 1930s roughly, what he found across these different countries, let's take a quick look and look at some of the samples. So we have the United States and when you characterize the diet of populations around the country most people who are eating roughly the same percentage of calories from protein. So that didn't change very much from place to place, but what did change from population to population is the amount of fat they were eating, how much of their calories came from fat. And in the United States, in this survey, 36% of the total calories came from fat and 51% came from carbohydrate. Let's compare with another country, Holland. Had about the same amount of fat but a little bit more carbohydrate. England and Wales had a little less fat at the time, a little more carbohydrate. You get the idea here, Scotland a little less fat, a little more carbohydrate. Italy, even much less fat and much more carbohydrate which is interesting, right? The traditional Mediterranean diet here in this survey was relatively low in fat compared to today. And then Japan here was the most dramatic. Very, very low fat diet, really zero added fat in the diet, very high carbohydrate in this particular survey.



So when you look at these various populations, what do you think is the diabetes death rate gonna be? How many people are dying from diabetes? If you're really worried about carbohydrates causing this disease you would think Japan would have the absolute highest rate of diabetes. That, of course, is not the case, the United States in this survey had about 20 diabetic deaths per hundred thousand people. Holland had a little less, England had a little less, Scotland had a little less, Italy even a little less, and Japan way less. So what you see here is that the diabetic death rate was about 7 times higher in the United States during this time than it was in Japan. Japan had 15% the rate of diabetes deaths, even though they were eating a very, very high carbohydrate diet and also a very, very low fat diet. So let's take another angle at this and look at one population over time. In much of the world in the early 1900's researchers were noticing that diabetes was actually becoming more common. The death rate was increasing among the population. So if we look for example at England and Wales, the diabetic death rate, we see that it is generally increasing until about 1915-1916, and there is a pretty big drop. And if we look at Prussia, we see the same thing, we see a big drop 1915 to 1916, an aberration from the trend. And similar to heart disease, of course, what do you think is causing this drop? It's the world war, it's World War I. So you can guess what's going on in World War I? By the way, there's another little drop in this slide about the early 1920s, that's when insulin was first introduced. And the diabetic death rate was briefly decreased because of insulin becoming widely available. So what changed, why this big drop? What changed during the war within one population? They did study this quite carefully, and what they found when they looked, for example at the percentage of total calories coming from carbohydrates, what they found was that during the war, as the submarine blockade, this was in Scotland. The German submarine blockaded around the Great Britain and the food pattern started to change, and the percentage of calories from carbohydrates spiked up during the Great War. The percentage of calories from fat on the other hand spiked down during the war, and of course this corresponded quite nicely with the diabetic death rates. So more carbohydrates, less fat, lower diabetes. Okay, more carbohydrates, lower diabetes. And it is important to note that there wasn't a major change in overall calorie intake during this time in this population. A slight change, slightly less calories, but it wasn't like people were starving and that's why things got better. They were changing the type of foods that they were eating. CNS602 -- 5.5 -- Observational Research - Diabetes Reversal Thomas Campbell, MD Just to remind you a little bit, the time we're talking about, this is a picture, can you recall who this is? If you can't, you're excused. This is actually a fictional character, this is Dr. Clarkson from the popular Downton Abbey TV show. And this is just to remind you that if you're familiar with the TV show, it's a story of a rich estate in the early 1920s. And this was a time when electric toasters were first being developed. And so we had this really, quite nice, observational data from around the world, really, already by this time, which was remarkable. And it wasn't just observational data. In 1935 there was a paper published by another famous physician, Dr. Rabinovitch, in Montreal. He was famous for his diabetes treatments, and in Montreal he conducted a controlled trial. So this was an interventional controlled trial looking at people with diabetes. And he took 50 patients, and he put them on the standard diet of the day, which was sort of a carbohydrate



