300-Special episode: Peter on exercise, fasting, nutrition, stem cells, geroprotective drugs, & more

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 hey everyone welcome to the drive podcast I'm your host pet [Music] AA Peter welcome to a special podcast how 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 the it it's launched in June 2018 but we were recording previous because the original episodes were you doing book research oh right right right yeah that's right so started record started started having some of these discussions in 2017 um no to honestly I never I never really thought about it to me it was like binary right it was you know we started it as a 12 part series and it was like either this is going to be you know you know uninteresting helpful useless in which it dies or it's going to be potentially interesting and valuable and we'll keep doing it but then I never you know once we hit that sort of 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 well 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 kind of shot as an AMA but um 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 patience 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 News letters 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 going to be more conversation where it's patient comes to you and said Peter I'm thinking about Rapa should 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 well yeah we actually you know 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 the the threads because obviously there were a lot of repetitive ones and 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 so you know at some point we're going to you know not going to wait till episode 400 to come back and finish the other half of that list but yeah everything that that we're talking about today has come out of listener questions that came out of that Instagram post um and then I guess I'll just say one more thing about sort of like we use the terms you know proven promising fuzzy as heuristics but what what do I really mean by those things so I want to be really clear and and people have heard me say this before in biology there is no such thing as proof right it is this is not physics or mathematics um uh and I would say even physics you you you might argue outside of theoretical physics but but in in biology it's just all probability and and the when we say proven what we're really saying is what we're talking about has such wellestablished data that the probability that it is untrue is so small that it would be foolish to not act on it right now conversely promising says the claim looks really good there are a lot of data um supporting it but you know there's there's a piece that's missing right there's something that's missing from a data perspective either you know there isn't just quite enough human data or there just isn't quite enough RCT data or there just isn't quite uh you know there's some some slight thing that's missing that that would keep you from saying this is effectively proven um fuzzy is really going to be shorthand for there are some data around this claim but they might be you know not the best data they might be inconsistent they might be contradictory um and I don't just mean like one study is contradicting another study but it's like no there's real contradictions here um and therefore we you know we clearly need to do more before we could Elevate this noise is an interesting category um and it largely says that the the data out there today are not of sufficient quality uh 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 right there might be a very compelling biochemical story around an idea um but the data have just been too small uh too incomplete to to even elevate it up to fuzzy and by the way noise can quickly turn into nonsense when you shine enough light on it um and nonsense basically says no actually this has been studied um and it's bunk right we really have a high degree of confidence in saying that there 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 and so again all of that takes a long time to explain so I I don't want to have to explain it every time but I think explaining it upfront hopefully gives people a sense of of where we are and then of course with each example we'll 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 100 episodes what we're going to 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 you know 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 100 episodes ago I can even look at this list and tell you things I would have said different 100 episodes ago and I would be foolish to suggest that 100 episodes from now if we we come back and revisit this list I will have the exact same things to say about it I I I think that's very unlikely awesome 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 Ramy metformin NAD Resveratrol and so we'll start with Ramy but before we do do you just want to quickly remind people your definition of a j protective drug and kind of how you think about that yeah so gero protection really talks more broadly about mechanisms that Target um you know Hallmarks of Aging so a geroprotective 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 um and so that's that's a very high bar uh there are lots of drugs that are really effective at doing things that wouldn't quite rise to the level of being sort of gero protective so with that said let's start with Rapa uh obviously a molecule we get asked about an insane amount seems like its popularity is gone up what do you put Rapa in so I'm going to put Rapa in the promising category um and hopefully in a minute or two or three I'd like to convince people of why I think it's promising um but clearly not proven right so again just we've covered rap ay and so much in other podcasts and this 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 um but at a high level right Ramy is a substance that was discovered from a bacteria discovered on Easter Island in the god probably the mid-60s 6667 uh bacteria if I'm not mistaken was streptomyces hydroscopic at the time a very novel organism that had never been discovered anywhere else and it secreted this chemical that was named rapy to honor the uh Island where it was discovered rapanui and um this molecule was clearly found to be a very potent antifungal and that made it a a very logical choice for a bacteria to have evolved to produce it right a bacteria is obviously trying to fight uh A fungi and so um you know by inhibiting uh that through through this this molecule uh you know the first thought was hey this might be the next uh you know cure for uh for for athletes foot um 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 um finally uh was championed through a guy named saren Seagal who has since passed away and and saren single-handedly basically figured out utility for this drug that ultimately put it uh on the map as a drug that found its ultim 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 I mean 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 mainly what we were taking care of fast forward to 2009 and um a very well done study is published as part of the interventions testing program that looks at the use of Ramy 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 you know the rest is history basically that study showed more convincingly than any other study in the ITP history that Rapa 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 um 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 um 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 um Lloyd klickstein and Joan manic um there are clearly short-term studies that demonstrate that the differential dosing pattern of rapid Amy 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 Romy intermittently as demonstrated by these shorter human clinical trials will that translate to not just better um immune function but a longer life um and so absent really good bio markers