The Coolest Fiber Paper & Biggest Keto Lie!

This is one of those things where like there is no easy answer.

May provide a very specific effect in the body.

What I'm anti is platitudes.

Any diet can be incredibly terrible for you if—

Screw what normal is. Screw what convention says. You don't need to be going down a normal path.

Inulin be incorporated into a lot of health-forward food products.

It was just such a beautiful demonstration of science.

There's some point along the way where your most dire held beliefs are shattered.

All right everybody, I'm back with now my fourth interview with Dr. Andrew Kutnick. He's becoming a regular, so I'll keep the intro short because hopefully you've heard it before. But this is a dear friend and colleague, PhD researcher, who is pushing the boundaries of, uh, clinical care and research around diabetes, glycemic control, particularly type 1. He's, uh, leading You've lived with type 1 diabetes for 17 years. How long has it been?

So my wife calculated it for me like last week. It's 19 years, 20 years will be in this July.

That's pretty amazing.

Any, or next July.

More amazing is the majority of that time you've actually had perfectly normal glycemic control, which puts you in like the 0.01% or something like that. So you can see our first interview about Andrew's backstory if you want more on that. But, I want to springboard off the conversation we just had to talk about, we're basically talking all about new 2025 studies in glycemic control diabetes. So last interview we put some caveats in about fiber broadly, but I read a paper that I shared with you and then you read that I am going to call the coolest fiber paper I've ever read. And I think we can deliver on that. So Before we get into mechanism, when you read this paper, what were your initial emotional reactions as a scientist?

Well, so I thought the, it's beautiful science. It's really, whenever you watch, watch, whenever you look at a paper, it'd be cool if every single paper was broken down by Nick so you could watch it all and, and have it broken down for you. But it's not always the case nowadays. Nick can't do everything. But it, it's a fascinating paper because they really go to illustrating why some of the foods that we consume elucidate positive effects. For a long time, we've talked about dietary fiber having a positive impact on, let's say, gut health or keeping your, your bowels regular. But what this paper goes so far as to show is that some of the foods or forms of fiber that we see in like chicory root, artichokes, garlic, onions, leeks, asparagus, that it can actually have a powerful effect at providing resilience against nutrients or components and often found in the Western diet that induce harm. And so I think it, it's a cool paper, but I also think it illustrates something that has given us answers as to why a lot of these things do have health benefits. Again, getting to the why of our health, the why and the precision.

I think one thing I'll emphasize, if I hadn't been clear with my audience before, I'm not anti-fiber. I'm not anti a lot of things. What I'm anti is platitudes. And this idea of, hey, you have this gross number, like on a nutrition label, grams of fiber, and you just want more of that, take a fiber supplement, boost it up, and that's the end of the story. That's what irks me. Irrespective of how fiber impacts, you know, my gut, I just don't like platitudes. Eat a balanced diet, this, that, and the other. To me, it's like hearing someone say, hey, eating is fantastic, but not differentiating between like, hey, having like salmon and vegetables after a workout to nourish your body and trying to put yourself in like a breadstick coma at the Olive Garden. Both are eating, but they're different. So this paper I found interesting because it wasn't just like more fiber is better. It's like, hmm, we have a hypothesis about how a particular fiber, in this case inulin fiber, impacts metabolism. And I'll, I'll quickly give the high-level overview and then I wanna hear your, your assessment of the mechanism and if I hit the nail on the head or if I missed something. But basically there was prior research showing that inulin fiber, you actually mentioned chicory root. They did, this is also a 2025 paper, I think it's Cell Reports Medicine. They did intrinsic fiber. So rather than just giving the isolated fiber, they gave it like as the whole plant cell, which might have additional benefits. Basically it improved insulin sensitivity and metabolic health markers in people with insulin resistance. Now, Inulin has a particular structure. Inulin is basically a chain of fructose molecules with little glucose head, like a long snake has a, you know, tail of 20 to 100 fructose molecules. So one could imagine a hypothesis: could this chain of fructose immunize an organism against fructose? Because fructose can be uniquely metabolically harmful if it goes to the liver or the microbiome. If it goes to the liver, it can cause fatty liver, insulin resistance. And this is even independent of caloric load. You can uncouple these things. And if it goes to the microbiome or the colon, you can have this microbiome dysbiosis. So could inulin actually change a body's metabolism through the microbiome to immunize, quote unquote, against fructose? And long story short, the answer was yes. And not only was the answer yes, the inulin increased fructose catabolism. So there was less spillover when high fructose corn syrup was given. It's more defended the liver and microbiome. And then, and I'll give the spoiler up front, but we can dig into it. What happens to the fructose if it's not spilling over?

Where does it go?