controlled, a low carbohydrate diet. It's much like it is today, and then he took another group of patients, and he put them on a high carbohydrate diet and 50 patients in each group. And you can see at the start of the diet that this group of patients, they required insulin, okay. So the high carbohydrate group, on average, required about 25 units of insulin a day. The low carbohydrate diet group of patients required about 32 units of insulin a day, and he actually gave them these different diets for five years. And the high carbohydrate diet had lots of carbohydrates, but it did have slightly fewer calories as well to try to maintain a slightly lower weight, but it wasn't strictly controlled. And many more carbohydrates. What he found was that the group having the high carbohydrate diet got better. Okay, so the insulin dose on average dropped from 25 to 11, and the insulin dose for the low carb group stayed the same. There was no improvement. About 8% of the patients in the low carb standard treatment group got off insulin, and about 24% of the patients on the high carbohydrate group were able to stop insulin altogether. So this was back in 1935. A good indication that a high carbohydrate diet was good for diabetes. In fact, in the introduction in this paper Dr. Robinovitch wrote that it was pretty well established by this time, 1935, that high carbohydrate diets increase insulin sensitivity and high fat decreases insulin sensitivity. So this is sort of the opposite really of popular perception. Let's move forward quickly here, Dr. Anderson was able to take diabetic patients, and actually put them in a metabolic ward, this was in 1970's. Put them in metabolic ward and control everything that they ate. And what he did was he put them on a very high carbohydrate diet, very low in fat and very, very high fiber. Okay, so this wasn't sugar, these were high fiber healthy carbohydrates, as much of this research was. And he showed that, this is a chart from his paper showing that these men who were on a relatively low dose of insulin everyday within about three weeks they were off of their insulin entirely, okay, with a very high carbohydrate, low fat diet. Now let me describe the diet a little bit. This was a diet that had almost no added fat, so less than 10% of calories from fat. It also had very, very high fiber, and where were they getting this fiber? About 40% of their fiber came from whole grains in breads and grains. So this was a high grain, high bread, high fiber diet, and within three weeks these men were able to get off their insulin entirely. The men who had higher insulin requirements were able to reduce their dosages within three weeks. And importantly both Dr. Robinovitch's work and Dr. Anderson's work, we see that their cholesterol groups in the high carbohydrate diet, the cholesterol dropped significantly as well. There is another paper published in the early 1980s in the Pritikin Center, which has become quite famous. And this was a group of 60 diabetics, they went again into a controlled environment residence program. And did basically a whole food plant-based diet, exercise, and some calorie restriction over a course of about three weeks. At the beginning of the program, about 17 patients were on insulin. Within one week, 10 of them were able to get off insulin entirely. Another week, another one off insulin. Another week, two more were off insulin. And during this time, it's important to note their blood sugars actually got better throughout the experience, so it was a win, win, their blood sugars were getting better, and they were getting often insulin, which is very powerful combination. CNS602 -- 5.6 -- Epidemiology - Transition in China Thomas Campbell, MD So there are a lots of intervention studies showing over the past 100 years now, almost, that a high carbohydrates diet is in fact good. There's observational studies showing that high carbohydrate diets are consistently linked with lower rates of diabetes. Let's take a look at a more recent observation. Let's look at diabetes in China, okay? And what I wanna do is look at the diet. The diet has changed very quickly in China. And I wanna look at the typical diet in 1991, 2000, and then



more recently 2011. Now in 1991 the diet had already been significantly changing. In the China project the fat content was really quite low, in the mid teens or so, maybe 15% of the calories. By 1991 the fat content had gone up to almost 20% of calories. Carbohydrate intake was 66% of calories, and protein was about 12% of calories. Now think about what's happening in China around this time. In 1987 the first Kentucky Fried Chicken came into China. In 1990 the first McDonald's came into China. And through the early 90s and mid 90s there was a lot of convenience stores, Walmart, supermarkets, supercenters, kind of opening out throughout China. So at least in the urban areas, the landscape was changing, it was really beginning to change very quickly. And by 2000, there was much more fat in the diet, so the percentage of calories you can see in this chart increased almost 28%. Where did it come from? Well, carbohydrates, they were decreasing their carbohydrate intake. Their protein intake was creeping up a little bit. Fat intake continued to increase. So by 2011, they're consuming over 30% of their calories from fat and only about 55% of calories from carbohydrate, with about a little increase in protein consumption. Now let me, rather than just look at the nutrients, let me put this more plainly in terms of dietary transition. The China dietary transition was characterized by two things for the first several decades. One is an increase in edible oils, okay? So that was a huge distinction from 1970s up to the modern day. As the increase in edible oils has been dramatic, and there's been a lot more frying of foods, for example. The second transition is increase in animal sourced foods, increased pork and other foods. And both of those things have been the main drivers of the dietary transition. It's only recently where there's been really rapid increases in sugar, in sugar sweetened beverages and colas, and processed foods like that. So with this increase in edible oils and animal foods, what do you think happened with diabetes? Around 1991, the prevalence was about 2.5% of the population. And by 2000, the rate had doubled, okay. The rate had doubled in about ten years to 5.5% of the population. And then as people continue to consume more fat, less