Dr. Mark Hyman:
Coming up on this week’s episode of the Doctor’s Pharmacy, there was a large study of 11,000 people who shopped at health food stores. Half of them were vegetarian or vegan, and half of them ate meat, but they ate meat in the context of a healthy diet. If your meat intake is with hamburgers and fries and coke, well, it’s probably not the hamburger, right?
Welcome to the Doctor’s Pharmacy. I’m Dr. Mark Hyman, and this is a place for conversations that matter. Now, it’s no secret that navigating the realm of nutrition has become a challenge for the general public, and even for people like me in health professionals who’ve been studying this for 30 years, one week, eggs are good for us only be vilified for allegedly raising cholesterol levels the next week. The narrative on dietary fats is no less tumultuous, and I wrote a whole book on this called efa. Yet then some experts say that it’s a chief culprit beyond heart disease. Others say it’s critical for over health and wellbeing. Well, more recently a study made headlines linking red feet consumption to an increased risk for type two diabetes, leaving the public once again confused and understandably. And that’s why in today’s Health Bites episode, we’re diving deep into the findings from this paper and unpacking the study’s design thoughts, it’s inaccuracies and where the researchers got it straight up wrong.
This is something new that we’re doing on the doctor’s pharmacy and my mission to help you sort through the whole slew of dietary misinformation. Now, let’s get started. This podcast is about a study and putting it in context that really upended a lot of people’s thinking and was all over every major newspaper, every headline, every television show, which was basically that red meat causes type two diabetes. Now let’s examine that. Is it true? What does the sign show? What does the paper actually tell us and what does it not tell us? And what are the major flaws of the paper and what are the conclusions we can draw and we can’t draw from this paper. The study was entitled Red Meat Intake and the Risk of Type two Diabetes in a prospective cohort study of United States females and males published in October of 2023. Now, this was a type of study design.
It’s important to understand study design because you have to understand science before you can interpret science, and you have to understand the type of studies that are done and which can show cause and effect and which can show correlation not causation. For example, every day I wake up and the sun comes up, it’s a hundred percent correlated, but it’s 0% causal. If I die tomorrow, the sun’s going to keep coming up. If I slept through the middle of the day, the sun’s going to keep coming up. So it has nothing to do with each other. And essentially that’s what these observational studies like this particular study did. They looked at correlation, not causation, and that means that we can’t prove cause and effect. So when you hear the headline, red meat is linked to causing type two diabetes, it’s bs. Okay? We have to look at what the data’s shown when it doesn’t.
And these studies are not wrong. They’re not bad to do. They’re done in order to help us understand what might be a useful avenue for further research, right? They’re not the end of the research. They’re useful for generating hypothesis. For example, in the study of smoking and lung cancer, they did observational studies, right? They weren’t going to do a randomized controlled trial because they’re not going to have people on cigarettes and half people are not on cigarettes. So basically they found that there was a 20 fold increase, maybe 10 to 20 fold increase in the risk of lung cancer in smokers. Now, to put that in perspective, that’s a thousand to 2000% increase in your risk of having a particular disease. And that ended up being correct because it was such a strong correlation. Whereas in this red meat diabetes study to cut to the punch, it was about a 20% increase, right?
Which essentially is relatively meaningless. And let’s just say 200% increase in a correlation study, you pretty much want to ignore the data. And then Dr. I from Stanford has written a lot about this is an incredible scientist who I dissected the value of different types of studies and what we can learn from them and what we can’t. So we have to start out really understanding that the study was not designed by his very nature, which all scientists would agree to prove cause and effect. It’s just the nature of science. Okay, so let’s get into the study. This is what we call a prospective cohort study, and it’s an observational study, a population study. An epidemiological study all means the same thing. Essentially studies a group of individuals over time to look at the association between certain exposures, behaviors, diets, and risk factors on specific outcomes.
So basically they track thousands of people over many, many years looked at what they ate and saw there was a correlation with diabetes and lo and behold, they found one. But let’s talk about the problems with why this may not actually be as clear as the study seems to generate. Now in this type of study, basically people are identified based on their exposure status and then they’re followed over time to observe and record outcomes. So in other words, what did people eat over many decades and what was that diet and was a correlated with any bad outcomes later in life. So you follow people for 30 years, you have ’em track their diet records, which we’ll talk about in a minute. And then you see whether or not a particular food or types of food seems to correlate, not cause correlate with some bad outcome like diabetes.
And that’s what they did. And basically the goal is just to assess relationships between various exposures, toxins, smoking, diet, whatever, and outcomes. So it essentially looks for things that may be worth further studying with a randomized control, double-blind trial. This was not done here. Now it can be helpful, but they say, well, we’re going to control for variables we call confounding variables, which means things that kind of can throw the study off. In other words, we’ll talk about this, but for example, there was a study done many years ago by the NIH and the A RP, the American associated persons that looked at meat eating and chronic disease and death and cancer and so forth. They found a big correlation, but that study showed also that the people who ate meat didn’t care about their health and smoked more, drank more, ate more calories, about 800 more a day, were more overweight, didn’t eat fruits and vegetables, didn’t exercise, just drank more alcohol, didn’t take their vitamins.
Of course they had more disease. It wasn’t because of the meat, it was just we’ll call a problem that was shown because of these confounding variables. And we’ll talk about more about that. Now, this study was published in the American Journal of Clinical Attrition, and it was published by folks at Harvard who or great scientists, but they’re focused on epidemiology, particularly at the School of Public Health, which is where the study was published out of. And unfortunately people have bias and the study authors are very biased toward a plant-based diet. And so right off the bat, you kind of look at, all right, well, they already have a bias and that affects the study, the outcome study. So basically the objective of the study was to assess the link between total processed and unprocessed red media take and type two diabetes, and then to estimate the effective substituting different protein sources like vegetable proteins, not seeds, beans, grains for red meat and type two diabetes risk.
So we’re doing, but again, just a hypothesis generating study. Now, again, this was a population study. It was based on the nurses’ health study, which was about 216,000 participants, the first and the second one, and the health professionals followed study, which was including men. Now, the first study started in 1976, female nurses and another 180 9 female nurses. And the health professional studies started in 86 and they followed people for a long period of time. They calculate the amount of years and people and they come up with a number called about 5.4 million person year. So that’s pretty good. And what they did was really interesting. They looked at something called a food frequency questionnaire, and this assesses that people’s diet every two to four years from the baseline. Now, can you remember what you had last Thursday for lunch? Can you remember the amount of this or that you had over the last week?
Probably not. And so these are flawed tools and there’s a lot of research and science about how flawed these tools are and how imperfect they are and how often they are very misleading. We see that in this study. The study findings, just to be clear, and this is association correlation, not causation. They found between the lowest and the highest red meat intake, there was a risk of diabetes that went up by 62%, right? Not 200%, 62% processed meat associated with 51% and unprocessed red meat was about 40% risk. If you substituted one serving of nuts or beans, then your risk was 30% lower. If you substituted for processed red meat, the risk was 41% lower and on processed meat was about 29% lower. So they’re basically saying if you had one serving of dairy for total processed or unprocessed red meat, you had a lower risk of type two diabetes.
Now, this study is really important because it kind of misses a lot the point, what is the mechanism here? Now they try to explain some of the mechanisms, but it’s pretty weak. We know that the sugar that you eat, sugar and refined carbohydrates is the primary cause of type two diabetes, not red meat and ancestrally, we’ve been eating meat for as long as we’ve been human. I just came back from the messai population in Africa, as I mentioned, on different podcasts. And these people ate the blood, the milk and the meat of their cows. That was their main diet. They were healthy, they were super thin, they were very fit, and they had no diabetes. I recently visited their community and the Coca-Cola truck drives up every day. They get processed cookies from the local town that are made by industrial food system and now they’re gaining weight.
And type two diabetes is rampant in this Messi community in Africa, and it’s just heartbreaking to see that within minutes, this entire Coca-Cola truck, a big truck just was emptied out by the local population not knowing what they were doing themselves, and they didn’t even know that it was connected. So this basically, this study fueled a lot of click plate headlines. For example, WebMD said Just two servings of red meat per week raises diabetes risk. Well, that doesn’t, it shows that it’s correlated, but not causing eating red meat more than once a week is linked to type two diabetes risk. That’s CBS. This is just bad reporting and bad journalism. And the social media was just all over the place, right? Some people were pro red meat, some anti red meat. People were super confused, and then nobody knows who to believe and everybody’s distrusting public health and dietary guidelines, and it’s just a mess.
So I’m going to try to unpack it for you so you really understand how to think about this, and also how to actually know what to believe around this whole issue of red meat and diabetes and what we know. So basically, the problem with this study, as we mentioned, is an observational study and we just cannot draw conclusions from an observational study. It doesn’t prove causality, and we have to look at also the limitations of the study. There were a lot of limitations. The study authors, for example, as I mentioned, are very biased toward a plant-based diet and veganism, how they pick the participants of the study, which may not be an issue. Industry funding, we want to look at that probably was an issue here, but there’s this thing called recall bias, which is common with food frequency questionnaires. People are more likely to report healthy food than unhealthy food and desserts, sugar sweetened beverages, alcohol are under-reported.
This is published. We’re ready to put all the references for everything I’m saying in the show notes. So have a look at those. Everything I’m saying is documented is well-researched and you can kind of dive in, but it’ll take me about 10 hours to I covered every study of detail. So basically I’ve had my practice, people overestimate how much extra they exercise and they underestimate how much they eat. It’s pretty difficult. My humans are pretty flawed now, 2012 from red meat consumption and mortality, it looked at prospective cohort studies from the people ate a lot of red meat. About the highest 20% had a 45% high risk of dying from heart disease compared to those who ate the least red meat, the lowest 20%. However, when they look more closely at the people in these extreme groups, they notice that besides eating red meat, they had other habits that made them more likely to have heart disease, like don’t exercise, they eat too much, they smoked, their cholesterol was worse, or they maybe had fish consumption, which affected their health and risks.
For example, maybe the people in their lowest risk group exercised and didn’t eat meat, but they also didn’t smoke and they also ate healthier food. So you can’t quite tell what’s going on. So the study supports the idea that eating a lot of red meat is the high risk of heart disease. People who choose to eat more or less red meat have other lifestyle issues that influence their health. Now, there are other factors, these confounding variables I mentioned. When you look at confounding variables, they try to control for these, but it’s really tough and they only control what we just think to control for, and it basically makes it really hard to determine true cause and effect. Like I mentioned with the A RP study, they smoked more, they drank more, they ate less fruits and vegetables. They didn’t exercise. They had all these other issues.
That’s why they had more disease, not because of the meat. So it’s basically other issues with the study could be designed flaws and maybe the study population is different from the regular population, so it may not be widely generalizable. And also they do all these weird statistical calibrations to normalize the data, and we’re going to talk about what that means. And they did this in that study. There was I think a scientist named Roger Williams who said, there’s liars, dam liars and statisticians, or maybe that was Mark Twain. I don’t know, but I think it’s true. You can kind of manipulate the data to make it show what you want, and that’s clearly been done here. And the other thing this study does is it actually supports dietary guidelines to limit red meat consumption. And why does it say that? Well, I mean, the study basically said, our study supports this current dietary recommendations for limiting the consumption of red media intake and emphasizes the importance of different alternative sources of protein for type two diabetes prevention.
But dietary guidelines, just like this study, are heavily based on observational data. The data that can’t prove cause and effect, and the systematic reviews and meta-analysis of observational data are the weakest types of studies, right? There’s confounders, there’s bias, there’s a lot of problems with the studies, and often the researchers have ties to industry. The expert panels are not independent. It’s kind of a mess. So how do we know what to do in science? Well, randomized control trials are the gold standard for drawing causal inferences between exposures and the outcomes. For example, you give people placebo or a blood pressure drug who have high blood pressure and you follow them for three months and you can see, okay, well the people taking the placebo lower their blood pressure or the people on the pill. That’s a randomized control trial, and you randomized people so they’re not stacking the deck in favor of a healthier, sicker population.
Now, they’re hard to do in nutrition. You need to control everything, and it’s really hard to do. It’s great in a lab rat, but it’s not really easy in humans what call free living and they do whatever they want. So you say, well, I want you to eat a low fat diet, or I want you to low carb diet, or I want you to exercise 150 minutes a week, or I want you to not smoke, or I want you to sleep eight hours at night or whatever you want. You tell ’em they’re not going to probably do it and it’s hard to do. You have to basically put people in a locked metabolic ward and put them there for years and give them the food that they eat and track everything they do in order to actually know what’s going on like a lab rat.
But we really can’t do that. We can’t take 10,000 people and feed ’em a vegan diet and 10,000 people and feed ade omni board diet, including red meat and healthy foods, follow ’em for 30 years and give them all the food and track that it would be billions and billions of dollars and impossible to do so. It’s not practical, it’s not ethical. It’s expensive. It’s hard to recruit volunteers for this, and it’s hard to do these nutritional studies. So we have to do the best for the data we have, which are systematic reviews and meta-analysis of randomized controlled trials, mechanistic studies, lab studies. There’s many different levels of evidence. So you have to look at the total communal benefit of all the evidence. So now let’s dive into this problem of study design and what was wrong with this paper and why it does not prove that red meat causes type two diabetes.
So what they did, as I mentioned before, they gave them a food frequency questionnaire and they’re highly inaccurate. Every two to three years people get asked, what do they eat? And they got a questionnaire, what’s their average intake of food and beverage over the last 12 months? Do you know what you ate over the last 12 months? I couldn’t have a clue. I mean, how often do you remember eating X and Y food, right? Do eat chicken with the skin on it or without the skin? Do you hamburgers, hot dogs, processed meats? They give all these questions. They also kind of weirdly track things like beef fork and lamb as a sandwich or mixed dish, but no serving sizes were noted. Sandwiches in lasagna have also bread and pasta and processed carbs. So it was that part of it, we don’t know. So they basically kind of looked at what they were eating.
The second issue is, and by the way, I can go way more into these food frequency questionnaires, but just trust me based on the data, and we’ll put the links in the show notes, they’re really highly inaccurate. They’ve really been proven to not be a good tool for looking at a nutritional intakes over time and don’t really correlate with the valid metric for tracking outcomes. So right off the bat, it’s a tough study to do. The second issue, and I mentioned it, is that the red meat definition included sandwiches and lasagna, which basically were counted twice as processed and unprocessed red meat. Now processed red meat is hot dogs, bacon meat sandwiches, sausage, unprocessed meat is like hamburgers, beef, pork, lamb, a sandwich. So it’s kind of weird. They kind of included other foods in the meat, so you have to be clear. The third issue is the serving signs has changed over time and why?
Because the food frequency questionnaires were different in the different parts of the study. So one was in 19 80, 1 was in 84, 1 had 61 items and 120 items, and they basically changed the definitions of what a serving is even in these food frequency questionnaires. So it’s super confusing. So the nurses in the study asked how often they consume two slices of bacon. Now the serving size of bacon is one slice, but before it was two slices, right? How did they adjust for this one serving of processed red meat? It’s considered 45 grams. How did they measure it? Did they weigh their lunch meat? Did they take their bologna or salami and put it on a scale? I doubt it.
What about chicken beef for or lamb? They say six to eight ounces was a serving today. One serving is three ounces. Did they know this? Did they translate three ounce serving to a six to eight ounce equivalent? Probably not, and it creates more error in the studies. Issue four in the study was that this is really crazy. They use statistics to massage the data to have the outcome they want. It calls this process calibration. We’re calibrating the results using a seven day weighted diet record and food frequency questionnaire from two other population studies. In other words, they kind of acknowledge that food frequency questionnaires are not that accurate, so they can use other ones to correlate and see if they can create this mishmash of data to show what they want. So what they found was that this is kind of crazy. The calibration doubled the effect for total red meat, processed meat and unprocessed red meat.
So before the calibration, for example, one serving an increment of total red meat was associated with a 28% high risk of diabetes. After the calibration, it was 47% before the calibration. One serving increment of processed red meat was associated with a 50% high risk of diabetes after it was 101%. So it’s like what are you doing here? Right? So guess what number was reported in the headlines? Not the uncalibrated, but the calibrated number, right? Too much red meat is linked to a 50% increase in type two diabetes. Well, in NPR, they didn’t really do a good job of doing a review of the study. They didn’t do investigative journalism, which I think is sorely lacking. And basically they found that this 50% increase in red meat. So like I said before, the calibration was 28% after it was 47%. The next issue was the authors compared the lowest intake of red meat to the highest intake, but have historically reported the risk using servings and for example, which a more quantitative metric.
So to explain what that means in the 2011 paper, another one called red meat consumption, the risk of type two diabetes, three cohorts of US adults and an updated meta-analysis, they reported 12% risk of diabetes for one serving and 32% for process meat and 14% for total red meat. But this paper compared the highest and lowest intakes claiming a 51% increased risk for eating unprocessed and 101% increased risk for processed and 40% for total. But basically this method using qualitative versus quantitative generated a lot more headline worthy statistics. So in other words, the way they reported this, it just makes it more sensational and look better for the agenda of having a study show that red meat causes diabetes. Another thing with the study is the women in this study, the nurse cell study compared to the men in this study showed that the women ate wore red meat than the men.
Now, this is the first study ever to claim this. Now, typically every other study is shown the opposite. So what does that mean? Well, I don’t know, but it just seems to kind of be a clue that maybe the study is a little wacky and doesn’t comport with all the other data we have around meat consumption and being female on male. The next issue was the total red meat intake had a higher risk of diabetes than both processed and unprocessed red meat. So that doesn’t make sense, right? How could the total red meat be worse than the individual types of red meat when total is a sum of both of them? So you don’t get one plus one equals three. It doesn’t make sense. So most studies are looking at the risks associated with red meat show that the processed meat is riskier than unprocessed red meat and total red meat.
The sum falls in between. So if you have processed ready meat being a higher risk and unprocessed lower risk, the average risk is going to be lower, kind of a combination. But in this study, they found the opposite, which doesn’t make any sense. If red meat its process makes you have a higher risk of diabetes and unpressed risk recipe meat lower, then if you add them together, you shouldn’t have a higher risk when you combine ’em. So it doesn’t make sense. The next issue of the study was what we call healthy user bias, and I think this is really, really important. Essentially, it is talking about what I mentioned earlier, which is the idea of confounders, this idea of why were the people in the study having more diabetes or not? Was it because of the meat they were eating or a bunch of other habits, right?