for some of these Hallmarks of Aging I think we still have a ways to go before we could say the following Ramy is geroprotective towards humans and taking Ramy according to protocol X will add years to human life and presumably improve health span uh that's a that's an enormous claim um 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 cllin is doing in the dog aging project uh and some of that worm some of that work actually is going to need to be done in humans using biomarkers that have yet to be developed um 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 Ramy 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 if I don't think 10% of our patients are taking rapy and um the the reason for that quite simply is um you know unless a patient is willing to go down the rabbit hole with me on understanding this and and sort of you know understanding the risks and probabilities and the uncertainty uh you know I just don't view this as something that is that is responsible and of course I know that there are many Physicians out there who are giving out Rapa mice and like it's Tic Tacs and chicklets um and the truth of it is you know we're not seeing a lot of horrible things happening so clearly in the short run that's doesn't appear to be a problem um but I also think it's uh I think it's irresponsible to represent that we know that that's going to lengthen life um and so you know I I mean that that's sort of why I think there's a bit of a a disconnect in my willingness to have been taking this drug um for the past six years uh and my my hesitation in just sort of giving it to to anybody who walks in the door moving on to the next topic within geroprotective drugs met Foreman where would you place that well I'll say today I would place it in the fuzzy category I I actually would have put this in the promising category a 100 episodes ago uh um and again you know I think we're going to point people back to a podcast that I did with Andrew huberman um last year it was a journal club that we did where I talked about what I believe were the two most important uh large epidemiologic papers that are trying to address this question indirectly um and um so so I I I obviously won't rehash that in all the great detail but these two studies which um 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 and I think this is a great example of where EP epidemiology is very helpful so in in 2014 uh banister at all published something that at the time was almost impossible to believe uh and I I certainly remember reading it in real time I I remember getting an embargoed copy before it came out um and and and just really being shocked so the 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 two diabetes are going to 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 6 and a half years to four years or something like that but in fact what the study found was no the the 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 followup period obviously is done in an enormous population um using a UK um biobank uh data set so you know that paper I believe more than any other paper set the stage for the excitement around met foran as a geroprotective compound because what's clear is that the diabetics taking metformin still had inferior glycemic control to the non-diabetics so in other words it's not that they are if they're living longer it's not because they have better glycemic control it would seem to be that it's they're better because of something else that metformin is doing outside of managing presumably hepatic glucose output now I've had near barsel on the podcast twice and will'll again encourage people who are interested in this to go back and listen to those podcasts as well uh because near has argued that indeed metformin is gero protective and that there are many benefits to metformin that completely transcend its uh properties within the liver for glycemic control um but I have become less convinced of that um and so I think as I talk about in the podcast with Andrew um I think there were a lot of holes in the banister study um and I think they center around methodology something called informative censoring where the patients who were in The metformin diabetes arm um were censored out of the analysis that demonstrated A reduced mortality if they were lost to followup um if they died or uh pardon me um if they um if or if they had a medication change so um and 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 uh 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 um you're also you know not doing this in a randomized fashion and I cover all of that detail elsewhere so the follow-up study was which was done by keys at all in 2022 uh basically sought to improve on the methodology of the banister paper and it did something quite clever which is it repeated the analysis um using a different uh patient cohort so it's a Danish um patient population cohort um but it set up two studies within the study one very similar to what the banister uh experiment was and then one using a set of twins who differed only in that uh you know one had diabetes and one didn't so um what was interesting here so again that's a that's a clever design right it's and it's hard to do and um 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 and it varied anywhere from 33% higher uh to 80% higher again depending on the covariant analysis and the Cort the cohort that was being looked at again this was much more consistent with with what one expect and and and you know this is kind of um I 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 banister paper and it turned out it wasn't in other words even when they repeated that methodology they still produced the finding you would expect so addition to this I think the other reason I would continue to keep met foran 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 um is that metformin has failed in the ITP and again 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 nitp was when it was comp combined with rapid M but metformin alone did not succeed whereas other drugs such as canaga floen a carbos Ramy have succeeded so I don't want to go on too much further because again this this content exists elsewhere and I just want to really focus people on the high level my view today is that met for 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 helpful 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 met foran again yeah definitely and kind of going down the gero protective we talked about Raa talked about met Foreman 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 so again when we talk about NAD um we we have to we're really talking about multiple things we're talking about NAD itself um but I'm also speaking a little bit more broadly when I'm I'm talking about precursors because NAD can't be taken orally it could be given intravenously um when there are lots of clinics out there that do that but you know 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 um but but again let's just again provide just a touch of context here right so NAD is discovered more than a 100 years ago um and over time I think people come to sort of 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 right so now you have this thing that's super interesting and super relevant and completely ubiquitous and as we age it goes down so understandably uh in the early 2000s uh it became a very highin topic it further became of interest when it became linked to something called cerin which I'm going to talk about in a minute so um basically cin are proteins that require NAD to deacetylase lysing residues um which is just fancy chemical talk for it it changes the modification of um of an amino acid but 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 right 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 um 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 uh abundance going down with age for a separate reason and oh if we only