carbohydrate, the rate doubled again to 11.6% of the population. Now, they have prediabetes, about 50% of the population has prediabetes. They have an epidemic that is as bad as the American population epidemic of diabetes. It's really spelling a disaster for China. And just to put this into perspective, the urban areas are always the quickest to adopt the bad habits. And in the megacities of China, they are consuming even more fat, less carbohydrates, and even more protein with animal-based foods. We don't have the prevalence just for those particular mega cities in this survey, but rest assured, this is a very, very dangerous, ominous trend for China. So this is just a skimming of the evidence of observational evidence and interventional evidence that goes back now over 80 years with diet and diabetes. And if you were an alien and you were going to now fly back to your home planet and present this information to the science minister, what would you say? Would you say, well, it's very clear that carbohydrates cause diabetes? No, of course you wouldn't say that. You would say, it seems likely that high fat diets, high animal food diets are linked to high rates of diabetes. And in fact, when you switch those diets on their head and have very high carbohydrate, high fiber diets, you actually can reverse diabetes with data going back 80 years. It's very important, I wanna to make a quick note that most of the carbohydrates in these studies were not Twinkies and gas station pastries. These were healthy carbohydrates, healthy starches that have the intact fiber, the whole plant foods, which has been shown to be very good for diabetes. So with that background, we can look at some of the more mechanistic evidence, and really, it



becomes very clear. There's this mountain of evidence for diet and diabetes really suggests more plant based foods, more fiber is good for diabetes. CNS602 -- 5.8 -- Insulin Resistance Michael Greger, MD, FACLM What is insulin resistance? In fact, what exactly is diabetes? What causes it? Studies dating back nearly a century noted a striking finding. If you take young, healthy people. Split them up into two groups, half on a fat rich diet, and half on a carb rich diet. Within just two days, this is what happens. The glucose intolerance skyrockets in the fat group. In response to the same sugar water challenge, the group that had been shoveling in fat ended up with twice the level of blood sugar. As the amount of fat in the diet goes up, so does one's blood sugar spikes. It would take scientists nearly seven decades to unravel the mystery, but it would end up holding the key to our current understanding of the cause of type 2 diabetes. The reason athletes carb load before a race is that they are trying to build up a fuel supply in their muscles. We break down starch into glucose in the digestive tract, it circulates as blood glucose, blood sugar and is taken up by our muscles to be stored or burned for energy. Blood sugar, though, is like a vampire. It needs an invitation to come into our cells, and that invitation is insulin. Here's a muscle cell, here's some blood sugar waiting outside patiently to come in. Insulin is the key that unlocks the door to let the glucose in the blood enter the muscle cell. When insulin attaches to the insulin receptor, it activates an enzyme which activates another enzyme, which activates two more enzymes as you can see. Which activates glucose transport, where it acts as a gateway for glucose to enter into the cell. So insulin is the key that unlocks the door into our muscle cells for blood sugar. What if there's no insulin, though? Blood sugar would just get stuck on the bloodstream banging on the door to our muscles, not being able to get inside. And so with nowhere to go, blood sugar levels would rise and rise. And that's what happens in type 1 diabetes. The cells in the pancreas just don't make insulin. The cells that do make insulin get destroyed and so without insulin, sugar in the blood can't get out of the blood into the muscles and blood sugar rises. But there's a second way we could end up with high blood sugar. What if there's enough insulin, but the insulin doesn't work? The key is there, but something's gummed up the lock. This is called insulin resistance. Our muscles become resistant to the effect of insulin. What's gumming up the door locks to our muscle cells, preventing insulin from letting glucose in? Fat. Intramyocellular lipid fat inside our muscle cells. Fat in the blood stream can build up inside the muscle cell, and create these toxic fatty breakdown products and free radicals that can block the insulin signaling process. So no matter how much insulin we have in our blood, it's not able to open up the glucose gates and blood sugar levels build up in the blood. This mechanism by which fat induces insulin resistance wasn't known until fancy MRI techniques were developed to see what's happening inside people's muscles as fat is infused into their bloodstream. That's how we found out that elevation of fat levels in the blood causes insulin resistance by the inhibition of glucose transport into our muscles. And this can happen within three hours. One hit of fat can start to causing insulin resistance, inhibiting glucose uptake within just 160 minutes. Same thing happens to teens. You infuse fat into their bloodstream and it builds up in their muscles and decreases insulin sensitivity, showing that increased in fat in blood is an important contributor to insulin resistance. And then, you can do the opposite experiment. Lower the level of fat in people's blood and insulin resistance comes right down. Clear the fat out of the blood and you can clear the sugar out of the blood. So that explains this finding.



