Nutrigenomics with Dr. Yael Joffe: Rational Wellness Podcast 199

Dr. Yael Joffe discusses Nutrigenomics with Dr. Ben Weitz.

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Podcast Highlights

1:40  Nutrigenomics has to do with the relationship between genetics and diet and lifestyle, including exercise, stress management, meditation, trauma, and anything that impacts our health.

3:06  Weight control.  We are all 99.9% identical genetically, but we can still have millions of places in our DNA where our code sequence is different. 1. One thing to consider is what drives us to eat?  We experience hunger differently and this is driven by our genes.

8:24  Epigenetics is how the choices we make in our environment change the way our genes express. When you switch on a gene it makes a protein and proteins are often enzymes that drive our metabolism. Let’s say we find out that we have a gene that means that we are not efficient at detoxifying. We can then encourage them to eat cruciferous vegetables like broccoli sprouts and brussel sprouts, which contain sulforaphane, which can switch on your detoxification genes once it is activated by an enzyme called myrosinase, which is also in the vegetable.


Dr. Yael Joffe has a PhD in genetics and the nutrition of obesity from the University of Cape Town in South Africa. She is part of the team that created the first nutrigenomic genetic test in 2000 and she cofounded 3X4 genetic testing and she is the Chief Scientific Officer and the website is 3X4genetics.com.

Dr. Ben Weitz is available for nutrition consultations specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also specializing in Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure and also weight loss, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111 or go to www.drweitz.com.


Podcast Transcript

Hey, this is Dr. Ben Weitz, host of The Rational Wellness Podcast. I talk to the leading health and nutrition experts and researchers in the field to bring you the latest in cutting edge health information. Subscribe to The Rational Wellness Podcast for weekly updates. And to learn more, check out my website, drweitz.com. Thanks for joining me, and let’s jump into the podcast.

Hello Rational Wellness podcasters, today our topic is nutrigenomics with Dr. Yael Joffe. To give us some idea of what nutrient genomics is, I looked at an article in Nature Magazine and here’s the quote, nutrigenomics is a study of the effects of food and food constituents on gene expression and how genetic variations affect a nutritional environment. It focuses on understanding the interaction between nutrients and other dietary bioactives with the genome at the molecular level, to understand how specific nutrients or dietary regimens may affect human health.

Dr. Yael Joffe has a PhD in genetics and the nutrition of obesity from the University of Cape Town in South Africa. She’s part of the team that created the first nutrigenomic genetic test in 2000, and she co-founded 3×4 Genetic testing. Dr. Joffe, thank you so much for joining me.

Dr. Joffe:   Hey, Ben. Thanks for having me join, thank you.

Dr. Weitz:  Absolutely. I do think that we really need some more detail and nuance about this whole concept of genomics and nutrigenomics and epigenetics. How how do you… I gave a definition of nutrigenomics from Nature Magazine, but how do you define nutrigenomics?

Dr. Joffe:   I actually thought that was a excellent definition, but I think you could probably break it down a little bit more and maybe just make it a little easier. So it was great for me, I’m not sure it was great for everyone else. So maybe we can start by just coming down to some really basic concepts of what is this story of the relationship between genetics and nutrition. And when I say nutrition, I’m always talking about diet but I’m also talking about lifestyle, exercise, stress management, meditation, trauma, anything that impacts our health. So-

Dr. Weitz:  By the way, I would think it would be great if in this next 50 or 60 minutes we have, if we could get some help on, is can we get some idea from genetics, what type of diet different people might do well with as well as a little more detail about some of these genetic SNPs and how to handle it?

Dr. Joffe:   All right. We can focus on one topic. So if you want to do weight, we can do weight or we can do exercise because we haven’t got enough time to cover them all, but I’m going to use weight as an example which is a great example. I think everyone can relate to it. Let’s start off with the idea that we are 99.9% identical genetically. And what I mean by that is we have a code, we have a blueprint in our body. Everyone’s heard of the word sequence, that’s our DNA blueprint. But at 0.1%, we’re different from each other.   And that means that at millions of places in our DNA, our sequence code is different. We call this genetic variation. Now, why is this important? It’s because these differences determine how we respond to the world around us. So we know that we’re different in the foods we respond to and the way we respond to exercise, training, how injured we get or how well we recover from training, but we’re going to talk a little bit about weight because we chose one topic. So why is it that we respond differently in terms of weight gain and weight loss? When I studied dietetics which was my first degree, I was taught calories in calories out. If you reduce the calories and increase the expenditure of calories, you would lose weight. And I soon found out this was absolutely not the truth, that patients would come to me and they would say, “But I did what you told me to do,” and yet they didn’t lose weight?  And because it was 20, 30 years ago, I’d be like, “Well, you must be lying to me and you must be cheating.” So what has genetics taught us? Genetics has taught us that actually there is an amazing amount of variability in how all of us respond to the food we eat, the way we eat, the behavior about eating, the way we store energy in our bodies, store fat and how we burn up fat. And this is around the concept of genetic variation. So I’m just going to touch on why that is because it used to be, my mother used to say like, “Oh, she’s got such a high metabolic rate, she just looks at food and burns it up.” But the reality is it’s much, much more complex than that.