And they basically showed that this particular fiber could shift microbiome to then partition the carbons. So, you know, you know, sugars, fats, and carbs are carbons. Carbon backbone, hydrogens and oxygens can partition the carbons through the synthesis of amino acids that are then used to generate a very powerful antioxidant in the body, glutathione. So high level, this particular fiber, at least in preclinical models, can quote unquote immunize against fructose, defending the liver and the microbiome. And then it shunts the sugar towards more protein generation, building up an antioxidant capacity. It was just such a beautiful demonstration of science. What do you have to add or react or what did I miss?

Well, so I think what's interesting is you brought up a point like, okay, could it immunize the body? And I actually think that one of the most interesting parts to me is, well, if it's structurally similar to fructose, could it be harmful also? You know, that, that's the potential devil's advocate there is like, actually, are we potentially inducing harm by having something that's identical to it? And what's interesting is there's actually a few molecules classified that as— I think they call them fructans. Yeah.

Yeah.

Which have similar structures to fructose but are largely non-digestible. And a lot of those molecules have had a lot of recent evidence illustrating their positive benefits, oftentimes as almost providing— again, I think you put it brilliantly— immunizing against these harmful effects. And I think you put it brilliantly on the head. I think a lot of this paper was largely framed about the risk. That we know fructose has, and it's so pervasive in the Western diet, you know, high fructose corn syrup being the one most people probably heard of, but it puts people at particular risk for fatty liver accumulation, a disease used to be called fatty liver, but actually is now called— or nonalcoholic fatty liver, now called metabolically associated steatotic liver disease, or MASLD. They reframed it because no one wants to say I have fatty liver, you know, which makes sense.

They've renamed it like 3 times. It's more like different names than Yeezy. They keep on renaming.

Exactly. But what's cool about this paper is that it shows that you can provide molecules that are recently very pervasive and nutritional products. You know, if anyone pays attention to the food labels, you've probably seen inulin be incorporated into a lot of health-forward food products. And so I had seen that over the years and I had previously looked into some of the literature on inulin. This may be the most impressive paper by far actually showing mechanism of action of how inulin works. But we usually associate fiber with health benefits. One, it makes your, you know, GI regular. We know that fiber, at least some forms of fiber, can be broken down into butyrate. Butyrate is known to signal antioxidant effects similar to how beta-hydroxybutyrate, something called a ketone body, may also act. And so we know there's a number of mechanisms by which, uh, fiber can be health-promoting. What this paper did is actually show a specific actionable form of fiber and actually when applying it into a therapeutic setting can have a powerful effect at providing resilience against the negative effects of what's one of the most pervasive negative health consequential molecules in our food environment, which is high fructose corn syrup. And I think you, you brilliantly stated the pathway by which this happens. And but it also gives an illustration, you know, the microbiome, Nick, for me has always been an interesting area of research. You know, the power of the microbiome is We know it impacts health. You know, we have billions of microbes in our body. But the problem of the microbiome is that we don't know how to identify— directly manipulate it or how each component may actually interact to obtain a desired outcome. It's an emergent field where we're trying to find out more information about how powerful it is. You know, we really started the field of metabolism. I mean, I guess you could go way far back, but you could cite it to maybe, you know, 100 years ago, really powerful science— Warburg effect, Krebs, other major researchers in this field started to emerge and develop mechanisms. The microbiome was really an emergent area over the last decade and a half. So we're really in an early stage. But we don't— what we do know is that much of the evidence in these initial forms of laboratory assessment, like cell culture models or preclinical models, animal model systems, that there is a powerful impact of the microbiome, incredibly powerful. But once you start testing this in complex human environments, it it gets a lot more complicated. So researchers often rely on these very controlled settings, um, to more accurately dissect out its direct effect. And I think with this paper, at least my reaction to it is, is, is number one, um, you know, the microbiome logically is very manipulated by diet. But what this shows is that you actually can have a fiber that may— I actually think at first glance you'd be concerned about it, right? It's bio, you know, chemical structure similar to fructose. Fructose is harmful, but actually it's not harmful. It could be protective. And it also helps illustrate how some forms of fiber can actually, actually improve health outcomes through a direct mechanism. You know, we know that things like fiber can target inflammation. We talked about that. We know it can slow digestion of some foods, although we also talked about on the prior episode that people can look at preceding this one. About how fiber may not always be as protective in all individuals, or at least the same way. But these type of papers allow us to be very precise, as you said, around a type of fiber, specifically inulin, may provide a very specific effect in the body to protect, protect against something like fructose. And I think this just gives you an illustration of confirmation and support that things like fiber may be a very important component of the diet, uh, and the type may be particularly important if you're trying to offset some of the negative effects of what is common in the American diet, such as, uh, fructose or high fructose corn syrup. Although I will say, to be determined, you know, what the actual effective dose of something like inulin is when we get to the, the human level, because in animals and human translation, there's always that opportunity to, uh, see some discrepancies, uh, particularly in things like dosing, because metabolism metabolic rates are a bit different. But and we get back to the individualized approach, Nick, where you can, you can test these things for yourself and see how you respond.

