The Peter Attia Drive - #300 - Special episode: Peter on exercise, fasting, nutrition, stem cells, geroprotective drugs, and more — promising interventions or just noise?

Episode Date: May 6, 2024

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this special edition celebrating 300 episodes of The Drive, Peter discusses a variety of popular topics and health interventions and classifies them based on their level of evidence and relevance using the following categories: proven, promising, fuzzy, noise, and nonsense. Peter first delves into the topic of geroprotective molecules, covering rapamycin, metformin, NAD and its precursors, and resveratrol. Next, he explores the significance of metrics like VO2 max and muscle mass, as well as emerging concepts like blood flow restriction and stem cells. The conversation extends to nutrition, addressing questions surrounding long-term fasting, sugar consumption, sugar substitutes, and the contentious role of red meat in cancer. Peter not only provides his current stance on each topic—most of which have been covered in great detail in the previous 300 episodes—but also reflects on how his opinion may have evolved over the years. We discuss: Defining the categories of “proven, promising, fuzzy, noise, and nonsense” [3:15]; Rapamycin [9:30]; Metformin [17:00]; NAD and its precursors [24:30]; Resveratrol [32:45]; The importance of VO2 max, muscle mass, and muscular strength for lifespan [38:15]; Blood flow restriction (BFR) training [44:00]; Using stem cells to treat osteoarthritis or injury [51:30]; Fasting as a tool for longevity (and why Peter stopped his fasting protocol) [55:45]; The energy balance theory [1:06:30]; The idea that sugar is poison [1:12:00]; The idea that sugar substitutes are dangerous [1:22:15]; The debate on red meat and cancer [1:28:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free.

If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to PeterAtiyaMD.com forward slash subscribe. Welcome to a special episode of The Drive. Today we celebrate our 300th episode. To celebrate this milestone, we're going to do something a little different for this episode, but it's going to mirror the structure of a recent interview I did, which I thought was kind of interesting. For today's episode, we're going to cover a variety of topics which you have all weighed in on and I'm going to rank them

into the following categories, proven, promising, fuzzy, noise, and nonsense. A couple of months ago, some of you may recall, I put out a video on social media where I asked people to weigh in on the types of topics that they wanted to hear covered and we got a lot of responses, literally thousands of responses. We've sorted those into different categories and we're about to cover half of them here. Turns out the response was far in excess of what we predicted and we'll have to finish this another time. But nevertheless, in this conversation, we're going to cover geroprotective drugs, including

rapamycin, NAD and its precursors, metformin, resveratrol. We're going to talk about VO2 max, muscle mass, blood flow restriction, stem cells, and then we talk about nutrition, specifically questions you had around long-term fasting, sugar, sugar substitutes and the role of red meat in cancer. All of these topics have generally been covered in greater detail across the previous 300 episodes and or across our newsletter over the past 10 years. We will certainly point you back to areas where we go into great detail into these topics. But the goal here today is that if you're coming to these topics without any background or you just want the TLDR, this is the place for you.

So as such, if you wanna learn more, of course, check out the show notes, both here and elsewhere. And I would just say before we jump into this, I wanna thank everybody for being a part of The Drive, whether this is your first episode or your 300th, it is an absolute honor to be learning in front of you. And that's exactly how I feel about this. So without further delay, please enjoy this episode

celebrating 300 episodes of The Drive and Counting. Peter, welcome to a special podcast. How are you doing? Very good. Thank you. So today for this episode, we are actually celebrating 300 episodes. So I think the first question is, did you ever think we would get to episode 300 when

we started this seven years ago, recording the first few? Was it seven years ago or six years ago? Well, it's launched in June 2018, but we were recording previous because the original episodes were you doing book research. Right. Yeah, that's right. So started having some of these discussions in 2017. I never really thought about it.

To me, it was like binary, right? We started it as a 12-part series and it was like either this is going to be uninteresting, unhelpful, useless in which it dies, or it's gonna be potentially interesting and valuable and we'll keep doing it. But once we hit that binary spot where after three months we said, yeah, let's keep doing it, I never... And I never really thought of milestones in that way. So what we like to do for every hundred episodes

is kind of just do a special episode, something a little different, release it to everybody, shot as an AMA, but just a little bit of a different style. And so when we were thinking of how we wanted to do this one, release it to everybody, shot as an AMA, but just a little bit of a different style. And so when we were thinking of how we wanted to do this one, we thought of a recent interview you did, which was structured in a way we kind of liked, which was you giving your opinion on various drugs,

supplements, behaviors, interventions, and putting them in the following categories, proven, promising, fuzzy noise, nonsense. And we thought it was kind of a cool way to go through and talk about some of these different things in a little detail and categorize them so people could understand how you think about them, how you apply them to your life, apply them to your patients. And so a lot of what we're going to cover here and a lot of these topics are things that we've covered in various podcasts, newsletters, and we'll link to those.

So the goal here isn't to be super in-depth, go through all these studies, all this background research. We'll link to those in the show notes for anyone who's interested. But this is gonna be more conversation where it's, patient comes to you and said, Peter, I'm thinking about rapamycin. Should I take it?

How do you think about it? That kind of style. So we have a lot to cover. I take it? How do you think about it? That kind of style. So we have a lot to cover. I think it will be really interesting. So with all that said, before we start anything you want to add, all the content for today's podcast is coming in from an Instagram post that I put up several months ago, basically saying that we were going to do just that and asking people to leave their comments and then some very unfortunate soul on our team had to go through two or three thousand comments

and tease out the threads because obviously there were a lot of repetitive ones. I think what we should also explain to folks is what emerged was a really good list of which we will do half right now because that's how much good stuff emerged. That's how many good questions emerged. Not going to wait until episode 400 to come back and finish the other half of that list, but yeah, everything that we're talking about today has come out of listener questions that came out of that Instagram post. I guess I'll just say one more thing about we use the terms proven, promising, fuzzy

as heuristics, but what do I really mean by those things? I want to be really clear and people have heard me say this before. In biology, there is no such thing as proof. This is not physics or mathematics. I would say even physics, you might argue outside of theoretical physics, but in biology, it's just all probability. When we say proven, what we're really saying is what we're talking about has such well-established data that the probability that it is untrue is so small that it would be foolish to not act on it. Now, conversely, promising says the claim looks really good. There are a lot of data

supporting it, but there's a piece that's missing. There's something that's missing from a data perspective. Either there isn't just quite enough human data, or there just isn't quite enough RCT data, or there just isn't quite... There's some slight thing that's missing that would keep you from saying this is effectively proven. that would keep you from saying this is effectively proven. Fuzzy is really going to be shorthand for there are some data around this claim, but they might be not the best data. They might be inconsistent. They might be contradictory.

I don't just mean one study is contradicting another study, but it's like, no, there's real contradictions here. And therefore, we clearly need to do more before we could elevate this. Noise is an interesting category. And it largely says that the data out there today are not of sufficient quality to make a judgment. But there might be something kind of compelling that could move this in the other direction. For example, there might be very compelling mechanistic data.

There might be a very compelling biochemical story around an idea, but the data have just been too small, too incomplete to even elevate it up to fuzzy. And by the way, noise can quickly turn into nonsense when you shine enough light on it. And nonsense basically says, no, actually this has been studied and it's bunk. We really have a high degree of confidence in saying that there is nothing there that should be paid attention to. And that doesn't necessarily mean it's harmful,

but it means that this is not doing what people say it is doing. All of that takes a long time to explain, so I don't want to have to explain it every time. But I think explaining it upfront hopefully gives people a sense of where we are. And then, of course, with each example, we'll provide enough detail to rationalize

that position hopefully. Yeah, another thing to add to there is, let's say we did this in another hundred episodes, what we're gonna talk about with new evidence can easily move up or down the chain. So it's not even like this is how it is and this is how it will be, and that's the beauty of science.

And what we've seen a lot of is as new evidence comes out, you're happy to change your opinion on what you think about things. Yep. And if we did this a hundred episodes ago, I can even look at this list and tell you things I would have said different a hundred episodes ago. And I would be foolish to suggest that a hundred episodes from now, if we come back and revisit this list, I will have the exact same things to say about it. I think that's very unlikely.

Well, let's get into it and we kind of categorize the different things we'll talk about. So there's themes to these sections. And the first theme is geroprotective drugs, molecules. These are rapamycin, metformin, NAD, resveratrol. We'll start with rapamycin, but before we do, do you just wanna quickly remind people your definition of a giroprotective drug

and kind of how you think about that? Yeah, so giroprotection really talks more broadly about mechanisms that target hallmarks of aging. So a giroprotective drug would be a drug or a molecule that you're taking, not because it necessarily provides benefit in one arena against one chronic disease or one symptom, but rather because you believe it is fundamentally altering the biology of aging. And as such, taking this drug moves things in your favor, and that should mean that you would live longer taking this drug.