had more NAD we could offset more DNA damage um I think it's safe to say we don't yet know the answer answer to that but nevertheless um I you know I 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 um 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 uh administration of NAD and its precursors um and it's it's actually surprising how little data is is out there so so what I thought I would do is try to highlight perhaps the most promising data I could see and and and hopefully by sharing why that's not so promising or why that's really really small um you might be um convinced of of my view which I should have said at the outset is I kind of think this NAD stuff is noise at the moment okay so I'm I'm I'm putting this in a category even below fuzzy but to be clear I'm not putting it in the nonsense category okay what that means is there may still be clinical scenarios under which this makes sense um even if it is not gero protective again very important distinction here I want 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 want to be disparaging to the studies but you know not not amazing studies um but reasonable first attempts at looking uh that you know maybe there's something there and maybe in these um uh scenarios there is a benefit but again we're asking this through the lens of Jiro protection we're really asking the question in this context of hey if I take a bunch of NAD or a bunch of NAD precursors such as NR and nmn am I going to live longer or even live significantly better uh and again I think the answer to that question is noise so the ALS study gave um patients you know a pretty high dose of a combination drug of nicotinamide riboside so NR and tertill bean for four months and then it followed basically symptoms of ALS on a functional scale so unfortunately for anybody who has known a patient with with ALS uh or a family member anything like that I mean it's it's top three most debilitating diseases in the history of our species um and unfortunately there is no cure um and and and the end is is 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 uh the answer appeared that yes this compound of nicotinamide and tertill bean actually delayed progression um by a short period of time for these patients now again this was a very small study um clearly this would be a phase one study so again first and foremost you're just making sure hey there's no toxicity which there wasn't um and you're and you're basically saying is there any smoke anywhere that makes me think there's a fire um I believe is a phase 2 trial ongoing and My Hope um is that the phase 2 trial is significantly larger has um robust inputs and therefore Can Shed light on this question because let's be clear if there is um a compound out there that can keep a patient off a ventilator longer when they have ALS or can prevent um you know secretion issues longer or respiratory distress longer by all means like that's a very important uh thing to know the other study I would uh reference is also a very small study that was done in 20 patients uh 10 of whom had um or 20 20 patients with Parkinson's disease 10 were put on nicotinamide riboside 10 on a placebo for four weeks and it saw some change in one of the movement disorder uh rating scales that's used to qu uh to subjectively uh quantify movement in patients with with PD um but there was a bit of a catch because that was the the patients were also um 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 so so that's I mean again it's it was not a very well done study um and again I I think the the most charitable thing one could say about that study is look at it maybe suggests that there's something there worth looking at um but you know 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 with Parkinson's disease um again there's one other study that looked at MCI I believe mild cognitive impairment um and it looked at NAD use in um I believe it was studying some aspect of memory and physical function it showed some improvements in physical function which again would not be the primary concern for MCI uh 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 um or that the that the test because it was a phase one study was too small um to actually see a signal right the signal wasn't you know you weren't powered to see a signal which by the way is not all always the case in a phase one so where do where do I where do I land on all this I think that the evidence that NAD and its precursors is geroprotective 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 I think this is uh very very low probability but not zero um and again I think the probability we're not going to be talking about this one in in another hundred episodes is pretty low um I you know in the uh in the spirit of like well how much do I believe in this and you know I don't take these compounds right I I I don't take NAD infusions I don't take NR I don't take nmn um and it's certainly not because there isn't an abundance of those things out there um but that's that's I guess tells you my level of confidence in this and then rounding out the kind of jro protective drug category is the final one we get asked about a lot which is RIS veratrol 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 RIS veratrol was on it because the implication is that it had been asked enough in that uh 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 RIS veratrol um this is absolute nonsense so I'm I'm I'm just saying we're going to put this in the nonsense category and we never need to talk about this again um I cannot in other words it's not just that the evidence you know there's not just an absence of evidence there's actually evidence of absence here so um RIS veratrol is a is a phenol it's a chemical that activates cerin so understandably in all the early 2000s hoopla around cerin um which we just talked about a second ago the view was like oh my God like cerin are good they're repairing DNA damage um R veratrol is an activator of cerin that's got to be good away we go um and so uh 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 one F uh so you know it's it's 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 on a serious level is this an explanation for the French paradox right on a sort of clickbait level does this mean we should just be drinking as much wine as possible I that's the only explanation Nick I have for why this story gathered traction and why it continues to this day to kind of cloud the Judgment of of folks but um as we have covered in great detail on the podcast the first episode with Rich Miller um the 2006 Mouse RIS veratrol study was was at best misinterpreted right so there there was indeed a longevity benefit um but uh you know it's a very obscure model right so it's a m model where the mice were fed a diet of 60% coconut oil um I 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 so like you know that that wouldn't be eating coconut oil right they're they're not eating that much fat um so so you you have these M on 60% coconut oil diet uh diet and the cause of death was uh 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 you know like in the case of rapy like you give rapamycin to these mice they get less cancer than these mice well no no no here were 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 um there was a shorter time or I should say a longer time to death um on average median lifespan um if they were on ratol than if they were not turned out by the way there's 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 for the the the median mice um some somehow that generated all of the interest in this drug and and very few people paid attention when the ITP came along and said we're going to study this really really rigorously right we're going to study this in mice that are not chronog gentic mutants and we're not going to force feed them you know fat we're going to give them normal Mouse food and watch them