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

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.540 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:53.200 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.020 head over to peteratiyahmd.com forward slash subscribe. Welcome to a special episode of

00:01:06.540 The Drive. Today, we celebrate our 300th episode. To celebrate this milestone, we're going to do

00:01:11.980 something a little different for this episode, but it's going to mirror the structure of a recent

00:01:16.040 interview I did, which I thought was kind of interesting. For today's episode, we're going

00:01:20.000 to cover a variety of topics, which you have all weighed in on, and I'm going to rank them into

00:01:26.360 the following categories. Proven, promising, fuzzy, noise, and nonsense. A couple of months ago, some

00:01:32.280 of you may recall, I put out a video on social media where I asked people to weigh in on the types

00:01:38.900 of topics that they wanted to hear covered, and we got a lot of responses, literally thousands of

00:01:44.500 responses. We've sorted those into different categories, and we're about to cover half of them

00:01:49.700 here. Turns out the response was far in excess of what we predicted, and we'll have to finish this

00:01:55.480 another time. But nevertheless, in this conversation, we're going to cover geroprotective drugs, including

00:02:01.000 rapamycin, NAD and its precursors, metformin, resveratrol. We're going to talk about VO2 max,

00:02:06.820 muscle mass, blood flow restriction, stem cells, and then we talk about nutrition, specifically questions

00:02:12.540 you had around long-term fasting, sugar, sugar substitutes, and the role of red meat in cancer.

00:02:18.420 So all of these topics have generally been covered in greater detail across the previous 300 episodes

00:02:25.860 and or across our newsletter over the past 10 years. We will certainly point you back to areas where we

00:02:32.420 go into great detail into these topics, but the goal here today is that if you're coming to these topics

00:02:38.280 without any background or you just want the TLDR, this is the place for you. So as such, if you want to

00:02:45.980 learn more, of course, check out the show notes both here and elsewhere. And I would just say before we

00:02:51.220 jump into this, I want to thank everybody for being a part of The Drive. Whether this is your first

00:02:56.760 episode or your 300th, it is an absolute honor to be learning in front of you, and that's exactly how I

00:03:03.600 feel about this. So without further delay, please enjoy this episode celebrating 300 episodes of The Drive

00:03:09.640 and Counting. Peter, welcome to a special podcast. How are you doing? Very good. Thank you. So today

00:03:21.200 for this episode, we are actually celebrating 300 episodes. So I think the first question is,

00:03:28.420 did you ever think we would get to episode 300 when we started this seven years ago, recording the first

00:03:35.620 few? Was it seven years ago or six years ago? Well, it's launched in June, 2018, but we were

00:03:43.560 recording previous because the original episodes were you doing book research. Right? Yeah, that's

00:03:49.820 right. So started having some of these discussions in 2017. I never really thought about it. To me,

00:03:53.600 it was like binary, right? We started it as a 12 part series and it was like, either this is going to be

00:04:00.400 uninteresting, unhelpful, useless in which it dies, or it's going to be potentially interesting

00:04:05.600 and valuable and we'll keep doing it. But once we hit that binary spot where after three months,

00:04:09.620 we said, yeah, let's keep doing it. I never, and I never really thought of milestones in that way.

00:04:14.180 So what we like to do for every hundred episodes is to kind of just do a special

00:04:17.840 episode, something a little different, release it to everybody shot as an AMA, but just a little bit

00:04:24.340 of a different style. And so when we were thinking of how we wanted to do this one, we thought of a

00:04:29.600 recent interview you did, which was structured in a way we kind of liked, which was you giving your

00:04:34.480 opinion on various drugs, supplements, behaviors, interventions, and putting them in the following

00:04:40.900 categories, proven, promising, fuzzy noise, nonsense. And we thought it was kind of a cool

00:04:46.380 way to go through and talk about some of these different things in a little detail and categorize

00:04:52.060 them. So people could understand how you think about them, how you apply them to your life,

00:04:56.060 apply them to your patients. And so a lot of what we're going to cover here, and a lot of these

00:05:00.000 topics are things that we've covered in various podcasts, newsletters, and we'll link to those.

00:05:05.980 So the goal here isn't to be super in-depth, go through all these studies, all this background

00:05:11.760 research. We'll link to those in the show notes for anyone who's interested, but this is going to be

00:05:16.140 more conversation where it's patient comes to you and said, Peter, I'm thinking about rapamycin.

00:05:21.700 Should I take it? How do you think about it? That kind of style. So we have a lot to cover. I think

00:05:27.880 it will be really interesting. So with all that said, before we start, anything you want to add?

00:05:33.320 All the content for today's podcast is coming in from an Instagram post that I put up several

00:05:39.220 months ago, basically saying that we were going to do just that and asking people to leave their

00:05:44.360 comments. And then some very unfortunate soul on our team had to go through two or 3,000 comments

00:05:50.800 and tease out the threads because obviously there were a lot of repetitive ones. I think what we should

00:05:56.360 also explain to folks is what emerged was a really good list of which we will do half right

00:06:01.740 now because that's how much good stuff emerged. That's how many good questions emerged. So not

00:06:08.320 going to wait till episode 400 to come back and finish the other half of that list. But yeah,

00:06:12.640 everything that we're talking about today has come out of listener questions that came out of that

00:06:17.100 Instagram post. And then I guess I'll just say one more thing about we use the terms proven,

00:06:22.740 promising, fuzzy as heuristics. But what do I really mean by those things?

00:06:25.920 So I want to be really clear. And people have heard me say this before. In biology,

00:06:29.180 there is no such thing as proof. This is not physics or mathematics. And I would say even

00:06:35.980 physics, you might argue outside of theoretical physics. But in biology, it's just all probability.

00:06:40.360 And when we say proven, what we're really saying is what we're talking about has such well-established

00:06:47.300 data that the probability that it is untrue is so small that it would be foolish to not act.

00:06:55.920 on it. Now, conversely, promising says the claim looks really good. There are a lot of data

00:07:02.460 supporting it, but there's a piece that's missing. There's something that's missing from a data

00:07:09.900 perspective. Either there isn't just quite enough human data or there just isn't quite enough RCT

00:07:15.700 data or there just isn't quite. There's some slight thing that's missing that would keep you from

00:07:21.360 saying this is effectively proven. Fuzzy is really going to be shorthand for there are some data

00:07:28.040 around this claim, but they might be not the best data. They might be inconsistent. They might be

00:07:33.280 contradictory. And I don't just mean like one study is contradicting another study, but it's like, no,

00:07:37.760 there's real contradictions here. And therefore, we clearly need to do more before we could elevate

00:07:44.720 this. Noise is an interesting category. And it largely says that the data out there today are

00:07:51.660 not of sufficient quality to make a judgment, but there might be something kind of compelling that

00:07:57.980 could move this in the other direction. For example, there might be very compelling mechanistic

00:08:02.580 data. There might be a very compelling biochemical story around an idea, but the data have just been

00:08:09.320 too small, too incomplete to even elevate it up to fuzzy. And by the way, noise can quickly turn

00:08:16.240 into nonsense when you shine enough light on it. And nonsense basically says, no, actually this has

00:08:20.980 been studied and it's bunk. We really have a high degree of confidence in saying that there is nothing

00:08:27.540 there that should be paid attention to. And that doesn't necessarily mean it's harmful, but it means

00:08:32.060 that this is not doing what people say it is doing. All of that takes a long time to explain, so I don't

00:08:37.040 want to have to explain it every time, but I think explaining it upfront hopefully gives people a

00:08:40.640 sense of where we are. And then of course, with each example, we'll provide enough detail to

00:08:44.300 rationalize that position, hopefully. Yeah. Another thing to add to there is,

00:08:49.420 let's say we did this in another a hundred episodes, what we're going to talk about with

00:08:54.520 new evidence can easily move up or down the chain. So it's not even like, this is how it is and this

00:09:00.580 is how it will be. And that's the beauty of science. And what we've seen a lot of is as new

00:09:05.380 evidence comes out, you're happy to change your opinion on what you think about things.

00:09:10.980 Yep. And if we did this a hundred episodes ago, I can even look at this list and tell you things I

00:09:15.680 would have said different a hundred episodes ago. And I would be foolish to suggest that a hundred

00:09:21.800 episodes from now, if we come back and revisit this list, I will have the exact same things to say

00:09:26.040 about it. I think that's very unlikely. Well, let's get into it. And we kind of categorize the

00:09:31.180 different things we'll talk about. So there's themes to these sections. And the first theme is

00:09:36.140 geroprotective drugs, molecules. These are rapamycin, metformin, NAD, resveratrol. We'll

00:09:43.840 start with rapamycin, but before we do, do you just want to quickly remind people your definition of a

00:09:50.180 geroprotective drug and kind of how you think about that? Yeah. So geroprotection really talks

00:09:56.140 more broadly about mechanisms that target hallmarks of aging. So a geroprotective drug would be a drug

00:10:04.860 or a molecule that you're taking, not because it necessarily provides benefit in one arena against

00:10:11.840 one chronic disease or one symptom, but rather because you believe it is fundamentally altering

00:10:18.600 the biology of aging. And as such, taking this drug moves things in your favor. And that should mean

00:10:25.840 that you would live longer taking this drug. And so that's a very high bar. There are lots of drugs

00:10:31.840 that are really effective at doing things that wouldn't quite rise to the level of being sort of

00:10:36.820 geroprotective. So with that said, let's start with rapamycin. Obviously a molecule we get asked about

00:10:43.520 an insane amount, seems like its popularity has gone up. What do you put rapamycin in?

00:10:49.920 I'm going to put rapamycin in the promising category and hopefully in a minute or two or three,

00:10:56.920 I'd like to convince people of why I think it's promising, but clearly not proven. We've covered

00:11:02.260 rapamycin so much in other podcasts and this podcast is in no way meant to displace or be a substitute for

00:11:09.120 those things. So if you really want to go deep on this, you got to go back and see the content in the

00:11:13.340 show notes. We will link to all the places where I've done this. But at a high level, rapamycin is a

00:11:20.060 substance that was discovered from a bacteria discovered on Easter Island in the, God, probably

00:11:27.240 the mid-60s, 66, 67. Bacteria, if I'm not mistaken, was Streptomyces hydroscopicus, at the time a very

00:11:34.440 novel organism that had never been discovered anywhere else. And it secreted this chemical that was named

00:11:41.480 rapamycin to honor the island where it was discovered, Rapa Nui. And this molecule was

00:11:49.380 clearly found to be a very potent antifungal. And that made it a very logical choice for a bacteria

00:11:55.360 to have evolved to produce it. Bacteria is obviously trying to fight a fungi. By inhibiting that through

00:12:02.900 this molecule, the first thought was, hey, this might be the next cure for athlete's foot. Through stories

00:12:09.240 that are really interesting to me from a historical perspective, but I won't get into for the sake of

00:12:13.440 time, ultimately that drug, which almost died a thousand deaths due to lack of interest, finally

00:12:19.540 was championed through a guy named Seren Segal, who has since passed away. And Seren single-handedly

00:12:25.640 basically figured out utility for this drug that ultimately put it on the map as a drug that found

00:12:32.320 its ultimate clinical application in organ transplantation as an immune suppressant. So

00:12:38.340 in 1999, the FDA approves this drug for organ transplantation, solid organ transplantation,

00:12:45.360 and it spends the next decade in relative obscurity. I mean, this is literally when I was in my residency

00:12:50.920 using this drug amongst a cocktail of others for patients who had received heart transplants,

00:12:58.260 kidney transplants, and liver transplants, which were mainly what we were taking care of.