I wanna respond to a few things. First, to kind of go backward in order with respect to human dosing, the nice thing about this particular study is it's building off prior human experiments, including ones published this year. So we can kind of intuit what the protective dose would be. In this case, probably 10 to 15 grams of inulin per day. Has shown metabolic benefits in humans. Now, what proportion of that benefit is mediated through this mechanism is another question. But, you know, further to your point, and I guess what I really wanna emphasize here is the precision. So in the prior episode, as you mentioned, we talked about the limitations of saying more fiber is better. I don't think that's the case. At the very least, it can cause gastrointestinal upset. So when you're talking to somebody with, in this case, we're talking about patients with diabetes or insulin resistance, we can say, hey, on balance, fiber in general is gonna give you a less protective effect on glucose. So bear that in mind. Maybe that oatmeal isn't the best choice for breakfast. And at the same time say, but, but, but this particular form of fiber, you actually mentioned the food list already, but I'll reiterate, chicory root, Jerusalem artichoke, garlic, onions to some extent, leeks that are found in these foods actually might change your microbiome. To not have an immediate effect on your blood sugar, but in a way that can improve your liver health, decrease liver fat. In fact, just as a sidebar, it changed the expression of genes in the liver to decrease what's known as quote, de novo lipogenesis. So it's generation of new fat in the liver, but there's a, an interplay between de novo lipogenesis, making new fat in the liver and fat burning in the liver. So basically it took the brakes off fat burning. So now you have a few things happening. Less fat generation in the liver, more fat burning in the liver, and you're increasing the antioxidant status of the liver by the mechanism I went over. I'll link more information below on that as well. But the word I want to keep saying is precision, because it's not just more X is better. It's this particular form of this broader category, inulin within the fiber group, could benefit you uniquely. And here's how. And I think that is incredibly powerful. And the last thing I'll say on this study before we, we jump forward, or I'll give you the final word on it, is the elephant in the room here is that it's protective against fructose. So I'm sure people are wondering, well, why don't I just not eat fructose? And I'll just say upfront, great. It's what I do for the most part. Maybe I'll have a few blueberries here or there, but that's a viable option. What we're talking about here is the awe and awesomeness of science and also providing precision tools for individuals to implement, you know, theoretically based on where they are. So that's all. I know people are going to be wondering, well, why don't you just 90/10 this? I'm like, yeah, you can do that. That's definitely an option. And I guess the last question I'll leave you with on this paper is just to broaden this out a little bit in general. We talk about one mechanism. It's like one thread on a web. What do you think about the microbiome's role in diabetes, both type 1 and type 2? And at a high level, like what do you do in your life to mind your blood sugar via the microbiome? Or what would you suggest?

I think that a lot of what we've understood about health does— some of it requires a reassessment, right? But this paper is a, a form of confirmation in many ways that there may be some positive benefits to particular types of fiber. And there's a lot of evidence that shows that the things that typically have fiber in them, such as, you know, green leafy vegetables, spinach, broccoli, asparagus, etc., they also have other things like phytonutrients and other components that may, at least historically in literature, have health benefits. So on a personal level, I predominantly use them as a hypothetical safeguard, right? Like, is it hurting me to include them? Well, if it disrupts my blood sugar control because I have diabetes, then yeah, I want to be very cautious about that. If it's going to disrupt my insulin, I'm going to be cautious around that. But in many ways, the placement of fiber prior to a meal— well, let's say you have a salad and, uh, salmon— I often will eat the salad first in a way of slowing down the absorption of food. And this paper provides an opportunity to illustrate, uh, that there might be particular types of fiber that have unique benefits. And so what I try to do is I try to incorporate a diversity of different high-fiber forms of, of foods in my diet, and I try to split those up across all meals if I can, and try to ensure— or as a, almost as a protective approach, not because I have all forms of evidence to say this is the best idea or not the best idea, It's accumulation of multiple pieces of evidence that say this is probably going to help me, it probably is good for me, uh, and let me see how it goes. And if it produces the desired outcome and I feel better and there's no negative consequences, I'm all for it. And so for me on a personal level, I often use these as just protective approaches to lower the impact of glucose from particular foods, uh, and then with the hope alongside that, Nick, that I can hopefully get some of the other additional benefits that that, that seems to be regulated through pathways of the microbiome, like this paper illustrates as well. So that's my strategy. Everyone has a different approach with their, with their nutrition and health. But one thing I also want to emphasize here is that—

before you do that, can I just emphasize something that you did that I think a lot of people might overlook? I love how you answered that question because what you did was like in the moment grapple with like the uncertainty in the data set and perform. I, I hope people saw you perform this risk benefit analysis that we were talking about at an individual level. There's so much we don't know about the microbiome. There's so much we don't know about the foods that we eat, the different fiber components, the different nutrients within them. And so then you're thinking through, okay, there's a lot we don't know. What are the risks for you? Probably pretty low. And having say like broccoli and what are the benefits to say having broccoli or Jerusalem artichoke. And on balance, feeding your microbiome with more diverse input can develop a more resilient ecosystem. And if there's something that metabolic health is, it's kind of resilience to challenge. So that's your risk benefit analysis, which you approached with like uncertainty and humility, which is how we all have to do it. Mine, there's a little bit more risk involved just because of how fiber impacts my pretty screwed up microbiome. It's a whole different medical history, but I just wanna double-click on how you went through that thought process because despite being like a highly trained PhD scientist, you're like, okay, there's just a lot we don't know and I'm not firm and confident on the evidence base for like where I'm landing, but this is why I'm hedging my bets here. Is that a fair summary?