die of normal Mouse deaths um 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 2 PPM parts per million of Resveratrol they're giving them 300 PPM um and nothing happened now the folks who say RIS veratrol Works have criticize that study saying the bioavailability is low and therefore you need much much much more than the 300 PPM uh that was given in that study uh but again that was a concern and a criticism that was only voiced after the study the proponents of R veratrol were involved in that study um and they signed off I mean they're they're on the paper I mean they they this was this was their view so um I I I just have a hard time believing that there is any value in RIS veratrol uh and again I you know that's why I don't take it reg you know independent of the fact that it's it's still a ubiquitous compound that's found everywhere yeah and I think that kind of wraps those four different drugs in that and I think that's why sometimes it's nice hopefully for people when you kind of 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 V to Max and that 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 this scale that we're doing today where would you put V2 Max where would you put the importance of muscle mass um and by the way with muscle mass I would put muscle strength right 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 right like they would be right up there with smoking cessation they would be right up there with you know blood pressure management so again there's you can't prove anything in biology but boy the probability that having a high V2 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 um so what can I say I mean there's very little on this topic I have not you know expounded on uh both on this podcast and and on and on others and social media I mean this is a topic I I I can't say enough about because the magnitude of the effects is so much greater than everything else and you you can you can see Nick why I get animated and why I get phosphorilated when people ask me about RIS veratrol and cerumin activators and NAD and NR and they're not exercising right or they're exercising but their exercise is 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 and you're completely missing this other thing over here um and and you know you've heard me tease you know folks including patients sometime and say look once you're once you've got your V2 Max here and your muscle mass here and your strength here then we can talk about you know the 37 supplements that you're interested in taking um so you know I 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 you know understanding where these things rank and how they compare to others right which you hadit 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 geroprotective 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 V2 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 y i 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 um 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 we that's a much harder one to quantify um but but I think that's there and and I guess the other point I will make to bring it back is like why is it that V2 Max muscle mass and strength stand out as the the the greatest predictors of lifespan which they do right they 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 um even smoking is a is a worse predictor of lifespan um than your Fitness level uh and 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 right so if a person has a high VO2 max they have been doing a lot of exercising for a long time doesn't have to mean their whole life but they didn't just decide a you know a week ago oh I'm you know I'm kind of unfit but I'm I'm going to start exercising and I'm going to get fit no no no no if if you're if your V2 Max is in the top two or 3% of your age group you've been at this for a while and 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 so 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 right you again 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 right and it's that work that is being captured through the integral of the final metric or the test and 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 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 Leni 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 um and again it depends on how you define the question but is the question um does using bfr and higher reps lower load weights produce Superior results to the same reps the same weights without bfr you know it's it's promising SL proven right I mean that that that is that is clearly the case um so so again just kind of backing up for a little bit and and for those who who didn't hear the podcast on this or who you know need need a little refresher so this is a topic that uh became of interest you know 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 um you would see Superior uh improvements in strength and muscle size relative to an unic limb uh again provided they were both doing the same amount of work so um the you know the question is why perhaps right so why is it that applying a tourni it well anybody who's done bfr uh can tell you it's not very comfortable right so when you impair Venus return slightly uh 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 right so more lactic acid is pooling uh more uh more metabolites of of of metabolism uh beyond that and um the the thought is that something about that is creating more of a stress signal um than would otherwise be present absent the uh tourniquet and and so an immediate use case became well look you know can we use far lighter weights um but produce you know still a profound amount of discomfort um and and then the obvious place where this showed up of course is around injury right so when a person is injured um you know let's use my example when I had shoulder surgery um I wanted 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 humoris 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 train effect and so the the data have largely borne this out right when they do and the nice thing about these Studies by the way this is what makes this this this type of research really elegant is every patient can be their own control because you're doing limb isolation right so 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 um but every patient can be their own control um uh and and so the analyses the studies and the meta analyses and and and Jeremy lyi who was the podcast guest we're talking about I think did a large meta analysis in 2011 it it showed that you know if you look at low-load resistance training in bfr without bfr it clearly results in Greater muscle strength and hypertrophy improvements uh and and it's it's not subtle right these are 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 and and that's a much harder head-to-head to design because the the the question is like um 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 um and so I I think that the answer there is still unknown um and as such I I just wouldn't recommend that somebody exclusively rely on bfr I I think that there there there might be things that you first of all it's not that comfortable and you can't do it for everything right like it's it's very limb Centric um but even if you were just to talk about restricting it to how you train your arms and your legs um I still think there are lots of scenarios where using bfr doesn't make sense um and my personal use of bfr which I've talked about is I really like to use it as finishers in um you know there's like finish you know I'll do some sort of upper body finishers and lower body finishers on on upper body and lower body days respectively um but it's not really like the bulk of what I'm doing um so so that that's that's kind of how I feel about this and again I think it is disproportionately useful in 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 so for example a patient that's had knee