The people in this study, when you look at their characteristics, they had much higher body mass index. In other words, they were heavier, they were less physically active, they were more likely to be smokers, and they were less likely to take vitamins. So of course they’re going to have more risk. So the healthier people didn’t eat red meat. Why? Because they thought that red meat is bad. That’s the propaganda that we have in our society, which is red meat causes heart disease, red meat causes cancer, so we should be eating less meat. In fact, we are, which is really another really important point when you look at the amount of meat we’re eating, it’s dramatically decreased over the last 30, 40 years dramatically because the message in the public health domain has been to eat less meat, but at the same time, what’s happened, the risk of diabetes has skyrocketed just double tripled in different populations.
So how could that make sense? Red meat’s going down, diabetes going up. Okay, well, that’s a problem. How do we explain that with this study? Well, what’s so interesting to me in this study was that they didn’t adjust for body weight or we call BMI. That’s nuts because the group that actually had more diabetes was more overweight. Now, was that attributed to the red meat intake? That’s what they say that red meat caused you to gain weight, but there’s just no data to support that. I mean, they basically said because the likelihood that weight gain mediates at least part of the association between red and media intake and type two diabetes, we did not adjust for adiposity in the primary analysis. In other words, they did not actually account for the fact that the people who ate more red meat were more overweight. Now, a lot of other things can cause that, and particularly they do particularly ultra processed foods, sugar and refined carbohydrates.
That’s clear from the data, not meat. The next issue was grains and sugar were excluded from the characteristics table. That’s crazy. How do you actually evaluate the effective diet if you exclude the very thing that’s causing diabetes, namely sugar and refined carbohydrates. They just said, oh, we’re not going to include that. Okay, we’re not going to look at that. Why? Well, I don’t know, but it doesn’t make any sense to me. The next problem with this study is that calorie intake was reported extremely low. Now, this doesn’t make sense because people we know eat a certain amount of food, they’re all starving themselves. And in the study they basically excluded, people ate less than 500 calories a day for women or more than 3,500 calories. They just got rid of them from the hour. It’s the same thing for men. Men who consume less than 800 calories a day or more than 4,200 calories a day were excluded.
And you can see how do you get these numbers? Because food frequency questionnaires are so problematic. People do all kinds of things that show that they’re not actually truly reporting on how much or what they ate because they’re getting all these extremes. Oh, men are eating 800 calories a day or 4,200 calories a day. It doesn’t make any sense. But what was really interesting is the average calorie intake for women was 1200 calories, and for men it was 1600 calories. That’s not a sustainable diet for people. They’re not going to eat that much. They’re going to be starving all the time. So it just shows you the flaw in these food frequency questionnaires. They don’t show you what people are actually eating. These very low averages for healthcare practitioners, people basically, nurses are on their feet all day. So that just kind of makes me want to throw out the study altogether because again, how do you rely on data that’s so imperfect where your calorie count is so off?
So how do you know what actually people are eating? Now, the other thing they do is this statistical dance where they focus on what we call the relative risk, not the absolute risk. Now, the relative risk is relative to the other population. How much did your risk go up? So when you see 51% or 61%, that’s what we call relative risk. The relative risk isn’t two, it’s probably not significant in an observational study. The absolute risk is how much does the absolute increase in the risk of that disease in a population? So for example, if the absolute risk of developing a certain disease is 5%, it means that five out of a hundred individuals in that population are expected to get sick. Now, we did this with, for example, processed meaning colon cancer. We said, oh, your risk of colon cancer goes up by about 20%.
If you eat bacon and processed food, and this is based on observational data, what did it actually show? Your risk of colon cancer went from five to 6%. Now that’s a 20% increase, but your absolute risk goes from five to 6% in the total population of getting cancer of the colon. If you eat two pieces of bacon a day, your whole life. So okay, whatcha going to do with that information? Absolute risk is really important. Now, relative risk, as I said, basically is the probability of an event occurring in one group that’s divided by the probability that occurring in another group. So it’s basically a ratio but not an absolute risk. So if it’s over one, there’s no difference. It’s one, there’s no difference. If it’s greater than one, it shows an increased risk. And if it’s less than one, it shows a decreased risk.
For example, we talked about the relative risk of smoking in lung cancer with observational studies where it was a 10 to 20 fold increase, which means a thousand to 2000% increase in heart disease is also a pretty big risk. If you look at smokers, their risk relative risk is two, as I said, 200%. So smokers have about twice as high risk of getting heart disease than non-smokers. But relative risk sounds good, but it doesn’t actually tell the true story. So when you look at the highest versus the lowest red meat intake in this study, the absolute risk, and this is not the relative risk, the absolute risk was your risk of getting diabetes went from 0.32% to 0.52%, which is so little, right? You’re talking about two tenths of a percent increase in your risk of getting type two diabetes if you eat red meat, okay?
Not a very big risk when they looked at the relative risk in this study. Sounds much better, right? The highest versus the lowest, lowest total red meat intake showed a risk that was 62% higher of getting type two diabetes in the high risk group versus the lowest, the lowest intake of red meat versus the highest intake. 62% not 0.2%. Okay? So is what I mean by the statistics, right? There’s liar, there’s damn liars and there’s statisticians. So I think if you really be careful and looking at also absolute risk, not relative risk, it sounds better when you say relative risk and fear, you’re trying to prove something. The next issue is there are a lot of vested interest in this study. Walter Willett, who’s a study author, great scientist, I know him personally, he’s a good guy, but I think he’s very biased towards a vegetarian diet, including little to no red meat since the early nineties.
And he’s been leaning much more towards veganism recently. And he was a leader of the Lancet section on diet and health, which essentially said we should all be vegan. Now, he used to publish more than 200 papers on epidemiological studies, which show association but can’t demonstrate cause and effect. So he’s, for example, found that red meat is bad for your health, that animal fats are bad for health, that a diet of grain, fruits and vegetables and vegetarianism is better for your health. And he’s also published three books that argue these things, and he has multiple serious potential conflicts of interest, which cast doubt on his ability to bring a really unbiased viewpoint to the question of whether vegan or vegetarian diet is preferable for good health. Now, Harvard in general, condemns animal foods, pushes plant-based diet. And when you look at who’s funding these studies, the American General Nutrition that actually published this study receives funding from General Mills, which is a big grain maker, the Mars and bear.
There’s a lot of conflicts of interest here. Now, the next issue with the study was what’s the mechanism of red meat causing type two diabetes? They do have some explanations, but they’re kind of bogus. And all these mechanisms propose that it’s a problem of meat driving issues with insulin sensitivity causing type two diabetes, but it doesn’t mention the role of sugar and refined carbohydrates, which is so well established in the research in randomized controlled trials and observational trials. So here’s the mechanism. Well, maybe saturated fat injures the beta cell function in insulin sensitivity. Now, saturated fat just for a fact is not a prominent fat in red meat. It’s oleic acid, which is a mono monounsaturated fat, and that’s high in oleic acid or linked to much better cardiometabolic health. Palmitic acid, which is in meat, also maybe linked to insulin resistance by inflammation. And steric acid is protective against insulin resistance and doesn’t really impact your cholesterol.
And there’s also something called CLA, which is conjugated linoleic acid, which is very protective against cancer, improving metabolic health and many other things. So the diet saturated fat diabetes connection is a little shaky, and also there’s really not a clear mechanism here, and I think meat is relatively low in saturated fat, so that’s makes the argument a little bit less relevant. There are also many, many meta-analysis showing that low carb diets are far more effective than high carb diets for reversing insulin resistance. So there’s really so much clarity in the literature that if you take someone who’s diabetic and you put ’em on a low carb diet, they burn more calories, they lose more weight, they potentially reverse their diabetes. The ketogenic diets have been used by a group called Virta Health Online and found profound changes in risk reduction in diabetes, for example, a hundred percent get off the main diabetes med, 90 plus percent get off insulin.
There’s about a 12% weight loss, 60% get complete reversal of type two diabetes, totally normal after being severe diabetics. So this is on a very basic almost zero carbohydrate diet. In 2006 in the British Medical Journal, low carbohydrate diet showed a lower A1C compared to the high carb diet. The greater the restriction of carbs, the greater the glucose lowering effect. And what was so weird about this study is they didn’t even look at carbohydrate intake, which kind of is strange. That’s the main thing we know across diabetes. They also talk about heme iron, how that increases oxidative stress and insulin resistance impairs beta cell function, but he iron is more of a proxy for a crappy diet. Again, healthy user bias. We talked about in a meta-analysis by FANG in 2015, he found that he iron in the context of a standard American diet was linked to cancer, Romania, fast food, fried food, but not in the Netherlands, Canada, Italy, France, Japan, and Sweden because they generally have a healthier diet.
They’re not eating the typical standard American or sad diet. So it’s not only what you’re eating, it’s what you eat it with. The next mechanism they proposed was processed meat, having a high concentration of nitrates and is byproducts, and those may promote insulin resistance. These nitrates and nitrites, which are basically food additives, they react to form nitrosamines under high heat and those are carcinogenic and they can’t increase insulin resistance, but so is it the processed meat or the way the meat is processed? What are the additives? For example, uncured meats in Italy and Sardinia, I’ve written a lot about this, how very low rates of diabetes, a lot of this, I was there and I ate lots of prosciutto and homemade cured meats, and it was quite a scene, Ari. We had, for example, this meat that was cured with all these incredible grape leaves and all kinds of stuff, salt from the ocean and this and that.
It was great. And they don’t have any real risk of type two diabetes except when they start eating our diet. So it doesn’t mention sugar as a mechanism which is often consumed with red meat. If you’re eating processed red meat, you’re eating a sandwich, eating bun rolls, sugary drinks, so you can’t blame what you don’t measure. And it’s really unfortunate that we don’t have this report in the study because we don’t know if the people eating red meat also ate a ton of refined sugar and carbs, likely because they were more overweight. So the whole thing is kind of, I don’t know, just kind of a messy, horribly done misinterpreted study, but we know that red meat contains no glucose. It doesn’t raise your blood sugar. A little confusing why it would increase your risk of type two diabetes and type two, type two diabetes is caused by resistance by high blood sugar and chlor glycemic control, and basically red meat has no glucose.
Now, let’s look at the other body of research because you can’t just look at one study, you have to look at it in the context of everything. Now, red meat consumption has been looked at and there was a study that was sort of a gold standard study, which is a review of meta-analysis of randomized controlled trials. So it wasn’t an observational study, it was a randomized controlled trial. This was published in the European Journal of Clinical Nutrition in 23. We’re going to put it in the show notes. There was no significant impact of diets to contain red meat versus diets with less or no meat on the following things, insulin sensitivity, fasting glucose, fasting insulin, A1C, which is basically your average blood sugar, the beta cell function of your pancreas, or GLP nm, which we know now is related to weight metabolism. And all the new weight loss drugs like PIC are GLP one agonists red meat resulted in a significantly lower postprandial glucose level compared to diets with less or no red meat.
In other words, when you eat meat, it blunts the response of your blood sugar rise. So these are not observational trials. It’s a meta-analysis of randomized controlled trials. So this completely opposite of what the study showed, but it wasn’t reported. What was reported was the study that showed red meat cause of diabetes, right? If you have a negative study, it’s usually not reported such and such doesn’t do this. Well, that’s kind of boring, but if oh, red meat’s going to kill you, okay, well let’s publish that. Let’s get PR on that. What they found was actually small and marginally significant improvements in insulin sensitivity with red meat intake in type two diabetes. In other words, those people who had diabetes and ain’t red meat had better improvement in insulin sensitivity. Another major study was looking at the effects of total red meat intake on glycemic control and inflammatory biomarkers.
Now, inflammation causes diabetes, heart disease, cancer, dementia, and this was a meta-analysis of randomized controlled trials published in advances in nutrition in 2021. So what did that study show? Well, total red meat consumption for up to 16 weeks did not affect changes in the biomarkers of glycemic control or inflammation in adults free of but at risk for cardiometabolic disease. In other words, if you ate meat for 16 weeks in this randomized control trial, it didn’t affect any of the biomarker related to your blood sugar or inflammation who were at risk for heart disease. Well, that’s important, right? The results showed no effect of total red ven intake on your blood sugar insulin, something called homa ir, which is a measure of insulin resistance on your A1C average blood sugar on inflammatory biomarkers that we really look at carefully like c raki protein, interleukin six T NF alpha.
These are really important biomarkers that correlate with heart disease and cancer and dementia. There were no changes in any of these from these randomized trials that were up to 16 weeks in duration. Now in this study, the research participants and most of these studies were asked to consume lean and unprocessed red meat in most of the articles Now from the study, the review was overall, red meat intake does not independently influence changes in cardiometabolic disease risk factors in the short term for those who should choose to consume red meat. Red meat, as with all other protein rich food sources should be consumed in the context of a healthy eating pattern, high in fruits and vegetables and whole grains, and within the energy needs to reduce cardiometabolic disease risk. Fair enough. In fact, just to kind of explain that a little bit more, there was a large study of about 11,000 people who shopped at health food stores.
Half of them were vegetarian or vegan, and half of them ate meat, but they ate meat in the context of a healthy diet. If your meat intake is with hamburgers and fries and coke, well, it’s probably not the hamburger, right? It’s all this other stuff. So what they found was that in both these groups who basically could be assumed eating a healthy diet because they shot the health food storage, both of their risk of death is reduced in half. Well, how do you explain that? Right? They’re basically saying if you eat red meat in the context of a healthy diet, there’s really no big deal. There was another study, again, randomized controlled trials that showed the same thing, right? And this study was titled, the effects of total red Meat Consumption on Glycemic Control and inflammation Systematically searched Meta-analysis and meta regression of randomized controlled trials, blah, blah, blah.
It doesn’t matter basic, it’s a randomized controlled trial review. So what they found in the study was those who ate above what’s commonly recommended, which is about 0.5 servings of total red meat a day, which is about three ounce servings per week, does not negatively influence markers of glycemic control or inflammation in groups of adults without diagnosed cardiometabolic disease. In other words, if you don’t have heart disease or diabetes and you eat more than the recommended amount of meat, it has no impact on your blood sugar control or inflammatory markers. So how do we think about type two diabetes from a functional medicine perspective? What’s the root cause? Functional medicine is all about root cause. The root cause is something called insulin resistance. And this comes from eating a diet that’s high in sugar, refined flour, grains, ultra processed food. There’s no doubt about this.
Also, from lack of exercise and being sedentary, not moving enough or being under muscle, right? Muscle is your metabolic Spanx, according to my friend JJ Virgin. And how do you address that? Will you eliminate alter processed food, processed grains, refined grains and starches, sweets, sugar sweetened beverages especially, and that improves your blood sugar balance and your insulin sensitivity? And what should you be eating then? Good quality protein and it can be meat, okay? That’s my view of the literature and not my opinion, but it’s pretty much evidenced by the randomized controlled trials that we talked about, fiber, fruits, vegetables, nuts, seeds, sometimes whole grains if you’re not fully blown diabetic, healthy fats, olive oil, avocado oil, macadamia oil, none of these will affect your blood sugar. And then you want to use testing to test your fasting glucose, your fasting insulin, your A1C triglycerides and other markers to understand of your insulin resistance.
Now, I co-founded a company called Function Health. You can go to function health com. We’ve created an initial test of over 110 biomarkers. It’s 4 99 a year membership and includes testing twice a year, and you get all the metabolic markers you need. You get insulin, which your doctor almost never tests A1C or blood sugar. But you also look at lipid particle size. We call lipoprotein fractionation, not just your regular cholesterol profile, but whether or not you have small particles, dense particles, larger or small triglycerides, or HDL, all of these will tell you about your cardiometabolic health. We also measure inflammatory markers like C-reactive protein and others. So you get a really good understanding of where you’re at. So you want to check it out, go to function health.com. You can use the code young forever if you want to jump the wait list. But it’s really a way to get testing to see what’s going on with you and what’s going on with your diet.
So again, tests, don’t guess. Now, over the years, my perspective on maybe this changed, I used to be vegetarian, vegan, but I’ve noticed after looking at the literature and doing experiments myself, my patients, and treating them using this approach of a high quality, low glycemic, fiber rich fruit and vegetable rich diet with lots of nuts, seeds, good fats, and modern amounts of healthy animal protein, which I would say is regeneratively raised meat, pasture raised chicken, safely, raised fish regener, raised fish or small fish, it’s fine. There’s nothing to worry about. And just in conclusion, you really have to take these observational studies with caution. Lean red meat doesn’t contain sugar. It’s not a plausible link to diabetes and it’s sugar and refined starches and grains and ultra processed food that cause diabetes. So all the studies are listed in this show notes. I encourage you to check them out.
Thank you for joining me today on the Doctor’s Pharmacy Podcast on the special episode called Health Byte. If you’re enjoying and learning from this podcast, I encourage you to subscribe to my YouTube channel. It’s a great low cost, actually no cost way to support me and learn more. In addition, please subscribe to the podcast on Apple and Spotify. Hopefully you’ll leave us a five star review. And if you have any questions or comments about the podcast or guests you’d like to have on the doctor’s pharmacy, please leave them in the comments section on YouTube. Do look at all the comments. Also, please check out the sponsors mention to his podcast. It’s a great way to support the podcast. And if you’re not currently following me on social media, you can find me on X formerly is Twitter, Instagram, LinkedIn, Facebook, and threads On all those channels, I cover all things health and wellness. My handle is Dr. Mark Hyman, that’s DUR Mark Hyman on all social media channels. And if you haven’t already subscribed to my newsletters, including Mark’s Picks, go to dr hyman.com and you can subscribe there. And I thank you for joining us today for this deep discussion about red meat and diabetes, and what I would say is pretty much junk science. Thanks so much and we’ll see you next time. I’m the Doctor’s Pharmacy.
Speaker 2:
This podcast is separate from my clinical practice at the UltraWellness Center, my work at Cleveland Clinic and Function Health, where I’m an Chief Medical Officer. This podcast represents my opinions and my guest opinions. Neither myself nor the podcast endorses the views or statements of my guests. This podcast is for educational purposes only. It’s not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. If you’re looking for help in your journey, seek out a qualified medical practitioner. Now, if you’re looking for a functional medicine practitioner, you can visit ifm.org and search there, find a practitioner database. It’s important that you have someone in your corner who is trained, who is a licensed healthcare practitioner, and can help you make changes, especially when it comes to your health. Keeping this podcast free is part of my mission to bring practical ways of improving health to the general public. And in keeping with that theme, I’d like to express gratitude to those sponsors that made today’s podcast possible.

