 Thank you very much. So actually I'm a medical physicist working at the University Hospital of Würzburg in Germany and doing some research on ketogenic diet together with my colleague Ulrike Kemmerer who is Advising patients on ketogenic diets for many years now and together we we founded the German Society for Paleoneutrition recently to provide a Proto basis for all the people interested in the paleo lifestyle in Germany now Originally, I was supposed to give this talk together with my colleague Dirk Lemke. You can see him up here And he should have spoken about the roles of exercise and vitamin D in cancer prevention and treatment But unfortunately he was not able to come to this symposium So I changed the title a little bit and we'll concentrate on the diet part today So what I'm going to do is to relate certain aspects of a Paleolithic diet with Biological mechanisms that play a role in cancer initiation and progression. I Think most of you agree with me when I say that cancer can be considered a disease of civilization and this notion is supported by Reports from the beginning of last century Which stated that there was almost almost no cancer prevalence among primitive hunter-gathered societies Including Eskimos, African tribes, American Indians or tropical islanders So this immediately leads us to ask what has changed in our lifestyles that gave rise to the still increasing cancer rates Most of you notice already and it was recently pointed out by Carrera Busters et al in a nice paper that the the main lifestyle factors in which our modern lifestyle differs from a more traditional Paleolithic diet paleolithic lifestyle include exercise Sun exposure with the accompanying vitamin D status Chronic stress which certainly has a role of its own in modern diseases and importantly the nutrition and It has been shown that for example hunter-gatherers consume a diet Which contains on average more protein and less carbohydrate than our modern Western diet and Especially carbohydrates seem to be important when it comes to cancer that there exists a strong Relation between carbohydrates and cancer has been known since the 1920s When several physicians found that tumor cells would take up much more glucose and in turn secret much more lactate than normal cells Even under normoxia and normoxia means normal oxygen concentrations This is therefore known as aerobic Lysus or the Warburg effect after Otto Warburg who performed the most the most well-known experiments Now usually when there is normoxia a cell will Take up glucose and convert it through like glycolysis to pyruvate which will then be transported into the mitochondria to yield citrate and fuel this the TCA cycle and oxidative phosphorylation and Normoxia will therefore shut down lactate production, but in tumor cells this mechanism no longer holds and most of the pyruvate gets converted to lactate by this enzyme here and exported out of the cell together with protons Now the tumor cell has several advantages By doing by having a high glycolytic rate first one is that it is independent of the actual oxygen supply in the microenvironment and For example aggressive tumors they grow too fast for concurrent vascularization Though will so they will always have hypoxic areas in which they depend or they have no other choice than to Use glucose as a fuel also a tumor cell no longer realized on intact mitochondria and If they have dysfunction mitochondria that allows them to evade apoptotic signaling because apoptotic signaling requires the presence of intact mitochondria now third advantage is that the lactate gets x ported out of the cell together with protons like I just said and the protons will disintegrate the extra cellular matrix and Lead to apoptosis in normal in normal a stromal cells and this allows tumor cells to more effectively proliferate and invade and metastasize and the fourth important point is that glycolysis yields high amounts of phosphor metabolites intermediates That can enter the pentose Phosphate pathway to yield reboses for RNA and DNA synthesis and redox equivalents for fatty acids in thesis And in fact every fast proliferating cell for example activated t-cells They have a high glycolytic rate because of this because they have to proliferate fast Now here are some data by eggard holland and co-workers Which just so the which quantify the varga effect basically they have measured in 19 colon carcinoma patients during an operation the substrate uptake and production in tumors and in peripheral tissues and What you can see here is that for free fat acids and ketone bodies there was basically no difference in uptake or production But when you look at glucose and lactate you see that tumor cells would take up about 30 fold more glucose than the peripheral tissue and on the other hand excrete but 20 fold more lactate Now it has long been a question what actually causes the varbo effect and varbo effect is also so intertwined with all the other hallmarks of cancer that you can basically ask for the Origin of cancer itself and the picture that emerged during the last 50 years Is that it is genetic mutations that give rise to hyperactivation of certain signaling pathways that will then then lead to aerobic like lysis proliferation et cetera and especially these caused by gain of function mutation of certain oncogenes and lots of function mutations of Tumor suppressor genes, but during the last 10 years or so a More complicated picture has emerged and there are now many reasons to believe that These genetic mutations are not the primary cause of cancer, but they arise secondarily due to some other causes and There seems to be a complex network of factors that can interact with each other and all give independently rise to tumor agenesis For example, there are good reasons to believe that cancer