surgery you know 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 surg iny put uh strain from the Patell tendon uh beneath any attachment and for people interested in learning more we'll link to podcast but if people want to try it um do you want to let people know which brand you use and obviously you can say too 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 um and um they make very different types of to I 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 the it's my sort of bread andand butter go-to one where I put the armbands on put the leg bands on whichever I'm using you know inflate it to the pressure uh and then go and exercise and then they 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 um you put this on and it just it'll do a I think it does like a 20 second inflate hold deflate repeat and I can just sort of if I'm sitting at the computer like I've got this thing cycling on my arms or on my legs um and uh if nothing else honestly it just feels great like I really actually enjoy the feeling of it um uh so so yeah those those are the devices that I use and um there is a real art to this so I think it's um you know there's a clinical way that you want to be able to go about doing this where you have to it's not just put a tourniquet on which is what I used to do and hope for the best uh because you 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 you have attached yeah it's 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 in meetings too it's also on brand um so the next one something we get asked about a ton it's come up on a few podcasts with um Alton Baron Adam Cohen looking at the upper body lower body but stem cells so how are you thinking currently about stem cells boy this is this is an area where um I you know I think it's I think it's really complicated I'm I'm going to put this somewhere between noise and fuzzy but but again I I 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 so I want to I want to reiterate that right so um 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 uh if I had a certain injury so if I tore my rotator cuff um and it was a marginal call as to whether it was surgical I would absolutely start with a stem Stell injection if it could mean avoiding surgery and waiting for a repair and I would love nothing more Nick than to see an actual randomized clinical trial that takes patients and 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 you know and again again 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 and 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 kind of existing either outside of the United States where it's not regulated by the FDA or it's sort of like you know there's some sort of gray areas where it can be done but it's you know it's obviously not covered by insurance or any of these other things um and again if you're presumably using I'm not even sure how much of these Protocols are using autola stem cells uh versus uh the stem cells of of others and uh so so so the 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 therefore it's 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 the the hardest part I would have is where am I going to do this like who do I trust because it's not like I can look at someone's data and and draw conclusions right you're basically looking at a bunch of marketing material not actual data um so I I would say when we talk about osteoarthritis at least we have the advantage that that there are like can9 models of osteoarthritis where they've looked at you know stem cells um and the truth of it is um they they have mixed results um some of them have shown that dogs with osteoar arthritis when injected with stem cells uh do tend to improve their gate uh do tend to see a reduction in lameness um which again is you know partially assessed by gate partially assessed by the use of medications or pain relief through medications um and other Studies have found no benefits whatsoever and again it's 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 plur potent stem cell um are we talking about you know uh a Doner derived stem cell are we talking about a fetal derived stem cell all of these things create uh and 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 um and it's I think it's unfortunate like I really 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 total is a total sham it shouldn't be done when in reality that the truth might be somewhere there so so 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 um so I clearly am not going to call this nonsense uh but this is not going to rise to the level of promising in my mind yet and 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 is 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 kind of 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 and 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 it's stuff people get as we get asked about a ton people are very interested in nutrition and and need to spend more time with my therapist understanding why I hate talking about nutrition because I do I do think I have a lot to say on it and and I I actually think I'm knowledgeable on the subject um and I know that therefore I should talk about it because I can add value in a sea of um you know bad information but but the visceral response it produces in me Nick is uh it's very it's difficult for me to quantify actually so um I've already forgot in your question that's how much I'm just in the throws of pain at the moment long-term fasting I'm going to I'm going to call this fuzzy um 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 um some people listening to this podcast might know that um and and there are many people I'm sure who are listening to this podcast who came into the orbit of you know our work through my uh you know work in the fasting space and so so you know for me fasting has historically been a very important part of my thinking about how to live longer how to use fasting as a is a geroprotective tool again I think a little bit of historical context is relevant here we spoke earlier about rap M which stands alone in the pantheon of molecules the only molecule the only molecule that has universally extended life across all model systems of ukar Nots which span 1 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 right so so there's clearly something magical going on with caloric restriction when it comes to elongating life um but the question is can we extend that into humans and perhaps the more important question is what what would what would the fasting protocol be and and I wrote a 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 okay you know you should you could do a complete fast you could do a 50% fast a 75% fast and just make it you know somewhat big and arbitrary and you could do it for one day or 3 days or 5 days and you could do it once a year or once a quarter or once a month like even if you took reasonable spots it quickly becomes impossible to test all of these um 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 um but what what I was doing was doing 7 to 10 days of water only fasting once a quarter and then three days once a month on the alternative so two months at uh you know short fast one month at a long fast repeat um now what data could I point to for that protocol none absolutely none I made it up I mean I literally made that up and again very transparently made that up um were things happening in my body from a cellular level that were beneficial probably um did I have great biomarkers to show that no cuz I was relying on very standard biomarkers you know um and unfortun I mean fortunately my standard biomarkers are generally quite good so it's not like you know yes your glucose is going to go down your ketones go up your insulin goes down a little bit but those things are transient um you know all of and by the way a lot of things got really bad when you fasted right your thyroid function