On the high fat ketogenic diet, insulin doesn't work as well. Our bodies are insulin resistant, but as the amount of fat in our diet is lower and lower, insulin works better and better. A clear demonstration that the sugar tolerance of even healthy individuals can be impaired by administering a low carb, high fat diet. But we can decrease insulin resistance by decreasing fat intake. As the level of fat rises, the body's ability to clear sugar from the blood drops. Now where's this fat in our blood that's wreaking all this havoc come from? Well, it comes from the fat we eat as well as from the fat we wear. The number of fat cells we have stays constant in adulthood. It's interesting the way they figure that out. It's actually by measuring the amount of radioactive carbon trapped in our DNA from all of the nuclear bomb tests. They can actually measure it that way. Anyway, after massive weight loss our fat cells shrink as they offload fat, but the number stays the same. Conversely, as we gain weight, our fat cells just stretch as we pack more and more fat into each individual fat cell. So when our belly, butt or thighs gets big, we're not just adding more fat cells. We're just cramming more fat into each cell and at a certain point our cells become so bloated that they start spilling fat back into the bloodstream. This is an illustration of the so called spillover effect. Not only do obese persons have more fat, they're constantly spilling that fat into their bloodstream. So that could explain the link between obesity and diabetes. Fat is spilling from our fat cells and gets lodged in our muscle cells, leading to the insulin resistance that promotes the onset of type 2 diabetes. Or, of course, the fat can enter our bloodstream through our mouth. If you put people on a low carb diet, fat builds up in our muscles within two hours compared to a low fat diet and insulin sensitivity drops. And the more fat in our muscles, the lower they build to clear fat from the blood. It doesn't take years for that to happen, just hours after these foods go into our mouths. A fat rich diet can increase fat in the blood and this increase is accompanied by a decrease in insulin sensitivity. Studies clearly demonstrate that fat in the blood directly inhibits glucose transport and usage in our muscles, which is responsible for clearing about 85% of the glucose out of our blood. So these findings also indicate an important role of nutrition, particularly increased consumption of fat, for the development of insulin resistance. Normally, we only have between 1 and 500 micromoles of free fat floating around our bloodstream at any one time. But those who are obese, constantly spilling fat into their bloodstream as you can see, have much higher levels. But we can reach those same levels eating a high fat diet. So a skinny person eating a low carb diet can have the same level of fat in their blood as an obese person does. Similarly, being obese is like eating a horrible bacon and butter diet all day. Even if you're eating healthy, because you're spilling fat from your own fat cells into the bloodstream no matter what goes into your mouth. The association between fat and insulin resistance is now widely accepted, so called ectopic fat accumulation, the accumulation of fat in places that it's not supposed to be within our muscle cells. But not all fats affect muscles the same, the type of fat, saturated versus unsaturated, is critical. Saturated fat like palmitate, found mostly in meat, dairy, and eggs, causes insulin resistance whereas oleate, found mostly in nuts, olives, avocados actually improve insulin sensitivity. What makes saturated fat bad? Well saturated fat causes more of these toxic breakdown products and mitochondrial dysfunction and increases oxidative stress and inflammation, establishing a vicious cycle of events In which saturated fat induce free radicals, cause a dysfunction in the little power plants within our cells, the mitochondria, which causes further increase in free radical production and impairment of insulin signaling. Fat cells filled with saturated fat activate an inflammatory response to a far greater extent. The increased inflammation along with eating more



saturated fat, has been demonstrated to raising some resistance through free radical and ceramide production. Saturated fat also has been shown to have more of a direct effect on skeletal muscle insulin resistance. Accumulation of saturated fat increases the amount of diacylglycerol in our muscles, which have been demonstrated to have a potent effect on muscle insulin resistance. Doesn't matter if the fat in our blood comes from our fat or from their fat in our diet. You can take muscle biopsies from people and correlate the saturated fat buildup in their muscles with insulin resistance. While monounsaturated fats are more likely to be detoxified or kind of safely stored away, saturated fats create these toxic breakdown products like ceramide that increases lipotoxicity. Lipo meaning fat like as in liposuction, and toxicity. This fat toxicity in our muscles is a well known constant for the explanation for this trigger of insulin resistance. I've talked about the role of saturating trans fats contributing to the progression of other diseases like autoimmune diseases, cancer, heart disease. But they can also cause insulin resistance, the underlying cause of prediabetes and type 2 diabetes. The human diet, saturated fats are derived from animal sources while trans fats originate in meat and milk, in addition to the partially hydrogenated and refined vegetable oils, as well. That's why experimentally shifting people from animal fats to plant fats can improve insulin