So when we think about weight, I like to think about genetics in three different ways. One is what drives us to eat? So when we see food, some of us are snacking, some of us are binge eating, some of us are hungry. So what are the drivers? Well, we experience hunger in a different way. I always used to think that everyone was the same hungry as me, but actually we experience hunger completely differently. And the same way that if we all eat a cheeseburger with fries, we experience fullness of the word satiety in a different way. So I might need two or three burgers to feel full and you might be okay on one burger. These differences in how I feel hunger and satiety are actually driven by our genes.  Now we walk into a buffet and we see this beautiful spread of food and we’re all kind of hungry and some of us will go and have a plate of food, we’ll load it up, we’ll come and we’ll eat and we’ll go, “Yeah, that was a great meal, I feel full,” but the others will just take a look at that buffet table and even if they have a sense of fullness, they’ll still go back again and again. So even our eating behavior when we see food is driven by genes, and that’s just the beginning of the story.  Because once that food is in our body, we manage those calories in different ways. Some of us are really efficient at storing and we hold on to it, it’s very evolutionary, it’s from when we were hunter gatherers from the plains of Africa, others of us are very good at burning that up. So how do we burn up energy? Two ways, through exercise and through what we call basal metabolic rate, which is sitting at our desk working, you’re burning up. And yet we are so different in our ability to burn it up.

Now suddenly I’ve just mentioned like six things that would change how you, Ben and I respond to the world of calories around us. So when a patient walks into your practice and says, “I’ve been battling my whole life, I’ve been tried every single diet, I just can’t lose weight,” what we really want to do is we want to use genetics to try and discern why. What is your story, your journey that is driving these calorie interesting conversations in a different way? That’s the first part of the story. Any questions on that part?

Dr. Weitz:  Well, I’ll wait a few minutes to let you drill down but I do want to drill down and come out with some practical ways of dealing with these things.

Dr. Joffe:   Okay. It’s like that’s where I was going. So when you did the definition from Nature, they spoke about two things. They spoke about genetic variation which is what I’ve just spoken about. It’s what gives us our insight about ourselves, it’s self knowledge. How do I react to the world about us? But there’s a second part, the other 50% of the equation, which is how do I change gene expression? And I call this the action part. So insight, I find out about myself or you find out about your patients, action, what are we going to do now? So what? So I find out all the stuff about you, now what difference does it make? I’m sure you’re all familiar with the word called epigenetics.

Dr. Weitz:  Yeah, yeah, yeah.

Dr. Joffe:   Epigenetics, that’s what we’re talking about now. Epigenetics is when choices we make in our environment change the way our genes express, or I like to say the way our genes behave or even better, think of genes as being light switches. When you switch on a gene, it makes a protein, when you switch it off, it stops making the protein. Proteins are enzymes, they drive our body. So I have found out something about myself, I have found out that… let’s talk about detoxification. Everyone understands detox, right?  We have exposure to toxins, we have exposure to internal metabolites that are made by body that we want to make sure that it’s clearing whether it’s through over-training exercise, whether through its exposure. Now I can have a genetic test done and understand how optimally my body is detoxifying toxins or hormones. Now I know that, and I’ve discovered that I am not so brilliant at detoxifying, I want to take action. And the best way to take action is to be able to switch on the genes that are responsible for detoxification in the body.  Because if I can get the genes to make enzymes that detoxify, that is way more powerful than anything I can do. So I’m not just going to take a supplement and plug a hole, I want to switch on enzymes that are going to do stuff that it’s going to heal my buddy and my body is much better at heating itself than me plugging it with another 25 supplements, right? Here’s an example. So you know the… because we want to be practical. So cruciferous vegetables, cauliflower, cabbage-

Dr. Weitz:  Brussel sprouts, yeah.

Dr. Joffe:   Brussel sprouts, and my favorite broccoli sprouts, the little sprouts. So they contain this extraordinary compound where you spoke in again, a fantastic Nature definition, bioactives, plant practice, but actually all they are, are molecules of compounds that we find in plants. But they’re very magical, they’re very powerful. And there is one called glucoraphanin, and this really amazing compound when it is acted on by an enzyme called myrosinase which is also in your vegetable, you bite into your cauliflower, when you bite, you actually break open that enzyme, it changes accurately and you land up with this very magical plant molecule called sulforaphane. Now this is what is so magical about sulforaphane, it can switch on genes. So sulforaphane, once it’s activated in your body, switches on your detoxification genes.  So you walk into the house and everything’s dark, you switch it on and suddenly you have light, sulforaphane’s doing the same thing in your body with detoxification. And your body is now able to clear those toxins from your system. And we could talk about sulforaphane for hours, but it is probably one of the most potent ability of a plant molecule to switch on genes. So we used to think vegetables were good for us, vegetables is still good for us but we never understood why are vegetables so incredibly good for us? It’s because they are more powerful than anything at switching on genes, epigenetic mechanism. But epigenetics can work the other way as well.

Epigenetics can be environmental toxins, pesticides and herbicides and fertilizers which are getting into our body, and those toxins also switch genes on. They just switch on the genes we don’t want, which is inflammation oxidative stress. Does that make sense? So insight is I want to understand myself, I do a genetic test to understand myself, action is I use what I have, be it exercise, meditation, cold water immersion or nutrition to change the way genes get switched on or switched off.

Dr. Weitz:  Let’s drill down on the weight loss thing. What are a couple of genes that affect whether or not we feel full and whether or not we feel full, is it related to other factors?  In other words if I’m constantly eating large meals, does my stomach get stretched out?  So maybe I don’t get full as quick, maybe I eat quick, so I haven’t even gotten to the point where my body’s getting a signal that it’s full because the food hasn’t even gotten to my stomach yet and I’m still eating. Maybe there’s psychological factors on eating because I feel stressed, I’m tired of this raging pandemic and I just want to eat myself into oblivion. How much do these other factors and then talk about somebody’s genes, maybe one or two of these genetic snips, and then what can we do about these genetic snips?

Dr. Joffe:   Yes, yes and yes, absolutely. There are many factors that contribute to how we experience fullness and you’ve actually named some really well. But here’s the interesting thing, they did a lot of the research on children, little children. Now we as grownups are really complicated and messed up when it comes to food, so it’s about overeating. It’s about watching TV and eating, it’s about comfort eating, it’s about soccer social dynamic of connection and loneliness and isolation, so complicated. And then it becomes really hard to say what is genetic, what is this? But I did a lot of the research in children and in twins, which is the best genetic research. And when they did them in kids, they found that there were certain children who would be very, very hungry. And when they were given the same amount of food as the other kids, they would just have no sense of being full.