00:13:01.100 Fast forward to 2009, and a very well-done study is published as part of the interventions testing

00:13:09.420 program that looks at the use of rapamycin in a very well-documented strain of mice that are far

00:13:18.560 more representative of what happens in biology than the typical strain of mice that are used in a

00:13:24.300 clinical research setting. The rest is history, basically. That study showed more convincingly than

00:13:30.100 any other study in the ITP history that rapamycin extended life in male mice, in female mice, and

00:13:38.520 most importantly, when initiated very late in life, a period of time in which no other drug had ever been

00:13:45.240 able to extend life. Of course, this was replicated many, many times in the ITP and elsewhere. It was

00:13:52.360 also replicated in other model systems, meaning it wasn't just replicated again in mammals. People went

00:13:58.220 back and asked the question, how does this drug, rapamycin, which inhibits mTOR, how does it work in

00:14:06.240 yeast, in fruit flies, in worms, which, by the way, constitute about a billion years of evolution?

00:14:12.800 And it turns out that it always seems to work. And so it's for all of those reasons that I say,

00:14:20.140 wow, this is really promising, but why can I not say this is proven? And the reason I can't say it's

00:14:24.460 proven is we don't yet have sufficient evidence in the organism of interest or the species of interest,

00:14:31.520 which is us. And the reason for that is that while there have been some interesting studies done in

00:14:38.420 human, and we'll point back to a podcast that I did with Lloyd Clickstein and Joan Manik, there are clearly

00:14:45.200 short-term studies that demonstrate that the differential dosing pattern of rapamycin can actually

00:14:51.900 produce immune augmentation and immune enhancement rather than immune suppression. That doesn't quite

00:14:57.840 translate to the question that many of us want to know the answer to, which is, hey, if I take rapamycin

00:15:04.860 intermittently, as demonstrated by these shorter human clinical trials, will that translate to not

00:15:12.380 just better immune function, but a longer life? And so absent really good biomarkers for some of these

00:15:20.380 hallmarks of aging, I think we still have a ways to go before we could say the following. Rapamycin

00:15:27.640 is gyroprotective towards humans, and taking rapamycin, according to protocol X, will add years

00:15:35.580 to human life and presumably improve health span. That's an enormous claim where I say a lot of work

00:15:43.160 still needs to be done, and some of that work I think needs to be done in other animal models,

00:15:48.040 such as what Matt Caberlin is doing in the Dog Aging Project, and some of that work actually is going to

00:15:52.420 need to be done in humans using biomarkers that have yet to be developed that will be substitutes

00:15:58.120 for some of these more important cellular markers of aging. And so I think it's important, too, because

00:16:03.940 you've been open in other podcasts, mainly with Matt, on how you take rapamycin, but even though you

00:16:10.720 take it, and with all you said on why you think it is promising, that doesn't mean you necessarily think

00:16:16.560 everyone should just go out and blindly take it. Not all of your patients are taking it as well, correct?

00:16:21.500 Very few of my patients are taking it. I would say, I don't think 10% of our patients are taking

00:16:26.840 rapamycin, and the reason for that, quite simply, is unless a patient is willing to go down the rabbit

00:16:33.200 hole with me on understanding this and understanding the risks and probabilities and the uncertainty,

00:16:39.160 I just don't view this as something that is responsible. And of course, I know that there are many

00:16:43.340 physicians out there who are giving out rapamycin like it's Tic Tacs and Chicklets, and the truth of it is

00:16:48.660 we're not seeing a lot of horrible things happening. So clearly, in the short run, that doesn't appear

00:16:54.260 to be a problem. But I also think it's irresponsible to represent that we know that that's going to

00:16:59.680 lengthen life. That's sort of why I think there's a bit of a disconnect in my willingness to have been

00:17:05.880 taking this drug for the past six years, and my hesitation in just sort of giving it to anybody

00:17:11.520 who walks in the door. Moving on to the next topic within geoprotective drugs, metformin.

00:17:17.300 Where would you place that? Well, I'll say today I would place it in the fuzzy category. I actually

00:17:23.220 would have put this in the promising category 100 episodes ago. We're going to point people back

00:17:28.700 to a podcast that I did with Andrew Huberman last year. It was a journal club that we did

00:17:35.060 where I talked about what I believe are the two most important large epidemiologic papers that are

00:17:43.960 trying to address this question indirectly. And I obviously won't rehash that in all the great detail,

00:17:50.680 but these two studies, the first one was done in 2014, the second one in 2022, I think represent

00:17:57.500 the bookends of an observation that creates a lot of interest. And I think this is a great example

00:18:06.320 of where epidemiology is very helpful. In 2014, Bannister et al published something that at the

00:18:13.120 time was almost impossible to believe. I certainly remember reading it in real time. I remember getting

00:18:19.700 an embargoed copy before it came out and just really being shocked. So the study at the surface looked at

00:18:27.500 people who had type 2 diabetes who were taking metformin and people who did not have type 2

00:18:33.220 diabetes and who were obviously not taking metformin. And it asked the question, who had

00:18:39.660 a lower all-cause mortality rate? Now, of course, we know that people with type 2 diabetes are going to

00:18:46.420 have their lives truncated by an average of six to seven years relative to someone without type 2

00:18:52.380 diabetes. So you wouldn't think that the addition of metformin to somebody with type 2 diabetes would

00:18:58.460 materially affect that. Maybe it would close that gap from six and a half years to four years or

00:19:03.640 something like that. But in fact, what the study found was no, the people taking metformin with type

00:19:09.040 2 diabetes actually lived slightly longer than the people who did not. In fact, there was about a 15%

00:19:16.600 reduction in all-cause mortality over a three-year follow-up period. Obviously, it's done in an

00:19:21.600 enormous population using a UK biobank data set. So that paper, I believe more than any other paper,

00:19:32.140 set the stage for the excitement around metformin as a geroprotective compound. Because what's clear

00:19:40.660 is that the diabetics taking metformin still had inferior glycemic control to the non-diabetics.

00:19:49.500 So in other words, if they're living longer, it's not because they have better glycemic control.

00:19:54.300 It would seem to be that they're better because of something else that metformin is doing

00:19:59.640 outside of managing presumably hepatic glucose output. Now, I've had Nir Barzali on the podcast

00:20:06.760 twice and will again encourage people who are interested in this to go back and listen

00:20:11.920 to those podcasts as well. Because Nir has argued that indeed metformin is geroprotective and that

00:20:20.340 there are many benefits to metformin that completely transcend its properties within the liver for

00:20:26.780 glycemic control. But I have become less convinced of that. And so I think as I talk about in the podcast

00:20:33.260 with Andrew, I think there were a lot of holes in the Bannister study. And I think they center around

00:20:41.680 methodology, something called informative censoring, where the patients who were in the metformin

00:20:49.380 diabetes arm were censored out of the analysis that demonstrated a reduced mortality if they were

00:20:58.220 lost to follow up or if they had a medication change. And usually a medication change on someone

00:21:04.220 who's only taking metformin is meaning that the disease is progressing. So you're adding another

00:21:10.060 medication. So the problem with that is, I think, obvious when you realize that you were censoring

00:21:18.780 out people who were sicker and you were actually selecting for the healthiest possible people, not to

00:21:27.660 mention the fact that you're also not doing this in a randomized fashion. And I cover all of that

00:21:33.260 detail elsewhere. So the follow-up study, which was done by Keyes et al. in 2022, basically sought to

00:21:40.380 improve on the methodology of the Bannister paper. And it did something quite clever, which is it repeated

00:21:46.820 the analysis using a different patient cohort. So it's a Danish patient population cohort. But it set up

00:21:53.260 two studies within the study, one very similar to what the Bannister experiment was, and then one

00:21:58.660 using a set of twins who differed only in that one had diabetes and one didn't. That's a clever design,

00:22:06.940 and it's hard to do. And they actually found the opposite. They found exactly what you would expect

00:22:12.220 to find, which is whether you were talking about identical twins, fraternal twins, unrelated people,

00:22:18.120 if you had type 2 diabetes, even if you were on metformin, your risk of mortality was significantly

00:22:24.720 higher. And it varied anywhere from 33% higher to 80% higher, depending on the covariate analysis and

00:22:32.000 the cohort that was being looked at. Again, this was much more consistent with what one would expect.

00:22:37.160 This is, I think, a better analysis for several reasons. Here's what's most interesting though,

00:22:40.780 Nick. They actually went and then did an informative censoring analysis to see if indeed informative

00:22:48.020 censoring was exclusively responsible for the results in the Bannister paper. And it turned out

00:22:52.900 it wasn't. In other words, even when they repeated that methodology, they still produced the finding

00:22:58.500 you would expect. In addition to this, I think the other reason I would continue to keep metformin in

00:23:05.520 a fuzzy category as opposed to a promising category at this point, and remember, fuzzy doesn't mean it

00:23:11.120 doesn't work. Fuzzy means we need more data to upgrade, is that metformin has failed in the ITP.

00:23:18.020 We'll link to both of the podcasts with Rich Miller, where we talk about the ITP in detail and why the

00:23:24.100 ITPs are such impressive studies and why so few molecules have succeeded in the ITP. But metformin

00:23:32.700 is not one of them. In fact, the only time metformin, to my recollection, has ever been positive in an

00:23:37.720 ITP was when it was combined with rapamycin. But metformin alone did not succeed, whereas other drugs,

00:23:43.780 such as canagaflozin, acarbos, rapamycin, have succeeded. So I don't want to go on too much

00:23:50.500 further because, again, this content exists elsewhere, and I just want to really focus

00:23:53.560 people on the high level. My view today is that metformin is in the fuzzy category.

00:23:58.500 One other thing I should say is that there is a study that is eventually getting funded. In fact,

00:24:03.660 it might, I mean, technically, I guess it is funded. I don't know if it's began enrollment yet,

00:24:07.920 called the TAME study. And the TAME study is going to attempt to answer this question in humans by

00:24:16.360 studying disease onset in susceptible but otherwise healthy individuals. And that's why I think it's

00:24:23.740 safe to say that, look, whether it's episode 400 or episode 500, we are definitely going to be

00:24:29.140 talking about metformin again. Yeah, definitely. And kind of going down the

00:24:34.620 geoprotective, we talked about RAPA, talked about metformin. Next one we get asked about all the

00:24:39.480 time is NAD. Also one we've covered in various podcasts, but looking at NAD, how would you put

00:24:47.260 it into a category? When we talk about NAD, we're really talking about multiple things. We're talking

00:24:52.980 about NAD itself, but I'm also speaking a little bit more broadly. I'm talking about precursors

00:24:59.880 because NAD can't be taken orally. It could be given intravenously when there are lots of clinics

00:25:05.120 out there that do that. But from a practical standpoint, we tend to look at things that you

00:25:09.740 can take orally. So we really tend to be talking about NR and NMN, which are oral precursors that

00:25:16.520 become converted into NAD. But again, let's just provide just a touch of context here, right? So NAD

00:25:22.880 is discovered more than a hundred years ago. And over time, I think people come to sort of

00:25:28.480 understand it's a very important signaling molecule. It's a very important part of cellular

00:25:34.660 metabolism. Oh, and by the way, it declines with age. So now you have this thing that's super

00:25:42.040 interesting and super relevant and completely ubiquitous. And as we age, it goes down. So

00:25:48.040 understandably, in the early 2000s, it became a very high interest topic. It further became of

00:25:55.680 interest when it became linked to something called sirtuins, which I'm going to talk about in a minute.