Ingredients:

Brownies

• 2 tablespoons ground flax seeds
• 6 tablespoons water
• 2 tablespoons coconut oil, divided
• 1 cup almond butter
• ⅓ cup coconut sugar
• 1 teaspoon vanilla extract
• ⅓ cup maple syrup
• ¼ cup cassava flour
• ¼ cup 100% cacao powder, unsweetened
• 1 teaspoon baking soda
• Pinch of sea salt

Optional Topping

• 1 tablespoon coconut oil
• 2 ounces 100% cacao chocolate bar, unsweetened
• Pinch of coarse sea salt

Method:

1. Preheat the oven to 350°F and line a 9×13 baking pan with parchment paper. Grease with 1 tablespoon of coconut oil and set aside.Combine the flax seeds with water in a small bowl and set aside.

2. In a mixing bowl, mix almond butter and coconut sugar together, until incorporated, then add the vanilla extract, maple syrup, and flax/water mixture. Mix until combined.

3. Add the dry ingredients into the wet ingredients. Fold it all together and stir until no lumps remain. The mix should be sticky.

4. Pour the brownie batter into the prepared oiled baking pan; it will be very thick. Use the remaining 1 tablespoon of coconut oil to grease another sheet of parchment paper. Place the oiled parchment paper on top of the batter and press with your hands to spread the batter evenly until completely flattened.

5. Remove the top piece of parchment paper and bake for 25 minutes, or until inserting a toothpick into the center comes out clean.

6. Wait 15 minutes until the brownies are cooled, then cut into squares.

7. For an optional topping, melt the coconut oil with chocolate and drizzle over the brownies. Then sprinkle with a pinch of coarse sea salt and enjoy!

Nutritional analysis (per brownie): Calories: 163, Total Fat: 11g, Saturated Fat: 2g, Cholesterol: 0mg, Fiber: 3g, Protein: 4g, Carbohydrates: 14g, Sodium: 31mg, Sugars: 9g, Net Carbs: 10g

Dr. Mark Hyman:
Coming up on this week’s episode of the Doctor’s Farmacy.

Dr. Nir Barzilai:
Remember Paul Simon had the 50 Ways to Live Your Lover. There are 50 ways to be centenarians. We’re trying to discover all of them.

Dr. Mark Hyman:
Welcome to Doctor’s Farmacy. I’m Dr. Mark Hyman, and this is a place where conversations that matter and today we’re going to learn about longevity science. It’s one of my main passions and it’s why I’m so excited to bring you today’s conversation with one of the top leaders in the field, Dr. Nir Barzilai. He’s the director of the Institute for Aging Research at the Albert Einstein College of Medicine and director of the Paul F. Glenn Center for the Biology of Human Aging Research and of the National Institutes of Health Nation Shock Centers of Excellence in Basic Biology of Aging. He’s just a rockstar when it comes to longevity science. He also studies the family of centenarians that have provided incredible genetic and biological insights on the protection against aging. Several drugs are developed based in part on these paradigm changing studies. He’s now leading a really important study looking at metformin called the TAME Trial Targeting or Taming Aging with Metformin to prove one way or another to the FDA that aging can be delayed and allow for next generation interventions.

He’s co-authored over 300 peer review science papers and is a recipient of numerous prestigious awards, including the 2010 Irving S Wright Award for Distinction in Aging. He’s also the 2018 recipient of the I-P-S-E-N Longevity Award. He’s on the board of many incredible organizations and he is a founding member of the Academy for Healthspan and Lifespan, the Longevity Biotech Association and the Healthy Longevity Medicine Society. He’s co-founded Cobar and Life bioscience and is featured in prominent papers, podcast, TV programs, documentaries, Ted Talks. He’s consulting for the Singapore government, several international banks, the Vatican, the Milken Institute, and the Davos Economic Forum. And his book age later was published in June, 2020. Now we get into it, really into it. In this podcast, the way we think about aging and disease is rapidly changing and Dr. Barzilai and I begin our conversation exploring why he’s moved away from the term anti-aging.

Together we explore the ways aging and chronic disease are closely aligned and what is at the root of accelerated aging. We’re seeing in so many people today. Dr. Barzilai is one of the two people who spent the most time studying centenarians or people who reach a hundred years old, and we dive deep into a vast array of his learnings, including why having a longer lived healthy population would actually be good for the economy. He also shares some very interesting and surprising characteristics of centenarians and breaks down what can and cannot be attributed to environment and lifestyle factors. We then dive into Dr. Barzilai ‘s research on the drug metformin and how it’s being used to target aging and prevent age-related disease. We discussed metformin’s effects on the gut microbiome on muscle mass and delayed aging, and I share my current thoughts on it if it’s something I would consider taking.

Dr. Barzilai also shares his thoughts on whether the intake of phytochemicals and other natural compounds might provide similar benefits to metformin without taking the drug. And we close our conversation with Dr. Barzilai’s personal longevity routine. If you’re interested in living to a hundred and beyond like me, this is the conversation for you. Now let’s dive into my conversation with Dr. Barzilai. It’s so great to have you on the Doctor’s Farmacy podcast. Nir you’re a legend in the field of longevity science. You’re doing groundbreaking research that is going to inform all of us about how we should live our lives, how we should think about the biology of aging and what kinds of things we can do to help extend our health span, our lifespan. And you’re not just some biohacker doing this on Instagram. You’re a scientist who spent your life studying this and has been inspired to do this for a number of different reasons. And one of the things I’d love you to start talking about is your grandfather. You recall him as a very robust, healthy, younger man who was able to do incredible feats of health and fitness, and yet when you knew him, he was older and he had diabetes, it was decre, and you’re like, what the heck? So maybe share how maybe that was part of the inspiration for you being interested in this field of longevity science.

Dr. Nir Barzilai:
But first, I mean, thank you for the flatter really, get you nowhere, but look, same with you. You are pioneering your own way and all of a sudden we find ourself in the same boat because aging went from hope to promise and now we have to realize the promise. So we merge now and it’s really important for me to make sure that we are kind of synchronizing more. So thank you. And yeah, my grandfather, so

Dr. Mark Hyman:
You’re from Israel, right? And you were

Dr. Nir Barzilai:
Kind of, I think the bottom line is when we were kids and we looked at our grandparents, we were like, where did they come from? I mean, what happened to them? You never really see yourself as Uhoh. That’s how I’m going to be right?
By the way, I found that this has changed because there’s so many younger people who are really interested in aging. But that was for me and for me, even through medical school, I always said, okay, so cholesterol in diabetes, you can bring me a hundred people and I wouldn’t know if they have high cholesterol diabetes, but I know that who’s old and who’s young, and that was the phenotype that was much more interesting to understand and can we do something about it? There’s also when I went through my residency, I had a professor and whenever we presented a patient, we said, so it’s a 68-year-old woman. And he said, does she look older or younger than her age? And I thought, what that has to do with everything? And all of a sudden you started through this just simple question, understanding that there’s a biology for aging, there’s chronological age, but there’s biology of aging and it actually has a clinical impact of what you want to do, who you want to give up on and things like that.