It's an absolute perfect summary, Nick. And that's, it's usually where our, our evidence is because a lot of times in science, you, you've been in across multiple premier institutes. You've done research experiments across both of those. And what you find is we're usually taking a very controlled setting, idealistically manipulating a very specific variable with the end goal of trying to understand how that variable produces a specific outcome. But there's so many constraints around how that may translate. But what I think is particularly important for the average user is to not just look at something and say, this is, this is, this is definitely on the science community. And I will call out our own community for this. They'll say, oh yeah, like this paper comes out and they say, oh yeah, but it wasn't proven in this particular way, in this way. I'm like, yeah, that's an important caveat, but what are you going to do today? Because we don't have an answer to your hypothetical question. What we have is this evidence today and in the context of the broader evidence in this category and putting it all together with the background knowledge that we have to ultimately come up with an actionable plan that we think is giving us the best answer possible.. And I think if you do that with the weight of the evidence, you're likely to be on the right course, likely. But then you need to experiment on yourself and ultimately develop an adaptive and iterative path on your own health journey, knowing that, hey, this is what the paper showed, but I am either seeing something similar or different. If you see something different, it doesn't mean that you discredit your own personal outcome. It means you may be unique compared to the study group of that unique study. And so you don't disregard your outcomes. You experiment, you try, and then learn how you may respond personally, because ultimately that's going to give you the best insight on how to improve your health. Don't discredit your own outcomes. Um, uh, trust— you might— you probably should trust that more than anything else. Uh, that's your best best objective measure.

N equals 1, for sure. Speaking of broad proclamations, up next, Dr.

Kutnick and I are going to dive into a headline-making study that claimed ketogenic diets are long-term harmful. But as you'll see, there are more nuances, and we're going to do some myth-busting. But before we get to that, I want to tell you about the sponsor of this video, Winnow Probiotics. Now, if you're like me, you're probably skeptical about probiotics by default. I get it. But I promise you, this one is different. Winnow is not just a best-in-class probiotic, it's been specifically engineered to address the very real and urgent problem of microplastics. You see, microplastics are everywhere in our environment, our food, our water, even the air we breathe. And they're not just gross, they're dangerous. A major New England Journal of Medicine study found that microplastics in your blood vessels can increase your risk of heart attack, stroke, and death by 300%. 350%. No, I didn't misspeak.

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Speaking of broad proclamations, um, it brings us to the next study I want to talk about. This is a study you actually shared with me, um, a day or so ago that came out in Science Advances. Speaking about carbohydrate restriction, it was taking shots at a ketogenic diet. So I'll just read an excerpt from the paper and then I'll ask a couple questions. It says, and I'll quote, ketogenic diet protects against weight gain and induces weight loss, but over time leads to the development of hyperlipidemia. So high lipids in the blood, that's bad. Hepatic steatosis. So the, you know, metabolic associated liver disease we talked about and severe severe glucose intolerance. It's a pretty scary claim. So let's unpack that first. What was unique about the mouse model? This was a mouse study that they used in this study. What was metabolically unique about it?

So when looking at this paper, first and foremost, I saw the paper and it was actually espoused by a lot of people in this community, particularly those who often look at the ketogenic diet with apprehension or fear. And say, look, like, this is— there's more confirmation that this— this— all the hypothetical risks we talk about with this diet are real. Like, look, it's causing all these long-term implications, so obviously you should or shouldn't do this approach. Well, the only problem is that, uh, I'm hesitant that many of those people actually read the paper or maybe have, uh, engaged in science in similar settings that this paper was conducted, which is animal research. And the reason I say this, because I have done animal research, and one of the first things you look at is the model system. Well, the model system was something called C57 black 6 models. They are the most commonly utilized animal in all of medical literature, and so most people lean on them. The one caveat is that this model is uniquely vulnerable to overconsumption of fat in caloric excess. It builds up excess amounts of fatty liver droplets within these animals' livers and leads them to get hepatic steatosis, or equivalence in humans. What we talked about earlier in this episode is, is MASLD, metabolically associated steatotic liver disease. Here's the big caveat. It's in caloric excess. Now, the paper specifically said that the ketogenic diet protected against weight gain. Well, against what? Well, they had a comparative model in there, which was a high-fat, like a Western diet, basically a high-fat Western diet. And so they said, well, the ketogenic diet protected against that. Well, yeah, of course. Like, of course it did, because that's the worst form of diet that someone could consume on average based on all the evidence. Now, did it protect you against weight gain compared to that? Well, yeah, it did. The problem is that this animal model system is known to overconsume the ketogenic diet. Okay? Now, the average human will not. That's what the evidence shows. If someone engages in a ketogenic diet, doesn't mean you can't overconsume it. If you just force-fed yourself, you certainly can. Um, everyone's a little bit individually different here.. But on the average, most people do this diet in an attempt— or a lot of people do this diet in an attempt to lose weight because it can reduce the caloric intake without much effort for many people. But in animals, it's totally different. They actually tend to overconsume on this diet. So the animals in Figure 1 of the paper, not Figure 10, not hidden in the supplemental data, in the very first figure, The keto— the animals on the ketogenic diet, as you would predict if you knew these animal model systems, overconsumed, gained weight, they gained fat, gained specific— they gained specifically fat weight at substantial amounts compared to all other diets that they compared it to, and then said, oh look, the ketogenic diet was inducing all these negative effects on insulin, causing insulin resistance.