And so that's a very high bar. There are lots of drugs that are really effective at doing things that wouldn't quite rise to the level of being sort of Giro protective. So with that said, let's start with rapamycin. Obviously a molecule we get asked about an insane amount seems like its popularity has gone up. What do you put Rappamycin in? I'm going to put Rappamycin in the promising category and hopefully in a minute or two or three, I'd like to convince people of why I think it's promising but clearly not proven. We've covered Rappamycin so much in other podcasts and this podcast is in

no way meant to displace or be a substitute for those things. So if you really want to go deep on this, you got to go back and see the content in the show notes. We will link to all the places where I've done this. But at a high level, rapamycin is a substance that was discovered from a bacteria discovered on Easter Island in the, God, probably the mid-60s, 66, 67. Bacteria if I'm not mistaken was Streptomyces hydroscopicus, at the time a very novel organism that had never been discovered anywhere else. It secreted this chemical that was named rapamycin to honor the island where it was discovered, Rapa Nui.

And this molecule was clearly found to be a very potent antifungal and that made it a very logical choice for a bacteria to have evolved to produce it. Bacteria is obviously trying to fight a fungi. By inhibiting that through this molecule, the first thought was, hey, this might be the next cure for athlete's foot. Through stories that are really interesting to me from a historical perspective, but I won't get into for the sake of time, ultimately that drug, which almost died a thousand deaths due to lack of interest, finally was championed through a guy named Suren Segal, who has since passed away. And Sureiren single-handedly basically figured out utility for this drug that ultimately put it on the map

as a drug that found its ultimate clinical application in organ transplantation as an immune suppressant. So in 1999, the FDA approves this drug for organ transplantation, solid organ transplantation, and it spends the next decade in relative obscurity. This is literally when I was in my residency using this drug amongst a cocktail of others for patients who had received heart transplants, kidney transplants, and liver transplants, which were mainly what we were taking care of.

Fast forward to 2009 and a very well done study is published as part of the interventions testing program that looks at the use of rapamycin in a very well documented strain of mice that are far more representative of what happens in biology than the typical strain of mice that are used in a clinical research setting. The rest is history, basically. That study showed more convincingly than any other study in the ITP history that rapamycin extended life in male mice, in female mice, and most importantly, when initiated very late in life, a period of time in which no other drug had ever been able

to extend life. Of course, this was replicated many, many times in the ITP and elsewhere. Was also replicated in other model systems, meaning it wasn't just replicated again in mammals. People went back and asked the question, how does this drug rapamycin, which inhibits mTOR, how does it work in yeast, in fruit flies, in worms, which by the way, constitute about a billion years of evolution. And it turns out that it always seems to work. And so it's for all of those reasons that I say, wow, this is really promising, but

why can I not say this is proven? And the reason I can't say it's proven is we don't yet have sufficient evidence in the organism of interest or the species of interest, which is us. And the reason for that is that while there have been some interesting studies done in human, and we'll point back to a podcast that I did with Lloyd Klickstein and Joan Manek, there are clearly short-term studies that demonstrate that the differential dosing pattern of rapamycin can actually produce immune augmentation and immune enhancement rather than immune suppression. That doesn't quite translate to the question that many of us want to know the answer to, which is, hey, if I take rapamycin intermittently, as demonstrated by these shorter human clinical trials,

will that translate to not just better immune function, but a longer life? And so absent really good biomarkers for some of these hallmarks of aging, I think we still have a ways to go before we could say the following, rapamycin is zero protective towards humans and taking rapamycin according to protocol X will add years to human life and presumably improve health span. That's an enormous claim

where I say a lot of work still needs to be done. And some of that work I think needs to be done in other animal models, such as what Matt Caberlin is doing in the dog aging project. And some of that work actually is going to need to be done in humans using biomarkers that have yet to be developed that will be substitutes for some of these more important cellular markers of aging. And so I think it's important too, because you've been open in other podcasts, mainly with Matt on how you take rapamycin, but even though you take it, and with all you said on why you think it is promising,

that doesn't mean you necessarily think everyone should just go out and blindly take it. Not all of your patients are taking it as well, correct? Very few of my patients are taking it. I would say, I don't think 10% of our patients are taking rapamycin. And the reason for that quite simply is, unless a patient is willing to go down the rabbit hole

with me on understanding this and understanding the risks and probabilities and the uncertainty, I just don't view this as something that is responsible. And of course I know that there were many physicians out there who are giving out rapamycin like it's tic-tacs and chiclets. The truth of it is we're not seeing a lot of horrible things happening. Clearly in the short run, that doesn't appear to be a problem.

I also think it's irresponsible to represent that we know that that's going to lengthen life. That's why I think there's a bit of a disconnect in my willingness to have been taking this drug for the past six years and my hesitation in just sort of giving it to anybody who walks in the door. Moving on to the next topic within Geoprotective Drugs, Metformin. Where would you place that? Well, I'll say today I would place it in the fuzzy category. I actually would have put this in the promising category 100 episodes ago. We're going to point people back to a podcast that I did with Andrew Huberman last year.

It was a journal club that we did where I talked about what I believe are the two most important, large epidemiologic papers that are trying to address this question indirectly. I obviously won't rehash that in all the great detail, but these two studies, the first one was done in 2014, the second one in 2022, I think represent the bookends of an observation that creates a lot of interest. I think this is a great example of where epidemiology is very helpful. In 2014, Bannister et al. published something

that at the time was almost impossible to believe. I certainly remember reading it in real time. I remember getting an embargoed copy before it came out and just really being shocked. So the study at the surface looked at people who had type 2 diabetes who were taking metformin and people who did not have type 2 diabetes and who were obviously not taking metformin. And it asked the question, who had a lower all-cause mortality rate? Now, of course, we know that people with type 2 diabetes

are gonna have their lives truncated by an average of six to seven years relative to someone without type 2 diabetes. So you wouldn't think that the addition of metformin to somebody with type 2 diabetes would materially affect that. Maybe it would close that gap from six and a half years to four years or something like that.

But in fact, what the study found was no, the people taking metformin with type 2 diabetes actually lived slightly longer than the people who did not. In fact, there was about a 15% reduction in all-cause mortality over a three-year follow-up period. Obviously, it's done in an enormous population using a UK biobank dataset. That paper, I believe more than any other paper, set the stage for the excitement around Metformin as a Giroprotective compound. Because what's clear is that the diabetics taking metformin still had inferior glycemic control to the non-diabetics.

In other words, if they're living longer, it's not because they have better glycemic control. It would seem to be that they're better because of something else that metformin is doing outside of managing presumably hepatic glucose output. Now, I've had Nir Barzili on the podcast twice and will again encourage people who are interested in this to go back and listen to those podcasts as well because Nir has argued that indeed metformin is Giro protective and that there are many benefits to metformin that completely transcend its properties within the liver for glycemic control.

But I have become less convinced of that. And so I think, as I talk about in the podcast with Andrew, I think there were a lot of holes in the Banister study. And I think they center around methodology, something called informative censoring, where the patients who were in the metformin diabetes arm were censored out of the analysis that demonstrated a reduced mortality if they were lost to follow up or if they had a medication change. Usually a medication change on someone who's only taking metformin

is meaning that the disease is progressing, so you're adding another medication. So the problem with that is, I think, obvious when you realize that you were censoring out people who were sicker, and you were actually selecting for the healthiest possible people, not to mention the fact that you're also not doing this in a randomized fashion and I cover all of that detail elsewhere.

So the follow-up study, which was done by Keys et al. in 2022, basically sought to improve on the methodology of the Bannister paper. And it did something quite clever, which is it repeated the analysis using a different patient cohort. So it's a Danish patient population cohort, but it set up two studies within the study. One very similar to what the Banister experiment was,

and then one using a set of twins who differed only in that one had diabetes and one didn't. That's a clever design and it's hard to do. And they actually found the opposite. They found exactly what you would expect to find, which is whether you were talking about identical twins, fraternal twins, unrelated people, if you had type 2 diabetes, even if you were on metformin, your risk of mortality was significantly higher. It varied anywhere from 33% higher to 80% higher depending on the covariate analysis and the cohort that was being looked at. Again, this was much more consistent with what one would expect. This is, I think, a better analysis for several reasons. Here's what's most interesting though, Nick.

They actually went and then did an informative censoring analysis to see if indeed informative censoring was exclusively responsible for the results in the Bannister paper. It turned out it wasn't. In other words, even when they repeated that methodology, they still produced the finding you would expect. In addition to this, I think the other reason I would continue to keep metformin in a fuzzy category as opposed to a promising category at this point, and remember, fuzzy doesn't mean it doesn't work. Fuzzy means we need more data to upgrade, is that metformin has failed in the ITP.