Dr. Mark Hyman:
Yeah, it’s so true. We all intuitively know if you see a 40-year-old smoker has been smoking two packs a day and an alcoholic for 30 years, they look pretty rugged. And if you look at someone who’s 65 who works out every day, who eats perfectly runs five miles a day, they look younger than that 40-year-old. So we know intuitively there’s something going on and that the chronology doesn’t actually always match the biology. So your work has really been to understand the root mechanisms of this change in the biology of aging and how we can impact that through lifestyle, through medication, through various compounds that we can study and use, whether it’s dietary factors or herbal factors or peptides and all sorts of stuff that are available to us to think about how we influence this process. But what’s going on now is this incredible revolution.
When I was in medical school, we never even talked about aging. It was like study diabetes, study, heart disease, study, dementia, study cancer, the disease of aging. But as you talk about the biggest risk factor for all of these things is chronological age. The older we get, the higher our risk is for all these conditions. And so now scientists are starting to think about, well, what is it the root cause of these diseases that maybe unifies them? It’s almost like the unified theory of aging and disease like Einstein. See the picture of Einstein behind your head there. I know you’re at the Albert Einstein College of Medicine, and I think he talked about this kind of unified field theory once this unified field theory relates to aging and how do we think about these key factors that are causing this acceleration of biological aging and the diseases of aging?

Dr. Nir Barzilai:
So our practice and our leadership has brought that to declare that there are hallmarks of aging. And let me tell you what are hallmarks of aging in my mind because there’s no total agreement, but to be a hallmark of aging, you have to show that something is wrong with aging. And when you correct it in animals or in people, actually you get an increase in health span and maybe decrease in mortality or increase in lifespan. This is how you become a hallmark in a conservative way. And the reason we have hallmarks is because something interesting has been observed. When you correct one hallmark, you influence all or a lot of the others.

Dr. Mark Hyman:
Yes,

Dr. Nir Barzilai:
You can improve autophagy, which is our cellular garbage disposal that takes our junk out. You can improve it, it goes down with, you can improve it, but you get better metabolism, you get less genetic instability, you get epigenetics changes.

Dr. Mark Hyman:
Mitochondrial function improves, right?

Dr. Nir Barzilai:
Mitochondrial function,

Dr. Mark Hyman:
Inflammation goes down all of it.

Dr. Nir Barzilai:
So there are practical issues here. First of all for me, when it comes to what do we call RO therapeutics, which we used to call anti-aging therapy, we don’t use anti-aging because we have jero science. It’s a little another.

Dr. Mark Hyman:
I’m not anti anything, I’m pro health wellbeing.

Dr. Nir Barzilai:
But when you use RO therapeutics, we can take as an example, metformin or rapamycin or SGLT two inhibitor or even GLP one agonist, other drugs,

Dr. Mark Hyman:
Ozempic, in other words, in other similar drugs. If you

Dr. Nir Barzilai:
Go and look at what happens to those hallmarks of aging, they all change. And people said, are you crazy? What God created 12 different aspects of this? And the real point is that those drugs are doing something to stop aging. So they take basically an old cell and make it younger or an old organ and make it younger or a whole body and make it younger. And when he does it, there are lots of things that are corrected. And I remember when it came to metformin, we started arguing this is what it does or this is what it does. No, we can decide what happens first, but when you correct aging, you get a lot of effects. So this is one practical aspect. The second practical aspect that is really important because we want to advance the field biotech. I’m also an executive in the longevity biotech Association. There’s a lot of biotech investment. And people would come to me, my job is to do help them due diligence and they come and say, Hey, which hallmark shall we target?

Dr. Mark Hyman:
By the way, what disease? That’s the wrong question. That’s the wrong question.

Dr. Nir Barzilai:
Which is your favorite hallmark? I remember this guy from Texas at five daughters. I said, who’s your favorite daughter? He said, I’m not answering. I said, I’m not answering. But the

Dr. Mark Hyman:
Point is, that’s great.

Dr. Nir Barzilai:
You can target one hallmark and you improve the others. But that also means that the hallmark, you can do the mitochondria, but you actually have influence not on things that are associated with mitochondria, but other aging thing. In other words, the fact that one hallmark effect the other means that some of the indications for drug development are going to be increased. So I gave you an example why those hallmarks are important. They’re not done by the way.

Dr. Mark Hyman:
There was nine now there’s 12, maybe 13.

Dr. Nir Barzilai:
And not only that, please understand this. We say hallmark, and you might understand, I’m not talking about you, mark, but others might understand that this is mechanism, this is the mechanism for aging. They’re not necessarily the mechanism for aging. We still have a lot of things to do in order to understand what and what comes first and what’s the combination. But those are practical things that we know that we can fix and have an impact. And that’s a good start.

Dr. Mark Hyman:
Yeah, it’s sort of like physics. We know there’s atoms and electrons and neutrons, and then there’s like quarks and boin particles and things we haven’t really discovered yet. We keep learning. So I agree,

Dr. Nir Barzilai:
But once we discover atoms, we already had a lot of advance, right? Yeah,

Dr. Mark Hyman:
Exactly.

Dr. Nir Barzilai:
Without the neutrons.

Dr. Mark Hyman:
I just want to drill down on what you just said because it’s so important and it speaks to the problem with the traditional science and traditional medicine, which is reductionist. What is the single pathway? What’s the single target? Which drug do we develop for inhibiting or affecting this particular pathway? And what you just said was revolutionary is that these are all interconnected. It’s a network and it’s a network effect. And these are all connected in a web-like fashion that all influence each other and are often redundant. So if you actually influence A MPK, which is a lot of the work you’re doing with metformin, you’re also reflecting autophagy and DNA repair and NF kappa B and inflammation and P 53 cancer genes, and you’re just doing so many different things that are redundant. And if you hit one of the other hallmarks, you’re going to do similar things.
And there’s so many ways to influence these that they’re very redundant pathways. So it seems to me that biology, whether you believe in God or not, how we designed evolution, the body was designed with so many redundant systems that we’re all designed to correct and repair and rejuvenate our system. So in a sense, what’s so exciting to me up about the hallmarks of aging is it’s explaining for the first time these kind of fundamental laws of biology where everything is connected. The body has this innate healing system, it has a profound and incredible healing regenerative repair renewal system, and that’s what we’re trying to target and activate. So we don’t treat diseases anymore. We treat these fundamental root causes. And I would even go further to say what are the root causes of the hallmarks of aging people? It’s a little bit still reductionist. What’s causing the hallmarks of aging?
What’s causing mitochondrial dysfunction? What’s causing exactly causing DNA damage? What’s causing deregulated nutrient sensing? And people say, what’s your favorite hallmark? I actually have one. I think the meta hallmark, and you can correct me, the scientist here, I’m just the doctor, is I think that one of the meta hallmarks is the deregulated nutrient sensing because it influences all the others in such a profound way. And if you regulate that, which is really through food and our way of eating, what we’re eating, when we’re eating, how we’re eating, all those other pathways that relate to the hallmarks speech, Kimberly influence,

Dr. Nir Barzilai:
First of all, by the way, when you edit this podcast, you should take out my stuff because you summarized it so beautifully. But then at the end you did what I kind of made sure you wouldn’t do. Who’s my favorite daughter?

Dr. Mark Hyman:
I know, I know, I know. And I’ll tell you. Well, that’s why I want you to correct me.

Dr. Nir Barzilai:
And I came from metabolism, so I don’t object it, but the last paper that we all have, the slide, the last slide that we have went from seven hallmarks to then nine hallmarks to now 12 hallmarks. And those 12 hallmarks are saying actually there are three groups and one of them are the ones that are more likely to be the initiators and the others are going to be the responders.

Dr. Mark Hyman:
Yes, that’s what I’m saying. Yeah.

Dr. Nir Barzilai:
So like genetic instability and prota might be more important than metabolism. It’s their failure that might lead the metabolic failure.

Dr. Mark Hyman:
Interesting.

Dr. Nir Barzilai:
I’m not judging, I’m just saying what it is.

Dr. Mark Hyman:
There may be a hierarchy in what you’re saying.

Dr. Nir Barzilai:
There is a hierarchy and yeah, we want to understand the hierarchy and we want to see if we missed any of the promoting. But I also want to say that exactly that when, so every one of us has hallmark or hallmarks, and we all try to do this picture to take this picture of hallmark and say, but ours is in the middle just like you did. Metabolism is correct to everything. And the answer is exactly what you gave before. When Anna Maria Cuervo, my dear colleague here at Einstein Codirector when she said, I think autophagy is in the middle because that leads

Dr. Mark Hyman:
To

Dr. Nir Barzilai:
Everything I say, well, why autophagy decline with aging?

Dr. Mark Hyman:
Yes,

Dr. Nir Barzilai:
Exactly. There’s something that leads the autophagy to decline with aging. Tell me what it is.

Dr. Mark Hyman:
Yes, it’s the cause of the cardio

Dr. Nir Barzilai:
MTOR that’s target for rapamycin increase with aging. We want to decrease it. Why does it increase with aging? We don’t know that.

Dr. Mark Hyman:
Yeah, yeah. It’s exactly right. I think we like to be simple in our thinking, but biology is infinitely complex. Physics is actually complicated, but it’s knowable. Biology is almost unknowable. I mean, when you think about there’s 37 trillion cells, and I think a billion reactions in there every second or something, it’s like 37 billion, trillion chemical reactions happening every second in the body. It’s mind boggling. And I think that most, and you

Dr. Nir Barzilai:
Even ignored the microbiome, which more sense, right?

Dr. Mark Hyman:
Yeah. I mean there was a hundred thousand terabytes of information just in your biome. And I was on a panel with Stan Hazen at Cleveland Clinic once talking about the microbiome and health, and I said, Stan, how much of our metabolites in our metabolome are from our microbiome? In other words, how much of the molecules floating around in our blood that regulate our biology come from metabolites produced by the microbiome, which is from their genetic expression? And he’s probably a third. And I’m like, whoa. A third of all our stuff in our blood comes from the microbiome. So we’re really, I think in the dark gauges in a way, we’re just sort of opening the door. I think with AI and the machine learning, we’re going to be able to ingest so much information and begin to see these patterns and connections and learn more. And I’m very excited about that,

Dr. Nir Barzilai:
But I really want to do it more positively. Not that what you describe is true, but okay, microbiome, will we know that sauerkraut and kimchi changed the microbiome and improve the health no matter what is, okay, so yesterday there was really the best biomarker. I’m in a group that is a consortium of biomarkers, and we had a meeting yesterday at the Buck Institute. It was a meeting that was supposed to be a hundred people, but 250 people showed up. Lots of people couldn’t register. I’m just saying it was a big deal. And people actually started saying, oh God, we have all those biomarkers and what do we do? And we have to have causative biomarkers in order. We have to understand aging first before even we get to biomarker. And I said, look, to diagnose diabetes, you need just one measure, and that’s hemoglobin A1C. That’s all you need. Okay? Do I know everything about diabetes? Not, but it’s not that biomarker are useless unless I know more. Okay, that right, right. So I think there’s a way, obviously we’re moving on no matter.

Dr. Mark Hyman:
I agree a hundred percent, a hundred percent. It’s true. You don’t need to know how something works in order to actually treat it. I mean, if you eat better, we know it creates thousands and millions of changes in your biology and you eat crap, you feel bad. If you eat good food, your body gets healthy. You don’t have to know how that works. But it doesn’t mean you shouldn’t exercise or eat healthy or do the basic things we know. So I completely agree with you, not like we have to have everything figured out before we do anything. Although sometimes some doctors and scientists are like that. So this moment is kind of an exciting moment. You’ve been working at this for decades and decades. It’s almost like all these billionaires somehow got the longevity bug and want to not die. So they’re pouring billions of dollars into this space, which is good for all of us, and it’s actually allowing the research to really accelerate.
And you’re one of the ones who’ve been saying for a long time. And I want to dive into a lot of the work you’re doing, particularly around the super agers and the centenarian study. I want to dive into the science around metformin and what that is because a lot of people out there are taking this diabetes drug for longevity, and I have some concerns about it. I know you’re the expert in it. You’re doing a study to show once and for all what we know and what we don’t know. And I want to get into that. But can you talk about this centenarian study that you’ve done that is about these super ages, what you’ve learned and how you sort of found that many of these people don’t get sick, they just kind of die. There was a really important paper about the compression of morbidity that was published I think in New England Journal 1980, which talked about people who exercise, didn’t smoke and were optimal body weight, lived long lives and then just died.
They had this rectangular of the survival curve. They just basically fell off the cliff, whereas people who didn’t exercise weren’t their ideal body weight. And smoked had this a long, slow decline, meaning their health span was a lot shorter than their lifespan. And this is what you saw with these centenarians where they sort of kicking along and going dancing at a hundred years old. And I just had a friend of mine, Norman Lear died today, and I was with him his hundredth birthday, and he was kicking up a storm, he was making jokes, and it was fantastic. And I was like, wow, this guy’s just great and very sharp and

Dr. Nir Barzilai:
Kissinger, Kissinger who wasn’t dancing, but he was mentally, he was really sharp. Yes. So absolutely. You described exactly, it’s not only that they live longer, they live healthier. It’s not only that they live healthier, they have a compression of morbidity. Like 30% of our centenarians don’t have a disease, they don’t take any drug, they just don’t wake up in the morning

Dr. Mark Hyman:
In one day.

Dr. Nir Barzilai:
It’s actually interesting, the C, d, C, we all know what’s the C, DC after covid? The CDC is looking at the medical cost in the last two years of life of somebody who dies after the age of a hundred versus those that die when they’re like 70 and it’s third the cost. So there is longevity dividend by those example of Lear of Kissinger. People who just live on have very few medical records and then they die. Like everybody, how come Lear died? What happened to him? And that’s very typical. But I want to say something else that, because it’s an economical thing that I think we should always include when we talk about health span and even lifespan. Because Andrew Scott, who’s a professor of economy in London School of Economy, said, guys, what are you talking about? You’re totally underestimating because you are saying you’re looking at medicine as people in the hospital. Okay, I’m looking at medicine on people outside of the hospital. So if they’re not in the hospital, what are they doing? They’re traveling, they’re shopping, they’re buying houses for the kids. And the economical value of just a little increase in health spend is absolutely amazing. And by the way, if we don’t do it, we’re going to bankrupt the governments anyhow. So I think this is very important. I

Dr. Mark Hyman:
Think the data on that was interesting. It was like 37 trillion for every year, and if you did 10 years, it was like $367 trillion add to the economy. And again, based on that compression and morbidity study, if you are doing bad behaviors and lifestyle, you’re going to die long, slow, painful, expensive deaths where is if you live long, you’re going to die quickly, painlessly and cheaply.

Dr. Nir Barzilai:
Exactly.

