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

29:25And 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 terastilbein 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?

30:08I believe there is a phase two trial ongoing. And my hope is that the phase two trial is significantly larger, has robust inputs, and therefore can shed light on this question. Because 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. Ten were put on nicotinamide riboside, ten on a placebo for four weeks, and it saw some change in one of the movement disorder rating scales that's used to subjectively quantify movement in patients with PD.

31:00But 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 and 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. But 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.

31:38I believe it was studying some aspects of memory and physical function. and 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 time frame, 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 in a phase one. Where do I land on all this? I think that the evidence that NAD and its precursors is giroprotective, meaning we are going to take a bunch of people who don't have disease, and we're going to make them live longer.

32:22I think this is 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 geo protective drug category is the final one we can ask about a lot, which is risk -veritrol. 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?

33:02I have to be honest with you. I was really surprised when you guys sent me the list that risk -veritrol was on it because the 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 risk vera troll. This is absolute nonsense. I'm just saying we're going to 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. So risk vera troll is a phenol. It's a chemical that activates sertuins.

33:36So, understandably, in all the early 2000s hoopla around Sir Tuenz, which we just talked about a second ago, the view was like, oh my god, Sir Tuenz are good, the repairing DNA damage, Rysvera Troll is an activator of Sir Tuenz, that's got to 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 1 -100th the level is found in red wine.

34:25I mean, 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.

35:06I 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 are herbivores, that wouldn't be eating coconut oil. They're not eating that much fat. You have these mice on 60 % coconut oil diet, it. And the cause of death was so much fat accumulation in the liver that the liver expanded into the hemithorax and collapsed their lungs. So again, usually when we do experiments with mice, they die based on their genetic predilection to die of cancer. And we're typically trying to ask the question, hey, like in the case of rapamycin, like you give rapamycin into these mice, they get less cancer than these mice.

35:49Well, 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 risk -vera -trol, then if they were not, 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.

36:36We're going to study this in mice that are not chronic genetic mutants. And we're not going to force feed them fat. We're gonna give them normal mouse food and watch them die of normal mouse deaths and It made no difference. So 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 two 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.

37:24But 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 risk of error at all. 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.

37:57And again, even you highlighting where your opinions changed and where it may change again in the next hundred 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 and 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?

38:44And 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.

39:23That's what I really mean by proven. So what can I say? It'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 risk -vera -trol and insert to inactivators and NAD and NR and they're not exercising or they're exercising, but they're exercises totally JV. And 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.

40:07And you're completely missing this other thing over here. And you know, 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. And we'll link to it in the show notes to 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 had 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.

40:50But 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, end in many cases emotionally.

41:36I 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.

42:16But 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. They 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 going to start exercising and I'm going to get fit. No, no, no, no. If your VO2 max is in the top 2 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.

42:53These things like why is 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.

43:32We 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 want to 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 Menakew, which is blood flow restriction.

44:04And 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 in their 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? are it's promising slash proven.

44:48That 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 unturnicated limb. Again, provided they were both doing the same amount of work. So the question is why, perhaps? So why is it that applying a turnicate? Well, anybody who's done BFR can tell you it's not very comfortable.

45:32So, when you impair Venus 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 turnipet. And so an immediate use case became, well, look, can we use far lighter weights, but produce still a profound amount of discomfort in the obvious place where this showed up, of course, is around injury.

46:20So, 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. 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.

47:08So 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. And so the analyses, the studies, and the meta -analyses, and Jeremy Linnikey, who was the podcast 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 or two, which is how does BFR training at higher reps lower weight compared to non BFR training with higher weight and presumably lower reps?

47:57And that's a much harder head to head to design because the question is how do you design the protocol in each? Because now you've broken one of the constants that have been preserved across all of these studies. And so 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. But 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.

48:31And my personal use of BFR, which I've talked about, is I really like to use it as finishers in, you know, I'll 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 and we want to do it with, I mean, even just using their body weight.

49:11So 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. So 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, you have no affiliation with them.

49:45We 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 Katzu. I use two different types of Katzu 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 22nd inflate, hold, deflate, repeat.

50:24If 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's wrong with this guy.

51:08It 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 Venice and 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. So 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.

51:49I want to reiterate that, right? So I still find it very plausible that there are arenas in which stem cells could be beneficial. And I would say there are actually scenarios under which I would take stem cells if I had a certain injury. So 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 -style injection if it could mean avoiding surgery and waiting for a repair. And I would love nothing more next 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.

