 V tom, da je vse pravno počet, je vse zelo, da je to, da je vse, da je vse, da je vse, da je vse, da je vse, tako ko je, da je vse, nekaj karboidet, kaj so dobro, nekaj karboidet, in vsega je, da je karboidetne dobro. Prevjeličček z mojj glasbov, z kajim profesorem Christopher Gardner, vsoči, da pričeljnih, nekaj nekaj nekaj nekaj rešist, nekaj nekaj nekaj rešist, nekaj nekaj rešist nekaj rešist, nekaj nekaj nekaj rešist, nekaj nekaj rešist nekaj rešist, nekaj nekaj rešist nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, nekaj rešist nekaj rešist, ere pokeršc Those 19 bar and low fat diets.arring 1.700 men in women in marks voix can serve to approach either low carb or low fat diet in led for one year. Name of the study is diet fits. Diet interventions examining factors interactive with treatment successor. Tako, v našelji. Veseli smo izvršiti faktor, ki se predivimo, kako se prišlo, je bolj nekaj, da je zelo, kako je zelo, kako je zelo, tako, faktor, ki nosi, metabolizovani, unik. Tako, imam zelo, Všeč, da se je uniki? Všeč, da se je uniki? Ja, imam... Ja, imam všeč? Zdaj, da se pridem v DNA, geni. Daj je deste všeč vse, da se predetem. Ne bo in dog geni, vočey da je, da je, da je. Tukaj moj아 je v konjemovom sprinu, tako, pa je naji, da je, da je, da je, da je, da je, da je, da je, da je, da je. Ja. To je, da je. Však so, da izvoji ni. Kaj bo tudi? A če ga pogomimo, da se moram, da te, ko je pošli, trajno ga se več. Pozirno, da biti naplito, So go ahead and don't worry too much. So now be ready for a shocking surprise. DNA wise, you are 99.9% similar to the person sitting next to you. So technically speaking, DNA can explain only 01% or what makes us unique. And this was one of the shocking surprises from the human genome project, which was completed in 2000. There are other two shocking surprises. The second one being that genes account for only 2% of your DNA. The remaining DNA was once called junk DNA because it doesn't contain genes. And there was the assumption that no gene means no function. And the third shocking surprise is that we humans have the same number of genes as mice, worms and fruit flies and 50 times fewer than an onion. So how we get along as a species with fewer genes than an onion? There must be something else that explains what makes us human and unique. And as many of you guessed here, these factors are our metabolites, the proteins in our body, microbes and lifestyle factors. Things like diet, exercise, lips, relationships, emotions that affect the way we use our genes. A process called epigenetics. And these are the factors that contribute to our metabolic fingerprint. And the factors that we are investigating in our study. In the next 20 minutes, I will give you an overview of the genetic and epigenetic component of this study, on which I am directly working. So a previous study from my group, the same one I mentioned you before, the A to Z study, identified, so found out that three gene variants, ADRB2, FABP2 and PIPAR gamma, might predict the predisposition of a person to lose more weight on a low carbohydrate versus a low fat diet. So might be good markers of carbohydrate tolerance. Now these three gene variants are technically single nucleotide polymorphisms, or SNPs for short. SNPs are what make us unique DNA-wise. Do you remember our first shocking surprise? So SNPs explain that 0.1% that makes you different from the person sitting next to you. And this is because, on average, different people have one nucleotide difference, every 1000 nucleotide in the DNA. So this is 0.1%. And now to understand how SNPs work biologically, they have a very quick genetics refresher. So the letters in your DNA sequence provide information to produce amino acids that in turn forms the protein that build up your cells. Now by changing one nucleotide in the DNA sequence, SNPs might change one amino acid of the protein produced by a gene. And these, together with lifestyle and epigenetics, can affect the way you look, your skin color, your height, your predisposition to diseases, and the way you metabolize food and drugs. Now, coming back to our study, we had identified these three SNPs that were very good candidate as biomarker to predict carbohydrate tolerance. These genes are all involved in fat storage and glucose metabolism. So we went and tested whether we could replicate the association between and carbohydrate tolerance in this new study. And actually we couldn't. So this reflects a general problem with genetic testing. Common SNPs have small effects on function. They can usually explain 1% of the variability between people. So knowing that you are carrying one SNP or a couple of SNPs usually doesn't provide any meaningful information about your visible traits or your health. And so, for example, according to 23andMe, I am 72% likely to have straight hair and the reason for that is that genes don't work in isolation, but in large networks. So a researcher at Stanford, Jonathan Prechard, published a paper a couple of weeks ago where he says that most traits are omnigenic, which means that they are influenced by thousands of SNPs spending the entire genome. So even traits which have a high genetic component like hair carliners or height are influenced by thousands genes. So height actually is affected by 300,000 SNPs and most of these shifted by just a seventh of a millimeter. There's no way you can predict your height just by looking at 10 SNPs. So, and this is the first problem with genetic testing. The second problem is that they don't account for environmental factors, which is epigenetics. So in the second part of my talk, I will introduce you to the field of epigenetics, explain how diet can affect epigenetics and give you an introduction about the work we are doing in our study. So epigenetics is one of the most exciting field of science today. In 2010, the Time magazine