Dr. Mark Hyman:
So you were talking about these super ages in the Arian study, and what are the key takeaways that you’ve learned from this work that you’ve done for decades? Because you and Thomas Pearls were the only few who’ve actually done this and looked at these people,

Dr. Nir Barzilai:
Right. So let me say few things before highlighting something. I want to say a few things. First of all, we have three hypothesis. One is that it was interaction with the environment, which is not true with centenarians. Half of our centenarians were over overweight or obese, even as centenarians, 60% of men and 30% of women were smokers. Exercise even moderate exercise, house cleaning and biking and walking. Less than 50% of the people vegetarian, a little over 2% of the people. In other words, as a group, that’s not what they’ve done. And let’s not be confusing because you exactly tell people what to do as far as exercise, nutrition, sleep, and social connectivity. But that’s not it. That’s the point. So the second question was, okay, hey,

Dr. Mark Hyman:
Although it’s a good bet, if you take care of yourself, you’re going to do better. So

Dr. Nir Barzilai:
I’m saying absolutely, it’s important to note it’s good for all of us, but they’re distinct by the fact that they didn’t do it, so they had something special. So what is something special? So the second hypothesis was maybe they have we all, now that we have Xs and lots of us are doing genotypes. So 23 and me, we have lots of things that are associated with disease. We have snips changes in the DNA that are associated with Alzheimer’s and with heart disease and with cancers and all that. Maybe one out of 10,000 just have perfect, we call it perfect DNA. Okay? You don’t find it. And in fact, when it’s already more than a decade that we had the sequence, the whole genome sequences of our first 44 centenarians, okay, no control, nothing, just 44 centenarians. And we went to this database clean var, and we asked how many of those variants that are pathogenic variant, which means you’ll get the disease, okay, if you have that, you’ll get the disease. How much do they have? And to our surprise, 44 people had 230 SNPs. In other words, they had five or six SNPs that should have made them sick, including we have centenarians who have a E four genotype. If you’re homozygous for a E four genotype, you’re most probably going to be demented at 60 and dead at 80, and they’re a hundred, and they’re not demented.

Dr. Mark Hyman:
I had one of those, she was 93-year-old dentist and was still working, and she was a OE double four.

Dr. Nir Barzilai:
Okay, so that’s the point. So the third hypothesis, which we’re really supporting by many ways, is that they have actually genes that slows their aging. In fact, they slow their aging to such effect that if you have some of the junk stuff, it doesn’t matter. It doesn’t

Dr. Mark Hyman:
Matter. Yeah. Yeah. That’s amazing. So basically you found that there were certain genes that they had that were protective genes. And the question is based on those protective genes and discovery of those, what are those genes and what can we do about it? Because just for people as background, they’ve listened to me. They know your genes are fixed. You can’t change the genes that you have, but you can change the expression of those genes, how they’re modified by what we call the exposome. Everything you’re exposed to throughout your lifetime, your diet, your thoughts, your feelings, your microbiome toxins, your gut microbiome said everything influences your gene expression. So these SNPs, these variations in the genetic code are not mutations, they’re just variations, but they highly influence our health and what we do. So what have you found are the most relevant SNPs that actually extend life and then increase health? And what can we do for those of us who may not have them? How can we optimize those variations?

Dr. Nir Barzilai:
Good. So let me give you an example. I would say that there’s, remember Paul Simon had the 50 ways to leave your lover. There are 50 ways to be centenarians. We’re trying to discover all of them, but there are certainly things that are leading, and I will take one example because I think it’s very important, and that’s that 60% of our centenarians, 60% of our centenarians have something that impairs the actions of growth hormones. Okay? 60% of them.

Dr. Mark Hyman:
Yeah, that’s like that Villa Baba, those little Ecuadorian people who have really short and they have these growth hormone deficiency and they live forever.

Dr. Nir Barzilai:
Those are the Lauren Dwarf, right? Yeah,

Dr. Mark Hyman:
The D, yeah.

Dr. Nir Barzilai:
They have a growth hormone receptor deficiency, and they don’t get diseases. We don’t know if they live longer. On the other end, in my studies, 12% of our centenarians have a deletion of exome three in the growth hormone receptor.

Dr. Mark Hyman:
Interesting.

Dr. Nir Barzilai:
The interesting thing in that though is they’re much taller than average, although they have this mutation, they’re much taller because it’s kind of a mutation that when they go through puberty and there’s high growth hormone level, it’s hyperactive. But when growth hormone drops, then growth hormone goes down. IGF one, which is a peripheral growth hormone, is down. Okay? So there’s interesting variation. In other words, if somebody stall and said, I heard that you don’t need growth hormone. I said, no, you might have mutation. That is good. Don’t be discouraged. But basically, and even in our centenarians, few things, our women centenarians, most of the centenarians are women. The ones with the lower half of growth hormone IGF one, it’s the growth hormone that we can measure. Half of the women that have the lower IGF one leave twice as long. They’re already centenarians. Okay? Centenarians have 30% chance of dying every year.
But those with the lowest leave the longest, also, those with the lowest have better cognitive function. Those with the lowest don’t have any difference in physical activity. Because the question is, does IGF affect muscle? Well, it makes the muscle may be better, even if not stronger. So those growth hormone mutation is really important. Now, what we did, because we start researching animals, we go to humans, now we have to go back to animals. So we took animals and gave them an antibody. Again, the IGF receptor that was developed for cancer didn’t work. Cancer is much more complicated than aging in my mind.

Dr. Mark Hyman:
And insulin is an insulin growth factor. One is a big driver of cancer. So

Dr. Nir Barzilai:
Exactly. So it made sense. But when we take animal and we give them the IGF one antibodies, they live longer and much healthier. So this is an important system. Now let me explain it in a way that people understand when we go, evolution is about having children. So growth hormone, our body stronger, we have more muscle, we’re able to get better partner. I don’t know. It all works well.

Dr. Mark Hyman:
Okay? Yeah.

Dr. Nir Barzilai:
Okay. Now we get to the age of 50, which by the way, life expectancy through of most of a hundred thousand years of evolution was between 20 and 30. So we didn’t get to enjoy 50 so much, but when we get to enjoy 50, then we started to go into aging, and now it really makes no sense for us to spend our energy in growth when we’re actually starting to break down. So I think that there’s a hypothesis in aging that’s called the antagonistic biography. The things that are good for you when you’re young are against you when you’re old. And that’s a perfect example. And we actually proved it by looking at this very good database from the UK Biobank. And we showed there that everybody young, when they have high IGF one level, they have less diseases, less mortality, and after the age of 50, it totally switches. Everybody with high IGF gets into a lot of trouble. So I’m pretty sure to tell you that this is important, and I’m pretty sure to tell you that that means that for elderly people to give them growth hormone is not a good idea.

Dr. Mark Hyman:
Okay? Yeah. Yeah. I was going to ask you about that. There were some studies. There was one in New England Journal published a number of years ago showing how it improved so many biomarkers and improved muscle mass and health in many ways. And in the whole a t aging field up until recently was really pushing growth hormone. I was very always concerned about it because of its increased risk of cancer and diabetes. And so I’d love your perspective on that because it sounds like wow, growth hormone is a good thing in some ways. It increases your capacity for exercise and fitness and wellbeing and sexual function and everything, but there’s a dark side to it.

Dr. Nir Barzilai:
And by the way, we’ll get to Metformin, but remember that because it’s the same story. I don’t think metformin is good when you’re less than 50 unless you have diabetic. Because there trade-offs, you have to realize that now we’re talking about the biology of aging that is different than the biology of young. And so we cannot assume that everything that was good for young people is good for old people so we can develop it.

Dr. Mark Hyman:
So we often look at IGF one levels, and there’s a lot of people out there in the sort anti-aging field that are looking at that and go, oh, your IGF levels one, let’s get that up. And I think to me, it’s a big concern because one of the might amend my favorite hallmark is the deregulated nutrient sensing. And the first part of that is deregulated insulin signaling. And I think insulin is, and we’re going to get to this with metformin, but as people know my work, I’ve talked so much about insulin resistance as the biggest driver of so much of the phenomena of aging, heart disease, cancer, diabetes, dementia, muscle wasting, and just aging itself. And it seems to be one of the primary drivers, and it seems to be why we’re seeing an increase in chronic disease because our diet is really inducing excess insulin signaling, and it’s why we see increased rates of cancers in people with the insulin resistance. And it’s a big factor with obesity. If you’re obese, you’re more likely to get breast cancer or prostate cancer, colon cancer, and many other cancers. So it’s a really interesting complicated story, but I think it’s like what is the right way to approach this? Should we be trying to reduce growth hormone as we get older? Is this something that we should be targeting saying these centenarians have lower IGF one and lower growth hormone. That seems like an interesting avenue for potential

Dr. Nir Barzilai:
Research. So by the way, metformin lowers IGF one. So for example, metformin does it. Not every drug is doing, but I gave the example, there’s already an FDA approved, no, it’s not FDA approved, but there’s IGF receptor antibody in humans that, so we have that. It’s safe. It was used in trial, and it’s kind of available to think about therapy for aging. So one of the thoughts that we had even in our study, it seems that the major benefactor for low IGF is women who had cancer in the past or tumor, any kind of tumor in the past, when they have low IGF one level, they kind of live forever. So the question is, should we women after breast cancer, which by the way they age, okay, another reason to have RO therapeutic is to treat cancer survivors. We give them chemotherapy and radiation, we accelerate aging, and then they’re older. So for example, should they be receiving IGF antibody? I talked with the companies that are doing that as an ideal, but unless aging will kind of be more an FDA approved indication, I think the pharmaceuticals are very reluctant to start doing that. Another thing that lowers igf, just that I know those fasting regimens are also lowering IGF, some of them,

Dr. Mark Hyman:
Well, because lowering insulin signaling, but other things, exercise and keeping metabolic healthy and actually reducing sugar and starch in your diet also, will that reduce IGF one as well?

Dr. Nir Barzilai:
I don’t know if it does much of it. I don’t know if it does as much. I don’t know. I have, if

Dr. Mark Hyman:
You become more insulin sensitive, do you have less IGF one?

Dr. Nir Barzilai:
Well, not necessarily. It’s from an insulin signaling. They share a hybrid receptor. But from a clinical point of view, the relationship between insulin level and IGF one are not really great. So I’m not sure. I haven’t seen a study that I can quote even though it’s

Dr. Mark Hyman:
ING question. Interesting. Now I want to talk about something else that you found in your super ager research, and that has to do with some of the other common traits that they have. You mentioned the really low levels of IGF one, but they also had high levels of HDL or high density lipoprotein cholesterol, which is people refer to as the good cholesterol, but there’s no good and bad cholesterol. There’s just different functions of the cholesterol. And I remember years ago I had this old guy who was like a pathologist from Quest Lab who came, gave a talk and he said, I realized we have all this data on people and we really don’t know what the phenotype is because we just get their lab data. We don’t know actually what happened to them. He wanted to research what affected longevity, and he decided to look at HDL.
And he basically went and found all these people who had a high HDL in the Quest database, and then he tracked all their death certificates. And he found this incredible correlation between high HDL and longevity now, which is fascinating because when we looked at certain drugs that are the CTP inhibitors and others that actually seem to raise HDL, they actually have the opposite effect. So naturally having it may be good pharmaceutically, elevating it may be bad. What’s your thought on this whole thing? And there’s new versions of these drugs that are about to come out as well that may, we don’t know. So I find it very fascinating. And I think the things we do know is that sugar and starch lower your HDL, and that exercise increases it and good fats, and also like coconut oil and saturated fats will increase your HDL. So we know some ways to modify it, but I’d love to kind of hear your perspective on

Dr. Nir Barzilai:
This. Right. So we discovered very common genotype, but by the way, what I’m describing are functional genotypes that we know there are lots of snips that they’re everywhere, and we don’t know if they’re functioning. I’m talking about functional genotypes. And we found functional genotypes on the CTP. That’s one of the gene that control those cholesterol, HDL, lower triglycerides. And another thing in a gene called APO C3. And the pharmaceuticals was very interested in our research. And actually Merck has developed, Pfizer failed another, Pfizer didn’t develop a right drug. It was a drug problem. It caused hypertension. It was something else. Merck developed a CT P inhibitor and a company that, what’s their name? They used to be isis, but then they had to change the name, the Ionis. Now Ionis develop an antagonist to APO C3. Both are changing. And by the way, they didn’t develop it for longevity. They developed it for lipids.

Dr. Mark Hyman:
And APO C3 will have, your triglycerides will go up if you have APO C3,

Dr. Nir Barzilai:
Right? No, right. But our genes are inhibiting the CTP and the APO C3, they have to be lower. And so those drugs that are inhibiting, those are coming out to the market with Merck. One of the interesting thing, our centenarians who had this mutation in CTP, they’re distinct from other centenarians because they had an incredible cognitive function. This was better even than heart disease or anything else

Dr. Mark Hyman:
If they had lower A OC three functioning.

Dr. Nir Barzilai:
And so I asked Merck on the CTP, I asked Merck when they did their study to look at cognitive function, and they didn’t have any association, but I think that they had the wrong population with the wrong test. If you do cognitive function on 50, 60 years old, you’re not going to get much change in cognitive function. You need some for the test we have. You need some other population. So I’m still thinking that this CTP will come in, people will start thinking about it, and I’m thinking, when this CTP will come in, I’m thinking I’m going to take it because the cognitive function signal was pretty amazing.

Dr. Mark Hyman:
It’s interesting. I actually have done my genes and I have the good version of the CETP and the bad version of the A PO C3, and it tracks my HDLs higher, and my triglycerides are also higher than I would expect given my diet and lifestyle. I mean, they’re not stupidly high, but I’m like, why is my triglycerides a hundred given what I eat? And I can get it lower. But it’s just so fascinating to see how we’re going to be able to track our genotypes and then see what works for us and create this personalized approach to health and longevity, which is where it’s all going really fast

Dr. Nir Barzilai:
In a total surprise. I have one by 23 and me, I have one of the IGF receptor genotype that I

Dr. Mark Hyman:
Published. Oh, okay. So you’re going to be doing this a long time then, huh? We’re going to keep going. We’ll do another podcast when you’re a hundred.

Dr. Nir Barzilai:
Yeah, let’s do a deal like this.

Dr. Mark Hyman:
And the other thing that you found was something else that was in the super ages called high levels of MDIs. Can you explain what are MDIs, what that is, why it matters and what you found?

Dr. Nir Barzilai:
So this is kind of a surprise, and I have to say I have a guy, the dean of gerontology at USC. We went to medical school together. By the end of medical school, we published together like eight papers. And we are collaborating ever since, though he’s a pediatrician, but he’s the head of gerontology now because I influenced his life so much. But we were looking, we had a grant together and he was looking at partners for not the IGF, but there’s IGF binding proteins. It’s a

Dr. Mark Hyman:
Complicated Yeah, IGF p3, right?