completely deteriorated uh uh your Androgen function completely deteriorated um so it wasn't like all good but what was really interesting is you know the thing we couldn't measure which was what was actually happening to those Hallmarks of Aging right were we improving at the cellular level things like syence autophagy all of those things well guess what we can't measure those things so we don't know um we can try to extrapolate and there was some rationale in my mind I suppose extrap ating from what we knew in mice which is that you know this many hours of fasting in a mouse does indeed produce cellular changes that 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 5 days I'm going to 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 5 days was a a sufficient length of time to fast should you do it 5 days a month 5 days a quarter 5 days a year no idea so you may ask the question why did I stop my fasting protocol and for me it 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 it was getting close to 20 lbs of muscle you know it might have been 16 pounds of muscle over that period of time because at at least at the frequency that I was fasting which I'm not saying was right or wrong um it's very difficult to gain back the lean muscle you keep losing right you 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 um and so I think in around 2021 I said you know what I I'm I'm going to just put the k BOS on fasting for now uh and I'm going to make it you know I'm going to make sure I gain back 20 lounds of muscle uh that I have lost and and so that that's 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 it's one of the tools we have in the crdr uh TR kit and by the way in that regard I still do it by the way so let me also establish I I am still a TR guy for the most part right so I'm you know I drink my coffee in the morning I will I will um 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 um but I don't eat a meal until 2:00 in the afternoon and then I have dinner at 600 or 7 um 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 um by you know not having meals spread throughout the day um to I guess just to put a bow on this topic um why is this fuzzy well I think it's fuzzy because we don't have the bio in many ways this suffers the same problem rap ay suffers in terms of getting into much more dispositive clinical trials which is we're clearly ever 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 and if we can do that then maybe we can start to get a sense of whether or not Ramy and fasting should be important parts of our armamentarium as we you know think about ways to impact those Hallmarks of Aging two followup 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 I also happened to be traveling a lot right so I was um it was very easy for me to fast when I was away from home so all those fasts were done while I was in New York and you know I lived 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 you know I would just sit there and drink you know soda water while they were eating dinner Joo famously tells a story about that one night um but once I stopped traveling uh it meant Oh all those fasts are going to have to be done at home and honestly like I just didn't I just didn't want to do it you know I didn't I didn't I don't want I don't want my kids to be wondering like why is Daddy never eating and all that kind of stuff so um that 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 you know if it's working at what dose how that works but yeah 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 start fasting again long term I don't know I would really need to see something incredibly compelling in a higher order model um maybe in a dog model or something like that you know again like this is a great example of where that's such a I I think I think companion dogs are such a great um model to study things that that you know cuz again I think most people find binary fasting far easier than caloric restriction and there's already a lot of controversy around caloric restriction I have an entire chapter on this in outlive where I talk about um the the Wisconsin niia Mouse uh uh sorry um the monkey studies but you know for most people like if I said oh you just got to reduce calories by 25% for 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 um it's actually easier to say well what if you just have to periodically do big fasts and so I think we would I would like to see an experiment of that done in a better model than just mice yeah definitely looking at the next topic something that like 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 and 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 truth so again I think it's worth stating what we're talking about so the energy balance Theory I believe would POS it and I you know 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 uh you know if if I am misrepresenting this I hope I hear about it um but you know what it's basically saying is that the um that energy balance is determined solely by the caloric density of the foods consumed less the energy expenditure um and that the caloric density the net available caloric density of a food is its contribution to energy balance um now there so so this is where again I 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 I've largely not paid attention to it truthfully um because in many ways I've sort of seen what I believe is a reasonable answer right which is and and and just for folks who maybe don't know part of the history here I mean I was once running um an organization that funded research directly to try to answer this question um 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 and and I think that that study while it 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 let's add a couple of caveats there is clearly differences in the thermogenesis of food so 1,000 calories of protein 1,000 calories of fat and 1,000 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 um but what we're really trying to tease out is you know 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 they somehow magically start burning a lot more energy and again I believe the answer to that question is no I I do not see any evidence to support that and 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 and what would you 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 know 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 and it's you know 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 you know how it could go up and down but just in general I think there may be at times in science a 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 you know why do you change your mind and should that affect what I hear you say today I so first of all that's kind of news to me that people are upset about that I 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 right so in other words if you can't change your mind in the present of new data I think by definition you're not a science you're not a scientist you're an advocate now you know advocacy has its place but um not without science so I me 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 right like is it is it is it vexing that I change my mind on things yes I suppose it is if it if it means that it impacts your you know belief about what is 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 or again I just can't I can't extract from that what the alternative is that is better than simply being uncomfortable with the fact that yep 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 I don't believe it anymore yeah 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 H 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 you traditionally don't want to talk about on amas yeah again a very loaded question but I would argue that the question the is the premise of the question even logical right so what is a poison um again I poison is a is a is a