We'll link to both of the podcasts with Rich Miller where we talk about the ITP in detail and why the ITPs are such impressive studies and why so few molecules have succeeded in the ITP. But metformin is not one of them. In fact, the only time metformin to my recollection has ever been positive in an ITP was when it was combined with rapamycin. But metformin alone did not succeed, whereas other drugs such as Kinega, Flosin, Acarbose, Rapamycin have succeeded. So, I don't want to go on too much further because again, this content exists elsewhere and I just want to really focus people on the high level. My view today is that Metformin is in the fuzzy category.

One other thing I should say is that there is a study that is eventually getting funded. In fact, it might, I mean, technically I guess it is funded. I don't know if it's began enrollment yet called the TAME study. And the TAME study is going to attempt to answer this question in humans by studying disease onset in susceptible but otherwise healthy individuals. And that's why I think it's safe to say that, look, whether it's episode 400 or episode 500, we are definitely going to be talking about Metformin again.

Yeah, definitely. And kind of going down the GER protective, we talked about RAPA, talked about Metformin. Next one we get asked about all the time is NAD. Also one we've covered in various podcasts. But looking at NAD, how would you put it into a category? When we talk about NAD, we're really talking about multiple things. We're talking about

NAD itself, but I'm also speaking a little bit more broadly. I'm talking about precursors because NAD can't be taken orally. It could be given intravenously when there are lots of clinics out there that do that. But from a practical standpoint, we tend to look at things that you can take orally. So we really tend to be talking about NR and NMN, which are oral precursors that become converted into NAD. But again, let's just provide just a touch of context here. So NAD is discovered more than 100 years ago. Over time, I think

people come to understand it's a very important signaling molecule. It's a very important part of cellular metabolism. Oh, and by the way, it declines with age. Now you have this thing that's super interesting and super relevant and completely ubiquitous. As we age, it goes down. Understandably, in the early 2000s, it became a very high interest topic. It further became of interest when it became linked to something called sirtuins, which I'm going to talk about in a minute. So basically, sirtuins are proteins that require NAD to deacetylase lysine residues, which is just fancy chemical talk for it changes the modification of an

amino acid. But this is something that occurs so much and is so important to maintaining DNA integrity and managing oxidative stress that basically there were two hypotheses, broadly speaking. One hypothesis is the reason NAD levels decline with age is because DNA damage goes up with age. That's true. We know that that's true. So are those two causally related?

Is the rise in DNA damage with age driving an increase in NAD utilization and that's why NAD is going down? Or are these uncoupled? Is DNA damage going up with age, which it is, and is NAD abundance going down with age for a separate reason and, oh, if we only had more NAD, we could offset more DNA damage? I think it's safe to say we don't yet know the answer to that, but nevertheless, I think a cottage industry around NAD has come up which says, look, we know the answer to this or at least we're going to postulate that the answer is of course NAD is going down with age and whether or not that's causal or not, giving more NAD is going to be a better

thing. Okay. So what do the data have to say? And again, this is an area where, I mean, there is a remarkably booming industry around the administration of NAD and its precursors. It's actually surprising how little data is out there. So what I thought I would do is try to highlight perhaps the most promising data I could see. And hopefully by sharing why that's not so promising or why that's really, really small, you might be convinced of my view, which I should have said at the outset is I kind of think this

NAD stuff is noise at the moment. I'm putting this in a category even below fuzzy, but to be clear, I'm not putting it in the nonsense category. What that means is there may still be clinical scenarios under which this makes sense, even if it is not Giroprotective. Again, very important distinction here. I'm going to talk about a couple of studies in neurodegenerative disease, one in ALS, one in Parkinson's disease, that are both so small and quite frankly, just so, I don't wanna be disparaging to the studies, but not amazing studies, but reasonable first attempts at looking

that maybe there's something there and maybe in these scenarios, there is a benefit. But again, we're asking this through the lens of Giro protection. We're really asking the question in this context of, hey, if I take a bunch of NAD precursors such as NR and NMN, am I going to live longer or even live significantly better? Again, I think the answer to that question is noise. The ALS study gave patients pretty high dose of a combination drug of nicotinamide riboside,

so NR and terastilbene for four months. Then it followed basically symptoms of ALS on a functional scale. Unfortunately for anybody who has known a patient with ALS or a family member or anything like that, it's top three most debilitating diseases in the history of our species. And unfortunately, there is no cure and the end is just a very tragic end. And so what this study was basically asking is, look, can we delay this in any way, shape or form? And the short answer is at least on one of the functional scales of progression, the answer appeared that yes, this compound of nicotinamide and

terastilbene actually delayed progression by a short period of time for these patients. Now again, this was a very small study. Clearly, this would be a phase one study. So first and foremost, you're just making sure, hey, there's no toxicity, which there wasn't. And you're basically saying, is there any smoke anywhere that makes me think there's a fire? I believe there is a phase two trial ongoing. My hope is that the phase two trial is significantly larger, has robust inputs, and therefore can shed light on this question. Let's be clear. If there is a compound out there that can keep a patient off a ventilator longer when they have ALS or can prevent secretion issues longer

or respiratory distress longer, by all means, that's a very important thing to know. The other study I would reference is also a very small study that was done in 20 patients with Parkinson's disease. 10 were put on mycotinamide riboside, 10 on a placebo for four weeks. It saw some change in one of the movement disorder rating scales that's used to subjectively quantify movement in patients with PD. There's a bit of a catch because there was a confounder in that some of those patients were closer in their last dose to levodopa, which is a medication that in the early stages of the disease is quite effective at improving movement.

It was not a very well done study. I think the most charitable thing one could say about that study is look at maybe suggest that there's something there worth looking at. I don't think that that would even rise to the level of being as compelling as the standard therapies that are used for patients with Parkinson's disease. There's one other study that looked at MCI, I believe, mild cognitive impairment, and it looked at NAD use. I believe it was studying some aspects of memory and physical function,

it showed some improvements in physical function, which again would not be the primary concern for MCI, but it did not show any improvement in cognitive impact. By the way, it might mean that there is an improvement in cognitive impact, but not over such a short timeframe. The test, because it was a phase one study, was too small to actually see a signal. You weren't powered to see a signal, which by the way, is not always the case was a phase one study, was too small to actually see a signal. You weren't powered to see a signal, which by the way, is not always the case in a phase

one. Where do I land on all this? I think that the evidence that NAD and its precursors is zero protective, meaning we are going to take a bunch of people who don't have disease and we're going to make them live longer. I think this is a very, very low probability, but not zero. And again, I think the probability we're not going to be talking about this one in another hundred episodes is pretty low. In the spirit of, well, how much do I believe in this? I don't take

these compounds. I don't take NAD infusions. I don't take NR. I don't take NMN. And it's certainly not because there isn't an abundance of those things out there, but that I guess tells you my level of confidence in this. Rounding out the kind of Giro protective drug category is the final one we get asked about a lot, which is resveratrol. So where would you rank that and kind of how do you think about that compared to the three we've talked about so far? I have to be honest with you. I was really surprised when you guys sent me the list that resveratrol was on it, because the implication is that it had been asked enough

in that survey we put out there that people wanted to hear it. And all I have to say is, wow, I'm amazed people are still talking about resveratrol. This is absolute nonsense. I'm just saying, we're gonna put this in the nonsense category and we never need to talk about this again. In other words, there's not just an absence of evidence,

there's actually evidence of absence here. Risveratrol is a phenol. It's a chemical that activates sirtuins. Understandably, in all the early 2000s hoopla around sirtuins, which we just talked about a second ago, the view was like, oh my God, sirtuins are good. They're repairing DNA damage. Risveratrol is an activator of sirtuins. That's gotta be good. Away we go. A landmark study, quote unquote, in 2006 garnered

an unbelievable amount of attention. Now, I think the attention was just as much from the fact that in minuscule amounts resveratrol is found in red wine. It wasn't just that, oh, we have another molecule that in some obscure mouse model maybe seems to extend life. I think it was, oh, and by the way, this molecule at about one one hundredth the level is found in red wine. On a serious level, is this an explanation for the French paradox? On a clickbait level, does this mean we should just be drinking as much wine as possible? That's the only explanation, Nick, I have for why this story gathered traction and why it continues to this day to cloud the judgment of

folks. But as we covered in great detail on the podcast, the first episode with Rich Miller, the 2006 mouse resveratrol study was at best misinterpreted. So there was indeed a longevity benefit, but it's a very obscure model, right? So it was a mouse model where the mice were fed a diet of 60% coconut oil. I can't imagine what that would be like for 10 minutes, let alone for the duration of a mouse's life, especially when we consider mice or herbivores that wouldn't be eating coconut oil. They're not eating that much fat.

You have these mice on 60% coconut oil diet and the cause of death was so much fat accumulation in the liver that the liver expanded into the hemithorax and collapsed their lungs. Again, usually when we do experiments with mice, they die based on their genetic predilection to die of cancer. We're typically trying to ask the question, like in the case of rapamycin, like you give rapamycin to these mice, they get less cancer than these mice. Well, no, no, no.