And this was before they had enough time to develop company eating or eating disorders or TV watching, this is when they were still really small. So they started looking at what are the genes in the body that are really driving them? So there’s a very famous gene called FTO, which is actually bizarrely named fat mass and obesity gene, barely you’ll find it in the media, it’s all over the place. What’s really interesting is it has been related to fullness. But what I find fascinating about FTO is that if you have the genetic variant, so the alternative version not a Deepak design mutation, it’s just a different version. You have less locus of control around food. So when I walk into that buffet and I see the food, I am likely to have less control in how many times I’m filling up my plate than if I had a different genetic variation that didn’t have the AA gene. There are other ones that drive taste. So we taste food-

Dr. Weitz:  Hang on a second. So if I have that AA variant of the FTO gene, what’s the solution?  Don’t go to buffets?  What else?

Dr. Joffe:   Don’t go to buffet. Two things I want to say, is you cannot make recommendations on a single gene. So I just did that with you, but actually I don’t believe man, you can never say, oh one gene and they’re like… and one gene, don’t ever do this. We look at all your genes that impact your weight, all of them and then we build schools around them and say, you know what? Your issue actually, because you only one gene that impacted fullness, but the other 10 genes that impacted fullness didn’t, so let’s not overreact. So I just want to say that. So we group genes together to understand that we don’t create recommendations phase one.

Now, what do we do? Where I’ve had patients who’ve come to me, I’ve said, “You know what? I’ve been dieting my whole life, and we do the genetics.” And the genetics do come back to say, “You know what? You hit the tough road. Your genes are not helping you. What are we going to do about it?” So the first thing is… And this has led to many patients crying in front of me, [inaudible 00:15:56] is saying, “I’ve been told my whole life, I’m a failure, I have no self control and no willpower. You’re the first person who’s seen me through who I am.” That’s the first thing, is we start dealing with self-acceptance. This is my inheritance, this is what I got. Once we can get positive and say, okay, now let’s think about realistic goal setting.

We’re not going to use the BMI which is based on population, let’s talk about you and your genes and say, you know what? If we can get to a BMI of 27, if we can get like… that is all, even like 20 or 30, that is not bad if we can make sure you’re healthy. So let’s focus on your health parameters. Let’s look at your insulin, your glucose, your lipids, let’s look at your apple versus pear. So we want to focus on what will make them overweight healthy, which is a real thing. You know that it’s that absolute real thing.

That we can keep people a little bit overweight or even completely overweight, but actually still have them extremely healthy by using exercise and making sure that the quality of the diet is right. The third thing I do is a lot of behavioral work. I work with psychologists and psychiatrists who do a lot of behavioral work. In the same way that they work with addiction, they work with eating. In the same way that I’m driven to drink or to gamble, how do I manage those triggers? With a buffet? Be at a bowl of pasta? Be at a party? How do I manage my triggers because my genes are pushing me to the table, but I want to use my mind and my brain to override those triggers?

Dr. Weitz:  Okay. Are there any secret sauces for influencing the FTO and the other genes?

Dr. Joffe:   Well, FTO responds really well to protein, and I don’t say like, everything was one’s protein, I’m not like everyone’s got to be on like a [crosstalk 00:17:48]-

Dr. Weitz:  We certainly heard they’re proteins, one of the foods that’s associated with society.

Dr. Joffe:   It definitely is. And that’s why FTO probably does respond well to protein, is because entirely protein works really well at driving society. So if I have a patient who’s got FTO-

Dr. Weitz:  By the way, does that drive satiety as well, or almost as well as protein?

Dr. Joffe:   It depends on the individual. So fat is much more complicated in terms of responsiveness on how people respond to fat, which is why we would see things like the ketogenic diet works extremely well in some people and really badly and others. That people’s response at part of that is that genetically, we learn about how you break down fat and which pathway fat goes on. And depending on where that pathway fat is, will determine your response to fat and that’ll determine lots of things, not just satiety, and what’s the ability to store and burn fat? Some people are super fat-burning efficient, and others are super fat-storing efficient. That’s also driven by genes.

Dr. Weitz:  Wait. I want to know that.

Dr. Joffe:   Which part?

Dr. Weitz:  How do we know if somebody doesn’t process that well? You’re talking about looking at their lipids and seeing if their LDL or… what-

Dr. Joffe:   No, no, no. We can look at your genes, so genes are going to give us some of that insight and to tell us about how efficient you are at metabolizing and storing fat. So those of us again who are really, they could have the refugee and apotheosis, that when we consume calories, particularly fat calories, we store that, we hold onto that fat, it’s actually a protection against the old evolutionary thing. We can see in your genes when we look at that, whether you’ve got more of these kind of fat storage hold onto energy genes, or whether you’re actually quite good at burning it up.

Dr. Weitz:  Can you name a couple of those?

Dr. Joffe:   The main ones would be ADRB2, the adrenergic receptor genes. We always think of ADRBs, there’s ADRB twos and threes as the burning up versus the storing. I don’t know how long we’ve got, but I’ve got a really great story I can tell you about a Japanese trial where they… Can I quickly tell it?

Dr. Weitz:  Yeah, sure.