dedicated an entire issue to it. The cover story why your DNA isn't your destiny. The new science of epigenetics reveals how the choices you make can change your genes and those of your kids. And since then, epigenetics is showing up in more and more places in our kitchen, in our supplements, in our face creams. But what are the facts and fantasies about epigenetics? So let's try to disentangle these things together and start from the basics. So epigenetics from the Greek epi, which means on the top, means on the top of genetics. So if your DNA is your genome, then your epigenome is a second genome, which is on the top of your DNA and is made of molecular switches that can turn genes on and off. Just like a dimmer switch can modulate lights up and down in a room. This process of turning genes on and off, up and down is called gene expression. And it can explain why there are different types of cells in our body. Fat cells, neuron cells, liver cells, all told 300 different types of cells that all have the same DNA. How is this possible? Think of the genome as a hardware. The epigenome is a software that tells each of your cells what to do, which genes to turn on and off. So, therefore, each single cell body has a different epigenome. And now scientists have sequenced 111 out of the possible 300 and more epigenomes in our body. And this was the result of another landmark project called the Roadmap Epigenomics Project, which is still ongoing. And another finding from this project is that most epigenetic marks lay outside genes. What was once called junk DNA. So they are hidden gold in the junk. And they can partly explain the paradox that we introduced before that we have 50 times fewer genes than an onion. We can make more out of our genome because we have a more complex epigenome. So epigenetics is not only what makes us human, but also can explain in part what makes us unique. And this is how. Lifestyle factors can send signals to enzyme inside our cells that write or erase epigenetic markers. And these in turn affect, can affect gene expression. Now you can think therefore of epigenetic markers as memo nodes placed on your genes. These memo nodes store information about your lifestyle, your environment. And this process is called epigenetic memory. Epigenetic memory can explain why, for example, identical twins with exactly the same DNA can start differing with time, not only the way they look, but also in their predisposition to diseases. And epigenetic memory is also key to understanding how our lifestyle can change our gene expression, thus affecting our health and disease. And this is because the notes, the memo notes that are taken before our birth tend to be written with a pen, to be permanent. That's why so important the nutrition of the mother and the prenatal environment. And the notes that are taken after our birth tend to be written with the pencil, to be potentially reversible. And this is where your lifestyle, your choices become very important because this pencil is in your hands. And diet is one of the most potent signals to our genes. There are many studies in animal models and human showings, but maybe the most famous example comes from a historic tragedy, the Dutch Hunger Winter in 1944. So in 1944, during World War II, the Germans imposed a food embargo in Holland, in Holland. And as a consequence, 20,000 people died. And the babies born during the famine were born under weight, of course, and had very severe health issues. And this is not a surprise. What is a surprise is that when these babies grew up, they were highly prone to obesity and to psychiatric conditions like schizophrenia. And even more surprising, when the famine babies had children of their own, these were also born under weight and with high presence position to become obese. Even if they were never exposed directly to the famine. So some scientists wonder whether the famine could have left some pen marks on the epigenome of the famine babies. And what they found out is that even six decades later after the famine, the famine babies had different epigenetic modifications compared with their same sex siblings who weren't exposed to the famine. And one of these modifications, Marx, was in a gene that promotes growth in the womb, IGF2. So this study clearly shows that you are what you eat and maybe also what your mother and grandmother hate. But also fathers should pay attention to what they eat because this might also affect the epigenome of their children. A study from 2015 shows that obese men have different epigenetic marks compared with lean men and these marks are in their sperm cells. So they could potentially pass to next generation and they are found in genes that regulate brain function and the appetite. So these two examples really show us that food is not only calories, but also information. It's information that can change the expression of our genes. And in our study, I'm trying to understand whether these changes of gene in gene ethics can help us understand whether, so predict whether a person is going to respond better to a low carb or low fat diet. And so if whether we can use these epigenetic marks as biomarkers for carbohydrate tolerance. So our approach is to compare the high responders and the low responders to high carbohydrate diet and then the epigenetic markers that will be specific of the high responders will be marker of high carbohydrate tolerance whereas those that are specific low responders will be a marker of low carbohydrate tolerance. Now, I have to stress an important difference between genetic and epigenetic markers in your journey to optimal health. Because you cannot change your genes, genetic markers can only tell you where your starting line was. But because epigenetic markers respond dynamically to the environmental and lifestyle, epigenetic biomarkers can tell you where you are now in