00:26:01.160 So basically, sirtuins are proteins that require NAD to deacetylase lysine residues, which is just fancy

00:26:11.480 chemical talk for it changes the modification of an amino acid. But this is something that occurs

00:26:18.020 so much and is so important to maintaining DNA integrity and managing oxidative stress that

00:26:25.620 basically there were two hypotheses, broadly speaking. One hypothesis is the reason NAD levels

00:26:32.280 decline with age is because DNA damage goes up with age. That's true. We know that that's true.

00:26:39.540 So are those two causally related? Is the rise in DNA damage with age driving an increase in NAD

00:26:47.080 utilization? And that's why NAD is going down? Or are these uncoupled? Is DNA damage going up with age,

00:26:53.560 which it is? And is NAD abundance going down with age for a separate reason? And oh, if we only had

00:26:59.560 more NAD, we could offset more DNA damage. I think it's safe to say we don't yet know the answer to that.

00:27:06.640 But nevertheless, I think a cottage industry around NAD has come up, which says, look, we know the answer

00:27:12.840 to this, or at least we're going to postulate that the answer is, of course, NAD is going down

00:27:16.880 with age. And whether or not that's causal or not, giving more NAD is going to be a better thing.

00:27:23.760 Okay. So what do the data have to say? And again, this is an area where, I mean, there is a remarkably

00:27:30.780 booming industry around the administration of NAD and its precursors. It's actually surprising how

00:27:39.100 little data is out there. So what I thought I would do is try to highlight perhaps the most

00:27:45.040 promising data I could see. And hopefully by sharing why that's not so promising or why that's

00:27:53.700 really, really small, you might be convinced of my view, which I should have said at the outset,

00:27:59.320 is I kind of think this NAD stuff is noise at the moment. I'm putting this in a category even below

00:28:04.420 fuzzy, but to be clear, I'm not putting it in the nonsense category. What that means is

00:28:08.900 there may still be clinical scenarios under which this makes sense, even if it is not

00:28:14.100 geroprotective. Again, very important distinction here. I'm going to talk about a couple of studies

00:28:18.660 in neurodegenerative disease, one in ALS, one in Parkinson's disease, that are both so small

00:28:24.280 and quite frankly, just so, I don't want to be disparaging to the studies, but not amazing

00:28:30.860 studies, but reasonable first attempts at looking, that maybe there's something there. And maybe in

00:28:37.440 these scenarios, there is a benefit. But again, we're asking this through the lens of geroprotection.

00:28:43.240 We're really asking the question in this context of, hey, if I take a bunch of NAD or a bunch of NAD

00:28:49.380 precursors, such as NR and NMN, am I going to live longer or even live significantly better? And again,

00:28:56.660 I think the answer to that question is noise. So the ALS study gave patients pretty high dose of

00:29:03.700 a combination drug of nicotinamide riboside, so NR and terastilbene for four months. And then it

00:29:09.960 followed basically symptoms of ALS on a functional scale. So unfortunately for anybody who has known

00:29:15.820 a patient with ALS or a family member or anything like that, I mean, it's top three most debilitating

00:29:22.140 diseases in the history of our species. And unfortunately there is no cure and the end is

00:29:28.920 just a very tragic end. And so what this study was basically asking is, look, can we delay this

00:29:35.180 in any way, shape or form? And the short answer is at least on one of the functional scales of

00:29:41.840 progression, the answer appeared that yes, this compound of nicotinamide and terastilbene actually

00:29:49.660 delayed progression by a short period of time for these patients. Now, again, this was a very small

00:29:57.180 study. Clearly this would be a phase one study. So first and foremost, you're just making sure,

00:30:02.300 hey, there's no toxicity, which there wasn't. And you're basically saying, is there any smoke

00:30:06.140 anywhere that makes me think there's a fire? I believe there is a phase two trial ongoing. And my

00:30:13.180 hope is that the phase two trial is significantly larger, has robust inputs, and therefore can shed

00:30:19.840 light on this question. Because let's be clear, if there is a compound out there that can keep a

00:30:27.220 patient off a ventilator longer when they have ALS or can prevent secretion issues longer or respiratory

00:30:33.620 distress longer, by all means, that's a very important thing to know. The other study I would

00:30:39.700 reference is also a very small study that was done in 20 patients with Parkinson's disease. 10 were put

00:30:45.320 on nicotinamide riboside, 10 on a placebo for four weeks. And it saw some change in one of the movement

00:30:53.560 disorder rating scales that's used to subjectively quantify movement in patients with PD. But there's

00:31:01.180 a bit of a catch because there was a confounder in that some of those patients were closer in their

00:31:06.520 last dose to levodopa, which is a medication that in the early stages of the disease is quite

00:31:11.500 effective at improving movement. It was not a very well done study. And I think the most charitable

00:31:17.300 thing one could say about that study is look at maybe suggest that there's something there worth

00:31:20.740 looking at. But I don't think that that would even rise to the level of being as compelling as the

00:31:26.460 standard therapies that are used for patients with Parkinson's disease. There's one other study that

00:31:31.860 looked at MCI, I believe, mild cognitive impairment, and it looked at NAD use. I believe it was studying

00:31:40.760 some aspects of memory and physical function. It showed some improvements in physical function,

00:31:48.800 which again would not be the primary concern for MCI, but it did not show any improvement in cognitive

00:31:54.140 impact. By the way, it might mean that there is an improvement in cognitive impact, but not over such a

00:31:59.060 short timeframe. The test, because it was a phase one study, was too small to actually see a signal.

00:32:06.120 You weren't powered to see a signal, which by the way, is not always the case in a phase one.

00:32:09.820 Where do I land on all this? I think that the evidence that NAD and its precursors is

00:32:14.840 zero protective, meaning we are going to take a bunch of people who don't have disease and we're

00:32:20.320 going to make them live longer. I think this is a very, very low probability, but not zero. And again,

00:32:26.560 I think the probability we're not going to be talking about this one in another hundred episodes

00:32:31.240 is pretty low. In the spirit of, well, how much do I believe in this? I don't take these compounds.

00:32:36.800 I don't take NAD infusions. I don't take NR. I don't take NMN. And it's certainly not because there

00:32:42.200 isn't an abundance of those things out there, but that I guess tells you my level of confidence in

00:32:46.680 this. Rounding out the kind of geoprotective drug category is the final one we get asked about a lot,

00:32:54.180 which is resveratrol. So where would you rank that? And kind of, how do you think about that

00:32:58.880 compared to the three we've talked about so far? I have to be honest with you. I was really surprised

00:33:04.120 when you guys sent me the list that resveratrol was on it because the implication is that it had

00:33:09.300 been asked enough in that survey we put out there that people wanted to hear it. And all I have to say

00:33:16.080 is, wow, I'm amazed people are still talking about resveratrol. This is absolute nonsense.

00:33:22.420 I'm just saying, we're going to put this in the nonsense category and we never need to talk about

00:33:27.060 this again. In other words, there's not just an absence of evidence. There's actually evidence

00:33:31.420 of absence here. So resveratrol is a phenol. It's a chemical that activates sirtuins. So

00:33:37.340 understandably in all the early 2000s hoopla around sirtuins, which we just talked about a second ago,

00:33:44.240 the view was like, oh my God, sirtuins are good. They're repairing DNA damage. Resveratrol is an

00:33:50.100 activator of sirtuins. That's got to be good. Away we go. A landmark study, quote unquote, in 2006

00:33:57.900 garnered an unbelievable amount of attention. Now, I think the attention was just as much from the fact

00:34:04.720 that in minuscule amounts, resveratrol is found in red wine. It wasn't just that, oh, we have another

00:34:13.620 molecule that in some obscure mouse model maybe seems to extend life. I think it was, oh, and by the way,

00:34:19.800 this molecule at about one 100th the level is found in red wine. On a serious level, is this

00:34:27.820 an explanation for the French paradox? On a clickbait level, does this mean we should just

00:34:32.800 be drinking as much wine as possible? That's the only explanation, Nick, I have for why this story

00:34:38.660 gathered traction and why it continues to this day to cloud the judgment of folks. But as we covered in

00:34:46.120 great detail on the podcast, the first episode with Rich Miller, the 2006 mouse resveratrol study was

00:34:52.080 at best misinterpreted. So there was indeed a longevity benefit, but it's a very obscure model,

00:34:59.620 right? So it was a mouse model where the mice were fed a diet of 60% coconut oil. I can't imagine what

00:35:07.580 that would be like for 10 minutes, let alone for the duration of a mouse's life, especially when we

00:35:12.460 consider mice are herbivores, that wouldn't be eating coconut oil. They're not eating that much

00:35:18.280 fat. You have these mice on 60% coconut oil diet, and the cause of death was so much fat accumulation

00:35:26.860 in the liver that the liver expanded into the hemithorax and collapsed their lungs. So again,

00:35:35.340 usually when we do experiments with mice, they die based on their genetic predilection to die of

00:35:41.780 cancer. And we're typically trying to ask the question, hey, like in the case of rapamycin,

00:35:46.120 like you give rapamycin to these mice, they get less cancer than these mice. Well, no, no,

00:35:50.320 here we're force feeding them coconut oil to turn their livers into big blobs of fat that expand into 1.00

00:35:57.920 their chest and compress their lungs. And it turned out that under those conditions,

00:36:04.580 there was a longer time to death on average median lifespan if they were on resveratrol than if they

00:36:13.700 were not. It turned out, by the way, there was no difference in maximal lifespan. So you didn't shift

00:36:17.920 the curve of mortality for the top 10% of mice. You just shifted it for the median mice. Somehow that

00:36:26.040 generated all of the interest in this drug. And very few people paid attention when the ITP came along

00:36:32.220 and said, we're going to study this really, really rigorously. We're going to study this in mice that

00:36:39.800 are not chronogenetic mutants, and we're not going to force feed them fat. We're going to give them

00:36:45.080 normal mouse food and watch them die of normal mouse deaths. And it made no difference. So they gave

00:36:50.980 them 300 milligrams of resveratrol per kilo of food, which is 300 PPM. Again, just for comparison

00:36:56.520 sake, guys, wine is like less than two PPM parts per million of resveratrol. They're giving them 300

00:37:03.060 PPM and nothing happened. Now, the folks who say resveratrol works have criticized that study saying

00:37:12.980 the bioavailability is low. And therefore, you need much, much, much more than the 300 PPM that was

00:37:23.600 given in that study. But again, that was a concern and a criticism that was only voiced after the study.