Dr. Joffe:   So they did this amazing research study in Japan and they took 127 Japanese men who were overweight. Not obese, overweight. They were like BMI 27. And they put them on a program for two years, 24 months, where they decreased their calories to about 1,200 calories a day and they increased the energy expenditure to 20,000 steps a day, which is a lot of training because we normally base on 10,000, it’s a lot of training. And they tracked them for 24 months. They tracked them to make sure that they were staying on the program, the calories and the expenditure, and they tracked them to see how they lost weight. Now being Japanese, and not American-

Dr. Weitz:  By the way, just for clarification. I believe that somewhere’s around two hours a day of same walking, right?

Dr. Joffe:   Correct, exactly. So they did, I think it was mostly cycling. So they managed to get it in a little bit less at a higher rate, but it was roughly an hour, hour and a half of training a day.

Dr. Weitz:  Okay. [crosstalk 00:21:08]-

Dr. Joffe:   You’re 100% right. I was saying that because they were Japanese and not American or South African, they listened and they did exactly what they were told. Non drops of the study. They all decreased their calories to 1,200 for 24 months and managed to train for 24 months. And at the end of the program, what they did was they took them and they put them into weight loss groups, and they observed that there were four different ways that they lost weight. So in group A, in the first six months, they lost the weight they needed to, they went from like BMI 27 to BMI 22. And after six months, they maintained their weight loss for another 18 months. Brilliant, that’s what we call very successful weight loss.

In the second group, at the six month, they hadn’t lost much weight, very slow to weight loss. But by 24 months, they had got to almost the same place as the first group. So they lost weight but it was extraordinarily. So think of all the programs are blues, 10 kilograms and 10 days. In this group, they lost very slowly but they got there. In the third group, they called the rebound group. At six months, they lost all the way to that the first group lost but by 24 months, all of the weight came back again, plus a little bit of extra.  Remember they never changed their intake or expenditure. So it’s not like six months they lost the weight then they started eating again and it bounced back. It didn’t change their calories, it bounced back. And the fourth group never lost any weight. They decreased their calories to 1,200, they did 20,000 steps a month for two years and they never shifted any weight. Now, why I love this study more than anything is it makes us understand that when we sit in with a patient or a client in front of us, we must always remember those four different groups, that we all react differently and we cannot start off with an assumption of what our expectation is of patients.

Now what they did was they then did their genetics. And I said, “Can we try understand why this group didn’t lose weight? This group lost weight?” And some of the genes that came up as being the most insightful were these ADRB2 genes and the ADRB3 genes. ADRB2 is around how do I store energy and store fat versus burning it up? And ADRB3 is really interested in how responsive am I to exercise training? Because some people will only use exercise to lose weight not successfully, and actually they really to manage their intake to be able to lose weight.

Other people can use exercise and it’s quite efficient. So the ADRB3 is really informative about understanding that nuance between them. And they came up exactly, they could divide them into four groups and see where the genetics were in the four groups. So really, really fantastic study. There are other genes, the FTO gene, the awesome MC4R, TCN2, that also are how do we store fat? How do we… and PPAR gamma. So you put up PPAR gamma, a very, very well-researched gene has been around for 20 years and it’s very much around insulin and glucose, which of course relates a lot to how we store fat. Our insulin levels driving fat storage, and and so PPAR gamma is always a gene that we look at when we’re interested in that.

Dr. Weitz:  So what do we do with the group that wasn’t able to lose weight based on these genes?

Dr. Joffe:   We make them believe that having a BMI of 27 is what is going to be their BMI. What we really want to do with those, that fourth group is we want to make sure they’re healthy. So we’re going to check all their parameters because 27 BMI is okay. If they-

Dr. Weitz:  But you’re saying they can’t lose weight, no matter what.

Dr. Joffe:   They can’t… So we could have tried some different stuff, right? Which of course wasn’t done in this study. So we can manipulate the macronutrients, we can have a look whether we can change around into kind of a different macronutrient distribution because remember they got the same macronutrient distribution. It was not low carbohydrate, it was very moderate carbohydrate. We could try that, that could shift things. We could also change the way they exercise. So there’s a lot of research that says in some people, that kind of aerobic endurance type exercise does not drive it but if we get them into gym and we do high intensity weight training, we might be able to change it. That’s when we start playing around and we can get some of those insights because remember, genetics is not about weight. We have a whole part of our panel which is about exercise potential. How should we be training? How do we respond to training?

Dr. Weitz:  But can you take a set of genes and say based on these genes, this person should do weight training, not cardio, this person needs a low fat diet, this person needs a low carb diet? And there are programs out there that we can send our patients for and they’ll give you this detailed panel that will tell you, this person should eat in this kind of way and this person should do this kind of exercise. What do you think about that?

Dr. Joffe:   In my genetic test, I do a lot of-

Dr. Weitz:  What is your genetic test?

Dr. Joffe:   My genetic test which is 3×4 Genetics, it looks at a whole lot of different stuff from what we call action, which is detox inflammation oxidative stress. So what’s the stuff that’s most caught your body?

Dr. Weitz:  Is it using more… I’m sorry to keep interrupting you, but-

Dr. Joffe:   No, no, it’s fine. Exactly.

Dr. Weitz:  Does it have more genes than I could get from a 23andMe or Ancestry or is it just organizing those genes and give me an explanation? In other words if I did a 23andMe or an Ancestry, and got the raw data, would I have what I need, or?

Dr. Joffe:   Great answer. So I have way less. I have like 134 genes in my report and you are going to get thousands from 23andMe, thousands and thousands and thousands.

Dr. Weitz:  So all the genes in your report, are they included in 23andMe if they were just analyzed the right way?

Dr. Joffe:   Not all of them.

Dr. Weitz:  Okay.

Dr. Joffe:   That’s one that comes to 23. But here’s the thing. I actually can test 600,000 of your genes, 600,000 of your snip genes, because we only have 25,000. But actually of that 600,000 snips of test, I believe and my science team believe that only 134 of them are well-researched enough to give me as a practitioner insight in what to do with you. So one of the problems we’ve had in genetics is everyone kept on coming out of the test and going, “I’ve got 500 genes, I’ve got 1,000 genes, I’ve got 6,000 genes for 29 99.” But actually there’s no value in that because what you need to make sure is, so what?