All other diets except for the high-fat, high-sugar. So just as a little bit of a sidebar, if you go look to the paper, they'll say HFD, high-fat diet in animal model literature. This is a pet peeve of mine. I'm sure it's a pet peeve of yours, but high-fat diet almost exclusively means high fat and high sugar, and then ketogenic diet separated. So effectively, just to reinforce what you're saying, it protected against weight gain relative towards the worst possible control you could have. So basically it's saying in this case, actually the mouse diet, the ketogenic diet was primarily calories from lard and soybean oil. So it's like saying, if you're translating to humans, hey, a diet of processed bacon and soybean oil is going to protect against weight gain relative to eating pizza and cookies and ice cream. And then you're top tap tacking onto that. This is a mouse model that is predisposed to be susceptible to this particular, you know, lard and soybean oil diet. And then, you know, how this gets amplified in the headlines, ketogenic diet might have these long-term harms when it's like you have a mouse model that is predisposed to negative outcomes to overeat this diet. You're feeding it lard and soybean oil, then it's gaining excess fat and you're just saying, well, it gains less weight than relative to a mouse eating basically the mouse equivalent of, you know, milkshakes and french fries. And then we come to that, you know, caution, severe glucose intolerance caused by ketogenic diet long-term. I just wanna be explicit about like how big a gap there is between what was actually shown and then what gets amplified. Sorry to interrupt. What were you?

Yeah, I, I, I agree with that. And I also think it's important to reflect, okay, this paper comes out, we don't discount it. Okay. We look at it, right? Number one. And, and what we see right out the gate is that almost completely all the negative consequences of any of these diets can be explained by weight gain and fat gain alone. Uh, that's, that's it. So if you're consuming a diet and gaining excess adipose tissue and over-consuming, that's probably not a good diet for you. Uh, however, that's not what we see with the ketogenic diet on average in most individuals. And by the way, let's compare it to all prior literature. Let's not just focus on this one particularly very interesting study that shows this diverse effect compared to what we've historically seen. Let's look all the way back to 200 years ago. Okay, so in 19— or 1796, when it was first used, or first reported to be used for diabetes, um, used for obesity at least some of the original reports from Banting in the 1860s. It's been used as standard of care for treating or preventing and reversing forms of diabetes, at least type 2, for over 200 years. So all of a sudden it's uniquely harmful in an animal model that's predisposed to overconsuming on a particular diet. You just got to be careful with that because it wasn't— didn't take long to look into it. You literally see in the very first figure that the ketogenic diet gained excess fat weight, uh, because the animals overconsumed it. But if you've never been in these animal model settings, you may just read the abstract that the author said they protected against it and think, oh well, look, uh, the ketogenic diet was everything we suspected it would be, but I was harmful long-term. That's what's novel about it. It's more long-term in these animals. But actually, if you look at the literature on anything that has looked at like a longevity effect of these style of low carbohydrate diets or ketone elevation, what you actually see is most of those studies on average— John Newman's lab, I know Luke Cantley did some studies in this a long time ago, like I think a couple of decades ago— that most of those show a positive long-term implication on diverse animal systems. Okay. Not just this one, but diverse. But also being careful that if you look at a study where they just gain excess adipose tissue, we already know obesity is bad for your health. No-brainer here. And that's what happened with these animals. I also want to add one more layer to this. When you work with these model systems and a lot of people tweeting about it don't— I'm not saying all don't, but a lot of these people who are tweeting about it have not. You also note that there is some unique aspects to this specific model system, the one that's most ubiquitously used in the US, medical research. It's a C57 Black 6 from Jackson Labs. It's one of the most common. There's also Harlan Labs and a few others. That said, because of how these mice are bred over time, they have lost key enzymes in the liver. One is called NNT that plays a key role in metabolism. Well, guess what? Me and you, Nick, we both have NNT. Oh, the vast majority of humans have NNT unless they have an inborn error of metabolism. Okay, mice from the most commonly used form of model for mouse model systems lack this enzyme. Okay. So this enzyme plays a critical role in the liver of balancing nutrient intake and being protective against disease, particularly fat-based nutrients. And so we've done experiments knocking in and knocking out NNT, and I can tell you that that molecule is particularly important for the ketogenic diet. Okay. Particularly important for ketone metabolism. And there can be harmful effects if it's absent. And that is another caveat with this particular model system revolving the ketogenic diet. It's actually one of my biggest concerns when using these model systems because they're almost the most commonly utilized ones that people are looking at ketogenic diets or exogenous ketone-based therapies. Yet we know that it lacks key enzyme— enzymes, uh, that are important for ketone metabolism in the liver. And that can be incredibly dangerous for the interpretation extrapolated with that particular model. So it's something we, we need to be careful about.