00:37:29.200 The proponents of resveratrol were involved in that study, and they signed off. They're on the paper.

00:37:35.400 I mean, this was their view. So I just have a hard time believing that there is any value in

00:37:40.180 resveratrol. That's why I don't take it, independent of the fact that it's still a

00:37:44.240 ubiquitous compound that's found everywhere. Yeah. And I think that wraps those four different

00:37:49.160 drugs in that. And I think that's why sometimes it's nice, hopefully for people, when you cover

00:37:53.360 a variety and you can see how they fit in different buckets and kind of how you think about it.

00:37:57.480 And again, even you highlighting where your opinions changed and where it may change again in the next

00:38:03.760 hundred episodes, depending on new science. And so looking into the next category, which kind of is

00:38:10.340 a little more focused around exercise, I thought it'd be helpful to maybe start with a few anchoring

00:38:17.080 things that you talk about often. And just so people can kind of understand where you put VO2 max,

00:38:23.860 that's importance and muscle mass and that's importance on this scale. And so obviously we don't

00:38:29.880 have to get into these because there is an insane amount of content on those. But if you had to

00:38:34.760 summarize quickly where you would rank them on the scale that we're doing today, where would you put

00:38:41.020 VO2 max? Where would you put the importance of muscle mass? And by the way, with muscle mass, I would

00:38:45.720 put muscle strength because we really think of muscle mass as a proxy for strength. But I would say that

00:38:50.900 those are the two closest things you could put to proven. They would be right up there with smoking

00:38:55.940 cessation. They would be right up there with blood pressure management. You can't prove anything in

00:39:02.100 biology, but boy, the probability that having a high VO2 max, high muscle mass and high muscle strength

00:39:10.580 are going to increase the length of your life and improve the quality of your life. That probability

00:39:16.680 is so high that to act in disregard of that is irresponsible. That's what I really mean by proven.

00:39:24.760 So what can I say? There's very little on this topic I have not expounded on, both on this podcast

00:39:30.760 and on others and social media. I mean, this is a topic I can't say enough about because the magnitude

00:39:36.440 of the effects is so much greater than everything else. And you can see, Nick, why I get animated

00:39:43.360 and why I get phosphorylated when people ask me about resveratrol and sirtuin activators and NAD and NR,

00:39:50.600 and they're not exercising or they're exercising, but their exercise is totally JV. And it's like,

00:39:55.780 wait a minute, you are picking up pennies in front of a steam train fighting over basis points of

00:40:03.640 theoretical possible benefits of something. And you're completely missing this other thing over

00:40:09.560 here. And you've heard me tease folks, including patients sometime and say, look, once you've got your

00:40:14.600 VO2 max here and your muscle mass here and your strength here, then we can talk about the 37

00:40:19.620 supplements that you're interested in taking. I don't know, Nick, how much more do you want me

00:40:23.220 to say on it that I haven't already said? No, I think that's good. And we'll link to it

00:40:27.100 in the show notes to all the other places. I think sometimes it's helpful for people,

00:40:31.600 or at least even myself included is understanding where these things rank and how they compare to

00:40:36.700 others, which you had a really important point, which I've heard you say over and over and over,

00:40:42.400 internal, external, which is if you're worried about taking all these geoprotective drugs and

00:40:47.480 you want to take them, that's your prerogative. But if you think that's going to save you from

00:40:52.580 needing to exercise, needing to have muscle strength, needing to have a higher VO2 max,

00:40:59.060 it maybe is not the best risk mitigation strategy. And I think how you look at all this is how can you

00:41:06.060 mitigate the risk of not being capable of having a longer lifespan, but also even more

00:41:12.320 importantly, a better health span. Yep. I do say a lot that even if exercise had no effect on

00:41:20.680 lifespan, so it was lifespan neutral or be more dramatic, even if exercise slightly shortened

00:41:28.020 your lifespan by a year, it's undoubtedly worth it for the improvement in the quality of your life,

00:41:33.900 both physically and cognitively, and in many cases, emotionally. I mean, that's a much harder

00:41:37.900 one to quantify, but I think that's there. And I guess the other point I will make to bring it back

00:41:41.800 is like, why is it that VO2 max muscle mass and strength stand out as the greatest predictors of

00:41:48.860 lifespan, which they do. These stand out as far greater predictors of lifespan than cholesterol

00:41:53.740 levels, blood pressure, blood glucose, all of these things that clearly relate to how fast you're going to

00:41:59.880 live or die. Even smoking is a worse predictor of lifespan than your fitness level. And the reason

00:42:08.120 I think is just, it speaks to how potent exercise is as a tool to impact the cellular processes of aging,

00:42:15.560 but it also speaks to the fact that you can't cram for the test when it comes to these tests. So if a

00:42:22.600 person has a high VO2 max, they have been doing a lot of exercising for a long time. That doesn't have to

00:42:28.880 mean their whole life, but they didn't just decide a week ago, oh, I'm kind of unfit, but I'm going to

00:42:34.400 start exercising, and I'm going to get fit. No, no, no, no. If your VO2 max is in the top two or three percent

00:42:39.820 of your age group, you've been at this for a while. Therefore, the VO2 max measurement is really an

00:42:45.800 integration of work that you have done. And the same is true for muscle mass, and more importantly, for

00:42:51.580 muscle strength. These things, like why is, you know, grip strength always comes up as this incredible

00:42:56.840 predictor of mortality. Is it because being able to squeeze things with your hand is especially

00:43:02.860 important? Yeah, there's probably some edge cases, but it's what does it imply if you have high grip

00:43:09.540 strength? You didn't just wake up and have high grip strength. By definition, you have been lifting

00:43:15.280 and carrying heavy things. You have been using your hands aggressively, manipulating things, carrying,

00:43:23.020 squeezing, all of these things, pulling, and it's that work that is being captured through the integral

00:43:30.000 of the final metric or the test. We won't get into it too much here, but one of the questions we always

00:43:36.100 get asked is by people in older populations, 50 plus, is it too late for me to start exercising? And

00:43:41.320 we have a special episode that will be coming out in a few weeks dedicated to that. So for those of you

00:43:46.960 who are maybe haven't been exercising, you're wondering how to start, and you are in that older category

00:43:52.340 where you don't want to get hurt, that will be a really good resource there. Moving to the next

00:43:57.360 topic, something we get asked about, especially after the podcast we did with Jeremy Leneke, which

00:44:02.760 is blood flow restriction. And I think when you look at the muscle mass, muscle strength, sometimes people

00:44:07.740 are dealing with injuries. Sometimes people maybe don't want to lift heavy weights, and they're kind

00:44:14.340 of dealing with various orthopedic injuries, whatever it could be. How do you think about blood flow

00:44:20.160 restriction? And where would you rank that in this ranking system? I put BFR in the promising

00:44:25.760 category. And again, it depends on how you define the question, but is the question, does using BFR

00:44:34.540 and higher reps, lower load weights produce superior results to the same reps, the same weights without

00:44:45.300 BFR? It's promising slash proven. That is clearly the case. So again, just kind of backing up for a

00:44:51.680 little bit and for those who didn't hear the podcast on this or who need a little refresher. So this is a

00:44:57.400 topic that became of interest not that long ago, right? Maybe in the last 25 years or so when it was

00:45:04.540 demonstrated that if you applied a tourniquet around a limb as it was exercising, you would see superior

00:45:12.400 improvements in strength and muscle size relative to an untourniqueted limb, again, provided they were

00:45:21.200 both doing the same amount of work. So the question is why, perhaps? So why is it that applying a

00:45:28.380 tourniquet, well, anybody who's done BFR can tell you it's not very comfortable. So when you impair

00:45:35.560 venous return slightly, and that's really the goal of blood flow restriction, it's not complete occlusion,

00:45:42.000 it's partial occlusion, you are allowing the accumulation of metabolites at a much higher

00:45:50.200 rate. So more lactic acid is pooling more metabolites of metabolism beyond that. And the

00:45:57.120 thought is that something about that is creating more of a stress signal than would otherwise be

00:46:04.080 present absent the tourniquet. And so an immediate use case became, well, look, can we

00:46:11.580 use far lighter weights, but produce still a profound amount of discomfort? And the obvious

00:46:18.240 place where this showed up, of course, is around injury. So when a person is injured, let's use my

00:46:23.700 example, when I had shoulder surgery, I wanted to be able to still exercise that arm. But for months

00:46:30.240 after surgery, I could not carry, for example, a barbell that was the same weight that I would have

00:46:36.300 carried before, right? It was still too much pressure on the humerus in its newly repaired

00:46:43.000 joint around the labrum. So what if I used a third of the weight that I might have previously used,

00:46:49.000 I'll do a lot more reps, but I'll create this blood flow restriction around it, and I experience a much

00:46:54.820 higher training effect. The data have largely borne this out. And the nice thing about these studies,

00:47:00.100 by the way, this is what makes this type of research really elegant, is every patient can be their own

00:47:04.760 control because you're doing limb isolation. So it's a little goofy for the patient because you're

00:47:09.740 going to have one leg that might get bigger or stronger than the other, but every patient can be

00:47:14.140 their own control. And so the analyses, the studies, and the meta-analyses, and Jeremy Lineke, who was

00:47:20.600 the podcast guest we're talking about, I think did a large meta-analysis in 2011, it showed that if you

00:47:26.020 look at low load resistance training in BFR without BFR, it clearly results in greater muscle strength

00:47:32.680 and hypertrophy improvements. It's not subtle. These are really pretty big effects. All of that said,

00:47:38.980 Nick, there is still a question that I don't think we know the answer to, which is how does BFR training

00:47:47.800 at higher reps, lower weight, compared to non-BFR training with higher weight and presumably lower

00:47:56.360 reps? And that's a much harder head-to-head to design because the question is,

00:48:01.520 how do you design the protocol in each? Because now you've broken one of the constants that have

00:48:07.780 been preserved across all of these studies. And so I think that the answer there is still unknown.

00:48:14.140 As such, I just wouldn't recommend that somebody exclusively rely on BFR. First of all, it's not

00:48:20.160 that comfortable and you can't do it for everything. It's very limb-centric. But even if you were just to

00:48:24.820 talk about restricting it to how you train your arms and your legs, I still think there are lots of

00:48:29.340 scenarios where using BFR doesn't make sense. And my personal use of BFR, which I've talked about,

00:48:35.360 is I really like to use it as finishers in, you know, I'll do some sort of upper body finishers and

00:48:40.460 lower body finishers on upper body and lower body days respectively. But it's not really like the bulk

00:48:46.880 of what I'm doing. So that's kind of how I feel about this. And again, I think it is disproportionately

00:48:53.480 useful in the case and setting of a person who is rehabbing something. And it's a great way. We use

00:49:00.980 it so liberally with our patients as we're trying to get them moving immediately post-surgical

00:49:06.900 intervention. And we want to do it with, I mean, even just using their body weight. So for example,

00:49:11.580 a patient that's had knee surgery, the minute we get permission from the surgeon, we've got them doing

00:49:16.940 leg extensions with just the weight of their leg, but doing it with a BFR cuff.