52:34Stem 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 it's sort of, 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.

53:11And 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. And 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. 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?

53:48You'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. And other studies have found no benefits whatsoever.

54:30Again, 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.

55:08I 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.

55:50And 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 long -gevity. So not fasting to counter -calories, anything of that nature, but more so, how do you think about, quote unquote, long -term fasting as it relates to long -gevity? 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.

56:30And then I came to this big block of nutrition. And I just wanted to start crying. I don't, 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 in this 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.

57:09I'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 going to tell you this is an area where I've seen an enormous change in my point of view over the past 300 episodes. So 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. So, for me, fasting has historically been a very important part of my thinking about how to live longer, how to use fasting as a Giro protective tool.

57:59Again, I think a little bit of historical context is relevant here. We spoke earlier about Rapa Myson, 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.

58:43But 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. And 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.

59:22And 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 ten days of water only fasting once a quarter and then three days once a month on the alternative. So two months shortfast one month at a long fast repeat.

59:59Now, 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. So 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 and by the way a lot of things got really bad when you fast it right your thyroid function completely deteriorated Your androgen function completely deteriorated so it wasn't like 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, atophagy, all of those things?

1:00:58Well, 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 are incredibly beneficial to disease prevention. And 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?

1:01:32So even if you could establish that five days was the 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, And 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. Might have 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.

1:02:16You 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. 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 gain back 20 pounds of muscle that I have lost. Against my personal story with it, unfortunately, I would still say, Nick, that, and again, And I'm glad you separated this out and said, look, it's fasting a viable tool for weight loss. Sure. It's one of the tools we have in the CRDR -TR kit. And 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.

1:02:53Drink 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 gonna 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, rapamycin 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.

1:03:52So, 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 called 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.

1:04:33It 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. And 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 while they were eating dinner, Jocco famously tells a story about that one night. But once I stopped traveling, it meant, oh, 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?

1:05:08So that became another reason independent of the biology. So the second followup 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 long term? 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 Chloric restriction.

1:05:52And there's already a lot of controversy around Chloric restriction. I have an entire chapter on this in Out Live 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.

1:06:35But, again, I put this right between promising and proven truthfully. So again, I think it's worth stating what we're talking about. So the energy balance theory, I believe, would pos 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. So if I am misrepresenting this, I hope I hear about it. But what it's basically saying is that 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.

1:07:24So 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 sort of seen what I believe is a reasonable answer. And just for folks who maybe don't know part of the history here, I mean, I was once running an organization that funded research directly to try to answer this question. And 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.

1:08:01And I think that that study, well, 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.

1:08:49So 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 3 ,000 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.

1:09:35They somehow magically start burning a lot more energy. And again, I believe the answer to that question is no. I do not see any evidence to support that. And therefore, I think that if a person is on 3000 calories a day of a balanced diet and they switch over to what they believe is 3000 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?

1:10:08Because 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'd 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?

1:10:50So, So first of all, that's going to 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 that 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.

1:11:27If 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, 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?

1:12:07What's your thought on that? All the hits, Nick, greatest hits right now, maybe. That 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 a creonicity, a cuteness. 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 a cutely?

1:12:45a poison. Okay, so let's start with something that everybody has in their house. The seed of menifin, time and all, is that a poison? I mean, doesn't have a skeleton on the cover with like bones through it, right? I mean, it doesn't look like the drainau 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.

1:13:20So 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.

1:14:01What 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 hyphryctose corn syrup or fructose in general at different doses and under different metabolic conditions. And understandably that's a mouthful but nobody wants to say so 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 isocoloric substitution of fructose for glucose is demonstrably worse for health outcomes if total energy intake is preserved.

1:14:52Now, 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 petitive 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.

1:15:48But 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?

1:16:26I 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.

1:17:09Other kids would drink in 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 thing 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 sort of focus on the overall dietary pattern that accompanies it.

1:17:51So 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 ones are twice a month that I want kind of a carbonated beverage that's sweet. It's a diet doctor pepper, as opposed to a doctor pepper. Okay. Would the doctor pepper kill me? No. But again, I'm only having like one a month.

1:18:29So 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 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.