Here we're force feeding them coconut oil to turn their livers into big blobs of fat that expand into their chest and compress their lungs. And it turned out that under those conditions there was a longer time to death on average, median lifespan, if they were on resveratrol than if they were not. It turned out, by the way, there was no difference in maximal lifespan. So you didn't shift the curve of mortality for the top 10% of mice, you just shifted it for the median mice. Somehow that generated all of the interest in this drug and very few people paid attention

when the ITP came along and said, we're going to study this really, really rigorously. We're going to study this in mice that are not kind of genetic mutants and we're not going to force feed them fat. We're going to give them normal mouse food and watch them die of normal mouse deaths. It made no difference. They gave them 300 milligrams of resveratrol per kilo of food, which is 300 ppm. Again, just for comparison sake guys, wine is like less than 2 ppm, parts per million of resveratrol.

They're giving them 300 PPM and nothing happened. Now, the folks who say resveratrol works have criticized that study saying the bioavailability is low and therefore you need much, much, much more than the 300 PPM that was given in that study. But again, that was a concern and a criticism that was only voiced after the study. The proponents of resveratrol were involved in that study and they signed off. They're on the paper. I mean, this was their view. So,

I just have a hard time believing that there is any value in resveratrol. That's why I don't take it independent of the fact that it's still a ubiquitous compound that's found everywhere. Yeah, and I think that wraps those four different drugs in that, and I think that's why sometimes it's nice, hopefully for people, when you cover a variety and you can see how they fit in different buckets and kind of how you think about it. And again, even you highlighting

where your opinions changed and where it may change again in the next 100 episodes, depending on new science. And so looking into the next category, which kind of is a little more focused around exercise, I thought it'd be helpful to maybe start with a few anchoring things that you talk about often. And just so people can kind of understand where you put VO2 max, that's importance and muscle mass and that's importance on this scale and so

Obviously, we don't have to get into these because there is an insane amount of content on those But if you had to summarize quickly where you would rank them on the scale that we're doing today Where would you put VO2 max? Where would you put the importance of muscle mass? And by the way with muscle mass I would put muscle strength because we really think of muscle mass as a proxy for strength But I would say that those are the two closest things you could put to proven They would be right up there with smoking cessation. They would be right up there with blood pressure management You can't prove anything in biology

But boy the probability that having a high VO2 max, high muscle mass and high muscle strength are going to increase the length of your life and improve the quality of your life, that probability is so high that to act in disregard of that is irresponsible. That's what I really mean by proven. So what can I say? There's very little on this topic I have not expounded on both on this podcast and on others and social media.

I mean, this is a topic I can't say enough about because the magnitude of the effects is so much greater than everything else. And you can see Nick why I get animated and why I get phosphorylated when people ask me about resveratrol and sirtuin activators and NAD and NR and they're not exercising. Or they're exercising, but their exercise is totally JV. It's like, wait a minute. You are picking up pennies in front of a steam train, fighting over basis points of theoretical possible benefits of something.

You're completely missing this other thing over here. You've heard me tease folks, including patients, sometimes and say, look, once you've got your VO2 max here and your muscle mass here and your strength here, then we can talk about the 37 supplements that you're interested in taking. I don't know, Nick, how much more do you want me to say on that that I haven't already said? No, I think that's good. We'll link to say on that that I haven't already said? No, I think that's good, and we'll link to it in the show notes too, all the other places.

I think sometimes it's helpful for people, or at least even myself included, is understanding where these things rank and how they compare to others, which you hit a really important point, which I've heard you say over and over and over, internal, external, which is if you're worried about taking all these geo protective drugs and you want to take them, that's your prerogative. But if you think

that's going to save you from needing to exercise, needing to have muscle strength, needing to have a higher VO2 max, it maybe is not the best risk mitigation strategy. And I think how you look at all this is how can you mitigate the risk of not being capable of having a longer lifespan, but also even more importantly, a better health span. Yep. I do say a lot that even if exercise had no effect on lifespan, so it was lifespan neutral or be more dramatic. Even if exercise slightly shortened your lifespan by a year, it's undoubtedly worth it for the improvement in the quality of your life, both physically and cognitively and in many cases emotionally. I mean, that's a much harder one to quantify, but I think that's there.

And I guess the other point I will make to bring it back is like, why is it that VO2 max muscle mass and strength stand out as the greatest predictors of lifespan, which they do. These stand out as far greater predictors of lifespan than cholesterol levels, blood pressure, blood glucose, all of these things that clearly relate to how fast you're going to live or die. Even smoking is a worse predictor of lifespan than your fitness level. And the reason I think is just it speaks to how potent exercise is as a tool to impact

the cellular processes of aging, but it also speaks to the fact that you can't cram for the test when it comes to these tests. So if a person has a high VO2 max, they have been doing a lot of exercising for a long time. That doesn't have to mean their whole life, but they didn't just decide a week ago, oh, I'm kind of unfit, but I'm gonna start exercising and I'm gonna get fit. No, no, no, no. If your VO2 max is in the top two or 3% of your age group,

you've been at this for a while. Therefore the VO2 max measurement is really an integration of work that you have done. And the same is true for muscle mass and more importantly, for muscle strength. These things like why is, you know, grip strength always comes up as this incredible predictor of mortality. Is it because being able to squeeze things with your hand

is especially important? Yeah, there's probably some edge cases, but it's what does it imply if you have high grip strength? You didn't just wake up and have high grip strength. By definition, you have been lifting and carrying heavy things. You have been using your hands aggressively, manipulating things, carrying, squeezing, all of these things, pulling. And it's that work that is being captured through the integral of the final metric or the test. Lyle Orr We won't get into it too much here, but one

of the questions we always get asked is by people in older populations, 50 plus, is it too late for me to start exercising? And we have a special episode that will be coming out in a few weeks dedicated to that. So for those of you who are maybe haven't been exercising, you're wondering how to start and you are in that older category where you don't wanna get hurt, that will be a really good resource there.

Moving to the next topic, something we get asked about, especially after the podcast we did with Jeremy Lenike, which is blood flow restriction. And I think when you look at the muscle mass, muscle strength, sometimes people are dealing with injuries. Sometimes people maybe don't want to lift heavy weights and they're kind of dealing with various orthopedic injuries, whatever it could be.

How do you think about blood flow restriction and where would you rank that in this ranking system? I put BFR in the promising category. And again, it depends on how you define the question, but is the question does using BFR and higher reps, lower load weights produce superior results to the same reps, the same weights without BFR, it's promising slash proven. That is clearly the case. So again, just kind of backing up for a little bit and for those who didn't hear the podcast on this or who need a little refresher. So this

is a topic that became of interest not that long ago, right? Maybe in the last 25 years or so when it was demonstrated that if you applied a tourniquet around a limb as it was exercising, you would see superior improvements in strength and muscle size relative to an untourniqueted limb, again, provided they were both doing the same amount of work. The question is why perhaps? Why is it that applying a tourniquet? Well, anybody who's done BFR can tell you it's not very comfortable. When you impair venous return slightly, and that's really the goal of blood flow restriction,

it's not complete occlusion, it's partial occlusion. You are allowing the accumulation of metabolites at a much higher rate. So more lactic acid is pooling, more metabolites of metabolism beyond that. And the thought is that something about that is creating more of a stress signal than would otherwise be present absent the tourniquet. So an immediate use case became, well, look, can we use far lighter weights but produce still a profound amount of discomfort? And the obvious place where this showed up, of course, is around injury. So when a person is injured, let's use my example, when I had shoulder surgery, I wanted to be able to still exercise that arm, but for months after surgery, I could not carry,

for example, a barbell that was the same weight that I would have carried before, right? It was still too much pressure on the humerus in its newly repaired joint around the labrum. So what if I used a third of the weight that I might have previously used? I'll do a lot more reps, but I'll create this blood flow restriction around it and I experience a much higher training effect. The data have largely borne this out. And the nice thing about these studies, by the way, this is what makes this type of research really elegant, is every patient can be their own control because you're doing limb isolation. It's a little goofy for the

patient because you're going to have one leg that might get bigger or stronger than the other, but every patient can be their own control. The analyses, the studies, and the meta-analyses, and Jeremy Linnecke, who was the podcast guest we're talking about, I think did a large meta-analysis in 2011. It showed that if you look at low load resistance training in BFR without BFR, it clearly results in greater muscle strength and hypertrophy improvements. It's not subtle. These are really pretty big effects. All of that said, Nick, there's still a question that I don't think we know the answer to, which is how does BFR training at higher reps, lower weight compared to non-BFR training with higher weight and presumably lower reps?