Dr. Nir Barzilai:
And he kind of fished a peptide that eventually was known as human in. Human is coming from the genome of mitochondria. So we have at some point of evolution, early evolution, our cells were kind of miserable and pathetic and we needed some energy and we got this bacteria and mitochondria is really SI of bacteria. And we adapted to be symbiotic, and that’s the source of energy. But those mitochondria and we often forget, have their own genome,

Dr. Mark Hyman:
DNA, right? Their

Dr. Nir Barzilai:
Own

Dr. Mark Hyman:
D. And this comes from your mother,

Dr. Nir Barzilai:
It comes from your mother, right? It has your own DNA, and also it has mutations on your DNA. But it’s not only that this DNA produces peptides that eventually you can measure in your blood. And when you give those peptides, they do stuff. So human in is one. So we started actually a company to try to develop at least good part of the things when you develop those peptides, when you develop the peptides, you actually have to have them act longer and you have to find things that are more with higher efficacy and stuff like that. So we developed a bunch of those peptides. And on the way we found really interesting things. I’ll give just one example. One of the peptides that we developed, we looked at genome of Asian, Korean, Chinese, Japanese, and they had 8% of them had mutation in this peptide.
And when Hasi measured those peptide activity in the lab, they weren’t so active. Now those people, those 8% had 30% increasing risk of having diabetes. So by the way, genetics is so important now because two thirds of the drugs that FDA approved last year were based on genetic studies. It’s no longer that you work on mice or nematode and say, let’s develop a drug. It doesn’t work anymore. Regeneron, all the pharmaceuticals, they want to see population that have overactivity, underactivity of this peptide and have a disease. And then you can develop the drug fast and more effectively. So it’s very important for us to get signal from population that also showed you that, by the way, it’s called motzi, this gene. So it’s very important to show that there’s relationship between genetic study and actually diseases in humans. So you have more confidence that there’s a causality here.

Dr. Mark Hyman:
Yeah, so interesting. A lot of people are using peptides now, like motzi human in, and you mentioned earlier when we were chatting before the podcast that MOTZI can be helpful, but then you develop antibodies to it, which may have other adverse effects we haven’t understood. So a lot of people are playing with peptides. Do you think it’s safe? Do you think it’s risky?

Dr. Nir Barzilai:
No. Look, I understand frustration of people, and I think that the frustration leads to shortcut. And when you say maximize your exercise or diet and stuff, you’re not really causing harm usually. But when you’re taking peptides that you don’t still understand everything about them and you manufacture in a way that’s probably doesn’t make sense. They’re companies that are happy to give you these peptides. But actually, for example, in the Mo Sea, it was hard to find actually a solution that will hold this mo sea without getting them to clink together. And we couldn’t get them any blood level. So there’s so many things with those peptides that you cannot assume I’ll order a peptide and inject and it’ll be thing. I think it’s, it doesn’t make sense from this sense. And then it can be dangerous because we don’t know how much, and generally drugs, there’s too much for drugs and too little for drugs. So I think it’s a wishful thinking. And I wish, look, we are playing, we, both of us, I mean, we went to medical school and the first thing they teach us is do no harm. So we are conservative, we belong to the half that will actually do something for people. But most doctors,
Let’s do no harm. So let’s not. And then by the way, the next day they teach us rightly that there’s no always a never in medicine. So what about using a drug that saves a hundred people and kill three? How do you weigh it? Yeah, exactly. I, it’s important for us to stay conservative. It’s important for us to say we need clinical studies. We need a real development and kind of stick to it, because otherwise, I think the chances of doing harm are really

Dr. Mark Hyman:
Much. And it’s so personalized too. I mean, I just remember a story of a young man, I think his name’s Fagan Bottom, who basically was a medical student and developed this very rare cancer. I forget the name of it. And there was no treatment for it. You probably know this guy. And he, he’s basic, and he was this super fit football player. And then he just became emaciated, went through multiple brands of chemo. They told him he was gone. He was just ready to get his affairs in order. And he decided, well, I’m a medical student, I’m going to start to research this. And he looked at the proteins expressed in his blood and used very basic scientific techniques and found this huge spike in mTOR. And he was like, mTOR is good because it helps you build muscle, but overexpression can cause overgrowth not just a muscle, but of cancer cells and other things. And so he said, well, I’m just going to try rapamycin one of the drugs that actually inhibits mTOR and it completely cured his cancer. And he’s amazing, healthy, great guy now. And he continues to take this drug. So it speaks to some of these pathways that are at the root cause of cancer. He’s not taking chemo. He wouldn’t do radiation. He didn’t do surgery, but he used sort of molecular medicine to understand what his particular tumor was doing and what he could do to modify it. So I think we’re just incredible

Dr. Nir Barzilai:
Story. It’s an incredible story. I forget the name of this guy, but incredible

Dr. Mark Hyman:
Story. I think it’s Jason Fabo. He wrote a book. It’s great. So I think that’s so important. So now I want to sort of shift to talk about your work around metformin because I think it’s really interesting. And I think as we talked at the beginning, there is no silver bullet or there’s no magic trick here that is going to fix everything. And I think people are always looking for, what’s the pill I can take? What’s the supplement I can take? What’s the peptide I can take? It’s going to fix it all, and I don’t have to worry about what I’m doing and how I’m living and whether I’m drinking or eating bad or exercising. And that’s really not the purpose of this, but you’re doing something that’s really important, which is you’re doing a very rigorous clinical trial on a compound that seems to have some evidence that it may improve many of the biological factors in the hallmarks of aging.
And this called Metformin, which is a drug developed in 1957 to treat diabetes. It’s been around for a long time and it’s one of the first line therapies for it. And you’re doing this not just to study metformin, I think, but you’re doing it to actually show that we can treat aging itself. And if this is successful, which I hope it is, I think it will shift the whole field of the NIH and of the focus of longevity research, which is what I hope it does. But I kind of want to just sort of set the stage for a minute and talk about why we think this is so, and I think there was a paper in 2014 with 78,000 diabetics who were studying this group on metformin versus non-diabetic controls. And it seemed that there was about a 15% lower survival time in people who were not taking the metformin. And there were some challenges with that study. There was another study published in 2022 that was another observational study, but completely contradicted that study, which was the Danish registry case control study where the metformin monotherapy group increased mortality, I think by 50 something percent compared

Dr. Nir Barzilai:
To nondiabetic.

Dr. Mark Hyman:
Yeah, compared to non-diabetic. So one study showed that if you were a non-diabetic, your risk of death was greater if you weren’t on metformin. And the other study showed the opposite in quite a significant way. So I think that’s kind of like it needs to be answered, and this is why you’re doing this clinical trial. Well,

Dr. Nir Barzilai:
No, look, I think that was a destruction. I think it was a discussion. But let me say first I want to correct something.

Dr. Mark Hyman:
Oh, please. 20

Dr. Nir Barzilai:
1920s and 1950s. Okay. Metformin is an extract of the French lilac, so it’s kind of nutraceutical, but it’s not. It’s modulated. You need a prescription, actually, you don’t need the prescription. You can go in Amazon and get it for a lot of money. Really, it’s not a lot of money, but it’s 10 times more than it costs. And at that time, why did people use it? Because people noticed that people who takes this French lilac extract, it was treating arthritis, it was preventing fluid. It was even preventing malaria. It had lots of benefits. And at that period, people noticed that people who had diabetes and took this drug, it lowered their glucose. So it was kind of hijacked for diabetes, but actually it had all those other properties that were ignored. Now since it’s used for 80 years for diabetes, there are lots of other studies that showed, and by the way, without studies have showed that it prevents mortality in variety of studies. Okay, I’ll get to those studies. So in clinical studies, those that you mentioned are not clinical studies, they are association studies.

Dr. Mark Hyman:
Yeah, they’re just population studies where they look for correlation, but it doesn’t prove cause and effect. And they showed the opposite.

Dr. Nir Barzilai:
So clinical studies, there was the UK PDS, there’s lots of evidence that metformin decreased mortality, but even or supporting of that, people on metformin have less. First of all, there’s the DP, they had less diabetes. Non-diabetic patients get less diabetes. People with diabetes have less cardiovascular disease, they have less cancer, they have less cognitive decline, they have less Alzheimer and a big effect in clinical studies. So for me, it’s not about proving metformin, it’s not that at all. The reason I’m doing tame is for the other reason that you said we have to show to the FDA that we target aging, the biology of aging, and we prevent age related diseases.

Dr. Mark Hyman:
Yeah. The study is called tame targeting aging with metformin,

Dr. Nir Barzilai:
With metformin. And really the idea is not to repeat the studies that were done. And by the way, because metformin is FDA approved, so it’s safe because there are so many other studies. A lot of doctors are repurposing metformin based on data that they have.

Dr. Mark Hyman:
I allow a lot of people who are taking metformin for longevity. And I

Dr. Nir Barzilai:
Exactly. Metformin is repurposed for PCOS. Metformin is repurposed for pre-diabetes, which all of them are not FDA indication. We repurpose drugs all the time. So the idea is to show the FDA in a clinical studies that a cluster of diseases that include cardiovascular disease, cancer and cognitive will be delayed or prevented in a certain period. It’s a hard concept in the sense that we are saying we’re targeting aging, so we are agnostic to what disease you’re going to get. If your mother was diabetic and you are obese, you’re going to get diabetes. But I don’t know, we’re going to change your aging. And for every disease that you’re going to get, you’re going to get the point over time, and we’re going to show that metformin will delay that based on existing study. So it’s all about how we prove to the FDA that aging is that we can prevent

Dr. Mark Hyman:
Treatable. It’s treatable,

Dr. Nir Barzilai:
Right? Well, we can prevent diseases. And by the way, they agreed, they don’t buy that we can do something with aging. But they said if you have a trial that shows that you can prevent all those old related disease, you should bring it on. And we don’t care. We kind of don’t care to call it aging a disease now because we know what to do. But this is really the main point. But it has consequences. First of all, this is there were really great team that planned how to do this study, and this is a template for the industry. You don’t need many patients If you were developing a diabetic drug, now you needed 12,000 people in a cardiovascular study. Also, to prove safety, we’re talking about 3000 people between the age of 65 and 80. Because we’re not looking at diabetes. We’re looking at every disease basically.
So you’re going to get one after 65, you’re going to get one no matter what. We need only 3000 people. The second thing is pharmaceuticals are waiting for that in order to jump in and get into buy those biotechs in aging and develop drugs because they need an FDA route, they need a business plan and business plan developed with FDA. And also for us, healthcare providers don’t have to approve any drug. That’s not FDA approved. Now, it’s easy with metformin because it’s the cheapest drug in the US formulary, but for industry, no doubt that some of the first drugs that will come will be as expensive as GLP one now, right? As any drug for a few years. But for the public, having metformin is going to be really an advantage immediately.

Dr. Mark Hyman:
Yeah, I mean, I think it’s important. I want to talk about the mechanism of action because as we sort of talked about earlier in podcast, about how all the hallmarks are connected and how there’s so many redundant pathways and how affecting one of these pathways can affect other pathways. So from my understanding, the main action that we understand of metformin is to activate one of these, I call ’em longevity switches, the deregulated NU and sensing pathways. And one of them is A MPK, which detects low nutrient energy levels in the body. And when you activate that, it creates a cascade that inhibits inflammation, that activates sirtuins, which improve DNA repair and improve mitochondrial function and inhibits mTOR and maybe has other mechanisms of action in the microbiome, which may be interesting to me. I know how that exactly connects into all this. Maybe the mechanism is that it optimizes your microbiome.
So I’d love you to talk about some of these. And I also want to dive into one of the, what I think are potentially a risky aspect of metformin. The things I just mentioned are all positive that all beneficially impact the hallmarks of aging, but it’s the inhibition of something called mitochondrial complex one. And this is one of the most important steps in producing energy in your cells and to build muscle. In some of the studies I’ve seen you actually giving metformin will limit or prevent any increase in muscle mass and muscle density gain when you take metformin and you exercise. So if you do weight training, it kind of blunts the effect of weight training, which kind of is worrisome to me as I think about frailty and aging and building and keeping muscle and preventing sarcopenia. So maybe you could talk about some of these mechanisms, how they all interconnect, how you think they influence all these phenomena of aging. And then maybe chat a little bit about this concern that I have and whether I’m right or wrong.

Dr. Nir Barzilai:
So I think it’s best maybe that I’ll give an example and follow it because I got involved in that at a certain time. So when you take a group of 75 years old, and this is a study by Charlotte Peterson in Kentucky, and she had the grant because she said if I exercise and give metformin, I’m going to get even better response. And so she took those 75 years old, half of them exercised, the other half also exercised, but they were also on metformin. And by the way, when they exercise, whether you’re on metformin or not, you build up more muscle, but you build significantly less muscle when you’re on metformin.

Dr. Mark Hyman:
This is the master’s trial you’re talking about?

Dr. Nir Barzilai:
Yes, the master’s trial. So basically the paper was like metformin inhibits muscle size. So that’s where scientists have to come in because I’m reading the paper with interest, including all the supplements and supplement two shows that they also did an assessment of muscle function for different things. And those four different things were not different between the people on metformin and without metformin. So if the people with metformin had bigger muscle, what does it mean? Does it mean that really for every gram of muscle, metformin is actually doing better? If we think in the Einstein way, that’s really what it means.

Dr. Mark Hyman:
Wait, I lost you there. Can you kind of explain that again? I didn’t make the connection.

Dr. Nir Barzilai:
If you and metformin have smaller muscle but you have the same power, then every gram of muscle is better.

Dr. Mark Hyman:
I see what you’re saying. So you don’t lose muscle function, but you lose muscle

Dr. Nir Barzilai:
Mass. Okay, so then I said to Charlotte, can I look at the muscle? And I did several things with the muscle, including the transcripts and the transcript shows. I think what we kind of knew

Dr. Mark Hyman:
The transcript is basically all the things that are transcribed in the proteins, right?

Dr. Nir Barzilai:
I’m sorry, I shouldn’t assume, but

Dr. Mark Hyman:
I’m a doctor. I get it, but I don’t think anybody was on transcript.

Dr. Nir Barzilai:
No, I know

Dr. Mark Hyman:
It’s a written transcript of a paper. No, it actually has to do with the DNA replication and transcription of proteins. Yeah. So

Dr. Nir Barzilai:
This is where the paradox is in order to build muscle, you need mTOR. Okay? So if you need mTOR, you already know that if you use rapamycin, which is a strong mTOR inhibitor or metformin, which is also a major inhibitor, which is really important for the aging of maybe the rest of your body, you’re going to pay with a muscle. So we showed on one hand that the transcript of mTOR related genes are really decrease. On the other hand, we found that other genes that are important for aging, such as for autophagy and for inflammation of the others are getting better. So basically you have a muscle that is smaller but is better in quality when you’re

Dr. Mark Hyman:
Interesting.