00:49:21.600 So there's actually a training effect in the quads, but without overloading the knee,

00:49:27.200 because clearly you wouldn't want to post knee surgery, put a strain from the patellar tendon

00:49:33.780 beneath the knee attachment. For people interested in learning more, we'll link to podcasts. But if

00:49:38.780 people want to try it, do you want to let people know which brand you use? And obviously you can say

00:49:43.720 to, you have no affiliation with them. We don't get paid by them or anything. It's just one you've

00:49:48.520 tried a lot of and you've found real enjoyment with it. Yep. I use a brand called Katsu. I use

00:49:54.360 two different types of Katsu devices and I apologize. I don't remember the exact name,

00:49:59.100 but one of them is like, maybe it's called the C3 and it's my sort of bread and butter go-to one where

00:50:06.060 I put the arm bands on, put the leg bands on, whichever I'm using, inflate it to the pressure

00:50:10.920 and then go and exercise. And then they have another one that I really quite like,

00:50:14.500 but it does what are called passive cycles. So if I'm just sort of trying to recover,

00:50:18.400 you put this on, I think it does like a 20 second inflate, hold, deflate, repeat. If I'm

00:50:25.040 sitting at the computer, like I've got this thing cycling on my arms or on my legs. And if nothing

00:50:29.700 else, honestly, it just feels great. Like I really actually enjoy the feeling of it. So yeah, those are

00:50:34.020 the devices that I use. And there is a real art to this. There's a clinical way that you want to be

00:50:39.460 able to go about doing this where it's not just put a tourniquet on, which is what I used to do

00:50:43.560 and hope for the best because you have to make sure the pressure is such that you are still

00:50:49.040 allowing both blood in and blood out. You're just trying to blunt that somewhat.

00:50:54.660 It is always funny when we hop on zoom calls with people who aren't internal and you do have those

00:51:00.840 things cycling because it really does make people wonder what's going on over there and what

00:51:06.260 what's wrong with this guy touch. Yeah. And it fits your brand. That's what I always say.

00:51:10.840 It's on brand when you're doing that. And when you're just chomping on venison sticks in meetings

00:51:16.440 too, it's also on brand. So the next one, something we get asked about a ton, it's come up on a few

00:51:21.740 podcasts with Alton Barron, Adam Cohen, looking at the upper body, lower body, but stem cells.

00:51:28.540 So how are you thinking currently about stem cells?

00:51:31.980 This is an area where I think it's really complicated. I'm going to put this somewhere

00:51:38.160 between noise and fuzzy. I'm talking about it through one application for this purpose,

00:51:44.200 which is osteoarthritis, which is where it's been most talked about and most studied in animals.

00:51:49.880 I want to reiterate that, right? So I still find it very plausible that there are arenas in which stem

00:51:56.780 cells could be beneficial. And I would say there are actually scenarios under which I would take

00:52:02.960 stem cells if I had a certain injury. So if I tore my rotator cuff and it was a marginal call as to

00:52:09.620 whether it was surgical, I would absolutely start with a stem cell injection if it could mean avoiding

00:52:16.700 surgery and waiting for a repair. And I would love nothing more, Nick, than to see an actual

00:52:23.180 randomized clinical trial that takes patients who have torn their rotator cuff. Again, let's try to

00:52:30.240 take people with comparable injuries and randomize them into three groups. Stem cell injection, surgical

00:52:36.340 repair, non-surgical repair rehab. We could debate the merits of each of these approaches, but I would

00:52:42.520 really love to see that provided there was a way to create a uniform protocol around what it means

00:52:49.020 to get stem cells. In many ways, that's what has been hampering this field, I believe.

00:52:55.240 To be clear, the FDA does not authorize the use of stem cells. So all of this is existing either

00:53:01.540 outside of the United States where it's not regulated by the FDA or it's sort of, there's some sort of gray

00:53:06.700 areas where it can be done, but it's obviously not covered by insurance or any of these other things.

00:53:11.480 And again, if you're presumably using, I'm not even sure how much these protocols are using

00:53:16.680 autologous stem cells versus the stem cells of others. And the total lack of consistency in what

00:53:23.340 the actual agent is, the actual stem cell, is a big part of what makes this very challenging.

00:53:31.060 And I would struggle with that. So if I were in that situation I just described where I tore my

00:53:34.480 rotator cuff and I was at least willing to consider doing this before surgery, the hardest part I would

00:53:40.240 have is where am I going to do this? Who do I trust? Because it's not like I can look at someone's

00:53:46.580 data and draw conclusions, right? You're basically looking at a bunch of marketing material, not

00:53:51.220 actual data. So I would say when we talk about osteoarthritis, at least we have the advantage

00:53:56.800 that there are like canine models of osteoarthritis where they've looked at stem cells. And the truth

00:54:05.160 of it is they have mixed results. Some of them have shown that dogs with osteoarthritis when injected

00:54:12.540 with stem cells do tend to improve their gait, do tend to see a reduction in lameness, which again is

00:54:19.960 partially assessed by gait, partially assessed by the use of medications or pain relief through

00:54:25.760 medications. And other studies have found no benefits whatsoever. Again, it's hard to tease out

00:54:32.100 what that means. Does it mean that the methodologies are flawed and that in some of these studies they're

00:54:38.740 not actually using the right stem cells? Again, stem cells are very broad term. What are we really

00:54:42.900 talking about? Are we talking about a pluripotent stem cell? Are we talking about a donor-derived

00:54:48.420 stem cell? Are we talking about a fetal-derived stem cell? By the way, then I haven't even got into

00:54:53.360 what's the concentration of stem cells? What's the protocol? How many injections do you need? All of

00:54:58.080 this stuff is still unclear. And as a result of that, we have a cottage industry that is the absolute

00:55:05.960 wild west. I think it's unfortunate. I wish there was greater financial incentive to study

00:55:11.980 for what the answer is, as opposed to just say, yeah, we know the answer. It works. Or we know

00:55:16.380 the answer. This is a total sham. It shouldn't be done. When in reality, the truth might be somewhere

00:55:20.200 there. So look, it's very hard to have this above noise right now because of a total absence of data,

00:55:28.340 not because there isn't biological plausibility. There really is, but it's just there's no data.

00:55:33.980 So I clearly am not going to call this nonsense, but this is not going to rise to the level of

00:55:39.280 promising in my mind yet. Moving on to the next category or theme, which is loosely nutrition,

00:55:46.960 which is something we know how much you love to talk about. And it's also something where I think

00:55:51.780 as we go through these, you can kind of not only give your opinion on where you're at now, but also

00:55:56.600 maybe how that's changed over time. And so first and foremost, what we see the most is questions

00:56:03.700 around long-term fasting and its potential benefits on longevity. So not fasting to count

00:56:12.300 calories, anything of that nature, but more so how you think about quote unquote long-term fasting

00:56:17.660 as it relates to longevity. You know, it's so funny when you and Josh and the team put this list

00:56:24.080 in front of me the other day and I got through the first few and I was like, oh sweet. I don't have

00:56:29.540 to talk about nutrition. And then I came to this big block of nutrition and I just wanted to start

00:56:35.600 crying. I don't, did you guys deliberately bury this? Well, you don't want to have it too early

00:56:40.280 so that your mood goes down right away. But we also know we get asked about a ton. People are very

00:56:47.400 interested in nutrition. And I need to spend more time with my therapist understanding why I hate

00:56:52.560 talking about nutrition because I do think I have a lot to say on it. And I actually think I'm

00:56:56.920 knowledgeable on the subject and I know that therefore I should talk about it because I can

00:57:00.660 add value in a sea of bad information. But the visceral response it produces in me, Nick,

00:57:07.560 it's difficult for me to quantify actually. I've already forgotten your question. That's how much I'm

00:57:12.540 just in the throes of pain at the moment. Long-term fasting. Okay. I'm going to call this fuzzy.

00:57:20.320 And to your priming earlier, I'm going to tell you, this is an area where I've seen an enormous

00:57:27.260 change in my point of view over the past 300 episodes. So by way of disclosure, some people

00:57:36.700 listening to this podcast might know that, and there are many people I'm sure who are listening

00:57:40.400 to this podcast who came into the orbit of our work through my work in the fasting space.

00:57:48.320 So for me, fasting has historically been a very important part of my thinking about how to live

00:57:55.660 longer, how to use fasting as a gyroprotective tool. Again, I think a little bit of historical

00:58:00.580 context is relevant here. We spoke earlier about rapamycin, which stands alone in the pantheon of

00:58:07.000 molecules, the only molecule, the only molecule that has universally extended life across all model

00:58:15.880 systems of eukaryotes, which span 1 billion years of evolution. That's a big deal. But we shouldn't

00:58:23.060 forget that there is one intervention, non-drug intervention, that has also done that, and it

00:58:29.380 did it long before, and that was fasting or caloric restriction. So there's clearly something magical

00:58:37.040 going on with caloric restriction when it comes to elongating life. But the question is, can we

00:58:45.580 extend that into humans? And perhaps the more important question is, what would the fasting

00:58:52.440 protocol be? And I wrote a piece on this a long time ago that maybe we should link to where I say,

00:58:58.420 look, the question is, how long should you fast? To what extent should you fast? And how frequently

00:59:03.980 should you repeat the fast? Those are basically your three variables. And there are obviously so

00:59:10.260 many combinations of those. I won't even say infinite because you could just draw a line in

00:59:14.580 the sand and say, you could do a complete fast, you could do a 50% fast, a 75% fast, and just make

00:59:20.440 it somewhat big and arbitrary. And you could do it for one day or three days or five days, and you

00:59:25.680 could do it once a year or once a quarter or once a month. Even if you took reasonable spots,

00:59:30.660 it quickly becomes impossible to test all of these. And so instead, what we're left with is a

00:59:36.840 cult of personalities where people tell you what they do. And I've been guilty of that, although I

00:59:41.300 hope I've always been clear at saying, I have no clue if this is quote unquote right. What I was doing

00:59:46.940 was doing seven to 10 days of water only fasting once a quarter, and then three days once a month on

00:59:54.020 the alternative. So two months short fast, one month at a long fast repeat. Now, what data could

01:00:01.160 I point to for that protocol? None. Absolutely none. I made it up. I literally made that up. And again,

01:00:08.820 very transparently made that up. Were things happening in my body from a cellular level that

01:00:14.080 were beneficial? Probably. Did I have great biomarkers to show that? No, because I was relying

01:00:20.340 on very standard biomarkers. I mean, fortunately, my standard biomarkers are generally quite good.

01:00:26.040 So it's not like, yes, your glucose is going to go down, your ketones go up, your insulin goes down

01:00:30.560 a little bit, but those things are transient. And by the way, a lot of things got really bad when you

01:00:34.600 fasted, right? Your thyroid function completely deteriorated. Your androgen function completely

01:00:40.820 deteriorated. So it wasn't like all good. But what was really interesting is the thing we couldn't

01:00:47.220 measure, which was what was actually happening to those hallmarks of aging. Were we improving

01:00:52.860 at the cellular level, things like senescence, autophagy, all of those things? Well, guess what?