That's a much harder head-to-head to design because the question is how do you design the protocol in each? Now you've broken one of the constants that have been preserved across all of these studies. I think that the answer there is still unknown. As such, I just wouldn't recommend that somebody exclusively rely on BFR. First of all, it's not that comfortable and you can't do it for everything. It's very limb-centric. Even if you were just to talk about restricting it to how you train your arms and your legs, I still think there are lots of scenarios where using BFR doesn't make sense.

And my personal use of BFR, which I've talked about, is I really like to use it as finishers in, you know, do some sort of upper body finishers and lower body finishers on upper body and lower body days respectively. But it's not really like the bulk of what I'm doing. So that's kind of how I feel about this. And again, I think it is disproportionately useful in the case and setting of a person who is rehabbing something. And it's a great, we use it so liberally with our patients as we're trying to get them moving immediately post surgical intervention.

We want to do it with, I mean, even just using their body weight. For example, a patient that's had knee surgery, the minute we get permission from the surgeon, we've got them doing leg extensions with just the weight of their leg, but doing it with a BFR cuff. There's actually a training effect in the quads, but without overloading the knee because clearly you wouldn't want to post knee surgery, put a strain from the patellar tendon beneath the knee attachment. For people interested in learning more, we'll link to podcasts, but if people want to try

it, do you want to let people know which brand you use? And obviously you can say to you have no affiliation with them. We don't get paid by them or anything. It's just one you've tried a lot of and you found real enjoyment with it. Yep. I use a brand called Katsu. I use two different types of Katsu devices and I apologize. I don't remember the exact name, but one of them is like, maybe it's called the C3 and it's my sort of bread and butter go-to one where I put the arm bands on, put the

leg bands on, whichever I'm using, inflate it to the pressure and then go and exercise. And then they have another one that I really quite like, but it does what are called passive cycles. So if I'm just sort of trying to recover, you put this on, I think it does like a 20 second inflate, hold, deflate, repeat. If I'm sitting at the computer, like I've got this thing cycling on my arms or on my legs. And if nothing else, honestly, it just feels great. Like I really actually enjoy the feeling of it. So yeah, those are

the devices that I use. And there is a real art to this. There's a clinical way that you want to be able to go about doing this, where it's not just put a tourniquet on, which is what I used to do and hope for the best because you have to make sure the pressure is such that you are still allowing both blood in and blood out. You're just trying to blunt that somewhat. It is always funny when we hop on zoom calls with people who aren't internal and you do have those things cycling because it really does make people wonder what's going on over there and what what's wrong with this guy attached. Yeah. And it fits your brand. That's what I always say.

It's on brand when you're doing that and when you're just chopping on venison sticks and meetings too, it's also on brand. So the next one, something we get asked about a ton, it's come up on a few podcasts with Alton Barron, Adam Cohen, looking at the upper body, lower body, but stem cells. How are you thinking currently about stem cells? This is an area where I think it's really complicated. I'm going to put this somewhere between noise and fuzzy.

I'm talking about it through one application for this purpose, which is osteoarthritis, which is where it's been most talked about and most studied in animals. I want to reiterate that. I still find it very plausible that there are arenas in which stem cells could be beneficial. I would say there are actually scenarios under which I would take stem cells if I had a certain injury. If I tore my rotator cuff and it was a marginal call as to whether it was surgical, I would absolutely start with a stem cell injection if it could mean avoiding surgery and waiting for a repair. I would love nothing more, Nick, than to see an actual randomized clinical trial that takes patients

who have torn their rotator cuff, again, let's try to take people with comparable injuries and randomize them into three groups, stem cell injection, surgical repair, non-surgical repair rehab. We could debate the merits of each of these approaches, but I would really love to see that provided there was a way to create a uniform protocol around what it means to get stem cells. In many ways, that's what has been hampering this field, I believe. To be clear, the FDA does not authorize the use of stem cells. So all of this is existing either outside of the United States where it's not

regulated by the FDA or there's some sort of gray areas where it can be done but it's obviously not covered by insurance or any of these other things. Again, if you're presumably using – I'm not even sure how much these protocols are using autologous stem cells versus the stem cells of others. The total lack of consistency in what the actual agent is, the actual stem cell is a big part of what makes this very challenging. And I would struggle with that. Like, so if I were in that situation I just described where I tore my rotator

cuff and I was at least willing to consider doing this before surgery, the hardest part I would have is where am I going to do this? Who do I trust? Because it's not like I can look at someone's data and draw conclusions, right? You're basically looking at a bunch of marketing material, not actual data. So I would say when we talk about osteoarthritis, at least we have the advantage that there are like canine models of osteoarthritis where they've looked at stem cells. And the truth of it is they have mixed results. Some of them have shown that dogs with osteoarthritis

when injected with stem cells do tend to improve their gait, do tend to see a reduction in lameness, which again is partially assessed by gait, partially assessed by the use of medications or pain relief through medications. Other studies have found no benefits whatsoever. Again, it's hard to tease out what that means. Does it mean that the methodologies are flawed and that in some of these studies, they're not actually using the right stem cells? Again, stem cells are very broad term. What are

we really talking about? Are we talking about a pluripotent stem cell? Are we talking about a donor derived stem cell? Are we talking about a fetal derived stem cell? By the way, then I haven't even got into like, what's the concentration of stem cells? What's the protocol? How many injections do you need? Like all of this stuff is still unclear. And as a result of that, we have a cottage industry that is the absolute wild

West. I think it's unfortunate. I wish there was greater financial incentive to study for what the answer is, as opposed to just say, yeah, we know the answer. It works. Or we know the answer. This is a total sham. It shouldn't be done when in reality that truth might be somewhere there. So look, it's very hard to have this above noise right now because of a total absence of data, not because there isn't biological plausibility. There really is, but it's just there's no data. So I clearly am not going to call this nonsense, but this is not going to rise to the level of promising in my mind yet.

Moving on to the next category or theme, which is loosely nutrition, which is something we know how much you love to talk about. And it's also something where I think as we go through these, you can kind of not only give your opinion on where you're at now, but also maybe how that's changed over time. And so first and foremost, what we see the most is questions around long-term fasting and its potential

benefits on longevity. So not fasting to count calories, anything of that nature, but more so how you think about quote unquote long-term fasting as it relates to longevity. You know, it's so funny when you and Josh and the team put this list in front of me the other day, and I got through the first few and I was like, oh sweet, I don't have to talk about nutrition. Then I came to this big block of nutrition and I just wanted to start crying. Did you guys deliberately bury this? Well, you don't want to have it too early so that your mood goes down right away.

But we also know, we get asked about a ton. People are very interested in nutrition. And I need to spend more time with my therapist understanding why I hate talking about nutrition because I do think I have a lot to say on it and I actually think I'm knowledgeable on the subject and I know that therefore I should talk about it because I can add value in a sea of bad information. But the visceral response it produces in me, Nick, it's difficult for me to quantify actually.

I've already forgotten your question. That's how much I'm just in the throes of pain at the moment. Long-term fasting. Okay. I'm gonna call this fuzzy. And to your priming earlier, I'm gonna tell you, this is an area where I've seen

an enormous change in my point of view over the past 300 episodes. By way of disclosure, some people listening to this podcast might know that, and there are many people I'm sure who are listening to this podcast, who came into the orbit of our work through my work in the fasting space. For me, fasting has historically been a very important part of my thinking about how to live longer, how to use fasting as a gyro protective tool. Again, I think a little bit of historical context is relevant here.

We spoke earlier about rapamycin, which stands alone in the pantheon of molecules, the only molecule, the only molecule that has universally extended life across all model systems of eukaryotes, which span one billion years of evolution. That's a big deal. But we shouldn't forget that there is one intervention, non-drug intervention, that has also done that and it did it long before and that was fasting or caloric restriction. So there's clearly something magical going on with caloric restriction when it comes to elongating life. But the question is, can we extend that into humans? And perhaps the more important question is,

what would the fasting protocol be? And I wrote a piece on this a long time ago that maybe we should link to where I say, look, the question is, how long should you fast? To what extent should you fast? And how frequently should you repeat the fast. Those are basically your three variables. There are obviously so many combinations of those. I won't even say infinite because you could just draw a line in the sand and say, you could do a complete fast, you could do a 50% fast, a 75% fast, and just make it somewhat big

and arbitrary. You could do it for one day or three days or five days, and you could do it once a year or once a quarter or once a month. Even if you took reasonable spots, it quickly becomes impossible to test all of these. And so instead, what we're left with is a cult of personalities where people tell you what they do.

And I've been guilty of that, although I hope I've always been clear at saying, I have no clue if this is quote unquote right. What I was doing was doing seven to 10 days of water only fasting once a quarter and then three days once a month on the alternative. So two months short fast, one month at a long fast repeat. Now, what data could I point to for that protocol? None, absolutely none. I made it up. I literally made that up. And again, very transparently made that up.