sensitivity. Insulin sensitivity was impaired on the diet with added butter fat, but not with added olive fat, for example, in this study. We know prolonged exposure of our muscles to high levels of fat leads to severe insulin resistance, with saturated fats demonstrated to be the worst. They don't just lead to inhibition of insulin signaling, the activation of inflammatory pathways, and this increase in free radicals. They cause an alteration in gene expression leading to a suppression of key mitochondrial enzymes, like carnitine palmitoyltransferase, which finally solves the mystery of why those eating vegetarian have a 60% higher expression of the fat burning enzyme. They're eating less saturated fats. That's why people eating plant-based diets have higher metabolism, burn more calories while they sleep. Because, we think, of this higher expression of the fat burning enzyme and the mitochondria thanks to our decreased saturated fat intake. So do those eating plant based diets have less fat clogging their muscles, less insulin resistance? Well there hasn't been any data regarding insulin sensitivity or how much fat was found in the muscle cells of those eating vegan or vegetarian until now. Research at the Imperial College of London compared the insulin resistance and muscle fat of vegans versus omnivores. Now those eating plant-based diets have an unfair advantage at being so much slimmer. So they found omnivores that were as skinny as vegans to see if plant-based diets could directly benefit as opposed to indirectly benefit by pulling fat out of the muscles, by helping people lose weight in general. They found significantly less fat trapped in the muscle cells of vegans compared to omnivores at the same body and weight, better insulin sensitivity, better blood sugar levels, better insulin levels, and excitingly, significantly improved beta cell function, the cells in the pancreas that make insulin in the first place. They conclude that eating vegan is not only expected to be cardioprotective, prevent our number one killer heart disease, but that veganism is beta cell protective as well, helping us prevent our seventh leading cause of death, diabetes. This is a graph of fasting blood sugars in the 13 years prior to the onset of diabetes. Insulin resistance starts over a decade before diabetes is actually diagnosed as blood sugar level slowly start creeping up. And then, all of a sudden, the pancreas konks out and blood sugars sky rocket. What could underlie this relatively rapid failure of insulin secretion?



At first the pancreas pumps out more and more insulin trying to overcome the fat induced insulin resistance in our muscles and high insulin levels can lead to accumulation of fat in the liver, called fatty liver disease. Before diagnosis of type 2 diabetes, there's a long silent scream from the liver. As fat builds up in our liver, it becomes resistant to insulin too. Normally, the liver's constantly producing blood sugar to keep our brain alive between meals. But as soon as we eat breakfast, though, the insulin released from the meal normally turns off liver glucose production. Which makes sense, we don't need it anymore, we're not sleeping. But filled with fat, the liver becomes insulin resistant like our muscles do and they don't respond to that breakfast signal. So keep pumping out blood sugar all day long on top of whatever we're eating. So the pancreas pumps out even more insulin to deal with the high sugars and our liver gets fatter and fatter. That's one of the twin cycles, the twin vicious cycles of diabetes. Fatty muscles, in the context of eating too many calories, leads to a fatty liver which leads to an even fattier liver. And this all starts before diabetes. But then the next vicious cycle starts. Fatty liver can be deadly, so the liver starts trying to offload the fat by dumping it back into the bloodstream in the form of something called VLDL. And that starts building up in the cells of the pancreas, that produce the insulin in the first place, so now we know how diabetes develops. Fatty muscles leads to a fatty liver which then leads to a fatty pancreas. It is now clear that type 2 diabetes is a condition of excess fat inside our organs. The only thing that was keeping us from diabetes from unchecked, skyrocketing blood sugars is that the pancreas was working overtime. We're pumping out extra insulin to overcome insulin resistance but, as the so called eyelet or beta cells in the pancreas are killed off by the fat build up, insulin production starts to fail and we're left with a worst of both worlds. Insulin resistance combined with a failing pancreas. Unable to then overcome the resistance, blood sugar levels go up and up, and we have type 2 diabetes. You may wanna have to watch that a few times to fully digest that, there's a lot of technical detail, but if any questions remain, please feel free to contact me through nutritionfacts.org. CNS602 -- 5.10 -- Glycemic Index & Glycemic Load David J.A. Jenkins, MD, PhD, DSc Well, basically, it's a way of looking at the quality of carbohydrates. So, what it does is it ranks the rise in blood glucose from eating 50 grams of a carbohydrate portion of a particular food as a percentage of a standard. Originally we used glucose, I prefer bread because it's more commonly placed with most people, but certainly many people use still the glucose standard. So, in other words, if your blood glucose rise after a meal is 100%, the area under the curve, we would call that 100%, then if you're taking something like bread it's less than glucose. So it would be under the 100%, it'll be about 71% of the glucose scale. So that if you made bread 100% and then you