Dr. Nir Barzilai:
Look, I think the reason that’s a controversy, and so by the way,

Dr. Mark Hyman:
Well just mitochondrial health is such an important feature of healthy aging. It’s one of the biomarkers mention of aging look

Dr. Nir Barzilai:
Targeting. So metformin does what you kind of described, let’s call it the metabolic, the MP kindness pathway. By the way, metformin works also when in animals they don’t have a MP kindness. Okay? It’s kind interesting, weird. And metformin also ends when you don’t have mitochondria in a row zero cell. So it’s really much more complex because it’s doing some things. But what happens on the mitochondria, yes, you increase the transport of electrons and by that you also decrease oxidative stress. And in this pathway you also decrease inflammation and other parts. So actually it’s important, but it’s also important for another reason because if you look at VO two max, which is a really good tool to assess your health, if you have mitochondria,

Dr. Mark Hyman:
Lemme just stop there. I want to tell people what that is. That VO two max is basically a measure of your fitness and the higher it is, the longer you live. And it’s really basically a measure of the function of your mitochondria and how quickly they can consume oxygen, how much energy they can burn in a minute. So Lance Armstrong has a very high VO two max, whereas a diabetic might have a very low one. And it’s really a reflection of your mitochondrial health and your fitness and it’s directly tracked longevity.

Dr. Nir Barzilai:
And this marker for metformin is not good because you have to understand, we’re not acting, we’re not on a VO two max in our life. It’s like you come from metabolism. Remember we used to talk about insulin sensitivity and insulin responsiveness. Insulin responsiveness was take the insulin level to thousand microns per ml not relevant to our life and see how much glucose you can actually push them to the muscle, which is not as relevant as let’s get your insulin level to a hundred microns, which is like after meal and see what’s your sensitivity in. And you can have the increased response. I think the same thing people are not thinking about, but VO two max, I think metformin is doing lots of things. It doesn’t prevent you to exercise. If you want to check if your VO two max, I think you’re not going to be at VO two max if you have a good metformin, but I don’t think this is really a measurement of health when you are in this drug, just like as you are not going not to take rapamycin ever because they inhibit muscle.
I think the more important point here is that when you are young, when you are old, those things help repair rapamycin and metformin, they touch a lot of the hallmarks. They have repair when you’re young, they’re going to lower your IGF one, they’re going to lower your testosterone in several instances, all those things that we don’t or your exercise capacity or your ability to do pushups and weight. So I think it’s very different how we think of those drug when it comes to old body and to young body. And yes, they’re tradeoffs. There’ll be tradeoffs.

Dr. Mark Hyman:
I’ve heard of some people saying, I’m not taking metformin on the days I do my string training. Does that make sense?

Dr. Nir Barzilai:
I know. Or the same hour or hours. Look, this is my spiel. The major side effect of metformin is that you might leave longer

Dr. Mark Hyman:
And

Dr. Nir Barzilai:
You might not be able to afford it or something. But those drugs have good because yeah, if you are a sport medicine, if you’re Peter Atia, then all you care is the muscle. But metformin just like exercise. Exercise is not about the muscle. Exercise, improve cognitive function and immune function and other things. So yeah, I’m not sure Metformin is good for bodybuilders, but it’s also good for other things outside of the muscle.

Dr. Mark Hyman:
Yeah. Yeah. That’s fascinating. That’s fascinating. So it’s such a nuanced story and you are right. There are so many benefits of metformin that are, we call pleotropic when a drug typically in medicine we think of a single drug with a single target. And anything we don’t like is called the side effect. It’s not really a side effect. They’re just effects of the drugs. We may not or that we may, in this case, when metformin has all these side effects that are beyond lowering blood sugar that actually may extend our life, which is so exciting. So I’m very, very excited for the TAME trial, I think.

Dr. Nir Barzilai:
Sorry, I just wanted to, before you move from foreman.

Dr. Mark Hyman:
No, I’m going to keep going. I have more to say about it. But you go ahead.

Dr. Nir Barzilai:
I just want to go back to, you started by those two studies. There were not good studies. And I have to say I populated the first one I populated because it was cool. I knew that it’s not a good study, but I thought it’s kind of study that you show that people with diabetes on metformin might live even longer than people who don’t have diabetes. The dentist study was a different study, a

Dr. Mark Hyman:
Twin study. Yeah.

Dr. Nir Barzilai:
But one of the, okay, there are few problems that we should know. First of all, the study didn’t show the mortality of people on metformin, diabetic people on metformin versus not on metformin, which is for me, because yes, when you’re diabetic, you’re running into more problems. So just show first you have the data, you have the registry. And I know that they showed that there is less mortality that they just didn’t want to put it in this study. But the reason there’s difference in my mind, and by the way, the twins, the problem with twins, the twins a lot of time are born low for gestational age. In fact, one twin might be born is usually born smaller than the other twin. And this is kind of the barker hypothesis. Those twins, those small for gestational age can run into aging rather quickly. They get diabetes, they get hypertension before others.
So the twin study, if you don’t adjust for birth weight, I’m very skeptical, is skeptical about it. But I think the major reason for the difference, I mean there are so many differences, but I think the one that explains a lot, one is in the UK where at that time obesity was 20% in the population, of course all the diabetic were obese, but also 20% of the other population were obese. When in Denmark, the rate of obesity was 10%. So basically it means that the Danish diabetics are obese when the rest of the population is not obese. So you took one of the risk factor that would adjust through insulin resistance and other right

Dr. Mark Hyman:
To those. So it’s the devil’s in the details. And the problem is most people just get the headlines in the newspaper and often the headlines get it wrong. And I read one study in actually the New England Journal, but abstracts don’t represent what’s in the body of the paper over half the time anyway. So it’s like it’s hard for the average person to make sense of it all. Well,

Dr. Nir Barzilai:
An example that’s relevant to metformin, and actually it’s a very important example. Look, there are nine studies in the Covid times around the world that people on metformin in half hospitalization and after deaths, and then there’s a New England Journal clinical study where they gave metformin to people within three days of getting covid. And it prevented 40% hospitalization, 40% death. And then there’s a follow-up study in the Lancet that it prevent long covid by 50% of. Well,

Dr. Mark Hyman:
It is interesting mechanistically because one of the drivers of that is uncontrolled inflammation. And one of the mechanisms of action is it inhibits this transcription factor, this thing that causes your genes to be expressed called NF kappa B, that influences cytokine production, which is a cytokine storm inflammatory signaling molecule. So basically if you take metformin, you’re inhibiting the driver that causes your genes to produce all these cytokines. So maybe that’s the mechanism, I don’t know

Dr. Nir Barzilai:
Way more than that because it has effects on the immune cells on inflammation, but on the immune cells. But it also affects the whole body to sustain a terrible heart disease. When you’re old, you need a body for that. But I think it makes the point that we talked about metformin and muscle and stuff like that, but look at metformin and covid. If you take it within the first three days, you can do much better.

Dr. Mark Hyman:
Interesting. Yeah. Okay. Well, I want to talk about a few more things about Formin. I’m not done yet. Okay. And you’re the guy. So while I got you, I’m going to ask us about the microbiome effects because I’ve talked to some folks about this and I think there’s some research in Israel around this and how maybe the impact on our gut and our gut microbiome may be playing a big role in some of these benefits. Can you share what we know about that and what it does to our microbiome?

Dr. Nir Barzilai:
Yeah, I totally agree. I think it’s a potential important link, but by the way, I’m kind of the fence with microbiome and the aging aspects.

Dr. Mark Hyman:
It’s one of the hallmarks of aging now, right

Dr. Nir Barzilai:
Now, changes in the microbiome. It just made it to a hallmark of aging. And I think it’s maybe not strictly, it’s not strictly my definition, but certainly I don’t think there’s enough models that show that you can increase survival with any manipulation of that. But there’s certainly a study that showed that people on metformin had a change in their microbiome that had a benefit effect. There’s more to the study than that. It’s very compelling. It’s not only metformin, which is another drug that in human prevents mortality, not related to diabetes, also has effect on the microbiome. So I’m pretty sure that microbiome are important, but that’s kind of the thing we are saying. Is the microbiome changed by metformin in the gut or is it changed by metformin in the body? Because metformin changes all the hallmarks of aging, so it changes microbiome. So is microbiome a bystander? Is it important? It’s kind of hard in this way to depict, but I want to say that there are drugs that change the microbiome, and I’m convinced that microbiome has a role. I don’t totally get it, but it has a

Dr. Mark Hyman:
Role. Have they mapped out the particular bacteria bugs that actually are increased or improved? Akkermansia, for example, is

Dr. Nir Barzilai:
Metabolic. They had the whole genome. It’s an old paper already, and there’s more sophistication and maybe more studies of the, it’s really not about the type of bacteria, but their metabolic profile. What’s the metabolite that are actually absorbed into the gut? Things like that. So I think there’s more sophistication, but I would take it as a fact that metformin changes microbiome.

Dr. Mark Hyman:
Okay. Now I want to play devil’s advocate for a minute here and challenge a little bit the theory of metformin. Because there was a study that was done, very famous study called the Diabetes Prevention Trial, and it was decades ago, but it showed the impact of lifestyle compared to metformin compared to nothing for preventing the progression from pre-diabetes to type two diabetes. It was about a thousand pre-diabetics. And they found that if you took Metformin, it reduced the progression to diabetes by about 31%. If you did a lifestyle intervention, which by the way, at the time, and I knew people were in the trial, was a low fat intervention, which is not the diet you want to put a diabetic on, but they had other things like exercise and social support and so forth. They reduced the progression by 58%. So in this case, I’m wondering, is it possible to achieve all the benefits that we get from Metformin and even more benefits with more aggressive lifestyle intervention? And do we actually need metformin? You’re

Dr. Nir Barzilai:
Assuming that they’re doing the same benefits and not different benefits. But look, first of all,

Dr. Mark Hyman:
And I understand there’s all these other kinds of influences, Metformin, besides blood sugar and diabetes,

Dr. Nir Barzilai:
And let’s agree that exercise, all the lifestyle, exercise, diet and stuff have a major impact and could be maximized at every time. Okay, let’s agree on that. This is my question. Look, I’m a diabetologist. I’m actually on Thursdays. If I’m in town, I’m seeing patients, okay? I’m not a geriatrician, I’m a ologist. And so psychologist 30 years in my clinic, and it’s a fellow clinic. So I see quite a lot of patients. So first we tell them, okay, diet and exercise, we send them to diet stuff and we tell them how to exercise. How many people are doing that? 3% in the Bronx. Okay. I’m sure you have more success. Well, sure.

Dr. Mark Hyman:
I mean, it’s not whether it works or not, whether you do it or not. Well, you have to take metformin in order for it to work. If you don’t take it, it’s not going to work. Right?

Dr. Nir Barzilai:
Right. Exactly. Diet. And I’m thinking, who needs metformin? Who needs metformin urgently? It’s not us. Okay? Because we know how to deal with our health. It’s poor people. Poor people are obese. Poor people don’t have access to exercise. You don’t give them money to buy trade off or to get into gym because they don’t have gyms for nutrition. You want them to have more vegetables. Well get them more vegetables. You want ’em to have more fish. They don’t like fish. So actually with Scott, with Andrew Scott, we did kind of this how many dollars metformin versus what you need to do to change lifestyle for a population. It’s one, 200,000.

Dr. Mark Hyman:
Maybe I have a different theory, but Yeah, I hear you. I hear you. I hear you.

Dr. Nir Barzilai:
Yeah. So I think we need Jira protectors and Jira protectors will get better and they’ll get in combination and they will enable us to go beyond the lifestyle. I have no doubt about that. And it’s a consideration, but I wouldn’t look. DPP was here in this area too, and I’m more used to show that, if you should say, does Metformin work on non-diabetic? Well, the DPP was non-diabetic. They were at increased risk, but they were non-diabetic. And it’s a 30% effect and a 30% effect of every drug is pretty incredible. And the lifestyle intervention of the DPP was amazingly, it was very, very expensive. They did have to go to the gym to train them, to give them food, things like that.

Dr. Mark Hyman:
We actually actually created a program. I did a program with a Cleveland clinic at our center, which is a lifestyle change program. And we actually measured the cost of the program compared to conventional care, the outcome improvements. And we basically saw it was three times as effective and more cost effective by doing shared medical appointments essentially. So there’s ways of delivering care and doing things that I think are not what we normally do that actually work. So it’s not that we just haven’t figured out how to get people to do their thing, but that’s a whole nother conversation. The other thing I wanted to talk about is for someone like me or asking for a friend, my insulin levels too. My lipids are perfect. My body fat’s 10%. I exercise all the time. I eat perfect, have a low glycemic diet. Am I going to get added benefit from taking metformin or have I already kind of tuned things up? Is there something that I should be thinking about? I want to live for a long time, and I’m sort of on the fence about it, and you don’t have to answer, but I’m just like someone like

Dr. Nir Barzilai:
Asking

Dr. Mark Hyman:
For a friend.

Dr. Nir Barzilai:
I’m making point that I’m a data person. No, I don’t have a data. And I wouldn’t really recommend you unless you get into some trouble. If you tell me I’m worried about my cognitive function in spite of everything, I would say, maybe you should consider rapamycin metformin or something else that’s coming. But no, I wouldn’t look, it goes back. Your biological age might be less than 50, right? It’s

Dr. Mark Hyman:
43. Yeah, so

Dr. Nir Barzilai:
So why would you take metformin? That’s my point.

Dr. Mark Hyman:
And

Dr. Nir Barzilai:
It’s not age. It’s the biological

Dr. Mark Hyman:
Thing. Right? Interesting. Yeah. So I think it’s interesting. I think we’re clear. Someone has metabolic health issues. It’s not a bad thing to do, and I prescribe it for those who need it. I think I’m not yet ready to prescribe it widely for healthy people who are looking for a longevity benefit. I want to see what the tame trial shows. So I’m holding out, so hurry up on that. The other thing I wanted to just bring up is other ways that we can have similar effects. And maybe I’m out of school here, but you mentioned that Metformin was from this French lilac, and we know there’s a lot of things that actually also influenced the same pathway, A MPK, which has all these downstream benefits. We talked about obviously exercise, saunas, various phytochemicals, and there are a lot of things that have been found to have similar benefits to metformin like saffron, berberine, resveratrol, ginseng, resi, mushrooms, artemesia, black human seed, bitter melon, which is like a Chinese food tangerines, chlorogenic acid from coffee, capsaicin from peppers. So I mean, if we start to include all these phytochemicals as a way of regulating A MPK, you think that might have similar benefit? Can we start to look at those things?