it's it's a it's a it's a word that that speaks to a dose speaks to a frequency speaks to chronicity uh acuteness I mean all of these things right so you know broadly speaking when I think of a poison I'm thinking is something chronically a poison is it acutely a poison okay so let's let's start with something that everybody has in their house acetaminophen Tylenol is it a poison I mean doesn't have a skeleton on the cover with like bones through it right meaning it doesn't look like the you know Drano you have under your sink that is clearly marked as a poison um tells you to take 500 to 1,000 Mig gr every 4 to 6 hours or whatever the instructions are but what happens if you took 20 gr of that stuff 20 times the dose well you would be dead of liver failure in 3 days if someone wasn't able to pump your stomach in time or get you a liver transplant so that sounds like a poison um that's actually acutely quite toxic right um is alcohol a poison depends on the dose right um um we've talked about and written about this at Great length there are clearly doses at which alcohol is quite toxic uh it's neurotoxic and um again there's there's certainly a scenario where you know 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 think I just think that the phrase sugar is poison is not helpful right um it's loaded it's emotional it's like it's just it's it's sort of nonsensical right what we should really be asking I think is a 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 and understandably that's a mouthful that nobody wants 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 um and it's changed because of the data right I 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 appetitive 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 um you know again I 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 and 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 9 months which in mice is an eternity under isocaloric conditions when these mice were fed um when their total calories were controlled and you had high fructose versus versus low fructose groups you did not see a statistically significant difference in body weight um that's 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 and I think what's 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 6 hours a day which I did right like I was I never ran less than 8 miles in the morning I mean I was in the gym like I I it was a training machine i i i i there's no way I was eating fewer than 200 grams of sugar a day right like a I mean I just ate everything that was in front of me I I mean I I had I would drink two lers of orange juice as my you know snack box other kids were drinking little juice boxes I had a 2 L can of orange juice um I didn't eat bowls of cereal I ate them a box at a time so was I unhealthy no chance right like I probably had four% body fat um but I was exercising 6 hours a day so so again like the context matters now if I ate that much food today never mind sugar I mean you wouldn't even know my name anymore I'd be dead right so um everything about this is problematic because I think people want to focus on just one macronutrient in this case fructose or sugar uh as a molecule and we don't want to sort of focus on the overall dietary pattern that accompanies it and um so 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 it's it's generally in the form of fruit right like I don't restrict my consumption of fruit uh um I generally don't drink calories outside of protein shakes um those happen to be sweetened with artificial sweeteners anyway these days they're mostly like sucrose and things like that um if I'm drinking a beverage like 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 um so you know I guess I do limit sugar intake um but what you're what you're hearing me kind of react to is not because I think sugar is poison but I think that sugar as part of a I think a high sugar diet is just a dietary pattern that is in congruent 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 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 2x two framework of of you know 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 because 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 2 x 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 and I'll say this like there's definitely an area where I'm still actively trying to investigate this and you know we'll even be doing a podcast on this topic right which is is there is there a unique role that fructose plays in the development of Naf D um so non-alcoholic fatty liver disease is obviously you know running rampant right now um in in the world and one hypothesis is that it's not just energy imbalance which is clearly associated with naph d in other words you take a person with naff d and they lose 20 pounds their fatty liver is going to get better no matter what um but then the question is should those people be restricting fructose um and again lots of great mechanistic data for why fructose rather than glucose would disproportionately play a role in the development of Na 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 um isocaloric substitution of fructose for glucose results in an improvement of um Na D that said if I have patients with naal d we're going to tell them not to drink alcohol and not to consume fructose out of you know 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 else in weight loss ultimately that's what we care about and then just to kind of and that little piece do you want to just walk through your 2x two framework for nutrition again we'll link to places you talk about more DET but I think it's just helpful for people who maybe aren't familiar to have that anchoring yeah I mean it's it's really three questions and it's you know kind of is a person overnourished or undernourished um and you know that's determined by total amount of body fat and visceral fat are they adequately muscled or underused looking at things like fat-free mass index or appendicular lean mass index and then are they metabolically healthy or not and so by understanding the answer to those questions you 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 and 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 um that have come out that caught a ton of press and so how do you think about the idea sugar substitutes and if they are dangerous well I mean this I would absolutely refer people back to our one of our premium newsletters on this topic I think it's one of our best premium newsletters ever it was uh maybe a bit long for people but again if you really want to get into serious topics you have to get serious um the the long and short of it is look sugar substitutes have been around for an awfully long time um and and certainly in the 70s and even as recently as in the last 20 years there have been you know concerns around the toxicity of them so especially kind of the OG ones which would be aspartame and sacran um the truth of it is though uh I think if you really want to talk about that type of toxicity um the doses of the sugar substitutes are are are literally orders of magnitudes greater than than what would be consumed by humans so even though there were maybe flaws in some of those studies even if you were to take them at face value um it it's hard to imagine so you know for example the the the study the rat study that got everybody worried about um uh sacran was you know rats that were being rats that develop tumors were being fed the equivalent of 800 diet sodas for every day of their life life um that's how much sacran those rats were being fed to develop these liver tumors um and again I 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 well but look by that logic I mean I told you that even if you took 20 times the dose of Tylenol you'd be dead and by the way you'd be dead like much quicker than you would die from this cancer um and here we're talking about 800 times the dose over the entire