look at something like pasta and spaghetti which is half or even better, beans, which is perhaps 30 or 40% of the bread scale. Then they will only give 30% or 40% of the blood glucose rise. Therefore the glycemic index would be called 30 or 40 for the bean, and 50 for the pasta on the bread scale. The glycemic load is not a 50 gram portion. It's basically what you eat in the meal. So your load may be less than 50 grams or more than 50 grams. And so what that does, it allows you to multiply the glycemic index by the amount of carbohydrate. So you get an idea of the total impact on blood glucose of the meal as eaten. Well, you may not care at all. I mean, it depends politically which side of the spectrum you're on almost. But why some of us care about it is because we believe that a raised blood glucose is one of the markers of impaired carbohydrate tolerance and that leads on to diabetes which is obviously gross impairment of your ability to handle a carbohydrate meal. And obviously an impairment of



other things, too. But we're thinking of the postprandial event. And we believe therefore that if you can control the postprandial event and you can with a drug called acarbose and other drugs like it which inhibit the digestion of carbohydrates in the gut. These foods, if you like, transform the whole of your diet into a low glycemic index diet. And these foods are used therapeutically to manage diabetes, and have been shown to reduce blood pressure and prevent heart disease in these high-risk people. So, in other words, what we're saying is, you can do it with a drug. But why not try doing it with food first and certainly in addition. Well, I think that in the early days, we said that cholesterol content of foods is the be end and all end of diet. And now people are even doubting whether we should worry about the cholesterol in our diet. I think we should, I think we should be concerned about it and I think the less the better. A zero cholesterol diet would be absolutely fine. Then there was a time when we thought it was all gonna be due to saturated fats in the diet. And now people are questioning saturated fat but I still think saturated fat is important when it comes from animal products. It may not be so important when it comes from plant foods, which it can. So there are many things that make up a diet, the cholesterol, the saturated fat, the protein, the calcium, all these things, and the glycemic index is just a way of classifying the type of carbohydrate so that one might look for more improved types of carbohydrate in the diet. So it's in no way the be all and end all of dietary goals. It's not the alpha and omega. But it's one component which we would like to see on packages of foods so that people could be at least more informed about how the carbohydrate may respond in their bodies. CNS602 -- 5.11 -- Glycemic Index - Protein, Fat, & Fiber Intake David J.A. Jenkins, MD, PhD, DSc I think one of the areas where there is a little bit more thought required is when we're talking of the glycemic load. One of the ways you can cut down on your glycemic load is not by eating beans, peas, lentils and steel cut oats etc. But by just cutting the carbohydrate out of your diet altogether and having two eggs over easy on a burger, with a load of butter on top of it. And that's true, you can do that and you'll get no rise in blood glucose. I have to say just as an aside, the one thing in favor of that diet and it's the only thing that I'm going to say that's in favor of it. Is that it is sufficiently unpalatable or boring that people don't eat too much so they lose weight. If I can anecdotally say that we did a study with medical students, as we used to do a lot of, for dietary studies. Because they used to work their way through medical school by doing studies where they got all their food free, and they got paid at the end. And we recruited for a study where we were going to look at the effects of, a colleague of mine, John Cummings, Was going to look at the effect of a high-meat diet, a high-beef diet on colonic function. Because John was concerned of the meat link to colon cancer. So he wanted to see, he wasn't trying to cause colon cancer in medical students, but he wanted to see what the effect was in terms of their colonic function. And I have to say that he never had so little difficulty in getting students to volunteer for a study. As when he said he was going to be feeding them about 140 to 160 grams of beef a day, they all volunteered. By the end of the four weeks, none of them wanted to eat beef again and two of them became vegetarians. So all I'm saying is that I think that that sort of a diet, that's what you're really focusing on, will cause weight loss. But as we've all said and people have often mentioned, may not be sustainable. In fact, we don't think it's at all sustainable. And I think more importantly, and I think much more importantly for people as today's thinking is a little bit more advanced. This is not right in terms of environmental impact, animal welfare and many other things. So, I think that there are many reasons why one