I'm gonna throw a big wrench at this. Do you ever, so I, I was looking up the paper because it just popped back into my mind. I read it like it was published in 2017. I read it when it came out. So what, been 8 years? It was in Cell Metabolism. I'll read you the title. A ketogenic diet extends longevity and healthspan in adult mice. From the abstract, this is what model they used. C57/BL/6 mice. It says these mice, the C57/BL/6 mice, were assigned to a ketogenic diet or control diet at 12 months of age. The ketogenic diet significantly increased median lifespan and survival compared to controls. In aged mice, only those consuming a ketogenic diet displayed preservation of physiological function. So my question to you is, how can you have— it sounds like the same model such discrepant effects. This study showing actually increases lifespan and healthspan. I, I wish I had done digging into this study and, and compared the two before we got on because I only just remember this study.

Yeah.

But it's just, I wanna add that level of like, you could not get more contradictory statements even maybe from the same model. So how do we grapple with that literature?

Yeah, so that's a great question because it needs, it actually provides more context to what I said before because you're talking about a very similar model. Number 1, you got to look at if they have the model that has NNT knocked back in. That's number 1. Number 2, you got to look at whether the animals were pair-fed, which is a very common but often difficult thing to do in research settings where you actually have both diets calorie controlled. That's not often the case in ad libitum feeding because it adds difficulty. I've done pair-fed studies and it's a lot of work. You have to directly weigh one group and it causes a delay in the calculated amount of food that you give the next. It's like all these— a lot of work, let me put it that way, which is why it often doesn't happen. If I'm remembering correctly, I think that's John Newman's work, um, at, uh, the Buck Institute. And I believe that they were actually showing— when they showed that effect, I believe they were also pair feeding these animals, which negates some of the excess weight gain aspect of it. Now, if the animals got morbidly obese, you would never expect that those benefits would have, would have come Okay. And if I remember that study also correctly, it wasn't just that low carb had benefits. The extension went even further when ketone bodies were elevated specifically. So it was, it was, it was this dose-dependent improvement with greater levels of caloric decrease. But that's also a savvy lab. That's a lab that knows about the ketogenic diet.

Newman at the Buck Institute?

Yes.

Okay. Yeah, I see people at the Buck Institute on the paper, but he's not on the paper. But it sounds like it was done by a partner institute and also UC Davis. I'll, I'll mention it below so we can come back for interview 5 and discuss it in more depth. Sorry to jump that one on you, but anyway, please continue.

Yep. Yeah. And so what that work— so there was 2 papers on that that came out the same exact time. There's one from John Newman's group. There's one that came out of a different group at the same time in Cell Metabolism, both showing very similar positive benefits. The one you're referring to There's an author named Keith Barr, muscle physiology expert, where they actually looked at muscle function experiments. But the other paper I'm referring to as well that also looked at the, the longevity aspect of these diets and both showed a positive impact. Both showed it over a very long period of time. And both groups are, to my knowledge, more well-versed in these dietary strategies. And I suspect take some additional precautionary measures on the type of diet that was administered across groups. Because sometimes, as you mentioned, the ketogenic diet is, is pure lard and soybean oil. And there's often a, a lot of researchers who are very familiar with these diets often try to use diets that more accurately represent the human condition of the ketogenic diet. So that's what we did, um, back when I was in grad school, that we would actually try to build two different types of diets that reflected specific food components of a ketogenic diet. Instead of just having lard and soybean oil, we would replace that for things like medium-chain triglycerides or other forms of fat within the diet that we know people would maybe consume on these diets. Not just, just throw the, the, the worst aspects of food, um, because any diet can be bad for you. Okay? Any diet can, can be incredibly terrible for you. If formulated in the wrong way.

Yeah, right.

And that, that also applies to animals. That also applies to animals. So very familiar with both those papers. They both came out in Cell Metabolism in 2017 and they were almost like they appeared like they happened at the same time, but they were both being run at the same time and they both got submitted at the same time. A little back-end story I don't think people realize. And both got published simultaneously and showed a very similar effect, which is kind of cool, right? How often do you get it to where you have papers from two different groups that didn't know about each other having confirmatory results on a nutritional intervention at that in a very high-impact journal. Not often.