Dr. Nir Barzilai:
Okay, so I’ll tell you my worry, and I’ll give an example. If let’s say you take metformin and rapamycin and you increase the dose and you stop mTOR.
So for example, your plasma cells are totally mTOR dependent. Okay? So what I’m saying, if you add, we are assuming that if you have those longevity nutraceutical or drugs and you’ll add them to each other, they’ll be additive or synergistic. And in fact, I’m afraid that a lot of them will be antagonistic. Interesting. Or you’ll get, and my worry is more our friend Brian Johnson, who takes 115 supplements, and we measured our green age together. And I’m three years younger than my age. He’s four years younger than my age, but I’m not doing 115 supplements. So I think he’s paying off. I think the supplements are problem. I always say they’re great for the economy, okay? They’re great for the economy. They drive a lot of business. But I would say that we don’t know enough, not about the supplements, but how you add them together. And at what point, I said before, every drug, if you take a lot of it can be of a problem and can be a problem with a specific person. So I would just say, yes, we need clinical studies, we need more clinical studies even in animals to show whether it’s additive or antagonistic exercise and metformin are antagonistic on the muscle, right?

Dr. Mark Hyman:
Right.

Dr. Nir Barzilai:
We have those examples. So I think it’s a good question. There are all those things, and my worry is that people just wrote down the list and they’re buying everything.

Dr. Mark Hyman:
No, don’t do that. Don’t do that. Don’t do that. No. The point is that there’s so many natural compounds in our food, and I think you can’t get into trouble if you eat all these things. If you have bitter melon in your diet and you have saffron in your food and you have coffee in the morning, these are not going to be problematic. It’s when you’re taking pharmaceutical doses of these things that you’re going to get in trouble. I also just want to, God, I’m going to want to talk to you forever. I know we have to end soon, but what are the top jar protective molecules and drugs that are under research Now, I think you’ve obviously focusing metformin, but there’s NAD, there’s rapamycin. What’s your take on what are the most promising things out there?

Dr. Nir Barzilai:
So we published, and now I’m submitting another update paper. We did a paper on repurposing FDA approved drug that showed to increase longevity in mammalians, not in nematodes

Dr. Mark Hyman:
On worms, humans, power mammals, right?

Dr. Nir Barzilai:
We have a scale of 12, six belongs to the RO science, hallmarks of aging lifestyle and health span of animals, and six are human. And the four drugs that are, and this will surprise you. Metformin comes only second. Okay? The first drug is SGLT two inhibitors. SGLT two inhibitors is a fascinating story, but in short, it’s developed to diabetes. Basically you peers your sugar, and that’s why your sugar will be okay, but for some reason, people notice with whether you’re diabetic and then non-diabetic, when you take it, you get less kidney disease, less heart disease, and decrease overall mortality. Checks out everything. You give it to animals, they live longer. Okay? So GLT two inhibitors actually, and I’m kind of considering maybe to switch from metformin to that for a while and see what happens. I think this is, and by the way, I’m taking it, I was pre-diabetic and I really benefited from it. But because you are not taking, I didn’t want to say, just wanted. And the second is metformin. The third is etidronate or bi phosphonates. Bi phosphonates is a guy. Another example is we don’t know where

Dr. Mark Hyman:
Osteo osteoporosis drugs.

Dr. Nir Barzilai:
Osteoporosis drugs. I heard about it the first time because it was a paper. Women in ICU on Biphosphonate, they don’t die. And then they started to test animal. They started to test in human studies and in control studies. And there’s decreased mortality for people on biphosphates, which we don’t understand the mechanism yet

Dr. Mark Hyman:
There a lot. And it’s not just because they don’t break their hip and die from that, no, it

Dr. Nir Barzilai:
Could be action, but the bone has your bone marrow, there’s immune cells. There’s a lot of stuff that happens. And the third that we got is the ozempic, the GLP one inhibitor. Remember when I went into aging, the only model that we had was caloric restriction. We took animals, grew brothers, half of them ate whatever they want. The other were calorically restricted. They lived 40% longer and much healthier like our centenarians. So GLP one is a calor medic, and I would say that obesity drives aging, okay? Obesity drives aging. So to use GLP one, and people are using it creatively. If you’re obese, they’ll give you GLP one for a while and then put you metformin to keep on the way, things like that. But those are the four drugs that should be considered for repurposing in that order. Now based on evidence.

Dr. Mark Hyman:
So the first one is metformin, or what was the first one?

Dr. Nir Barzilai:
SGLT two inhibitors,

Dr. Mark Hyman:
But then the ozempic,

Dr. Nir Barzilai:
The second is metformin, the osteoporosis drugs, and then the ozempic.

Dr. Mark Hyman:
Okay, got it. But the thing about ozempic, I remember this study where is it the weight loss or is it the ozempic? Right? There was a study where they looked at gastric bypass in diabetics, and they essentially divided them into two groups where one group got the gastric bypass and the other group got the diet that the gastric bypass patients would have to eat after they had the gastric bypass. They both had the same benefit, exactly the same weight loss, exactly the same benefits on metabolic health. So is it the surgery or is it the diet? Is it the or is it the weight it loss. And I think that’s important to think about. So just to close, I would love to hear what you’re most excited about that’s coming up in this field. And then two, what your personal regimen is for staying healthy and living a long time, given everything.

Dr. Nir Barzilai:
Okay. So let me tell you, I’m also the scientific director of the American Federation for Aging Research, and I drove three big projects. One is the tame, so we talked about it, okay? This is under the umbrella of the American Federation for Aging Research. The second initiative, we kind of talked about it, but it’s the Super ages initiative. So I have 750 centenarians. Tom Pearls have thousand centenarians. It’s not enough to do validation and to do discovery. So we’re driving to recruit 10,000 centenarians and one of their offspring and somebody who’s married to the offspring, triple things because we have to adjust for the diversity of the population.
So this is a main thing, and it’s important because if you guys, anybody knows of a centenarian, you go to the far web and there’s the super initiative, or you just put super initiative. We are sending the to spit, the DNA, that’s all. It’s a genetic study for now, but it’s a community. The far community is not the sick people. It’s the people who live longer and healthier. So this is a very exciting project. And the third project, it’s called fast. It’s about biomarkers, right? And biomarkers is a hot, hot new topic because we have what we call an omic way to look at them. We don’t measure one biomarker at a time. We’re measuring thousands or maybe hundred thousands at a time. And we have a project.

Dr. Mark Hyman:
You mean DA methylation or you’re talking about something else?

Dr. Nir Barzilai:
No, everything. Proteomic, metabolomic, methylation, everything. And what are strategies to go to studies that already were completed in the four examples that I gave you? SGLT two, Metformin, GLP one, and get samples of the first year of the study before and after, and do all those omics and discover, first of all, what are the biomarkers for aging, different ages, what are the biomarkers of aging? Second, what changed specifically after treatment? Some of it will be specific for the drug itself, but then we’ll have all studies and we’ll ask what commonly changes with aging? Because it’s not only, we’re pretty good at telling you your biological age, but that’s not important enough. We want, if you come to mark to treatment, we want to show that those biomarkers change if they don’t change, and methylation don’t change within a year, or if ever or not, all of them change. So we want to have biomarkers that you will use, and maybe in two months you would see where the trend is. And for longevity, biotech association not to spend money on phase three trial and fail, but get the signals like we get from cholesterol or hemoglobin A one.

Dr. Mark Hyman:
So what you’re talking about are these sort of intermediate things that are easier to measure than whether you get a heart attack, a stroke, or cancer or diabetes or dementia or death. But that actually correlate with these things. And that you’re talking about a kind of network of biomarkers that not just one that we’re going to be using that reflect a larger pattern of dysfunction or function in the body.

Dr. Nir Barzilai:
So we are going to look to use hundred thousand, but we hope that maybe 10 are depicting everything okay. Or a hundred, I mean, it’ll be eventually some are going to be enough. We don’t want everybody to spend a thousand dollars per test, per patient to figure out what is not going to be necessary, but we hope to do reduction. That is significant.

Dr. Mark Hyman:
That would be amazing. It’s sort of like the Immunos project from David Furman where he looked all the cytokines and he found four that were most highly predictive. And if you just measure those four, how close are we to that? How close are we to having a true biological age set of biomarkers that we can replicate and use with our patients?

Dr. Nir Barzilai:
I have an answer in May.

Dr. Mark Hyman:
Yeah,

Dr. Nir Barzilai:
As long as you don’t ask me the year

Dr. Mark Hyman:
By

Dr. Nir Barzilai:
May.

Dr. Mark Hyman:
Okay. May. May, 2050. Okay. No, no.

Dr. Nir Barzilai:
There’s a huge progress in the field. There’s a huge progress in the field. But with the progress comes also problems. Okay? Becomes problems, comes noise. It’s people who are, there are three different kind of people involved. The biologists, the doctors, and the computational people who talks different languages. We have committees that are dealing with that. It’s not as fast. I call this initiative fast. It’s not as fast as I was hoping

Dr. Mark Hyman:
It should be. Like the Manhattan Project for it is so important. I think it’s so important. Well, this is amazing. Okay, well, let’s follow all that. We’re going to track all that, and we’re going to put in the show notes, all of your papers, all the things we’ve talked about so people can follow up on it. But I want to know, what’s your longevity protocol for you, NIR? What do you do to keep yourself healthy and everything you know about longevity, aging? We want to know what’s your protocol?

Dr. Nir Barzilai:
So let’s start with the obvious. I exercise every day, by the way, which is almost 365 days a year. I missed this week. I was on a plane, I usually don’t miss, but exercise now, what? Exercise very briefly, I Peloton is my to go to, but I’m doing other things too. But twice a week I have a trainer that mostly works on my muscle and flexibility, and I think he’s getting me. I’m always trying to maximize it and getting to a better place. But this is the regime. As far as eating, it’s mainly intermittent fasting. Okay? I had dinner last night at seven 30. It’s already one 30 here, so I’m 17, 18 hours. And unless I see the podcast and I talked lots of nonsense. I think I’m fine.

Dr. Mark Hyman:
You were good. You were good.

Dr. Nir Barzilai:
And that has improved my health tremendously, by the way, including my exercise capacity in a mysterious way. And by the way, again, this is not for everyone. It’s better for men than women for some reasons, at least for weight loss. But some people are saying, I cannot do it. I get hypoglycemia. They don’t. But anyhow, it’s not for everyone. But it’s

Dr. Mark Hyman:
Really great. If you’re a pre-diabetic and your grandfather was diabetic, your metabolically probably do better with it. That’s what

Dr. Nir Barzilai:
I got. Yeah, exactly. Right.

Dr. Mark Hyman:
And what do you eat when you’re eating? What do you eat when you’re eating though? You can’t just have McDonald’s and cola, right?

Dr. Nir Barzilai:
I’m, when I’m eating, look, it’s all more aspirational, but I’m trying to cut on carbohydrates. I’m trying to eat more fish than beef. I’m kind of successful. It’s very different than 10 years ago, let’s say olive oil. But really, I think the intermittent fasting already cuts lots of the stuff that I shouldn’t eat. And I’m not hungry in return. It’s not that I eat more because of that. I don’t believe that. And my weight has been good. The third thing is sleep. And so dark room for eight hours. I don’t sleep for eight hours, but I try. It’s actually by my Fitbit. It’s interesting. Every week I sleep exactly six hours and 40 minutes on average. And social connectivity, that is important. It’s not my problem. I’ve never met a stranger in my life, so I have this deficiency. But yeah, those are the things. Now, on top of that, so let me say that I take metformin. Everybody knows that they take metformin, but I do other things and the way I do other things, I have a longevity doctor, and I come with a longevity doctor, and I say, are

Dr. Mark Hyman:
Cheating on me?

Dr. Nir Barzilai:
What should I try? By the way, I’m on the council of the Healthy Longevity Medicine Society. Are you aware of this

Dr. Mark Hyman:
Society? No.

Dr. Nir Barzilai:
Okay, I’d love to connect you there. For sure. We need you because look, this is going to be right. I mean, we are going to be the medicine of the future. We’re going to improve your health and not get the disease. It’s going to be, medical schools will be taught differently. Totally. Yeah. So we need your input there. I’ll contact you about
Later. But so the longevity, I sit with the longevity doctor. He says, why don’t you try X? And I said, okay, if I try X, what should I test now and after? What will be the decision to go on? And so I tried. I’m not going to tell you what, but I tried other things. Some had effects, some had no effects. But I thought that I want to try just in order to, it’s not an n plus one for anyone, but for me to understand what it is, what it means, what is measurable and things like that. And I get some information about that. Because of that, I don’t care to share Metformin. I can share, because we have studies. This what I’m doing, I cannot share, but I am trying to

Dr. Mark Hyman:
Different supplements or different things You try.

Dr. Nir Barzilai:
Yeah.

Dr. Mark Hyman:
Yeah. Okay. Well, we’ll stay tuned for when the data comes in. I mean, this has just been such a great conversation. I could talk to you for hours. I think everybody’s learned a lot, and I think if people want to learn more, they can read your book age later, healthspan Lifespan and the New Signs of Longevity, they can follow you at Nearby Lie MD on social media. It’s not hard to find them online. Just Google ’em and we’ll put all the links in the show notes. But thank you for your work. Thank you for being so tireless and helping us figure out a way to actually understand aging and do something about it. We all want to

Dr. Nir Barzilai:
Live. Thank you. We’re soldiers in the same war, and you’ll win.

Dr. Mark Hyman:
We’ll win. I love that.

Dr. Nir Barzilai:
We can also do another podcast between now and a hundred. Okay.

Dr. Mark Hyman:
Okay, great. Okay. Down, down. Well, after the Tame trial’s done, which is what, another four or five years, right? Yeah. We’ll come back. Well maybe sooner. We’ll see what’s up. But anyways, it’s great to have you, and you have a fabulous, thank you very

Dr. Nir Barzilai:
Much. It was a pleasure for me to talk with you too. Thanks for the tough questions.

Dr. Mark Hyman:
Thanks for listening today. If you love this podcast, please share it with your friends and family. Leave a comment on your own best practices on how you upgrade your health, and subscribe wherever you get your podcasts and me on all social media channels at Dr. Mark Hyman. And we’ll see you next time on The Doctor’s Pharmacy. This podcast is separate from my clinical practice at the Ultra Wellness Center, my work at Cleveland Clinic and Function Health, where I’m the Chief Medical Officer. This podcast represents my opinions and my guest opinions. Neither myself nor the podcast endorses the views or statements of my guests. This podcast is for educational purposes only. It’s not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. If you’re looking for helping your journey, seek out a qualified medical practitioner. Now, if you’re looking for a functional medicine practitioner, you can visit ifm.org and search their find a practitioner database. It’s important that you have someone in your corner who is trained, who’s a licensed healthcare practitioner, and can help you make changes, especially when it comes to your health.