wouldn't go in that direction. Can we take a little bit more fat and little bit more protein? And we've been doing a number of studies, we've called it the Eco-Atkins diet. Where we green the Atkins diet, in other words we make it a vegan diet. And look at the effects of a vegan diet, which has some of the Atkins profile, in other words higher protein and higher fat of plant origin. And I have to say, I have to say, that for many people, this seems to make a positive difference. I can't tell you about the long term effects, but certainly when they're losing weight loss in the acute stage, and being able to keep their cholesterol and their triglycerides down, which we'd like them to do. This seems to have worked very well. So, I used to be, as you can imagine, a very high carbohydrate man but I'm now mellowed. And I accept that a higher fat, higher protein intake of plant origin, may also will be very useful metabolically. And that fits in well with the lower glycemic load and it allows one still to have one's low glycemic index carbohydrate foods. One isn't as excessive, obviously, as the Atkins diet but it's just a somewhat lowering of the amounts eaten. Well fiber, unless it's a certain type of fiber, may not modify the glycemic index greatly. Unless it's in case is a grain, a whole grain, so if you have oats, steel cut oats, or if you have bulgur, which is cracked wheat. The fiber tends to protect the grain somewhat from your digestive enzymes. So it encases the grain, so it may act as a barrier and slow your digestion of that food up so you don't get a big spike in blood glucose. So it's very true that steel-cut oats and bulgur are associated with their fiber and have a lower rate of digestion. But that's also because they've got a granular size. Do you know what I mean, they're not just fine flower. Once you take the grain and mill it, which is an artificial thing anyway. Mill it completely to make that wonderful bread that we like, which is whole wheat or finely ground flour. And the fiber is also finely ground too. It doesn't make a great deal of difference in the rate of digestion and you can see that. You can imagine the digestive fluids pouring in, they can easily find the starch molecules to digest. They're not protected by the fiber, so I think that makes sense. And you can also see that, if you have brown rice, for example. Where, if you've ever cooked brown rice, you'll note that very often the brown part of the rice splits, in other words the grain opens up. You can see the brown rice on it. But you can also see a large area where digestive enzymes can look at naked starch and digest it very rapidly. So you can see why grains and why cereal fiber may not, when it's ground, or when it's very cooked and where the grain doesn't keep its casing on completely. You can see why it doesn't provide much of a barrier, so it doesn't make much difference. The next question you're going to say is, well, why do I bother then? Why do I say, not just eat white bread because it's the same glycemic index as brown bread, as whole wheat bread. Well, cast your mind back to what we were saying. We were saying the glycemic index is only one aspect of a food or one aspect even of a carbohydrate food. And the whole wheat will have higher protein content, higher vegetable protein content. It will have a lot of minerals associated with it. It will also keep your bowels regular because of the fiber content. So there are lots of good reason for still having the brown over the white, it's just not a glycemic index reason. CNS602 -- 5.12 -- Diabetes - Low Glycemic Index Foods David J.A. Jenkins, MD, PhD, DSc Yes, I think that one of the interesting things to me is that the nations that have some of the highest rates of diabetes are those who used to eat a lot of beans. People from the Indian subcontinent Dal, lentils, chickpeas. These have been part of their dietary habits. The Chinese and Japanese have had mung beans, aduki beans, a lot of beans in their diets in the past. Just interestingly, and I can't say that it's anything more than an association.



As these cultures have given up on their beans, and changed to a more Western type diet, obviously, physical activity and many other things have played into this. But they've also given up their beans and what we would call their lower glycemic index carbohydrates. But you'll note they've all kept their rice. They've all kept their higher glycemic index food. And interestingly, they may be more vulnerable to diabetes. And there are attempts made. Our friend, Frank Hu, at the Harvard School of Public Health, has got a study in China where he's trying to reverse this by changing the nature of the rice that's being eaten. And possibly later on he'll be putting in the beans. So one of the things that interested us a long time ago when we started screening foods was that all the legumes, all the pulses. The beans, peas, lentils, chickpeas, black-eyed peas, all had low glycemic indices by comparison with bread. And we thought that was very interesting because beans were a staple and so was bread, and you could choose between two different types of staple. And we've been exploring why the bean may have a low glycemic index. And I have to say that one of the reasons, and that's why it spills over onto our fat and protein part of our discussion. One of the reasons is they're also high in vegetable protein. And it may not be just the fiber in the bean that reduces the glycemic index of the bean. But it's also the vegetable protein in the bean which also seems to hold the starch in position and stop it from being digested too rapidly. So, we think that the protein, possibly, the fiber, perhaps not so much the fiber but certainly the protein and the nature of the starch is more amylopectin than there is. Sorry there’s more amylose starch than amylopectin. Amylopectin is more rapidly digested. Amylose starch is more slow digested. So the bean has amylose and amylose starch and vegetable protein. That makes it a slower release type of carbohydrate food. So, we believe that they are sort of ready made for those who want a low glycemic index stat, for those who want to have a good vegetable protein intake, for those who want to increase their fiber intake and their