01:00:58.360 We can't measure those things. So we don't know. We can try to extrapolate. And there was some rationale

01:01:03.200 in my mind, I suppose, extrapolating from what we knew in mice, which is that this many hours of fasting

01:01:11.040 in a mouse does indeed produce cellular changes that are incredibly beneficial to disease prevention.

01:01:19.280 And therefore, given what we know about the relationship between mice fasting and human fasting,

01:01:24.000 it should be that by about five days, I'm going to be experiencing some of those benefits. But then

01:01:28.420 even if you knew that were true, then the question would be, well, how often do you need to do that?

01:01:32.400 So even if you could establish that five days was the sufficient length of time to fast,

01:01:36.260 should you do it five days a month, five days, a quarter, five days a year? No idea. So you may

01:01:42.980 ask the question, why did I stop my fasting protocol? And for me, it really came down to two

01:01:48.400 things. But I think the most important was that I just took a kind of look at the data,

01:01:53.380 the bigger data of myself and realized over the course of three years, I had lost, I don't remember

01:02:00.140 the exact number, but it was getting close to 20 pounds of muscle, might've been 16 pounds of muscle.

01:02:06.260 Over that period of time, at least at the frequency that I was fasting, which I'm not saying was right

01:02:11.260 or wrong. It's very difficult to gain back the lean muscle. You keep losing, you lose a ton,

01:02:17.820 you regain some of it, you lose a ton, you regain some of it. But I just couldn't dig out of that

01:02:22.600 hole. And so I think in around 2021, I said, you know what, I'm going to just put the kibosh on

01:02:28.280 fasting for now. I'm going to make sure I gain back 20 pounds of muscle that I have lost.

01:02:32.780 And that's my personal story with it. Unfortunately, I would still say, Nick,

01:02:38.180 that, and again, I'm glad you separated this out and said, look, is fasting a viable tool for weight

01:02:42.020 loss? Sure. It's one of the tools we have in the CRDR TR kit. And by the way, in that regard,

01:02:47.600 I still do it, by the way. Let me also establish, I am still a TR guy for the most part. Drink my coffee

01:02:53.860 in the morning. I will slug a protein shake in the morning that is very low in calories because it's

01:02:59.880 just protein. So it's going to be 120 to 150 calories, but I don't eat a meal until two o'clock

01:03:06.920 in the afternoon. And then I have dinner at six or seven. But again, I'm doing that for caloric

01:03:12.100 restriction purposes. I'm doing that to manage total caloric intake, not because I think that

01:03:17.260 there's some magical benefit that I'm getting by not having meals spread throughout the day.

01:03:22.260 I guess just to put a bow on this topic, why is this fuzzy? Well, I think it's fuzzy because

01:03:28.020 in many ways, this suffers the same problem rapamycin suffers in terms of getting into

01:03:34.540 much more dispositive clinical trials, which is we're clearly never going to do the experiment

01:03:43.480 that asks people to undergo different fasting protocols for the entirety of their life to

01:03:49.600 determine if indeed they live longer. So we're going to have to come up with better proxies,

01:03:55.060 meaningful biomarkers of the hallmarks of aging. If we can do that, then maybe we can start to get

01:04:02.960 a sense of whether or not rapamycin and fasting should be important parts of our armamentarium

01:04:10.800 as we think about ways to impact those hallmarks of aging.

01:04:15.260 Two follow-up questions there. One of which is, you mentioned there was kind of two things that

01:04:19.940 caused you to change your mind. The first was the muscle loss and just that. What was the second?

01:04:26.840 The second one is actually was just more of a social issue, which was at the time that I was

01:04:30.200 fasting, I also happened to be traveling a lot. It was very easy for me to fast when I was away from

01:04:36.080 home. So all of those fasts were done while I was in New York and I lived in San Diego. So I didn't

01:04:43.820 have to be fasting around anybody. I was just fasting in my apartment alone. And even if I went

01:04:50.040 out to dinner with friends, which was weird, but I did, I would just sit there and drink soda water

01:04:54.400 while they were eating dinner. Jocko famously tells a story about that one night. But once I stopped

01:04:59.220 traveling, it meant, oh, all those fasts are going to have to be done at home. And I just didn't want

01:05:04.040 to do it. I don't want my kids to be wondering like, why is daddy never eating and all that kind of

01:05:07.980 stuff. So that became another reason independent of the biology. So the second follow-up would be,

01:05:13.960 and you kind of hinted at it there, which was, you would love to have biomarkers to know

01:05:19.280 if it's working at what dose, how that works, but what would have to be true or what would have to

01:05:24.980 change outside of that? If there's anything that would cause you to start fasting again, long-term.

01:05:31.680 I don't know. I would really need to see something incredibly compelling in a higher order model.

01:05:37.980 Maybe in a dog model or something like that. Again, like this is a great example of where

01:05:42.160 I think companion dogs are such a great model to study things. Because again, I think most people

01:05:49.140 find binary fasting far easier than caloric restriction. And there's already a lot of

01:05:53.220 controversy around caloric restriction. I have an entire chapter on this in Outlive where I talk about

01:05:57.380 the Wisconsin NIA monkey studies. But for most people, like if I said, oh, you just got to reduce

01:06:03.520 calories by 25% for the rest of your life and you're going to live longer. Most people would say,

01:06:07.160 I don't want to live longer. That's torture. It's actually easier to say, well, what if you

01:06:10.400 just have to periodically do big fasts? I would like to see an experiment of that done in a better

01:06:15.180 model than just mice. Definitely. Looking at the next topic, if you look historically since the

01:06:21.220 podcast started, it's a topic that we get asked about an insane amount, which is the energy balance

01:06:26.440 theory. And we've had tons of guests on who maybe have different opinions on this. It's something that

01:06:31.940 you've written about a lot. But how do you think about the energy balance theory right now as it

01:06:37.480 relates to the ranking system? Again, I put this right between promising and proven truthfully.

01:06:43.580 So again, I think it's worth stating what we're talking about. So the energy balance theory, I

01:06:48.080 believe, would pause it. Again, I don't live in this world at the moment. So I want to be very

01:06:52.260 sensitive to those who does. And I don't want to misrepresent it. So if I am misrepresenting this,

01:06:56.600 I hope I hear about it. But what it's basically saying is that energy balance is determined solely

01:07:05.420 by the caloric density of the foods consumed, less the energy expenditure. And that the caloric

01:07:16.340 density, the net available caloric density of a food is its contribution to energy balance.

01:07:24.320 So this is where, again, I feel a little bit bad talking about this because I haven't been as

01:07:30.460 diligent as maybe I should be in staying up on this world over the past decade. I've largely not

01:07:36.540 paid attention to it, truthfully, because in many ways, I've sort of seen what I believe is a reasonable

01:07:42.300 answer. And just for folks who maybe don't know part of the history here, I mean, I was once running

01:07:47.960 an organization that funded research directly to try to answer this question. And I think I went into

01:07:54.280 that thinking the answer was going to be one thing, but actually very excited to see regardless a

01:08:00.920 swing at this. And I think that that study, while it had some flaws, actually came out and showed

01:08:06.260 something else, which was if indeed isocaloric manipulations of macronutrients change energy

01:08:14.620 expenditure, it's not an enormous difference. What does that mean in English?

01:08:20.320 If you give two people equally caloric diets that are radically different in macronutrients,

01:08:29.280 do you have a significant difference in energy expenditure? That's what was being tested by that

01:08:36.000 theory. And I think that the evidence is much more clearly in favor of the fact that no, you do not.

01:08:42.880 Now, let's add a couple of caveats. There is clearly differences in the thermogenesis of food.

01:08:49.440 So, a thousand calories of protein, a thousand calories of fat, and a thousand calories of

01:08:54.420 carbohydrates are going to have different processing amounts of energy that will result in different

01:09:00.240 amounts of net available energy. Furthermore, different types of foods are going to differentially

01:09:08.120 impact appetite. And therefore, in a free living environment, this isn't to say that macronutrients

01:09:14.940 don't matter. But what we're really trying to tease out is, is there truly a scenario under which a

01:09:21.080 person who's eating 3,000 calories of a balanced diet can switch to 3,000 calories of a ketogenic diet

01:09:30.800 and have weight melt off them just because they're on a ketogenic diet? They somehow magically start

01:09:36.180 burning a lot more energy. And again, I believe the answer to that question is no. I do not see

01:09:41.840 any evidence to support that. And therefore, I think that if a person is on 3,000 calories a day

01:09:47.660 of a balanced diet and they switch over to what they believe is 3,000 calories a day of a ketogenic diet

01:09:52.960 and the weight starts pounding off them, I think they're either moving more or eating less than they

01:09:56.940 realize. I've asked you this before and I think it's applicable here, which is how would you respond to

01:10:02.500 people who maybe get frustrated at your ability to change your mind if new data comes out? Because I think

01:10:08.720 you mentioned there, you could have people who came in maybe through the fasting content that we put out

01:10:14.120 and was talked about. And now they're hearing this, which is why I think again, I like this ranking scale

01:10:20.240 because it allows anchoring to things, which is, this is how I think about it. And this is our confidence

01:10:25.980 interval and this is how it could go up and down. But just in general, I think there may be at times

01:10:33.580 in science, a resentment if you do change your mind. And I think that leads to potentially people

01:10:39.800 sticking with their beliefs maybe longer than they should. And so how do you respond to people who say,

01:10:45.380 why do you change your mind? And should that affect what I hear you say today?

01:10:50.960 So first of all, that's kind of news to me that people are upset about that.

01:10:53.640 I would bet that it's not scientists who are upset at that. I think that any scientist who doesn't do

01:11:00.640 that needs to be questioned. So in other words, if you can't change your mind in the presence of new

01:11:06.500 data, I think by definition, you're not a scientist, you're an advocate. Now, advocacy has its place,

01:11:13.300 but not without science. The only thing I would ask of those people, if there are people that are

01:11:18.860 indeed upset at me, is what would you propose as the alternative? Is it vexing that I change my mind

01:11:24.880 on things? Yes, I suppose it is, if it means that it impacts your belief about what is good to do,

01:11:31.000 what is not to do. But if the alternative is, I'm confronted with new data, but I ignore it,

01:11:37.620 or I pay attention to it, and I lie about it, I can't extract from that what the alternative is that

01:11:42.860 is better than simply being uncomfortable with the fact that, yep, I used to believe this thing,

01:11:49.840 and I believed it, and I lived it, and blah, blah, blah, blah, blah. But now I'm like, yeah,

01:11:53.420 I don't believe it anymore. Another topic in this realm of nutrition that we get asked about a lot,

01:11:58.900 it seems there's a ton of confusion, and we're going to very simplify it just for this conversation,

01:12:03.680 is an idea of, like, is sugar poison? What's your thought on that?

01:12:10.740 Oh, all the hits, Nick. Greatest hits right now, maybe.

01:12:14.620 It is the greatest hits. That's why you can't agree to doing these things. We get to ask you

01:12:18.740 all the stuff that you traditionally don't want to talk about on AMAs.