duration of a life so you you know at that level just to be glib Nick 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 uh the the amount of free radicals you would develop would kill you so uh everything gets toxic at some point uh the the aspartame data I think was a little less extreme basically this was a paper in 2006 2007 um and it did look at higher rates of cancer in rats that consumed uh you know pretty high amounts of aspartame uh from the day they were born uh right on to you know the duration of their life but you know truthfully they were still consuming the equivalent of 20 cans of diet soda every single day um to to get to some of those outcomes so um is it possible that these things are are cancer causing at normal doses it is possible um I don't think it's that probable um 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 um and so I think that's probably worth spending a minute on um as opposed to you know worrying too more about some of these animal models that are using uh not non-physiologic doses of of those so um so where where do we want to start I mean 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 and um I would say that the the first generation version of these so sacran aspartame sucralose seem to have a slightly negative effect on those parameters when calories are controlled uh conversely the kind of I don't know newer ones some of them that are not even what we would consider non-nutritive like Xylitol ariol Stevia and allulose uh appear to have less detrimental effects in fact even allulose may even have slightly beneficial effects on glycemic control due to sglt1 signaling um but it's a little too soon to say that so this now comes back to a hurric which is like how do I behave around these things and I a moment ago said like 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 generally have uh sucralose in them that seems to be the the the one dour um so I'm going to get a little bit there I already kind of alluded to the fact I don't really drink diet sodas because I'm mostly just drinking sparkling water um I don't add it to anything I consume so if I'm drinking coffee it's it's you know I put a little cream in it but I'm not sweetening it um so more or less it doesn't really appear in what I do although I do chew gum with xylol in it all the gum I chew has xylol in it and that's more around some of the potential benefits of Xylitol on the enamel of teeth um 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 right so go from drinking diet coke to drinking water water not drinking Coke CU I think that's probably a worse outcome um if no other uh uh reason just from more calories coming in um but but I but I think that if you're struggling on that front getting rid of those things might matter the the area where I still think we are most interested in understanding things is what is the impact of these things on the on the on the gut um and how much how foreign are these things to the bacteria in our gut uh and are they being provided in a high enough quantity to even materially impact the guts you know there's some data uh some animal studies that suggest that this is a big issue uh but I think it's a bit too soon to say that so um yeah that's that's sort of how I would talk about sugar substitutes and again 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 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 seems you know it always comes back around you written about this you know 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 um 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 the answer 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 coloral cancer so um you know the the debate on red meat and cancer goes back for for long periods of time um and again It suffers from all of the usual trappings of nutritional epidemiology which is why John iones famously said that all nutritional epidemiology belongs in the waist basket um 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 questioners uh it's almost impossible and secondly uh and I think more seriously it's very difficult to disentangle the variable of interest from the other lifestyle variables that are co-variates 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 um and 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 so um when you when you look at the most compelling case for people who eat the highest amount of you know meat and their risk of cancer um you know there was a there was a study that was done in Europe that looked at nearly half a million people and it divided them into uh a cohort that were eating more than 160 grams per day of uh of protein from red meat and processed meat and it compared them to people that were eating virtually none 20 G per day so again I like when they do this because you're at least taking like the most extremes um and indeed there was a difference but it was relatively small right so even under that setting um there was the difference between a 1.7 uh increase in the uh increase in the risk of cancer uh versus a 1.33 uh uh percent risk absolute risk for um coloral 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 uh uh 4% of actual percentage points um so that means you know basically you have to put you know 250 people on a low meat diet to reduce one case of coloral cancer um and again that's assuming that you arrived at this through randomization which you didn't um so again there was another study that was done uh it was a 10year observational study that looked at about 150,000 people uh with the highest tertile uh of red meat consumption and you know they had a 50% increase in absolute risk uh pardon me in relative risk uh to those uh in the lowest herti again I could you know the 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 um net net 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 um to come up with a meaningful uh 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 you know uh uh you know gas station bot jerky and stuff like that so um you know we could talk a lot more about this but I I really think that the health effects the ill health effects for red meat consumption is incredibly weak um the hazard ratios themselves for this are very very small even with all of the limitations that I've mentioned um and so therefore if you go back to kind of the Austin Bradford Hill criteria of epidemiology which um you know I outline in great detail in the book uh very hard to imagine that there is causality here in fact the epidemiology here is so underwhelming that it almost draws the opposite conclusion that there 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 like those are so overwhelming that it it it it factors into what we see as is the overall causality narrative all right so Peter I think really interesting and I think that kind of wraps a 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 item 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 you know 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 we'll we'll obviously look to do that more it's it's certainly been kind of fun to to do this um yeah what would I say it's hard for me to imagine where we're going to be in a 100 episodes but um and and what's exciting to me is to imagine how many more things I will know in 100 episodes and how many things I will have changed my mind on that that actually it it it's it's the evolution of the podcast for me has been so exciting uh because you know I just it's such an amazing way to be forced to learn so much all the time yeah definitely and I think it's too it's 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 Naf D and we talked about excise 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 [Music]

Channel: Peter Attia MD

Views: 122,761

Keywords: Peter Attia MD, Dr. Peter Attia, Early Medical, The Drive Podcast, The Drive, Longevity, Zone 2

Id: Io5xV9rtbm4

Length: 108min 22sec (6502 seconds)

Published: Mon May 06 2024