So you can get raw data of 600,000 snips and you can know nothing about yourself. What do you need to make sure that whatever company you choose to work with genetically is what can I do with this information? Will it be useful to me with my clients and practitioners? How would it change my decision-making? Will it help me decide, should I go to the gym? Should they do endurance? How many days a week should they train? What kind of active recovery should we build in? What about collagen and bone and joints? What are the susceptibilities to ACL injuries? So you need to make sure that we’re answering very specific questions. So the problem is by-

Dr. Weitz:  So if we order your panel, we’re going to get a specific report telling us how this person should eat, how they should exercise, what they should do for bone density?

Dr. Joffe:   Yes. All of that, except a test does not come to you directly. So 23andMe, you can order get at home or send you an answer. We do not do that, we only work with practitioners. Chiropractors, nutritionists, doctors, naturopath. Here’s the reason why. Genetics does not exist in isolation. All the answers to your problems are not just in your genes. You raised this earlier on, right? So when someone comes to me, “Tell me about yourself.” Like, why did you come here? What are you trying to look for? What’s worrying you? What are you looking to get out of it? Tell me what happened when you were growing up. What has your training been? What’s your diet like? What’s your connection like? Do you have friends? How are you feeling? What’s your stress levels?

So I want to take some black tests, I want to understand who you are but I also want to know your genes because if I can know your genes, remember insights of knowledge and know who you are sitting across me and know what you want to get out of this consultation with me, now as a practitioner, I’m super powerful to be able to personalize what you need.

But if I just produce… So there are many companies that you can buy genetic tests from and it’ll say to you, “You’ll do really well on a low fat, high carb diet or a high carb, low fat diet.” I don’t believe that’s true. So for me, the science cannot determine that. We can give you many insights about fat storage and fatty acids and protein and FTO, but you as a practitioner need to take the information and the insights we give you and put it together with everything you know because you’re a practitioner and give the advice. So I, that’s why I like practitioners and that’s why we train our practitioners. We teach them, we mentor them so that they’re able to integrate genetics, but you should never only do a genetic test and believe that they know who you are.

Dr. Weitz:  Now, of course you know in the functional medicine world that there’s a tendency to have the patient get one or several gene tests and then on a result and the basis of that, claim to know the answer to why they’re having this problem that nobody else has solved because we just measured your MTHFR and in case you’re heterozygous or one of the variants, that proves that you need methylated B vitamins which you weren’t taking, or you weren’t taking the right amount and now all your problems will be solved because you have MTHFR. And by the way, you should walk around with a sign that says I have MTHFR.

Dr. Joffe:   And what your sign says, you can have a tattoo and it says MTHFR defect, which is my favorite. So thank you for raising the MTHFR-

Dr. Weitz:  I have the disease of MTHFR.

Dr. Joffe:   I’m going to join the 6,000 MTHFR forums that I can find on the web. So you’re 100% right that one of the worst things [crosstalk 00:32:16]-

Dr. Weitz:  We should not let MTHFRs cross the border. No, I’m kidding.

Dr. Joffe:   Oh, we should board the wall and [inaudible 00:32:22] MTHFR. We’ve got to stop. Stop, stop, stop.

Dr. Weitz:  Okay.

Dr. Joffe:   But MTHFR is a problem because the genetic testing, and MTHFR is one of the first genes that was ever researched and it’s beautifully researched-

Dr. Weitz:  And we couldn’t have a discussion without mentioning MTHFR.

Dr. Joffe:   Right. But here’s the thing. 15, 20 years ago, everyone got so excited at MTHFR, they stuck MTHFR’s really big pedestal and they said, “Oh my God, I can make so much money from this gene because what I can do is I can say, if you have MTHFR which is just a snip,” it’s just a single snip, it’s just one of 600,000. But if you have it, I can sell you lots and lots and lots of supplements, I can sell your diet plan, you’re going to come to my forum because if you have MTHFR, you’re going to have 6,000 diseases. Well, this MTHFR has been the absolute worst thing that happened to the genetic testing industry. It made some individuals very, very wealthy, I will not name them, but it made them very, very wealthy. But what it did was it actually undermined the true value of genetics for the individual.

And so if you study one of my courses I teach, you get a whole module on what we’re drawing with MTHFR and why it is so damaging and why it is wrong. So when you hear people say I have MTHFR mutation or defect and I’m going to take 20 supplements and I’m going to get these diseases because I have it, this should be the biggest red flag and fireworks going on. It’s like, no, no, no, these genes are not that powerful. They’re informative, they’re interesting, they give us some information about the biochemistry of our body, but by themselves and that’s what I said early on, we never make a recommendation on a single gene or a single snap, whether it’s FTO, APOE, MTHFR, I don’t care. We group genes together that are interesting to us in methylation, in cognitive, in detox, in fat storage, we group them all together and we evaluate what did you inherit altogether? And we get a sense whether we should address that issue.

And one of the things that happen in MTHFR is that the supplement industry made so much money that they took people who had MTHFR and made them more sick because they gave him so many methylated B vitamins. And I think people are starting to wake up. So you’ve got to be really careful about what genetic… Genetics is awesome, it gives us self knowledge and insight but you’ve got to be very careful. It is [crosstalk 00:34:56]-

Dr. Weitz:  I have gone down the MTHFR rabbit hole a little bit. It’s been that much time with it. And then I ran a couple of these detailed methylation panels that look at say 15 or 20 different genes and then correlate it with various factors like homocysteine and still after all that, it seemed to me almost every one of these genes said check vitamin B2 and B3, check folly, check B12. And we ended up with the same thing. So I couldn’t help but think, okay, if I just give everybody methylated B vitamins, I guess that pretty much takes care of.