1:19:06And 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 and healthy, that whole piece? So it kind of, I think paints a bigger picture on and why you don't just look at sugar being toxic poison whatever it is, but how you kind of look more holisticly. Cause I think a lot of what you said there would relate to you because you are metabolically healthy and you know where you're sitting at too 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.

1:19:51Yeah, and I'll say this, like 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, right? Which is, is there a unique role that Fructose plays in the development of Natholde? So non -alcoholic fatty liver disease is obviously running rampant right now in the world. And one hypothesis is that it's not just energy imbalance, which is clearly associated with Nafel D. In other words, you take a person with Nafel D 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?

1:20:29And again, lots of great mechanistic data for why fructose rather than glucose would disproportionately play a role in the development of Nafel D. 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 Nafolde. That said, if I have patients with Nafolde, we're going to tell them not to drink alcohol and not to consume fructose out of mild amounts of fruit.

1:21:10So 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 coloric intake, which would also result in weight loss, ultimately, that's what we care about. Just a, and that little piece, do you want to just walk through your two -by -two framework for nutrition? Again, we'll link the 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.

1:21:48Are they adequately muscled or under muscled looking at things like fat -free mass index or apendicular lean mass index? And then are they metabolically healthy or not? So 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 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?

1:22:30I would absolutely refer people back to one of our premium news letters on this topic. I think it's one of our best premium news letters 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.

1:23:18So even though there may be 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 study, the rat study that got everybody worried about saccharin, rats that developed 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. And again, I think it's just, it's 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.

1:23:57And by the way, you'd be dead much quicker than you would die from this cancer. And here we're talking about 800 times the dose over the entire duration of a life. You know, at that level, just to be glib, like oxygen is toxic to people, right? 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. So 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.

1:24:42But truthfully, they were still consuming the equivalent of 20 cans of diet soda every single day to get to some of those outcomes. So 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. And so, I think that's probably worth spending a minute on, as opposed to, you know, worrying too much more about some of these animal models that are using non -physiologic doses of this.

1:25:30So, where do we want to start? I mean, I think the two biggest areas to talk about with non -sugar are sweeteners is what is the impact on body weight and what is the impact on glycemic control or metabolic health. And 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, I don't know, newer ones, some of them that are not even what we would consider non -nutritive like xylitol, erythritol, stevia, and alulose appear to have less detrimental effects. In fact, even alulose may even have slightly beneficial effects on glycemic control due to SGLT1 signaling.

1:26:17But 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 these things? And 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. In the protein powders and drinks that I use generally have sucralose in them. That seems to be the one de jour. So I'm going to get a little bit there. I already kind of alluded to the fact that I don't really drink diet sodas because I'm mostly just drinking sparkling water.

1:26:53I don't added to anything I consume. So if I'm drinking coffee, it's, I put a little cream in it, but I'm not sweetening it. So 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.

1:27:41But 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 and how foreign are these things to the bacteria in our gut? I don't know, they're 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. 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.

1:28:16Yeah, 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.

1:29:03And so if you had to look at that statement, let's say 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?

1:29:46I 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. So the debate on red -maintain cancer goes back for long periods of time. And again, it suffers from all of the usual trappings of nutritional epidemiology, which is why John Aionidis famously said that all nutritional epidemiology belongs in the waste basket.

1:30:29The 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. And 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. So 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.

1:31:15And 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, and it compared them to people that were eating virtually none, 20 grams per day.

1:32:04So again, I like when they do this because you're at least taking like the most extremes, and indeed there was a difference, but it was relatively small. So, even under that setting, that 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.

1:32:51And again, that's assuming that you arrived at this through randomization, which you didn't. So 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 fertile of red meat consumption. and they had a 50 % increase in relative risk to those in the lowest her tile. The error bar on this study was so big that it barely made statistical significance despite this sample size there, which I think again, just speaks to the heterogeneity of this. Nat, 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 to consuming certain patterns of meat like gas station bought jerky and stuff like that.

1:34:04So 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 of the Austin Bradford Hill criteria of epidemiology, which I outlined 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.

1:34:48Whereas, 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 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, and 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.

1:35:32But 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 would I say? It's hard for me to imagine where we're going to be in a hundred 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.

1:36:07And the evolution of the podcast for me has been so exciting because it's 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 in the topics and themes that we'll be covering. You know, you mentioned their naffledee 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. Until then, have a good one. YouTube. Thank you for listening to this week's episode of The Drive. It's extremely important to me to provide all of this content without relying on paid ads.

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