Were things happening in my body from a cellular level that were beneficial? Probably. Did I have great biomarkers to show that? No, because I was relying on very standard biomarkers. I mean, fortunately, my standard biomarkers are generally quite good. It's not like, yes, your glucose is going to go down, your ketones go up, your insulin

goes down a little bit, but those things are transient. By the way, a lot of things got really bad when you fasted. Your thyroid function completely deteriorated, your androgen function completely deteriorated. It wasn't all good, but what was really interesting is the thing we couldn't measure, which was what was actually happening to those hallmarks of aging. Were we improving at the cellular level, things like senescence, autophagy, all of those things? Well, guess what? We can't measure those things.

So we don't know. We can try to extrapolate. And there was some rationale in my mind, I suppose, extrapolating from what we knew in mice, which is that this many hours of fasting in a mouse does indeed produce cellular changes that are incredibly beneficial to disease prevention. Therefore, given what we know about the relationship between mice fasting and human fasting, it should be that by about five days, I'm gonna be experiencing some of those benefits.

But then even if you knew that were true, then the question would be, well, how often do you need to do that? So even if you could establish that five days was a sufficient length of time to fast, should you do it five days a month, five days a quarter, five days a year? No idea.

So you may ask the question, why did I stop my fasting protocol? And for me, it really came down to two things, but I think the most important was that I just took a kind of look at the data, the bigger data of myself and realized over the course of three years, I had lost, I don't remember the exact number, but it was getting close to 20 pounds of muscle. It might've been 16 pounds of muscle over that period of time, at least at the frequency that I was fasting, which I'm not saying

was right or wrong. It's very difficult to gain back the lean muscle you keep losing. You lose a ton, you regain some of it. You lose a ton, you regain some of it, but I just couldn't dig out of that hole. And so I think in around 2021, I said, you know what, I'm going to just put the kibosh on fasting for now. I'm going to make sure I gained back 20 pounds of muscle that I have lost. That's my personal story with it. Unfortunately, I would still say, Nick, that, and again, I'm glad you separated this out and said, look, is fasting a viable tool for weight loss? Sure. It's one of the tools we have in the CRDR TR kit. By the way, in that regard, I still do it, by the way. Let me also establish, I am still

a TR guy for the most part. Drink my coffee in the morning, I will slug a protein shake in the morning that is very low in calories because it's just protein, so it's going to be 120 to 150 calories. But I don't eat a meal until two o'clock in the afternoon and then I have dinner at six or seven. But again, I'm doing that for caloric restriction purposes. I'm doing that to manage total caloric intake, not because I think that there's some magical benefit that I'm getting by not having meals spread throughout the day. I guess just to put a bow on this topic, why is this fuzzy?

Well, I think it's fuzzy because in many ways this suffers the same problem Rappamycin suffers in terms of getting into much more dispositive clinical trials, which is we're clearly never going to do the experiment that asks people to undergo different fasting protocols for the entirety of their life to determine if indeed they live longer. So we're going to have to come up with better proxies, meaningful biomarkers of the hallmarks

of aging. If we can do that, then maybe we can start to get a sense of whether or not rapamycin and fasting should be important parts of our armamentarium as we think about ways to impact those hallmarks of aging. Two follow-up questions there, one of which is, you mentioned there was kind of two things that caused you to change your mind. The first was the muscle loss and just that. What was the second? The second one was actually was just more of a social issue, which was at the time that I was

fasting, I also happened to be traveling a lot. It was very easy for me to fast when I was away from home. So all of those fasts were done while I was in New York and I live in San Diego. So I didn't have to be fasting around anybody. I was just fasting in my apartment alone. Even if I went out to dinner with friends, which was weird, but I did, I would just sit there and drink soda water while they were eating dinner. Jaco famously tells a story about that one night. Once I stopped traveling, it meant all those fasts are going to have to be done at home and I just didn't want to do it. I don't want my kids to be wondering like, why is daddy never eating and all that kind of stuff.

So that became another reason independent of the biology. So the second follow-up would be, and you kind of hinted at it there, which was you would love to have biomarkers to know if it's working at what dose, how that works, but what would have to be true or what would have to change outside of that if there's anything that would cause you to start fasting again longterm? I don't know. I would really need to see something incredibly compelling

in a higher order model, maybe in a dog model or something like that. Again, like this is a great example of where I think companion dogs are such a great model to study things. Because again, I think most people find binary fasting far easier than caloric restriction. There's already a lot of controversy around caloric restriction. I have an entire chapter on this in Outlive where I talk about the Wisconsin NIA monkey studies. But for most people, like if I said, oh, you just got to reduce calories by 25% for the rest

of your life and you're going to live longer, most people would say, I don't want to live longer. That's torture. It's actually easier to say, well, what if you just have to periodically do big fasts? I would like to see an experiment of that done in a better model than just mice. Definitely. Looking at the next topic, if you look historically since the podcast started, it's a topic that we get asked about an insane amount, which is the energy balance theory. We've had tons of guests on who maybe have different opinions on this. It's something that you've written about a lot, but how do you think about the energy balance theory right now as it relates to the ranking system?

Again, I put this right between promising and proven truthfully. Again, I think it's worth stating what we're talking about. The energy balance theory, I believe, would pause it. Again, I don't live in this world at the moment, so I want to be very sensitive to those who does and I don't want to misrepresent it. If I am misrepresenting this, I hope I hear about it. What it's basically saying is that energy balance is determined solely by the caloric density of the foods consumed less the energy expenditure.

And that the caloric density, the net available caloric density of a food is its contribution to energy balance. This is where again, I feel a little bit bad talking about this because I haven't been as diligent as maybe I should be in staying up on this world over the past decade. I've largely not paid attention to it truthfully because in many ways, I've seen what I believe is a reasonable answer. Just for folks who maybe don't know part of the history here, I was once running an organization that funded research directly to try to answer this question. I think I went into that thinking the answer was going to be one thing, but actually very excited to see regardless a swing at this. I think that that study, while it had some flaws, actually came out and showed something else, which was if indeed isocaloric manipulations of macronutrients

change energy expenditure, it's not an enormous difference. What does that mean in English? If you give two people equally caloric diets that are radically different in macronutrients, do you have a significant difference in energy expenditure? That's what was being tested by that theory. And I think that the evidence is much more clearly in favor of the fact that no, you do not. Now let's add a couple of caveats. There is clearly differences in the thermogenesis of food. So, a thousand calories of protein, a thousand calories of fat, and a thousand calories of carbohydrates are going to have different processing amounts of energy that will result in different amounts of net available energy. Furthermore, different types of foods

are going to differentially impact appetite. And therefore in a free living environment, this isn't to say that macronutrients don't matter, but what we're really trying to tease out is, is there truly a scenario under which a person who's eating 3000 calories of a balanced diet can switch to 3,000 calories of a ketogenic diet and have weight melt off them just because they're on a ketogenic diet. They somehow magically start burning a lot more energy. Again, I believe the answer to that question is

no. I do not see any evidence to support that. therefore, I think that if a person is on 3,000 calories a day of a balanced diet and they switch over to what they believe is 3,000 calories a day of a ketogenic diet and the weight starts pounding off them, I think they're either moving more or eating less than they realize. I've asked you this before and I think it's applicable here, which is how would you respond to people who maybe get frustrated at your ability to change your mind if new data comes out? Because I think you mentioned there you could have people who came in maybe through the fasting content that we put out and was talked about and now they're hearing this which is why I

think again I like this ranking scale because it allows anchoring to things which is this is how I think about it, and this is our confidence interval, and this is how it could go up and down. But just in general, I think there may be, at times in science, a resentment if you do change your mind, and I think that leads to potentially people sticking with their beliefs maybe longer than they should.

And so how do you respond to people who say, why do you change your mind? And should that affect what I hear you say today? So first of all, that's kind of news to me that people are upset about that. I would bet that it's not scientists who are upset at that. I think that any scientist who doesn't do that

needs to be questioned. So in other words, if you can't change your mind in the presence of new data, I think by definition you're not a scientist, you're an advocate. Now, advocacy has its place, but not without science. The only thing I would ask of those people if there are people that are indeed upset at me is what would you propose as the alternative? Is it vexing that I change my mind on things? Yes, I suppose it is if it means that it impacts your belief about what is good to do, what is not to do. But if the alternative is I'm confronted with new data, but I ignore it, or I pay attention to

it and I lie about it, I can't extract from that what the alternative is that is better than simply being uncomfortable with the fact that, yeah, I used to believe this thing and I believed it and I lived it and blah, blah, blah, blah, blah. But now I'm like, yeah, I don't believe it anymore. Another topic in this realm of nutrition that we get asked about a lot, it seems there's a ton of confusion. And we're going to very simplify it just for this conversation is an idea of like, is sugar poison?