01:12:23.080 Yeah. Again, a very loaded question, but I would argue that the question,

01:12:27.240 is the premise of the question even logical? So, what is a poison? Again, poison is a word that

01:12:33.300 speaks to a dose, speaks to a frequency, speaks to chronicity, acuteness, I mean, all of these things,

01:12:39.600 right? So, broadly speaking, when I think of a poison, I'm thinking, is something chronically

01:12:43.940 a poison? Is it acutely a poison? Okay, so let's start with something that everybody has in their

01:12:48.300 house. Acetaminophen, Tylenol. Is it a poison? I mean, it doesn't have a skeleton on the cover with,

01:12:55.280 like, bones through it, right? Meaning it doesn't look like the Drano you have under your sink that is

01:13:00.000 clearly marked as a poison. Tells you to take 500 to 1,000 milligrams every four to six hours or

01:13:06.560 whatever the instructions are. But what happens if you took 20 grams of that stuff, 20 times the dose?

01:13:13.420 Well, you would be dead of liver failure in three days if someone wasn't able to pump your stomach

01:13:18.020 in time or get you a liver transplant. So, that sounds like a poison. That's actually acutely

01:13:23.260 quite toxic. Is alcohol a poison? Depends on the dose. We've talked about and written about this

01:13:29.600 at great length. There are clearly doses at which alcohol is quite toxic. It's neurotoxic. And again,

01:13:37.320 there's certainly a scenario where, you know, you have a glass of wine a few times a week and it would

01:13:41.180 be almost impossible to discern or measure a negative effect of that. So, I say all of those

01:13:47.960 things just to kind of anchor people in what we're talking about. And I think this type of word,

01:13:52.100 I just think that the phrase sugar is poison is not helpful. It's loaded. It's emotional. It's

01:13:59.080 sort of nonsensical. What we should really be asking, I think, is a question that's more along

01:14:05.880 the lines of what are the biochemical effects of sucrose or high fructose corn syrup or fructose in

01:14:13.440 general at different doses and under different metabolic conditions? And understandably, that's a

01:14:19.020 mouthful that nobody wants to say. So, it's just easier to just say sugar is poison.

01:14:22.100 But again, I think this is an area where my view has changed quite a bit. And it's changed because

01:14:29.500 of the data. I just don't see the data to demonstrate that an isocaloric substitution

01:14:41.000 of fructose for glucose is demonstrably worse for health outcomes if total energy intake is

01:14:50.720 preserved. Now, does that mean that eating sugar in an unrestricted manner in a free living environment

01:15:01.220 is of no consequence? No, it doesn't mean that at all. And it certainly appears that in at least a

01:15:09.740 susceptible individual, a high consumption of fructose, and it seems even more clear in liquid

01:15:17.380 fructose, can drive appetitive behavior. Meaning, to put that in English, if you're drinking a lot of

01:15:24.400 sugar, it makes you want to eat more calories. Now, we can debate how many calories, and I believe

01:15:33.420 that these data have been misrepresented. I think that these data have been misrepresented and

01:15:39.000 overstated. I think that in a free living environment, people will consume more energy if

01:15:47.080 they have more access to sugar. But if you control for calories, you may recall I had this discussion

01:15:53.740 on the podcast with Rick Johnson using what I think was probably one of the most robust experiments I had

01:16:00.000 seen on this topic, given how long it lasted. And my recollection was it lasted nine months, which in

01:16:04.680 mice is an eternity. Under isocaloric conditions, when these mice were fed, when their total calories

01:16:11.980 were controlled, and you had high fructose versus low fructose groups, you did not see a statistically

01:16:17.700 significant difference in body weight. That's a big deal. Now, would you see a statistically

01:16:23.020 significant difference in metabolic parameters? I think you might if the fructose dose gets high enough.

01:16:30.400 But this comes back to something I said at the outset, the dose makes the poison. What appears

01:16:35.040 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

01:16:41.740 other parameters. So when I was young, when I was a teenager, and I trained six hours a day, which I did,

01:16:51.460 I never ran less than eight miles in the morning. I mean, I was in the gym, like it was a training

01:16:56.480 machine. There's no way I was eating fewer than 200 grams of sugar a day. A, I mean, I just ate

01:17:03.380 everything that was in front of me. I would drink two liters of orange juice as my snack box. Other

01:17:09.380 kids were drinking little juice boxes. I had a two liter can of orange juice. I didn't eat bowls of

01:17:15.120 cereal. I ate them a box at a time. So was I unhealthy? No chance. I probably had 4% body fat,

01:17:22.760 but I was exercising six hours a day. So the context matters. If I ate that much food today,

01:17:29.840 nevermind sugar, I mean, you wouldn't even know my name anymore. I'd be dead. So everything about this

01:17:35.640 is problematic because I think people want to focus on just one macronutrient, in this case,

01:17:42.420 fructose or sugar as a molecule. And we don't want to sort of focus on the overall dietary pattern

01:17:49.540 that accompanies it. And so I would say the following, if I was going to try to sum this up,

01:17:54.680 when I consume fructose, which I do all the time, it's generally in the form of fruit. I don't restrict

01:18:01.420 my consumption of fruit. I generally don't drink calories outside of protein shakes.

01:18:09.420 Those happen to be sweetened with artificial sweeteners anyway, these days, they're mostly

01:18:12.680 like sucralose and things like that. If I'm drinking a beverage, the once or twice a month that I want

01:18:18.940 kind of a carbonated beverage that's sweet, it's a diet Dr. Pepper as opposed to a Dr. Pepper.

01:18:25.120 Okay. Would the Dr. Pepper kill me? No. But again, I'm only having like one a month,

01:18:29.680 so it probably doesn't matter. But truthfully, Nick, that's more because of my teeth. Like what

01:18:34.320 I really care more about is not putting an overall strain on my teeth than I do in the belief that

01:18:41.540 sugar is somehow uniquely poisonous. So I guess I do limit sugar intake. What you're hearing me kind

01:18:48.300 of react to is not because I think sugar is poison. I think a high sugar diet is just a dietary pattern

01:18:55.380 that is incongruent with eating the right kinds of foods that I generally want to eat anyway.

01:19:00.840 I hope that makes sense and it's not too waffly, but I'll let you push back on it.

01:19:05.240 No, I think it does. And I think even though you've talked about this so much,

01:19:09.080 I think, and we can link to it where you go in more detail, but I think it would be helpful for

01:19:12.140 people just how you look at nutrition. Do you want to give your quick two by two framework of

01:19:18.320 metabolically healthy, unhealthy, that whole piece? So it kind of, I think paints a bigger picture on

01:19:24.080 why you don't just look at sugar being toxic, poison, whatever it is, but how you kind of look

01:19:30.180 more holistically. Cause I think a lot of what you said there would relate to you because you are

01:19:35.720 metabolically healthy and you know where you sit in that two by two framework. But if you have patients

01:19:40.140 who maybe are metabolically unhealthy and they need to lose weight, they need to increase their muscle

01:19:48.480 mass. You might not be so liberal with the sugar for them. Yeah. And I'll say this,

01:19:53.580 like there's definitely an area where I'm still actively trying to investigate this and we'll

01:19:59.740 even be doing a podcast on this topic, right? Which is, is there a unique role that fructose

01:20:04.340 plays in the development of NAFLD? So non-alcoholic fatty liver disease is obviously

01:20:09.420 running rampant right now in the world. And one hypothesis is that it's not just energy imbalance,

01:20:17.360 which is clearly associated with NAFLD. In other words, you take a person with NAFLD

01:20:20.880 and they lose 20 pounds. Their fatty liver is going to get better no matter what. But then the

01:20:26.420 question is, should those people be restricting fructose? And again, lots of great mechanistic

01:20:31.780 data for why fructose rather than glucose would disproportionately play a role in the development

01:20:38.000 of NAFLD. And I think there's even more compelling evidence for why liquid fructose is potentially

01:20:45.220 playing a greater role. But what I haven't seen yet is a really compelling clinical trial

01:20:50.660 that can demonstrate that independent of weight loss, isocaloric substitution of fructose for glucose

01:20:58.540 results in an improvement of NAFLD. That said, if I have patients with NAFLD, we're going to tell

01:21:05.360 them not to drink alcohol and not to consume fructose out of mild amounts of fruit. So again,

01:21:11.460 we're making a recommendation that is not necessarily one for which we would have

01:21:15.180 incredible evidence, but we're saying, look, even if nothing else, that change in behavior

01:21:22.020 reduces in less caloric intake, which results in weight loss. Ultimately, that's what we care about.

01:21:27.560 Just to end that little piece, do you want to just walk through your two-by-two framework for

01:21:31.240 nutrition? Again, we'll link to places you talk about in more detail, but I think it's just helpful

01:21:34.900 for people who maybe aren't familiar to have that anchoring.

01:21:37.780 Yeah. I mean, it's really three questions and it's, is a person overnourished or undernourished?

01:21:45.000 That's determined by total amount of body fat and visceral fat. Are they adequately muscled

01:21:50.580 or under-muscled looking at things like fat-free mass index or appendicular lean mass index? And then

01:21:56.620 are they metabolically healthy or not? So by understanding the answer to those questions,

01:22:01.660 you pretty quickly can come up with a point of view on how a person needs to train

01:22:07.060 and how a person needs to eat. And maybe even in some cases, how you want to tweak their

01:22:12.220 macronutrients. I think if you talk about sugar, you also have to talk about sugar substitutes

01:22:17.320 because it's something that we've written about a lot. There was studies that have come out that

01:22:22.420 caught a ton of press. And so how do you think about the idea of sugar substitutes and if they are

01:22:29.600 dangerous? I would absolutely refer people back to one of our premium newsletters on this topic.

01:22:35.880 I think it's one of our best premium newsletters ever. It was maybe a bit long for people, but again,

01:22:41.540 if you really want to get into serious topics, you have to get serious. The long and short of it is,

01:22:46.460 look, sugar substitutes have been around for an awfully long time. And certainly in the 70s and

01:22:53.760 even as recently as in the last 20 years, there have been concerns around the toxicity of them,

01:22:58.960 especially kind of the OG ones, which would be aspartame and saccharin. The truth of it is,

01:23:04.620 though, I think if you really want to talk about that type of toxicity, the doses of the sugar

01:23:10.880 substitutes are literally orders of magnitudes greater than what would be consumed by humans.

01:23:18.200 So even though there were maybe flaws in some of those studies, even if you were to take them at

01:23:22.700 face value, it's hard to imagine. So for example, the study, the rat study that got everybody worried

01:23:30.120 about saccharin, rats that develop tumors were being fed the equivalent of 800 diet sodas for

01:23:39.040 every day of their life. That's how much saccharin those rats were being fed to develop these liver 0.88

01:23:44.500 tumors. And again, I think it's just, it's a very slippery slope to then say, oh, well then these things

01:23:49.680 are poisonous because it's sort of like by that logic. I mean, I told you that even if you took

01:23:53.700 20 times the dose of Tylenol, you'd be dead. And by the way, you'd be dead like much quicker than you

01:23:59.740 would die from this cancer. And here we're talking about 800 times the dose over the entire duration

01:24:06.800 of a life. You know, at that level, just to be glib, Nick, like oxygen is toxic to people, right? We have

01:24:12.620 21% oxygen in the air that we're breathing. If I put you in a 100% oxygen environment indefinitely,

01:24:18.900 the amount of free radicals you would develop would kill you. So everything gets toxic at some

01:24:24.700 point. The aspartame data, I think was a little less extreme. Basically, this was a paper in 2006,

01:24:31.280 2007, and it did look at higher rates of cancer in rats that consumed pretty high amounts of aspartame

01:24:38.080 from the day they were born right on to the duration of their life. But truthfully, they were still

01:24:44.800 consuming the equivalent of 20 cans of diet soda every single day to get to some of those outcomes.