your journey to optimal health. And this is also what our data suggests. We are in the process of analyzing the data. I cannot share any specific details, but I can tell you that what we see is that your carbohydrate tolerance may depend on your carb history. So how many carbs are you eating now and you have been eating before? And this history is stored as an information in your epigenetic marks and these marks may be potentially reversible. So when you lose weight and when you do change your carb intake, these markers change and your carbohydrate tolerance can change as well. And there are studies already published that point to these hypothesis. For example, this is a study from last year showing that carbohydrate intake affects epigenetic marks that influence then carbohydrate tolerance. In this case was an epigenetic mark in a clock gene, the BMAL1. But this is just to say that science is showing that our carbohydrate tolerance is not something that is set in stone but is more dynamic than we used to think. And there are many studies supporting these hypothesis. I reviewed them in a recent open access review that I published just a couple of months ago in the journal Epigenomics. So you are encouraged to check it out. And so to end up this talk, I would like to leave you with two important messages. The first one is use your genes. Don't let them use you. And the second one is that we are truly unique in two ways, because of our genes, the book we are born with and because our epigenom, the book you are the author of. So I would like to thank you very much for your attention. I was on time. Great, great, so please. Yeah, thank you, great talk. Aren't there theoretical reasons to be a little bit skeptical of epigenetic programming generationally? We don't really know what the weather is going to be like next year. So let's list what the nutrient availability is going to be like in the lifetime of a long-leaving organism. Perhaps a shorter lifespan organism in insect or a rodent, the predictive adaptive response wouldn't make sense, because you are predicting less into the future. In general, generationally? So you are asking me what is the evidence of transgenerational epigenetic inheritance. Yeah, especially in long-leaving organisms. Yes, yes. Okay, so what, for example, the study I showed you doesn't necessarily mean that this was a transgenerational epigenetic inheritance. And the reason for that is that we have to distinguish between inutero effects and epigenetic transgenerational inheritance. The transgenerational inheritance is something that happens through the sperm or egg cells. Okay? The inutero effects can be direct effects due to exposure of the baby. So the baby, because the problem is that, especially for women, this is a problem, the egg that produced me is made by my grandmother. Okay? So if my grandmother was exposed to the feminine, I might have been directly affected by the feminine, not through the germline, so not through transgenerational epigenetic inheritance, but through inutero effects. So the experiment that I showed you doesn't demonstrate transgenerational inheritance because we should go to the fourth generation and test this. Right? So we don't have approved for that for human studies. And this is because we just need to go further and demonstrate that these modifications are truly permanent after the fourth generation. But there are studies, after the fourth generation and demonstrating that there is an effect, actually a professor working here, Michael Skinner, did an important experiment in mice showing this. And for humans, no, there is not a definitive answer. So we don't know if these are inutero effects. Epigenetics is surely involved. We just don't know if it's transgenerational inheritance this is a... On the low-carb cruise when I heard your talk. Yes, one thing I liked, I don't know if this falls under what you can't talk about now due to the analysis, but you discussed how having a low carbohydrate tolerance may be a benefit. Is that off-limits right now? Yeah, I was discussing an example. Yeah, so actually one of the SNPs that I showed you that that SNP actually was in ADRB2, I think was one of the SNPs that I showed you, the ADRB2 that basically makes the gene works better. So respond better to insulin as a result your... this gene produce is a sort of fat plug that allows your fat fat cell to release fatty acids and burn them as a fuel. Plug respond to adrenaline but also to insulin. So and this SNP actually makes the plug work better. So it responds better to insulin and it was useful for us because we were going through period of starvation and feeding and so this was only to point out that SNPs, we think of SNPs as something that is pathological but actually they just reflect long-term adaptation of the DNA sequence to allow us to thrive better in response to environmental changes. So they're actually part of a natural mechanism that to prevent disease and not to cause disease. So I think this was, yes, the point I was trying to make and I think this is very important because we see this over and over, especially now with the raise of personal genomics. You hear about MTHFR, EPOE4 and blah, blah, blah. All these are gene variants and most of these variants are actually associated with protective effects in other. So sometimes they make you, they predispose you for one condition but they protect you for one other. And they are not rare. They affect 25% of the population, 50% sometimes. So they are not disease-causing genes. So, yeah. Thank you for making this question. Just something interesting what you mentioned about the, from the Dutch hunger winter and the thrifty phenotype hypothesis of Barker, which obviously you know about. Is that there is reasonable evidence to suggest calorie deprivation in utero triggers the baby's epigenome to anticipate a