What's your thought on that? All the hits, Nick. Greatest hits right now, baby. It is the greatest hits. That's why you can't agree to doing these things. We get to ask you all the stuff that you traditionally don't want to talk about on AMAs. Yeah. Again, a very loaded question,

but I would argue that the question is the premise of the question even logical. So what is a poison? Again, poison is a word that speaks to a dose, speaks to a frequency, speaks to chronicity, acuteness, I mean, all of these things, right? So broadly speaking, when I think of a poison, I'm thinking is something chronically a poison?

Is it acutically a poison? Is it acutely a poison? Okay, so let's start with something that everybody has in their house. Acetaminophen, Tylenol. Is it a poison? I mean, it doesn't have a skeleton on the cover with like bones through it, right? I mean, it doesn't look like the Drano you have under your sink that is clearly marked as a poison.

Tells you to take 500 to a thousand milligrams every four to six hours or whatever the instructions are. But what happens if you took 20 grams of that stuff, 20 times the dose? Well, you would be dead of liver failure in three days if someone wasn't able to pump your stomach in time or get you a liver transplant. So that sounds like a poison. That's actually acutely quite toxic. Is alcohol a poison?

Depends on the dose. We've talked about and written about this at great length. There are clearly doses at which alcohol is quite toxic. It's neurotoxic. And again, there's certainly a scenario where you have a glass of wine a few times a week and it would be almost impossible to discern or measure a negative effect of that. So I say all of those things just to kind of anchor people in what we're talking about.

And I think this type of word, I just think that the phrase sugar is poison is not helpful. It's loaded, it's emotional, it's sort of nonsensical. What we should really be asking, I think, is a question that's more along the lines of, what are the biochemical effects of sucrose or high fructose corn syrup or fructose in general at different doses and under different metabolic conditions? Understandably, that's a mouthful that nobody wants to say. It's just easier to just say sugar is poison. But again, I think this is an area where my view has changed quite a bit and it's changed because of the data. I just don't see the data to demonstrate that an isocaloric substitution of

fructose for glucose is demonstrably worse for health outcomes if total energy intake is preserved. Now, does that mean that eating sugar in an unrestricted manner in a free-living environment is of no consequence. No, it doesn't mean that at all. And it certainly appears that in at least a susceptible individual, a high consumption of fructose, and it seems even more clear in liquid fructose, can drive a repetitive behavior. Meaning, to put that in English, if you're drinking a lot of sugar, it makes you want to eat more calories. Now, we can debate how many calories, and I believe that these data have been misrepresented. I think that these data have been misrepresented and

overstated. I think that in a free living environment, people will consume more energy if they have more access to sugar. But if you control for calories, you may recall I had this discussion on the podcast with Rick Johnson using what I think was probably one of the most robust experiments I had seen on this topic given how long it lasted and my recollection was it lasted nine months which in mice is an eternity. Under isocaloric conditions when these mice were fed, when their total calories were controlled and you had high fructose versus low fructose groups, you did not see a statistically significant difference in body weight. That's a big deal.

Now would you see a statistically significant difference in metabolic parameters? I think you might if the fructose dose gets high enough, but this comes back to something I said at the outset, the dose makes the poison. What appears to be the case to me is that I don't think we know yet what that dose looks like as a function of the other parameters. So when I was young, when I was a teenager and I trained six hours a day, which I did, I never ran less than eight miles in the morning. I mean, I was in the gym, like it was a training machine.

There's no way I was eating fewer than 200 grams of sugar a day. A, I mean, I just ate everything that was in front of me. I would drink two liters of orange juice as my snack box. Other kids were drinking little juice boxes. I had a two liter can of orange juice. I didn't eat bowls of cereal. I ate them a box at a time.

So was I unhealthy? No chance. I probably had 4% body fat, but I was exercising six hours a day. So the context matters. If I ate that much food today, never mind sugar, I mean, you wouldn't even know my name anymore, I'd be dead. So everything about this is problematic because I think people want to focus on just one macronutrient,

in this case fructose or sugar as a molecule and we don't want to focus on the overall dietary pattern that accompanies it. I would say the following if I was going to try to sum this up. When I consume fructose, which I do all the time, it's generally in the form of fruit. I don't restrict my consumption of fruit. I generally don't drink calories outside of protein shakes. Those happen to be sweetened with artificial sweeteners anyway these days. They're mostly like sucralose and things like that. If I'm drinking a beverage, the once or twice a

month that I want kind of a carbonated beverage that's sweet, it's a diet Dr. Pepper as opposed to a Dr. Pepper. Okay. Would the Dr. Pepper kill me? No. But again, I'm only having like one a month, so it probably doesn't matter. But truthfully, Nick, that's more because of my teeth. Like what I really care more about is not putting an overall strain on my teeth than I do in the belief that sugar is somehow uniquely poisonous. So I guess I do limit sugar intake. What you're hearing me kind of react to is not because I think sugar is poison. I think a high sugar diet is just a dietary pattern that is incongruent with eating the

right kinds of foods that I generally want to eat anyway. I hope that makes sense and it's not too waffly, but I'll let you push back on it. No, I think it does. anyway. I hope that makes sense and it's not too waffly, but I'll let you push back on it. No, I think it does. And I think even though you've talked about this so much, I think, and we can link to it where you go in more detail, but I think it would be helpful for people just how you look at nutrition. Do you want to give your quick two by two framework of metabolically healthy, unhealthy, that whole piece? So it kind of, I think paints a bigger picture on why you don't just look at sugar being toxic, poison, whatever it is,

but how you kind of look more holistically. Cause I think a lot of what you said there would relate to you because you are metabolically healthy and you know where you sit in that two by two framework. But if you have patients who maybe are metabolically unhealthy and they need to lose weight, they need to increase their muscle mass, you might not be so liberal with the sugar for them. Yeah, and I'll say this, there's definitely an area where I'm still actively trying to

investigate this and we'll even be doing a podcast on this topic, which is, is there a unique role that fructose plays in the development of NAFLD? Non-alcoholic fatty liver disease is obviously running rampant right now in the world. One hypothesis is that it's not just energy imbalance, which is clearly associated with NAFLD. In other words, you take a person with NAFLD and they lose 20 pounds, their fatty liver is going to get better no matter what.

But then the question is, should those people be restricting fructose? And again, lots of great mechanistic data for why fructose rather than glucose would disproportionately play a role in the development of NaflD. And I think there's even more compelling evidence for why liquid fructose is potentially playing a greater role. But what I haven't seen yet is a really compelling clinical trial that can demonstrate that independent of weight loss, isocaloric substitution of fructose for glucose results in an improvement of Nafl-D. That said, if I have patients with Nafl-D, we're going to tell them not to drink alcohol and not to consume fructose out of mild amounts of fruit. So again, we're making a

recommendation that is not necessarily one for which we would have incredible evidence, but we're saying, look, even if nothing else, that change in behavior reduces in less caloric intake, which results in weight loss. Ultimately, that's what we care about. Just to end that little piece, do you want to just walk through your two-by-two framework for nutrition? Again, we'll link to places you talk about in more detail, but I think it's just helpful for people who maybe aren't familiar to have that anchoring. Yeah. I mean, it's really three questions and it's, is a person overnourished or undernourished that's determined by total

amount of body fat and visceral fat. Are they adequately muscled or undermuscled looking at things like fat-free mass index or appendicular lean mass index and then are they metabolically healthy or not? By understanding the answer to those questions, you pretty quickly can come up with a point of view on how a person needs to train and how a person needs to eat, and maybe even in some cases, how you want to tweak their macronutrients. I think if you talk about sugar, you also have to talk about sugar substitutes because it's something that we've written about a lot.

There was studies that have come out that caught a ton of press. And so how do you think about the idea of sugar substitutes and if they are dangerous? I would absolutely refer people back to one of our premium newsletters on this topic. I think it's one of our best premium newsletters ever. It was maybe a bit long for people, but again, if you really want to get into serious topics, you have to get serious. The long and short of it is, look, sugar substitutes have been around for an awfully long time and certainly in the 70s and even as recently as in the last 20 years, there have been concerns around the toxicity of them, especially kind of the OG ones which would be aspartame and saccharin. The truth of it is though, I think if you really want

to talk about that type of toxicity, the doses of the sugar substitutes are literally orders of magnitudes greater than what would be consumed by humans. Even though there were maybe flaws in some of those studies, even if you were to take them at face value, it's hard to imagine. So for example, the rat study that got everybody worried about saccharin, rats that develop tumors were being fed the equivalent of 800 diet sodas for every day of their life. That's how much saccharin those rats were being fed to develop these liver tumors. Again, I think it's just a very slippery slope to then say, oh, well then these things are poisonous because it's sort of like by that logic, I mean, I told you that even if you took 20 times the dose of Tylenol, you'd be dead.