Dr. Joffe:   Yeah. That is a problem. So the companies have [crosstalk 00:35:48]-

Dr. Weitz:  And maybe a slight variation like this one, [crosstalk 00:35:51] a lot of it just is around these B vitamins, right?

Dr. Joffe:   Well, not in my test.

Dr. Weitz:  Okay.

Dr. Joffe:   Not in my test. So methylation is a single pathway, right?

Dr. Weitz:  Right.

Dr. Joffe:   I have six pathways that we analyze and each pathway has 10, 15, 20 snips it. But methylation isn’t an important pathway but a single pathway. So we never say that one pathway [inaudible 00:36:17]. And so what happened to many of the companies that were testing MTHFR, when they got into trouble for only testing MTHFR, they’re like, “Well, let’s just test methylation because if MTHFR is awesome, methylation must be more awesome and we can make a million decisions just of methylation. Wrong, right? Because there are multiple biochemical processes happening in our body and they all interrelate with each other.

So we can’t understand what’s going on in methylation and not understand oxidative stress, what’s happening with our mitochondrial stuff, glucose, insulin, hormone metabolism? Methylation is important but the same way that you cannot make a recommendation based on a single gene, you should never make a recommendation based on a single pathway. Because otherwise we’ll land up where we started, which is too many methylated B vitamins, which actually, excuse me for saying, you don’t actually need because methylated B vitamins bypass MTHFR. So the amount and the dose you need is actually really low.

Dr. Weitz:  And on his methylation pathway, methylation is a way to actually get a sense for anti-aging now as we look at these methylation time clocks. However, it’s not just whether all the genes are methylated, but it’s whether some of the genes are demethylated, and you mentioned the FTO gene, and this is actually a gene that demethylates. And so you don’t necessarily want all your genes methylated, some of the genes should not be methylated with health, right?

Dr. Joffe:   Yeah. And so there’s a huge confusion here which is a great place to address it. Huge confusion about methylation. You actually spoke about methylation and there’s two different kinds of methylation, is what I’m trying to say, right?

Dr. Weitz:  Okay.

Dr. Joffe:   Two different kinds, and this is where everyone gets completely confused. There is genetic variation methylation. That means… We know that there’s the methylation pathways. And if you have a whole lot of genes, MTR, MTRR, CBS, MTHFR, and they have snips in them. So they have speeding changes in the sequence that change how efficient they are. We get a sense for how efficient or inefficient or optimal or suboptimal our methylation pathways are working. And those methylation pathways are involved in DNA repair and making new DNA. So they’re like the basic engine. Now the other methylation you spoke about is actually epigenetics, which is attaching a methyl group onto a gene which either switches it on switches it off, which is what you spoke about. Demethylated or methylated.

And this goes back to our previous conversation where we switch on genes and then we switch off. And there’s some choices we make in our life that will either switch on and switch of genes. So methylation is so complicated and [crosstalk 00:39:07]

Dr. Weitz:  So there’s two methylation processes in the body, are they related, directly related, somewhat related or totally separate?

Dr. Joffe:   They are related in the sense that those first ones I told you about, the ones that have gene variants and they’re producing methyl groups. And they need to produce enough methyl groups to be able to switch on and switch of genes. So that’s how they’re related, but they’re actually doing two different things. One is we’re looking at genetic variation and how optimal we are at producing those methyl groups. I mean, looking at epigenetic methylation, I call it epigenetic methylation, it makes more sense of how efficient are we at switching on and switching off genes without methyl groups? Now, the problem is there’s a couple of tests in the marketplace that are being sold to consumers of epigenetics. They say that they can measure how your genes are being switched on and switched off. There’s about three companies out in the marketplace at the moment.

Dr. Weitz:  Yes.

Dr. Joffe:   Here’s the thing, is I think they all, genetics was 30 years ago, where they can measure something, it doesn’t mean they’re able to understand what they’re measuring and here’s why. If you wake up in the morning and you go to the coffee shop and you have a double kotato, double shot espresso caffeinated thing, that’s not just the caffeine, but the other compounds in the coffee are going to switch on a whole lot of genes, either through methylation or demethylation. Anyway, they’re going to switch on a whole lot of genes. So if I measure your epigenetic profile, your methylation profile, after your double espresso, I’m going to get a reading. Then you’re going to go home and you’re going to do your 30 minutes meditation and then I’m going to test your epigenetic prevalence. Guess what, I switched on and I switched off a whole lot of different genes.

Dr. Joffe:   So when I test you, what actually am I testing? And that is the problem. If we just… I’m going to say one more thing and then you can bug in there. Every single decision we make, sorry, you and I be like, every decision we make every minute of the day changes the way our genes express themselves. When I wake up in the morning and I choose what coffee, if I wake up in the morning and grab my phone to look at as opposed to going to do 20 minutes of meditation, changing the way my genes behave. So health is not something that we decide of a month or year, it’s a decision we make every minute of every day.

Dr. Weitz:  So you’re saying that all this research being done by Steve Horvath at UCLA and these other folks and they described this as epigenetic methylation clocks, that it’s not an accurate way to assess our biological aging because minor things that you do switch on and switch off before you get the test.

Dr. Joffe:   I think his research is brilliant and I definitely think he’s leading the charge, but just because we can measure it in a research which came out of research doesn’t mean we understand how to translate it yet. And I think he is at the forefront and I think he will lead the forefront but personally, I don’t think we’re close to understanding how we’re measuring it, what it means because we haven’t been able to figure out what is the influence of the decision I made two minutes before I took your test even more? So I’m waiting.  I’m waiting and I’m watching, we’re definitely going to be doing in the future. We can definitely do it in clinical trials, but there’s a difference remember between insights measuring and then actually what do we do? And so I’m going to stay on the fence for a little bit longer.