can more be considered a disease of altered Metabolism or a metabolic disease like a Tom Safer. It will tell you after me In this case defect or dysfunctional mitochondria are the primary cause and only Secondarily lead to genetic mutations. They can also lead to chronic inflammation and chronic inflammation by itself Is has been known for I think more than 100 years as a potent a stimulator and driver of tumor growth Similarly epigenetic modifications for example in silencing of certain tumor suppressor genes can give rise to the To the malignant phenotype Also hypoxia by itself and in aggressive tumors we have hypoxic areas We'll make sure that these tumor cells are dependent on glycolizes and they will up regulate their their glycolite grade and A very important point is that hyperglycemia and hyperinsulinomia Can both cause defect or dysfunctional mitochondria and they can lead to chronic inflammation Which then? Stimulates all these processes of tumor agenesis So it seems that genetic mutations are necessary, but not necessarily sufficient for cancer progression and The microenvironment for example is a very important role and tumor promoters in the white microenvironment include For example abnormal metabolism and up air and extra cellular matrix inflammation and fibrosis the presence of growth factors like insulin and Ig of 1 presence of certain hormones mutagens and reactive oxygen species But the good news here is that most many of these factors can be in principle countered by a paleolithic diet For example a paleo diet is usually diet low in carbohydrates and this by itself will lead to lower blood glucose levels now blood glucose directly impact insulin and insulin indirectly impacts Ig of 1 and Both insulin and Ig of 1 when they've been to their specific receptors They will trigger a signal in cascade through the PR 3k aqt and mTOR which leads to stimulation of proliferation and resistance to apoptotic signaling Now imagine you have a cell which is on the border between Going into apoptosis or becoming malignant then Chronically high levels of insulin and Ig of 1 in the microenvironment like they occur in patients with metabolic syndrome They might lead to favor the malignant transformation of the cell Dietary restriction is also Good could be could be considered part of a paleolithic diet for example in folks who do intermittent fasting regularly and Dietary restriction by itself will activate a mpk which will then have a negative effect on the mTOR pathway So let's go back one more time. I want to stress that this pathway is also Frequently up-regulated in many tumors and this is part of the cause that part of the reason why tumor cells Have such a high resistance to apoptosis and such a drive for proliferation on the other hand the hyper activation of this pathway by genetic mutations Renders tumor cells somewhat less flexible to the availability of nutrients and the metabolic pathways They are more addicted to glycolysis and therefore the varbo effect or Arabic like lysis has been considered by some as Kansas Achilles heel and is now been explored explored for metabolic drugs for example and Indeed in vitro experiments have shown that Cancer cells are very vulnerable when you deprive them of glucose However, Jean just pointed out that in vivo this effect might be questionable because By gluconeogenesis you always make sure that your blood glucose level has a certain range or a certain physiological value however, imagine a patient who has hyperglychemia and What you see here is The oxygen gradient So this is distance from the closest blood vessel and you have here the oxygen gradient and the glucose gradient it reaches fast into the tissue imagine the tumor and Here this area would be a hypoxic area. It's no longer reached by by oxygen, but it's still reached by glucose and It's well known that hypoxic areas are also the most came on radio-resistant ones Now if you are able to lower these patients blood glucose level then theoretically at least you could deprive those hypoxic cells from the blood glucose supply and Eventually slowed on the tumor proliferation and lead to necrosis or tumor cell death in this area But even if this mechanism does not Make a large difference in vivo then we still know that there are some indirect effects of blood glucose and We know this because for example Starved animals which have blood glucose levels on the lower physiological range They survive long and have slower tumor growth than their normal fat counterparts We also know that and Colin Jam had a nice poster yesterday about that We know that hyperglychemia leads to elevation of insulin and free IGF one It leads to a state of inflammation or inflammatory signalling and A competitive inhibition of ascorbic acid transport into immune cells thereby planting the immune response to cancer cells Also hyperglychemia hyper insulin amia elevated free IGF one and obesity are all independent Prognostic factors for cancer occurrence and poor survival in cancer patients, and it's important to stress that these are all All marks of the metabolic syndrome and it's it shows that cancer that cancer patients have very common many things in common with those who have the metabolic syndrome and this is because the tumor manipulates whole body metabolism in We know that in metabolic syndrome patients the adipose tissue will excrete certain inflammatory cytokines and In the cancer patient these cytokines get excreted by the tumor tissue now these cytokines will signal to the liver that there's some inflammation going on and Both liver and muscle will become more insulin resistant even at a very early stage of tumor progression now in this early stage already the synthesis of glycogen in the liver and in muscle tissue is impaired and Muscles to either have a normal fatty acid