01:24:52.540 So is it possible that these things are cancer causing at normal doses? It is possible. I don't

01:25:00.040 think it's that probable. And therefore, when I think about sugar substitutes, I'm less concerned with

01:25:07.840 the cancer stuff and more concerned with the metabolic stuff, the impact on gut health and

01:25:15.800 those other things. And so I think that's probably worth spending a minute on as opposed to, you know,

01:25:22.120 worrying too much more about some of these animal models that are using non-physiologic doses of this.

01:25:30.100 So where do we want to start? I mean, I think the two biggest areas to talk about with non-sugar 1.00

01:25:35.700 sweeteners is what is the impact on body weight and what is the impact on glycemic control or metabolic

01:25:40.920 health? And I would say that the first generation versions of these, so saccharin, aspartame,

01:25:47.980 sucralose, seem to have a slightly negative effect on those parameters when calories are controlled.

01:25:56.700 Conversely, the, I don't know, newer ones, some of them that are not even what we would consider

01:26:02.440 non-nutritive like xylitol, erythritol, stevia, and allulose appear to have less detrimental

01:26:09.480 effects. In fact, even allulose may even have slightly beneficial effects on glycemic control

01:26:15.140 due to SGLT1 signaling. But it's a little too soon to say that. So this now comes back to a

01:26:22.200 heuristic, which is like, how do I behave around these things? And I, a moment ago said, well,

01:26:28.700 I'm clearly consuming some of them. So it's hard to get a protein drink out there, even the cleanest

01:26:34.100 ones out there that doesn't have some amount of these products in them. And the protein powders

01:26:38.880 and drinks that I use generally have sucralose in them. That seems to be the one du jour.

01:26:46.180 So I'm going to get a little bit there. I already kind of alluded to the fact that I don't really drink

01:26:49.920 diet sodas because I'm mostly just drinking sparkling water. I don't add it to anything I consume. So if I'm

01:26:55.640 drinking coffee, it's, I put a little cream in it, but I'm not sweetening it. So more or less,

01:27:01.200 it doesn't really appear in what I do. Although I do chew gum with xylitol in it, all the gum I

01:27:07.140 chew has xylitol in it. And that's more around some of the potential benefits of xylitol on the

01:27:13.220 enamel of teeth. So my advice to people who are consuming lots of artificial sweeteners, who are

01:27:20.780 struggling with glycemic control, body weight, or things like that is substitute them out, but don't

01:27:26.200 substitute sugar in, just get rid of it, period. So go from drinking diet Coke to drinking water,

01:27:32.680 bubbly water, not drinking Coke. Cause I think that's probably a worse outcome if no other reason,

01:27:39.080 just from more calories coming in. But I think that if you're struggling on that front, getting rid of

01:27:44.600 those things might matter. The area where I still think we are most interested in understanding

01:27:49.560 things is what is the impact of these things on the, on the gut and how foreign are these things

01:27:55.420 to the bacteria in our gut? And are they being provided in a high enough quantity to even

01:27:59.760 materially impact the guts? You know, there's some data, some animal studies that suggest that this is

01:28:04.160 a big issue. I think it's a bit too soon to say that. So yeah, that's sort of how I would talk about

01:28:09.040 sugar substitutes. For people who want to dive deeper into that, we'll link to all the other content

01:28:15.060 on that in the show notes. And yeah, I think that sugar substitutes piece was, I can't think of a

01:28:20.400 piece offhand that you and the team have worked on that was longer. I remember reading that for the

01:28:26.520 first time and you just kept scrolling and scrolling and scrolling. So it's an insanely good resource

01:28:30.660 for people to kind of look at, but then also to go back to, and it's broken out by all the

01:28:34.540 different substitutes. And it's a really awesome piece. The last thing to look at in nutrition

01:28:40.040 is something else that I feel has been talked about for such a long time. And what always comes

01:28:47.780 back around, you've written about this back in the early stages of the blog, even before there was

01:28:53.220 a podcast. And I feel every now and then there's a new documentary that comes out or a new piece of

01:28:57.960 content. And it raises the question again, which is, does red meat give you cancer? And so if you had to

01:29:05.580 look at that statement, let's say just red meat gives you cancer, where would you rank that in

01:29:12.660 our ranking system today? So this is going to sound bold, but I would actually put this in the nonsense

01:29:17.400 category, which is not to say that a dietary pattern high in red meat could not play a role in the

01:29:26.460 development of cancer, but that's very different than the question. So if the question is, does red meat

01:29:32.520 cause cancer? I think that is not correct. And I think there's plenty of evidence that that is not

01:29:37.840 correct. If the question is, do people who eat a lot of red meat or do people who eat a lot of

01:29:43.340 processed red meat have a higher risk of getting cancer? I think the answer to that question is yes,

01:29:48.000 but it's probably less because of the meat. Although in the case of certain processing, it may be the case,

01:29:53.920 but it's probably much more because of what they're not eating. It's probably much more because

01:29:59.340 their diets tend to be much lower in vegetables and specifically much lower in insoluble fiber,

01:30:07.520 which plays a very important role in the prevention of colorectal cancer. So the debate on red meat and

01:30:12.900 cancer goes back for long periods of time. And again, it suffers from all of the usual trappings

01:30:19.920 of nutritional epidemiology, which is why John Ioannidis famously said that all nutritional

01:30:27.360 epidemiology belongs in the wastebasket. The two most obvious problems with nutritional

01:30:33.280 epidemiology in this regard are that it's very difficult to get an accurate reflection of what

01:30:38.980 people consume using food frequency questionnaires. It's almost impossible. And secondly, and I think

01:30:45.120 more seriously, it's very difficult to disentangle the variable of interest from the other lifestyle

01:30:52.540 variables that are covariates within the problem and that speak to what we refer to as the healthy

01:30:58.620 user bias. So I don't dispute for one moment that every time you do an epidemiologic survey and you

01:31:06.000 compare people who live on hot dogs and pepperoni to vegetarians, the epidemiology will always tell you

01:31:13.340 that the vegetarians are going to live longer. And while that might be an extreme example,

01:31:17.760 you do appreciate that on average, those vegetarians have a much higher socioeconomic status.

01:31:23.440 They are much more health conscious. They are exercising much more. They are much less likely to

01:31:28.380 be smoking, doing yoga, all these other things. And therefore, how can we disentangle the variable

01:31:35.760 from the effect? When you look at the most compelling case for people who eat the highest amount of meat

01:31:43.660 and their risk of cancer, there was a study that was done in Europe that looked at nearly half a million

01:31:48.960 people and it divided them into a cohort that were eating more than 160 grams per day of protein from

01:31:56.720 red meat and processed meat. And it compared them to people that were eating virtually none, 20 grams per

01:32:03.420 day. So again, I like when they do this because you're at least taking like the most extremes. And indeed,

01:32:08.920 there was a difference, but it was relatively small. So even under that setting, that was the

01:32:14.940 difference between a 1.7 increase in the risk of cancer versus a 1.3% absolute risk for colorectal

01:32:24.520 cancer over the period of study. So just again, what does that mean? It means that the difference in

01:32:29.360 risk between the super high protein consuming meat group and the low group was 0.4% of actual percentage

01:32:38.580 points. So that means basically you have to put 250 people on a low meat diet to reduce one case of

01:32:49.920 colorectal cancer. And again, that's assuming that you arrived at this through randomization,

01:32:55.340 which you didn't. So again, there was another study that was done. It was a 10-year observational

01:33:00.460 study that looked at about 150,000 people with the highest tertile of red meat consumption. And they had a

01:33:08.420 50% increase in relative risk to those in the lowest tertile. The error bar on this study was so big

01:33:16.500 that it barely made statistical significance despite the sample size there, which I think, again, just

01:33:22.560 speaks to the heterogeneity of this. Nat, I would say that every one of these studies basically ends up

01:33:29.560 having the same issue with it, which is when you look at the details, you realize it is very difficult

01:33:38.820 to come up with a meaningful view that it's red meat specifically that is driving cancer, as opposed to

01:33:47.700 the absence of vegetables, the absence of fiber, or maybe the presence of some of the ultra processing

01:33:56.500 things that go into consuming certain patterns of meat, like gas station bot jerky and stuff like

01:34:03.620 that. So we could talk a lot more about this. I really think that the health effects, the ill health

01:34:10.640 effects for red meat consumption is incredibly weak. The hazard ratios themselves for this are very,

01:34:18.300 very small, even with all of the limitations that I've mentioned. And so therefore, if you go back to

01:34:25.320 kind of the Austin Bradford Hill criteria of epidemiology, which I outline in great detail

01:34:30.560 in the book, very hard to imagine that there is causality here. In fact, the epidemiology here is

01:34:38.120 so underwhelming that it almost draws the opposite conclusion. It's almost hard to believe there is a

01:34:44.680 signal given how underwhelming the epidemiology is. Whereas conversely, when you look at the epidemiology

01:34:50.360 of smoking or the epidemiology of exercise, those are so overwhelming that it factors into what we see

01:35:00.280 as the overall causality narrative. All right. So Peter, I think really interesting. And I think

01:35:06.940 that kind of wraps the nutrition section. And so you mentioned it earlier on, there is a really large

01:35:13.620 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,

01:35:20.540 even though it's the first one on this topic. And so if people do like this theme of kind of going

01:35:25.020 through and ranking these things, let us know, because we have a huge list of items that we can

01:35:30.420 hit kind of moving forward. But with all that said, anything else jump out to you before we end what

01:35:38.440 is the 300th episode of the podcast? No, I would reiterate that though. If people like this style

01:35:45.100 of, Hey, yeah, normally we just do super deep dives, but maybe once in a while we do a summary

01:35:49.920 synthesis of evolving positions on things, let us know. And we'll obviously look to do that more.

01:35:54.880 It's certainly been kind of fun to do this. Yeah. What would I say? It's hard for me to imagine

01:35:58.620 where we're going to be in a hundred episodes. And what's exciting to me is to imagine how many more

01:36:02.940 things I will know in a hundred episodes and how many things I will have changed my mind on the

01:36:07.880 evolution of the podcast for me has been so exciting because it's such an amazing way to be forced to

01:36:14.800 learn so much all the time. Yeah, definitely. It's really interesting seeing some of the guests we

01:36:19.920 have lined up and the topics and themes that we'll be covering. You know, you mentioned there

01:36:23.600 NAFLD and we talked about exercise in the aging population. So I think we have some really good 0.99

01:36:29.280 and interesting episodes coming up on topics that I think people will be excited about. So

01:36:34.080 until then, have a good one. You too. Thank you for listening to this week's episode of the drive.

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01:39:49.740 I'll see you soon.

01:40:07.340 Then I get started.

The Peter Attia Drive - May 06, 2024

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

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