Dr. Weitz:  My methylation epigenetic measurement test, it should be arriving today.

Dr. Joffe:   Well, let me know. With the true age. Did you do true age?

Dr. Weitz:  True age, yeah.

Dr. Joffe:   So let me know how that goes, I’d be fascinated to… It’s cutting edge but I’m not happy yet that the science is ready, but that’s how it works, that’s how science works. You get… When we built the first nutrigenomic test in 2000, it was three years before the human genome was developed and everyone said to me, “It’s too soon, you don’t have enough,” and they were right right?

Dr. Weitz:  Right.

Dr. Joffe:   So someone’s got to start it.

Dr. Weitz:  I know this is a huge topic in every one of the categories we’ve talked about you could spend a week with and I know I’m taking you down another topic that could take a week to discuss, but it’s on my mind and I had to ask you about the APOE gene. So maybe we can just talk about that for the last 10 minutes or so. For those of us who aren’t aware, if you have the APOE 34 or 44 snap, that increases your risk for heart disease and Alzheimer’s disease. And I know in practice, it’s not unusual to put somebody on what seems to be a healthy program or maybe get somebody who comes in the office who’s on what seems like a healthy program, and then you find out they have a 34, 44, and a lot of times they don’t respond in the same way.

But we’re still debating in the literature what that means. Do you have any insights? I know we haven’t had enough long-term large-scale prospective randomized clinical trials, but we know on patients who have APOE 34 or 44 if they’re going to do better on a ketogenic diet or a vegetarian diet, or do we have any idea?

Dr. Joffe:   I have a deep fascination with this gene, it’s an amazing gene. Do you know that it’s called the God gene?

Dr. Weitz:  Oh, is that right? I hadn’t heard that.

Dr. Joffe:   It’s referred to as the God gene. And I’ll tell you something even more interesting is that if you look at evolutionary biology, because of course genetics is evolutionary and then we got this really bad, dark messed everything up. The original version of APOE was E4.

Dr. Weitz:  I thought it was E2.

Dr. Joffe:   No, it was E4.

Dr. Weitz:  Okay.

Dr. Joffe:   So when we were hunter gatherers on the plains of Africa, E4 was the common variant, not E2.

Dr. Weitz:  That’s right, that’s right, that’s right, that’s right.

Dr. Joffe:   E2 came later. So why would we have this E4 variant to help us survive on the plains of Africa? And then suddenly we’ve got E2, E3 and everyone’s terrified of E4, right? It’s because it’s such an interesting gene, it’s an inflammatory gene. And when we were attacked by the tiger and we needed to heal quickly, you actually want to be able to get a very quick acute inflammatory response to be able to heal. But the problem is we don’t get attacked by tigers anymore and we have these very bad diets and all the various entry and everything. So suddenly the inflammatory aspect of APOE became harmful instead of helpful.

Dr. Weitz:  And the biggest risk to survival was starvation, not getting some chronic inflammatory disease. So having a lot of inflammation was beneficial, whereas now the predominant cause of disease are chronic inflammatory conditions like diabetes or heart disease and cancer.

Dr. Joffe:   [inaudible 00:46:55] Cancer, they’re all inflammatory diseases, right. So it’s fascinating how the gene itself has evolved because the problem of health is the problem of the disconnection between our genetics which is ancient and evolutionary and our diet, which is very modern and very quickly changing and very bad. And it’s this clash between the two that we’re seeing is causing so much disease. Anyway, back to APOE. APOE when you start studying is actually not this great body that actually everyone thinks, but one thing it is, is hyper responsive. So we talk about the E4, whether E 44 makes you hyper responsive, which means when I change your diet plan to a health diet plan, you are unlikely to be very responsive to those changes, which is a really good thing, it’s a really good thing.  So if I have a patient with hot stuff happening, particularly like lipids, lipid metabolism, and I see they have a three, four or a four, four, before I go in yet any start on, I’m going to do everything in my data and lifestyle, because they’re more likely to respond to a healthy data and lifestyle intervention than to resend to medication. Let’s talk about Alzheimer’s and cognitive decline. There is absolutely-

Dr. Weitz:  By the way… I’m sorry. When you say they’re more likely to respond to healthy diet, what type of healthy diet?

Dr. Joffe:   Well, that depends on what impact [crosstalk 00:48:23]-

Dr. Weitz:  It depends on the person still?

Dr. Joffe:   Yeah, it depends on the person, depends on the other genes. It depends on… there’s so many things I don’t want to say, but we know that we’re going to move them towards a healthier diet. It’s going to have less sugar and it’s going to have more plant foods and it’s going to have great diversity and it’s going to be safer and not have… et cetera, et cetera.

Dr. Weitz:  But just on APOE, there’s no way we could say better to be on a vegetarian diet or better to be on a ketogenic diet?

Dr. Joffe:   No, not just on APOE. First, I’m going to send you an article that they did about APOE and ketogenic that is absolutely fascinating. I’m going to send it to you, you’re going to find it very interesting. But there isn’t a single definitive job. Here’s what’s interesting. So I’ve got a family history [crosstalk 00:49:07]-

Dr. Weitz:  I guess one thing we could say is whatever diet they’re on, if they come to us and they have heart disease, then we know that’s not the right one.

Dr. Joffe:   Probably not the right one. You need to make some change, that’s always a good start. Most people don’t come to us with the perfect diet. So there is interesting stuff around APOE 34 and the ketogenic and I’m going to send it to you.

Dr. Weitz:  Thank you.

Dr. Joffe:   I don’t want to talk about it now because I actually contract with the detail and I’m part of making this of it.