Very cool. Very cool. Yeah, I want to be respectful of your time. So, well, actually, quickly on the animal model thing, I realize we've talked a lot about animal models over the past few interviews. For example, we kind of lauded their importance when talking about our first paper, the Stress Makes Sugar one. And I'm putting myself in the mind of an audience member now. I will be kind of confused, like, do we, do we discount animal models? Do we value them? And I just want to name, I'm sorry, it is not straightforward. You can't just say animal models don't matter. Sometimes we need them to dissect. And there isn't, I'm sorry, anybody who says there is, but there isn't an easy heuristic for saying, hey, discredit this paper, value this paper. It actually, I don't know if you agree, but I actually just think it, it requires experience with knowing what the models are and also knowing what questions we can ask in humans and what we need animals for and what the caveats are of different models in different contexts. So there isn't like a, a checklist I can give the audience saying, hey, these ones count, these ones don't. This is one of those things where like, there is no easy answer. You just need to kind of have scientific background. Do you agree with that?

I agree, but I wanna add additional layer that you can also, if you lack that experience, look at the weighted of the evidence across the board and look at, does this, is this singular paper which seemed to show an effect that's different than what I've seen before, how does it weight and stack up against all the evidence that I'm aware of? And that's when I think it's— it's that alone, I think, fixes the issue for most people. Because in all model aside, Nick, like, if this was a real phenomenon, we want to know about it, you know, we'd want to know that these effects are causing negative long-term effects, but we'd want to know it's real too. And the way to know if it's likely to be real for the average person across the board is to look at all the studies that we can think of in this category and then also look, has this been done in humans? And there There are a lot of examples of long-term ketogenic diet use. In fact, we talked about that in the first and second interview, uh, with some of the studies that we've done. Um, and you guys are ongoing with a large cohort analysis on your own looking at cardiovascular implications of these diets. So you— I, a weight of the evidence, I think, is, is going to fix all the problems and give you the best answer based on what we understand today if you don't understand animal models. But yes, the animal models give a level of resolution for each individual paper. In each case-by-case example.

I, I love playing devil's advocate too much. I always wanna go a little deeper, like, well, does the preponderance of evidence really apply to X, Y, and Z? That's a whole different kettle of fish. So I won't go there. Like I said, I wanna be respectful of your time, so I wanna have one last closing question, which was, you recently had the honor of being on one of the biggest podcasts in the world, Diary of a CEO with Stephen Bartlett. Everybody should go listen to it.

What can you tell me about this? Well, if you look at the science, it's enhancing cognition.

You did a great job. But, um, you know, there's this phenomenon after you get out of a conversation like that, you were like, shoot, I should have said X. What is X for you, Andrew? What should you have told all the CEO listeners and Stephen Bartlett that you didn't, that you want them to hear?

Well, first off, they should put you on there. I think you'd be an amazing guest on some of the work that you guys have done, um, and kind of dissecting that out with them. Uh, but So it's interesting, Nick. The episode was— came out as an hour and a half long, and understandably they want to make it the most compelling and engaging. But actually, me and Steven sat down and spoke for like 3 and a half hours. And so I actually haven't gone back and watched my whole episode. I tend to not really do that very much, just the hour and a half. So I don't even know what might have got clipped out of that that is of high value or not high value, to be totally fair. But I guess I'd come back to some some fundamental things for people that can take away from the conversations we've had over the last 3 episodes that we've had together, Nick. And I think, you know, for— because most people are probably listening because either they're very curious about their own health or about health in general. And I think when you think about that, it— I think it's, it's important to, to promote and empower individuals on their own journey to realize that you have power in this situation. You have power to control your own health. You don't have to rely on just someone else telling you what to do at every single doctor's visit. You can take that information, take the information you find on your own, put it all together. Maybe there's something I said, Nick, that someone's like, hmm, that doesn't apply to me, and throw it in the trash. Good, because you should be taking all information you hear and process it to understand how does this apply to me? How do I take these, these these tidbits and is it applicable for my life? How do I apply it to my life? Because everyone's different. You have different cultural considerations, lifestyle, kids, job, location. All these things emerge together to give you a unique set of opportunities and constraints in your life. And so as a result, when we talk about diet and its benefits, we talk about— we haven't talked too much about this, but we know there's tons of evidence around exercise benefits, sleep, keeping a normal body weight, a healthy body weight. And healthy body composition. You know, those are things that you have to embark on your own journey and continue to try to learn as much as you can. So what I would say for the, the individual who's looking or going on the journey, one, find a trusted resource, Nick Norwitz, and other people that are out there who provide evidence and try to be reasonable with evidence they're providing. Um, but take all the information you have, process it, and look at what how it applies to you and be a skeptic too. Don't just say, "Oh, Andrew said it, I believe it." Take what I say, be skeptical about it. Look at what other people say. Try it on your own and see if it works for you. And I think that's an important principle that people can take away. I mean, that's, that's the field of science. You have MD, PhD behind your name here, Nick. If people are not just listening to this, they may not see it, but if they watch it, they'll see this. That means you went through a process of being extremely skeptical, and you still are, about a number of topics. And I think that that gives you, uh, an opportunity to dissect information as a critical thinker and get better answers out of it.