lifetime of starvation. And then when they get access to lots of calories like they did after World War II their metabolism was trained to store it and keep it and they developed all those problems in midlife. Well, oxygen is we call it a respiratory nutrient or respiratory substrate. Oxygen deparation in utero as is what's seen when women who are pregnant and they snore and have apnea. We're speculating that it's a similar sort of phenomenon that the metabolism is adjusted because the fetus thinks it's going to be born on top of Mount Everest and they're born shorter like mountainous, indigenous people are because of the largest reservoir of mitochondria is in the musculoskeletal system so it behooves them to be short. So I just wanted to bring that up that it might I know Gary Tubbs likes to attack new things so maybe. Thank you very much for bringing this up. I think that this is the beauty of the field is ever growing. I was not actually aware of this scientist that are studying how many, many conditions can affect epigenetics so this is actually exciting, I didn't know. So thank you very much for bringing this up. Are you working in the field? Thank you. Question? Hi. Hi everyone. Three years ago I went to the University of Camerino and took so they were talking about nutrigenomics and nutrigenetics. I wonder if that summer school is still going on and whether you are going to be a part of it or anyone from your team in the next summer school. Thanks a lot for telling me about it because as you may know I may imagine so I'm on one side I'm a typical scientist I work in the lab in my science so I'm not aware of these things but I just created an online course for the Stanford Continuing Studies Program in nutrigenomics so I would be very interested to be there and nutrigenomics and nutrigenetics is so what is speaking about is this even and take these conversations between our genes and environment nutrigenetics is how our genes our snips can affect the way we process food and nutrigenomics is the opposite process how the food we eat can modify the activity of our genes through epigenetics and this is a fascinating field I think although science is still growing we don't we don't know a lot yet but every time I give this course I I'm very happy to see that people are empowered because they to take action on their life on their life because they see that science is just explaining what we have known for years that you should like exercise and a good diet help but now that they see that this is evidence based they are really encouraged to take action and I think this is also one positive aspects of personal genomics so I told you that is not so useful yet but on the other side some people need to know that they have the MTHFR gene to go and eat their spinach it's sometimes it can be useful because and studies show that providing genetic information actually can enhance so diet adherence and people hit better so there is there is a good use for that so maybe you can tell me more about this program I would love to thank you I thought I heard you say that there are epigenetic markers that you are born with that you really can't do anything about is that true? so there's nothing so if your mother was a chronic dieter or you were born to a family who was multiple generations of junk food eaters there's nothing you can do about that except try to do better for the future generation ok, so first of all I tried as you to make also things simple in my presentation and sometimes this doesn't reflect the complexity of things so it is true that all these statements are based mostly on studies from animals and we do see that in general there are some epigenetic changes that occur before birth and they are not reversible we don't know what makes with an impen versus impencil of course one factor for that is that before birth we are more sensitive to environmental signals because after when the sperm and the egg fuse together actually all the epigenetic marks are erased not all but most of them are erased so you are almost epigenetically naked the embryo the stem cells in the embryo are epigenetically naked that is what stem cells are they are epigenetically naked cells that can become everything because they don't have the epigenetic marks they don't have the program to say ok, you express these genes and you don't express these genes they can express potentially everything because they are epigenetically naked they are stem cells but then once they start differentiating and form the tissues of your body they acquire epigenetic changes so I'm telling you this to say ok, these cells that are still epigenetically naked and they are they are forming their epigenome of course they are more sensitive but there are also some other factors that can explain why some markers are impen or impencil there are some local specific factors so some sequencing in our DNA because of their sequence or because of some DNA elements present in them are more fragile are more prone to epigenetic changes that are permanent so anyway there are studies in animals showing that these epigenetic changes are not reversible I don't know there is nothing like that that was shown in men in human so I don't know if we are more protected towards these or just there is no science showing this so I cannot tell you but I think likely there are some epigenetic changes and very likely they are anyway compatible to life but most of them their epigenetic changes are actually very very quick so quick that is very difficult to study epigenetic you have to control I may have different epigenetic changes and then if you measure my epigenetic changes after the talk so is this because I had a huge breakfast or because I wasn't at the talk we don't know right so epigenetic is very dynamic influence by lifestyle factor just take the pencil part of my talk and try to use that