Dr. Weitz:  Okay, sounds good.

Dr. Joffe:   But what makes… I come from family of Alzheimer’s. My father had two sisters, they both got Alzheimer’s young in life, so young Alzheimer’s [crosstalk 00:49:40] and I’ve known since I first started in genetics that I had E 34, so I’m carrying one of the E4s, right? Someone has got a family history like I do, and he’s having that E 34, I was convinced, but convinced that Alzheimer’s was going to be my burden to carry. That it was going to happen to me and it was going to be my life.  When I started learning more about genetics and became a bit more experienced in it, I started understanding again, this idea that a single gene, a single snip cannot determine a disease, not even Breca which is the breast cancer gene, not even Breca which is 10 times more powerful than APOE. And when we both, these what we call polygenic risk scores, where we look at a pathway, so the pathway is cognitive decline dementia, that’s the pathway.

We get more plugs, we lose connection, the neurotransmitters. So we looked at all the genes that would impact that. APOE is definitely one of them, it’s definitely significant but it’s one of them. And when we built these polygenic risk scores, so a score based on all my genes and cognitive decline, I actually landed up with a no risk. I was like, come on, I’ve spend my whole life believing I’m going to get Alzheimer’s, how’s that possible?   And the reason was I only had the E 34. But actually all the other genes that are driving cognitive, I was actually doing well. So I embrace APOE because it’s the one thing that gives us so much we can do. If you look at Dale Brisbane’s protocols now, there is so much we can do and that includes with APOE. It is not a sentence, it is not a disease, it is none of that. What it does do, and in fact they’ve done research to show that people who knew the APOE results, particularly if there was E4 made better and more lifestyle changes than those who didn’t know the APOE result.  So we teach our practitioners not to be fearful of APOE but rather to embrace it because the patients are responsive. If they understand how powerful their diet and lifestyle choices are, and especially because since Brisbane came into our lives and many other great scientists, we understand that there are so many ways we can reverse cognitive decline and APOE being a responsive gene, APO, really helps with that. So actually there’s some Alzheimer’s with E2 is more of a problem because it’s not a non-responsive one.

Dr. Weitz:  Interesting, interesting. I think it’s probably time to wrap.

Dr. Joffe:   Yeah, we can talk about APOE also for hours. I’m going to send you a link to a webinar I did on APOE [crosstalk 00:52:26]-

Dr. Weitz:  Peter T I just had like a two hour some researcher talking about APOE. So that was an interesting one. So how can, which scenarios practitioners find out about your genetic test? And by the way is there one version of it or multiple versions?

Dr. Joffe:   Single version, only one. So I don’t want you to have to figure out whether you want to buy energy, which is we don’t talk about weight, energy, exercise, everything is important to you. So it’s a single test, you can come to a 3x4genetics.com or email info@3x4genetics.com-

Dr. Weitz:  Saliva, [crosstalk 00:53:13]-

Dr. Joffe:   Saliva, Cheek Swab, easy peasy, [crosstalk 00:53:15].

Dr. Weitz:  Okay.

Dr. Joffe:   We’re drug shop, so we send it to your house, you send it back to us, goes to our lab, but remember we will always do it through a practitioner. So if you contact us, you tell us what you’re looking for, we’ll find you the best practitioner that suits what you’ve come looking for. And they are trained, they’re mentored, they’re nurtured, they’re looked after, they’re really what we call expert practitioners.

Dr. Weitz:  So what does that say for somebody like me? Let’s say if I want my patient to get that.

Dr. Joffe:   If you want to, you’d have to come. So we do a basic three-hour training. You’re not allowed to go near our product until you’ve done the basic training, which is… I’m sorry. And we want to make sure you know what you’re doing. I can hear you understand what you’re doing, right?

Dr. Weitz:  Right.

Dr. Joffe:   It’s going to be easy for you, you’re already deeply into genetics. But we want to make sure you understand polygenic risk scores. We want you to understand scientific and clinical utilities. A couple of things we want to make sure you understand before you represent our tests to your patients. When you do that, you get an amazing portal which has got an incredible back end clinical guide, everything you need to research is there. And then you go, you have access to a mentorship program.  So we have these amazing mentors that’ve been working with me for 10, 15 years that you can access in every way. We have webinars, we have a next level education program for practitioners. If you want to take your expertise to a higher level and become more specialists, we’ve got layers of education, layers of mentorship and we have an incredible community of practitioners in the U.S. totally multidisciplinary.  So chiropractors, dentists, psychiatrists, psychologists, nutritionists, doctors, natural paths who are working with our tests and are also teaching and learning from each other. We have amazing, I can see you’re in a very sports space, we have amazing sports dietician, sports people who… And I haven’t even touched on sports unfortunately, because one of our absolute areas of expertise is sports and genetics. And I have three scientists whose only job is sports genetics. So maybe another time you’ll invite me back.  And in fact not even me, you can invite them back. And they’re actually world-class to athletes as well and they’re geneticists. So they’re really, really great to talk to and it’s another whole fantastic conversation.

Dr. Weitz:  Cool. So what’s the website again?

Dr. Joffe:   3×4 Genetics. Three and then the little X, four genetics.com.

Dr. Weitz:  Excellent, excellent. Thank you so much, Dr. Joffe.

Well, thank you listeners for making it all the way through this episode of The Rational Wellness Podcast. Please take a few minutes and go to Apple podcasts and give us a five-star ratings and review. That would really help us so more people can find us in their listing of health podcasts.

I’d also like to let everybody know that I now have a few openings for new clients for nutritional consultations. If you’re interested, please call my office in Santa Monica at 310-395-3111. That’s 310-395-3111 and take one of the few openings we have now for a individual consultation for nutrition, with Dr. Ben Weitz. Thank you and see you next week.


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