I think you're being overly generous, and I know what people are going to be thinking, and I'm thinking the same thing too, and I think you're thinking the same thing too, and you're trying to butter my biscuit, which is— let me bounce off the whole letter thing. I went through a process that gives me good optics and credibility. And ideally medical school and doing a PhD should cultivate curiosity and asking hard questions. I think we probably both agree that it doesn't. Then I might select for those people. I actually think my formal education, not intentionally, I'm not pointing fingers at any instructor, but beats it out of you a little bit. It tries to get you in line with the mainstream and puts taboos on certain questions. And I hate that. So I think a lot of people with letters are genuinely curious people by nature. To go through a PhD program, we've both done it, but you kind of need to like science to sign up for this. But I don't know that the training program actually cultivates asking hard questions. And so I guess what I broaden and say is like, I believe, and I think you believe too, this idea of being skeptical and asking questions and quite honestly being a scientist, it's completely distinct from letters, which have their utility optics-wise, and neither of us will disagree with that. But the process of, hey, apply this to yourself, experiment, be skeptical, iterate, and come to conversations with openness and true curiosity. That is universally human. And the last thing I'll say is, you know, there's a lot of pessimism when you look at population health, the direction our metabolic health is going with, you know, as a country. But the conversations we have here and the access to information and the information you provide via, you know, your conversations with Stephen and, and elsewhere, it provides the power for people not to be a statistic. Screw what normal is. Screw what convention says. You don't need to be going down a normal path. You can take the information provided to you, apply it to you, and always be the outlier. Like, it's not a roll of the dice where you fall. It is through a systematic, controllable approach that you end up where you end up. So take you, for example, you've had like perfect glycemic control, which doesn't happen for a type 1 diabetic for, I think, 12 years. That is not you roll the dice lucky. It is that you understood the physiology in your body and you applied science-based approaches that are out of the mainstream to get the result you wanted. Not a roll of the dice, but controllable and actionable. I just really wanna emphasize that.

So I'm gonna disagree with you here, Nick. I'm gonna disagree. I'm gonna say that number one, it's very much about the process of this. So, Nick, you're very curious, you're very skeptical. So, but I will agree on one— I disagree that the process is inherently beating you, beating it out of you. I will say that there are key moments that are very inconvenient along the way in science, where it's easier to go the path of least resistance and it's easier to not be skeptical. And that does lean people into a lane of following the mass of opinion and consensus. Absolutely. And if I had done that, I wouldn't have normal glycemic control for the last 12 years. So that's Absolutely true. However, I think that science in and of itself as a practice hopefully teaches people that there is an opportunity to look at prior literature, come up with a novel question, and actually test it and rely on the evidence you see in front of you. And if you— and ideally duplicate that or maybe do even more than that. To come to a solid ground on what you see. But there's always a moment that I've seen for most people in the journey of, let's say, if they decide to get a PhD or not, or whatever the training may be, but it doesn't require a PhD by any means to be able to understand a lot of the stuff we're doing. Again, it is just letters, but the process in and of itself, what I found along the way, and I found is the case for a lot of other people, is that there's some point along the way where your most dyed-held beliefs are shattered by some information you come across. Things that you thought were just absolutely true, uh, essential and important, like they must be true, are absolutely shattered. I have seen that a lot of people who have that experience come out and realize Wow, the things that I thought were true when I held dear, almost like almost to my heart, were obliterated. And I think that is an opportunity to go forth with an open mind, even to the beliefs that you hold most dear. And I think that if you have that experience, it can be incredibly, incredibly powerful. But it is about the type of experience you have, and there is absolutely a whole system in academia and evidence that, that leans into just going with incremental, very slow progress along consensus lines. 100%. Anyone who says otherwise is lying. It is absolutely the case. It's totally incentivized right now by how things are funded, and hopefully that will change. But it— but I hope that those who go about the process have an opportunity like I did, where some of the most dire hell beliefs were literally shattered and obliterated. And actually, in my case, multiple times. And it gives you an opportunity to, to be apprehensive, to just inherently believe and go into it with a curious mindset. Actually, you know, hashtag stay curious for Dr. Norwitz here.

So yeah, no, that's very well said. So I'm going to reluctantly let you go. But before I do, where can people find you?

People looking for more information? I stay as active as I can be on X and Instagram. I also have a website called andrewkutnick.com where I try to put a lot of resources or a place to contact me if you do have a question or otherwise. So look for me there.

So thanks so much, Andrew.

Thank you, Nick.