oxidation rate or they have an upgraded regulated fatty acid oxidation rate in which case this will increase the increase the rate of lipolysis from adipose tissue now with more tumor growth as the disease progresses and we enter a late stage where the Liver up regulates its gluconeogenetic rate and the substrate for that comes either from more breakdown of fat from from the adipose tissue it It comes from the lactate excreted by the tumor and it comes from protolysis, which occurs in muscle to yield alanine the amino acid alanine and This will be converted to glucose by the liver further fueling the tumor so this could be seen as a vicious cycle that develops and The end result is that the cancer patient loses muscle mass and he loses adipose mass and turns into a caractic patient But this also implies that cancer patients need fat and not carbohydrates Because fat and ketone bodies they will provide they will still provide a fuel for muscle cells even in the caractic state While they can hardly be utilized as a fuel by cancer cells It has been shown that if you increase the amount of fat in the patient's diet This will lead to an attenuation of weight loss and fat free muscle loss even if the patient's already caractic if you replace carbohydrates with fat that will also lead to a lower glucose insulin and free IGF one level and Cato genetic diets may have additional special beneficial effects For example ketones have been shown to block like lysis they act neuro protective and they interfere with signaling pathways like the Amto pathway Some in vitro studies have been published that show direct anti tumor effects of ketone bodies like for example a study by by Eugene fine and There are there's a large amount of animal studies which show that animals on a ketogenic diet Will survive longer they have less tumor growth. They have less metastasis they show a genetic normalization of the tumor tissue and They have no loss of body substance a normal weight gain if you use unrestricted diet and the animals are usually fit in contrast to their normal fat counterparts Unfortunately, there are there's a lack of clinical studies. We are all we have there are some positive Case reports and preclinical studies. However, this these studies give rise to hope that ketogenic diet is beneficial for the cancer patient positive effects that have been shown include weight stabilization or weight gain an improved quality of life diminished glucose uptake by tumors now one study found that there were hints towards less proliferation of the tumor a Study done at our clinic by Schmid et al showed improvements in many blood parameters and You just heard the talk by gene Who showed that ketosis correlated with stable disease or partial remission in his patients? so One last point that I want to stress is that When you think about doing a ketogenic diet for a cancer patient, it's important to not just focus on the macro nutrients, but The quality of the nutrients this can be learned from the the paleolithic approach because in paleo diets Quality plays a larger role usually than just the quantity of micronutrients For example, it's important that the omega-6 to omega-3 fatty acid ratio is Is not so high as it is in the standard diet because more omega-3 will lead to more anti inflammatory signaling and Omega-3 fatty acids have have been shown to have some beneficial effects against the cancer caraxia Usually a paleo diet contains no gluten and grain lectins in this way. You are able to avoid additional inflammation You can ideally substitute with a lot of coconut oil Which has these medium-chain triglycerides that get readily converted to codon bodies and usually on the paleo diet you don't have to worry about vitamins and secondary blood substances and For example from red wine green tea curcumin broccoli, etc And some many of these substances have to be show have been shown at least in vitro to protect against reactive oxygen species and inflammation and they They are thought to have an epigenetic regulation of anti tumor processes so to summarize this talk a paleo diet and unfortunately, I Wasn't able to go into other aspects of a paleo lifestyle, but they have similar mechanisms like exercise and vitamin D So they can contribute to cancer prevention through reduced inflammation Normalization of blood glucose insulin and IGF-1 levels they positively affect body composition and They have an epigenetic suppression of tumor-promoting factors And the same principles might improve the prognosis of cancer patients whereby ketogenic diets could be especially effective Thank you. One question Hi, um, I have a girlfriend. She's 35 and she's Looks very healthy. She's a dance instructor and stuff and um, she's been a vegetarian her whole life and she's just Been diagnosed brain cancer, you know, so I'm just wondering If it's possible for her to do a ketogenic diet if she's vegetarian like just do all fats That is it that's still something that can help her. I Think so I would try it. So I mean you can derive Most of your calories from fat. You should derive most of your calories from fat And this does not necessarily have to be animal fat. You can coconut fat and pollen fat are very effective for stimulating ketosis So and because right now she's following like a alkaline alkalizing diet Is it is it you know, just adding a lot more fat to that her vegetarian diet with that I don't know if grains and stuff are part of that for her, but is that that could help maybe I Would make so I would make sure that she is in a ketotic state. I think that's important So it depends for some people can eat as much as 60 gram carbs per day and be in a ketotic state for some people It's only 20 grams That's individually different, but And I think the next talk will address exactly that Thank You dr. Clement