Dr. Peter Attia: Supplements for Longevity & Their Efficacy

Welcome to the Huberman Lab podcast where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Peter Attia. Dr. Peter Attia is a medical doctor who did his training at Stanford University School of Medicine and Johns Hopkins School of Medicine.

Dr. Attia is one of the world's most trusted voices on the topics of health span and lifespan. And with good reason, he is known to systematically review the research literature, the clinical trials, and he maintains an avid clinical practice.

So when it comes to the topic of whether or not a particular molecule or supplement or prescription drug is indeed something that we should be thinking about and perhaps even taking in order to improve our health span and lifespan, Dr. Attia is the person that I choose to sit down with and discuss it.

So today we are going to discuss the so-called NAD pathway. This is a pathway that's received a lot of attention in recent years as a potential target for improving lifespan. That is for living longer. Today we discuss the various molecules in this pathway and the various approaches to increasing NAD, which is the N target goal of anyone that's trying to augment the NAD pathway, so to speak.

So for instance, we talk about taking NR versus NMM versus direct infusions or even orally taking NAD. And we compare them in terms of both what's known and what is not known about their ability to get into cells and any efficacy they may have for either longevity or health span. Dr. Attia and I compare and contrast the literature on this. Again, both research and clinical literature and we discuss whether or not he or I take NAD, NMM or NR. And if so or if not, the reasons for that.

We also each go through our own supplement regimen, which of course reflects what we do believe can potentially have an effect on health span and or lifespan. So by the end of today's episode, you'll learn a lot about NAD. You'll learn a lot about the biological pathway. You'll learn a lot about the delivery routes, the various supplements and why people think they may be useful, why others.

Perhaps even Dr. Attia and myself think they may not be useful for longevity. You don't have to listen to find out what the answer is there. I should also mention that we give somewhat of an overview or a framework for thinking about approaches to longevity. So if you're interested in things like rapamycin, metformin and whether or not fasting can improve longevity, we get into that as well.

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Element. Element is an electrolyte drink that has everything you need and nothing you don't.

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8 sleep currently ships to the USA, Canada, UK, select countries in the EU and Australia. Again, that's 8sleep.com slash Huberman. And now for my discussion about NAD and longevity with Dr. Peter Atiyah. Peter Atiyah, welcome. How are you? Great to see you again. Great to be here again. Should we parse this NAD thing? I think we should. Do you mind if I set up a little bit of a framework? Great.

So for people that want to live as long as possible, I figure there are at least four categories of approaches, broadly speaking. The first I'll just call the do's and don'ts. You've talked a lot about these, your book outlive, beautifully covered these. And I tend to regurgitate some of what you say on this podcast. Namely, you want to move appropriately and often enough. Get enough zone to cardio, do your resistance training, keep nerve to muscle connections strong.

Avoid the sorts of things that would lead to falling and being immobile. Eat right. There's a whole category of things there. We're not going to talk about today, although we might touch on a bit. And know your genetics and make some good decisions on the basis of your genetics. So the do's and don'ts. The second category I would put under the umbrella of calories, glucose, insulin, etc. That all kind of funnel in at least in my mind to emtore, mammalian target of rapamycin.

A molecule that's robustly expressed during development and essentially all cells of the body. And then across the lifespan tapers off. During puberty, especially, well, let's say infancy through puberty, cells are expressing so much emtore and they're growing like crazy. And we often associate that early stage of life as youth, not aging because we think of it as a kind of a time stamp as opposed to the verb.

But I would argue as a developmental neurobiologist by training that it's one of the most rapid phases of aging of our entire lifespan. Look at a picture of you when you were five, look at a picture of you when you were eight versus 15. You look very different and your sizes robustly different. By the way, I just did this exercise because my daughter, her birth, her 16th birthday is around the corner. And we take a picture of her every single year at the minute of her birth.

So we have a picture of her every single year holding a clock that says 356 at 356 pm because that's when she was born. And I just went through and pulled each of the last 16 of them from the day she was born all the way up and you're right. The biggest changes are actually in about the first 10 years. The difference between being 13 and 14 and 15 and 15 and 16 becomes incrementally less and less and less. Whereas going from 2 to 3 and 3 to 4 and 4 to 5 are ridiculous changes.