By the way, you'd be dead much quicker than you would die from this cancer. Here we're talking about 800 times the dose over the entire duration of a life. At that level, just to be glib, Nick, oxygen is toxic to people. We have 21% oxygen in the air that we're breathing. If I put you in a 100% oxygen environment indefinitely, the amount of free radicals you would develop would kill you. Everything gets toxic at some point. The aspartame data, I think, was a little less extreme. Basically, this was a paper in 2006, 2007, and it did look at higher rates of cancer in rats that consumed pretty high amounts of aspartame from the day they were born right

on to the duration of their life. But truthfully, they were still consuming the equivalent of 20 cans of diet soda every single day to get to some of those outcomes. Is it possible that these things are cancer causing at normal doses? It is possible. I don't think it's that probable and therefore when I think about sugar substitutes, I'm less concerned with the cancer stuff and more concerned with the metabolic stuff, the impact on gut health, and those other things. I think that's probably worth spending a minute on as opposed to worrying too much more about some of these animal models that are using non-physiologic doses of this.

So where do we want to start? I think the two biggest areas to talk about with non-sugar sweeteners is what is the impact on body weight and what is the impact on glycemic control or metabolic health. I would say that the first generation versions of these, so saccharin, aspartame, sucralose seem to have a slightly negative effect on those parameters when calories are controlled. Conversely, the newer ones, some of them that are not even what we would consider non-nutritive like xylitol, erythritol, stevia, and allulose appear to have less detrimental effects. In fact, even allulose may even have

slightly beneficial effects on glycemic control due to SGLT1 signaling. But it's a little too soon to say that. So, this now comes back to a heuristic, which is like how do I behave around So, this now comes back to a heuristic, which is like, how do I behave around these things? And I, a moment ago said, well, I'm clearly consuming some of them. So it's hard to get a protein drink out there, even the cleanest ones out there that doesn't have some amount of these products in them. And the protein powders and drinks that I use generally have sucralose in them. That seems to be the one de jour.

I'm going to get a little bit there. I already alluded to the fact that I don't really drink diet sodas because I'm mostly just drinking sparkling water. I don't add it to anything I consume. If I'm drinking coffee, I put a little cream in it, but I'm not sweetening it. More or less, it doesn't really appear in what I do, although I do chew gum with xylitol in it. All the gum I chew has xylitol in it.

And that's more around some of the potential benefits of xylitol on the enamel of teeth. So my advice to people who are consuming lots of artificial sweeteners, who are struggling with glycemic control, body weight, or things like that is substitute them out, but don't substitute sugar in, just get rid of it, period. So go from drinking diet coke to drinking water, bubbly water, not drinking coke, because I think that's probably a worse outcome if no other reason just from more calories coming in.

But I think that if you're struggling on that front, getting rid of those things might matter. The area where I still think we are most interested in understanding things is, what is the impact of these things on the gut? How foreign are these things to the bacteria in our gut? Are they being provided in a high enough quantity to even materially impact the guts? There's some data, some animal studies that suggest that this is a big issue. I think it's a bit too soon to say that. So yeah, that's sort of how I would talk about sugar substitutes. For people who want to dive deeper into that, we'll link to all the other content on that in the show notes. And yeah, I think that sugar substitutes piece was, I can't think of a piece off

hand that you and the team have worked on that was longer. I remember reading that for the first time and you just kept scrolling and scrolling and scrolling so it's an insanely good resource for people to kind of look at but then also to go back to and it's broken out by all the different substitutes and it's a really awesome piece. The last thing to look at in nutrition is something else that I feel has been talked about for such a long time and it always comes back around. You've written about this back in the early stages

of the blog even before there was a podcast. And I feel every now and then there's a new documentary that comes out or a new piece of content and it raises the question again, which is does red meat give you cancer? And so if you had to look at that statement, let's say just red meat gives you cancer, where would you rank that in our ranking system today? So this is going to sound bold, but I would actually put this in the nonsense category,

which is not to say that a dietary pattern high in red meat could not play a role in the development of cancer. But that's very different than the question. So if the question is, does red meat cause cancer? I think that is not correct. And I think there's plenty of evidence that that is not correct. If the question is, do people who eat a lot of red meat,

or do people who eat a lot of processed red meat have a higher risk of getting cancer? I think the answer to that question is yes, but it's probably less because of the meat, although in the case of certain processing it may be the case, but it's probably much more because of what they're not eating. It's probably much more because their diets tend to be much lower in vegetables and specifically much lower in insoluble fiber, which plays a very important role in the prevention of colorectal cancer. The debate on red meat and cancer goes back for long periods of time.

Again, it suffers from all of the usual trappings of nutritional epidemiology, which is why John Ioannidis famously said that all nutritional epidemiology belongs in the wastebasket. The two most obvious problems with nutritional epidemiology in this regard are that it's very difficult to get an accurate reflection of what people consume using food frequency questionnaires. It's almost impossible. Secondly, and I think more seriously, it's very difficult to disentangle the variable of interest from the other lifestyle variables that are covariates within the problem and that speak to what we refer to as the healthy user bias.

I don't dispute for one moment that every time you do an epidemiologic survey and you compare people who live on hot dogs and pepperoni to vegetarians, the epidemiology will always tell you that the vegetarians are going to live longer. While that might be an extreme example, you do appreciate that on average those vegetarians have a much higher socioeconomic status. They are much more health conscious. They are exercising much more. They are much less likely to be smoking, doing yoga, all these other things. And therefore, how can we disentangle the variable from the effect? When you look at the most

compelling case for people who eat the highest amount of meat and their risk of cancer. There was a study that was done in Europe that looked at nearly half a million people and it divided them into a cohort that were eating more than 160 grams per day of protein from red meat and processed meat. It compared them to people that were eating virtually none, 20 grams per day. Again, I like when they do this because you're at least taking the most extremes. Indeed, there was a difference, but it was relatively small. Even under that setting, there was the difference between a 1.7 increase in the risk of cancer

versus a 1.3% absolute risk for colorectal cancer over the period of study. So just again, what does that mean? It means that the difference in risk between the super high protein consuming meat group and the low group was 0.4% of actual percentage points. So that means basically you have to put 250 people on a low meat diet to reduce one case of colorectal cancer. Again, that's assuming that you arrived at this through randomization, which you didn't. Again, there was another study that was done, it was a 10-year observational study that looked at about 150,000 people with the highest turtile of red meat consumption. And they had a 50% increase in relative risk to those in the lowest turtile.

The error bar on this study was so big that it barely made statistical significance despite the sample size there, which I think again, just speaks to the heterogeneity of this. Now I would say that every one of these studies basically ends up having the same issue with it, which is when you look at the details, you realize it is very difficult to come up with a meaningful view that it's red meat specifically that is driving cancer as opposed to the absence of vegetables, the absence of fiber, or maybe the presence of some of the ultra processing things that go into consuming certain patterns of meat like gas station

bought jerky and stuff like that. We could talk a lot more about this. I really think that the health effects, the ill health effects for red meat consumption is incredibly weak. The hazard ratios themselves for this are very, very small, even with all of the limitations that I've mentioned. And so, therefore, if you go back to kind to the Austin Bradford Hill criteria of epidemiology, which I outline in great detail in the book, very hard to imagine that there is causality here.

In fact, the epidemiology here is so underwhelming that it almost draws the opposite conclusion. It's almost hard to believe there is a signal given how underwhelming the epidemiology is. Whereas conversely, when you look at the epidemiology of smoking or the epidemiology of exercise, those are so overwhelming that it factors into what we see as the overall causality narrative. All right. So Peter, I think really interesting. And I think that kind of wraps the nutrition section.

And so you mentioned it earlier on, there is a really large list of topics that people want us to hit. So it's safe to say that this won't be the last one we do, even though it's the first one on this topic. And so if people do like this theme of kind of going through and ranking these things, let us know, because we have a huge list of items that we can hit kind of moving forward.

But with all that said, anything else jump out to you before we end what is the 300th episode of the podcast? No, I would reiterate that though, if people like this style of, hey, yeah, normally we just do super deep dives, but maybe once in a while we do a summary synthesis of evolving positions on things, let us know, and we'll obviously look to do that more.

It's certainly been kind of fun to do this. Yeah, what I say, it's hard for me to imagine where we're gonna be in 100 episodes. And what's exciting to me is to imagine how many more things I will know in a hundred episodes and how many things I will have changed my mind on. The evolution of the podcast for me has been so exciting because it's such an amazing way to be forced to learn so much all the time.

Yeah, definitely. It's really interesting seeing some of the guests we have lined up and the topics and themes that we'll be covering. You know, you mentioned there, NAFLDLD and we talked about exercise in the aging population. So I think we have some really good and interesting episodes coming up on topics that I think people will be excited about. So until then, have a good one. You too. Thank you for listening to this week's episode of The Drive. It's extremely important to

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