mineral intake because they're also good sources of minerals. So, I think, the bean is a little sort of capsule of many good things. What the results showed was that we got what we saw was an expected reduction in blood glucose level. There are also effects that have been shown in meta-analyses of big effects on blood lipids, cholesterol, which we've also shown independently in other studies in high cholesterol people. So it does do good things for serum cholesterol. But one of the things they're interested in most was it seemed to have a really good affect on blood pressure. And that in this study was unexpected for us. And so that's the thing that I'm now talking about beans more about is their blood pressure effect. Which goes back to the old Alcobar study where slowing carbohydrate release was shown to reduce hypertension in people at risk. So I think that beans do exemplify that aspect of low glycemic index foods in that they appear to be associated with lower blood pressure results. So that's very, very satisfying. So we've got something that may positively affect glucose. Positively affect cholesterol, and now positively affect blood pressure. So it's no surprise that in epidemiological studies, bean consumption is also been associated with less heart disease. And as they used to say, beans, beans, good for the heart, the more you eat the more you, whatever. So I think that it will be, it's an old wives tale almost, that beans are good for the heart. CNS602 -- 5.14 -- Plant-Based Diets & Diabetes Improvement Neal Barnard, MD In 2005, we wanted to find out could people change their diet in such a way to lose weight without counting calories, without limiting carbohydrates. But instead, by changing the kinds of foods their eating. So, the idea was to try an entirely plant-based diet. Prior to that, researchers like Dean



Ornish had shown that a plant based diet is really, really effective for people with heart disease. Our question was what if I don't have heart disease? What if I just wanna lose weight? So, we brought in 64 women. Everybody was past the age of menopause. Everyone was moderately to severely overweight and they just felt stuck. And so we did not tell them how much to eat, but we said, let's throw out the animal products, keep the oils to a bare minimum and see what happens. And it was a 14 week study initially and what we found was that in 14 weeks, the average person lost 13 pounds, which is pretty good, but then we tracked for them for another year that way they did not come back. We tracked them for two years and the weight never came back. So unlike every other study where you put people on a calorie restriction and they lose some weight, but then their hunger returns and they don't want to keep dieting. They gain the weight back when you're just changing the type of foods people eat. What you can see is that weight loss becomes effectively permanent, but there's one other part of this. We also tested their insulin sensitivity, which you can do with a test called a glucose tolerance test and what we found was that their bodies were responding more efficiently to the insulin in their bodies and that suggested that this is not only a great way to lose weight, but it's also probably a good way to deal with diabetes. Now we hadn't done any of that research yet, but we had shown that at least among these people, it looked like it might be helpful for diabetes. In 2006, we put this kind of diet to the test for people with type two diabetes. We brought in 99 people, they all had type 2 diabetes and they'd all been doing the typical diets that people do for diabetes. Don't eat carbohydrate. Limit your calories, that kind of thing and they hadn't really been getting the results that they wanted. In other words, they were still on plenty of medication. They were not losing weight, their diabetes was not in good control. So the diet that we tried at this time was completely vegan, no animal products at all. We kept oils to a bare minimum. So, you're not adding oil to your pasta or your salads using nonfat products. But third, we also ask people to have what we call low glycemic index foods. So instead of white bread, which spikes your blood sugar, it might be rye bread or pumpernickel, which is more gentle on your blood sugar. So three rules, vegan, low-fat, low glycemic index. And what we found was that people's blood sugar, it went down very, very rapidly. It was really quite amazing to see. The drop in blood sugar was bigger not only than any other diet, but it was better than even oral diabetes medications. So, that was huge. But in addition to that, people found that their cholesterol improved. Their blood pressure improved. They lost weight very, very nicely and then we tracked these individuals for an additional year to see what would happen. And what we found is that even after, at this point now, it's a year and a half, their blood sugars never came back to where they had been before. They maintained their improvements and many of them reduced the amount of medication they were requiring. Or in some cases, got off their medication altogether. So we now feel that the healthiest diet for people with type two diabetes is not the old-fashioned count your carbohydrate diet. Don't eat so many calories to try to lose weight. The approach is get away from the animal products. And if you do that, you'll lose weight gently and naturally. And your blood sugar comes under better control, because your insulin sensitivity is improving and that's really the healthy prescription for type two diabetes.

cns602 -- front page -- diseases of affluence thomas ...€¦ · cns602 -- front page -- diseases...

Documents