I mean, the same brain has to learn an entirely new body every year in terms of how to move it, limb length, etc. So a lot of the so-called anti-aging or longevity approaches that fall under the umbrella relate to things like chloric restriction or taking drugs such as rapamycin. And of course, mammalian target of rapamycin is the target of rapamycin. In an effort to essentially remove excess insulin blood glucose and thereby reduce mTOR activity.

So essentially slow cellular growth and all that fits nicely into the logic that mTOR is associated not just with development but with aging because development is aging. And then I would say there's a third category and it's the one we are going to talk about today which is targeting specific cellular pathways that some people have deemed potentially interesting for longevity. And the pathway that we're going to spend some time on is the so-called NAD pathway.

NR, NMN, NAD being the major players and we'll talk about some of the biochemical and enzymatic steps in between. And then I suppose there's a fourth category which we could say is, you know, the do everything even the most esoteric of things category. This is a rare category. There are folks like Brian Johnson who spend a lot of time in this category specifically, you know, taking very high doses of polyphenols, limiting their caloric intake to just early part of the day.

I think he's dinner at 11 a.m. I don't know if it still qualifies as dinner at 11 a.m. But his final bite of calories is I believe at 11 a.m. Doing everything from red light to PRP plate, plate lit rich plasma, excuse me. And essentially the kitchen sink approach to longevity and agent. Did I miss any categories? So I would frame it slightly differently because I like categories to be more me see mutually exclusive collectively exhaustive.

So I don't know that I would formulate it that way. I might say look category one are sort of the essential behavioral things that you have no choice but to engage in whether you want to or not. You have to eat, you have to sleep, you have to move. You just have a choice and do you want to do those things correctly or not correctly or do you want to do those things in a manner that promotes health or erodes health.

So again, there's nobody listening to us who doesn't eat. But again, you can choose how much you eat and what you eat and when you eat. There's nobody who's alive who isn't moving because locomotion is life and the absence of life is the absence of locomotion. But you can certainly choose to move very little. You can choose to move a lot.

You can choose to decide on how you move you alluded to it already right you can you can move in a certain way that puts your aerobic system in a zone that maximizes fat oxidation we call that zone two. You can move at a level where you consume incredible amounts of oxygen at your maximum aerobic level. You can choose to move in a manner that uses resistance and and gravity against you and all those sorts of things.

Similarly, we all have to sleep right Matt Walker would probably tell us the number of days you could go with sleep without sleep before you would literally perish. But again, you have a lot of choices and how you do it. So anyway, I agree that's kind of category one, but that's kind of the way I would frame it. And then I would put in category two sort of what are the molecules that you would exogenously take to try to impact any of those systems and maybe.

And again, I'm not saying my framework is correct in yours isn't I'm just saying this is the way I think about it. I would then say what are the molecules that I could take that specifically target disease processes. So I kind of think of like if you want to live longer. And I described this I think in chapter four about live. There's a that's that turns out to be mathematically equivalent in the modern society to delaying the onset of chronic disease.

Now, I wasn't true 100 years ago 100 years ago if you wanted to live longer a few things had to be true. You couldn't die during childbirth. And that because that was a huge hit on mortality. And then you had to not get an infection or succumb to trauma. And then maybe 150 years ago that was the case, but today most of those things are taken care of by antibiotics, sanitation, and you know the modern miracle of childbirth in the in this era.

So now for you and I to live longer, we basically have to delay the onset of cardiovascular disease, cerebral vascular disease, cancer, neurodegenerative disease, dementing diseases and metabolic diseases. We have to delay the onset of those things. The longer we delay the onset, the longer we will live full stop.

So you can use everything that you talked about in the first category plays into that. But you also have this other category of where you can take molecules that specifically target those things. You can take metformin or an SGLT2 inhibitor or a GLP1 agonist and you will directly impact those things. You could take a PCSK9 inhibitor or a statin or benpidoric acid. You will directly impact those disease processes.

You will delay the onset of those diseases and you will reduce the mortality associated with them. Then I'm going to go to a third category that says are there exogenous molecules that you can take that don't target a disease per se specifically, but we're going to put them in a category called zero protective, which is the target hallmarks and pathways of aging that you've described.

We talk about all of these things that occur in an aging phenotype where we see more inflammation. We see a greater abundance of senescent cells. We see reduced nutrient sensing capacity of MTOR, which you described as the most important nutrient sensing system in our body. We have somewhere between 9 and 14, the number just keeps changing arbitrarily, but it doesn't really matter. We have these central things that everybody would agree define what an aging phenotype is.

We use exogenous molecules to target those specifically. You gave one example, which I would argue is the single best example, which is rapamycin. So rapamycin targets a very specific hallmark of aging and we can talk about what the experimental evidence is to suggest that that makes you live longer.

I would say those are the big three categories. Basically, the fourth category you could just say is how do you put them all together and how aggressive do you want to be in culminating those? Of course, none of this touches on another area that I want to talk about that we won't talk about today, which is how does all that factor into emotional health and happiness and well-being where none of this other stuff matters if you're kind of unhappy.

You've done so many podcasts on that topic, right? You've had Paul Conteon where you kind of go through the understanding of ourselves and our minds and why that's also a very important part of it because it actually does impact how long you live. Because if that piece isn't working, it's very difficult to regulate the first bucket because the first bucket takes so much work. So if you can't regulate yourself, it's very difficult to regulate the dos and don'ts.

But even absent just length of life stuff, it impacts quality of life, which is this idea of health span as well. So I guess that's just my slightly different way to frame it, but it's a little bit more measy in that we talk about the behaviors, the exogenous molecules that target diseases, the exogenous molecules that target aging. Aside from food, what exogenous molecules do you take?

I take a few, right? So I take some that are disease specific, right? So I take a PCS K9 inhibitor, I take Bampadoic acid, I take an SGLT2 inhibitor, and then I take at least one that is purely just based on the belief of its capacity and zero protection, which is Rizrapa Mison.

And also the SGLT2 inhibitor, I think is probably just broadly zero protective, and we can even talk about that a little bit in terms of the success of one of those molecules called Kanagaflose in the interventions testing program, the ITP, which I am sure we'll talk about in the context of NAD as well. What dosage of Rrapa Mison do you take? I take 8 milligrams once a week for as long as I can tolerate it, but I usually have to take breaks. Why is that?

I get these vicious apthasalcers, little mouth sores. Canker sores. Yes. About 10% of people get them. It's paradoxically the only biomarker we probably have. I secretly rejoice in knowing that at least I'm getting a good batch of Rrapa Mison. But in reality what it works out to is I'm probably on it for two months and then off it for a month. And the idea there is that you're limiting emtore, you're causing yourselves to grow less mature slower and in that sense slowing down aging.

Yeah. Yeah. I mean, you know, and this will be an important theme today, right? We can talk all day long about mechanisms and theoretical arguments for why it would work. And I think my conviction around taking Rrapa Mison is less about sort of looking at the molecular explanation for why Rrapa works. Although I find that to be quite convincing and why does the inhibition of emtore stimulate a topology, why would that suppress in essence cells?

But truthfully my conviction around emtore is far more based on the experimental data. Something that is actually sorely lacking in the NAD story, which we'll discuss. So the experimental data are far more convincing, right? Which is when you look at the administration of Rrapa Mison or its analogs, for example, Evalymas, when you look at the administration of these molecules to organisms that are as close as possible to the species of interest, where the species of interest.

So looking at mammals such as mice and small primates, looking at fruit flies, looking at worms, and even looking at yeast, although that's so far from us that you would argue that's the least important. You see something that you don't see for a single other molecule, which is uniform life extension. Now whether molecule has done this, it's very important to understand that there are only two interventions full stop that have ever extended life across those four categories of eukaryotes.

Chalore, Chris, Drichin, and Rrapa Mison. Very important point, right? How do you feel when you're on Rrapa Mison, aside from the canker source? Yeah, I wish fortunately aren't that frequent. I don't feel anything, and the very few of my patients who take it, because maybe 10% of my patients also take it, I've probably heard two people say they feel better on it, but I don't know what to make of that. Maybe they do, and maybe that's just a placebo effect.

Does it synergize with caloric restriction or collide with caloric excess, meaning if you're taking Rrapa Mison, but you're slightly over your caloric needs, maybe you're trying to add a little bit of body weight, or happen to overeat a little bit just because is it going to collide with Rrapa Mison's potential positive impact on slowing aging? Yeah, that's a good question, Andrew. I don't know. I don't think we know.

We do know that there's one other really important readout we're waiting for, which is Matt Kaborlin's dog aging study, which is going to be an exciting readout in 2026. We're also waiting for another readout out of the University of San Antonio, looking at another trial in mammals, and again, I think those two will be really interesting, right? Because we have a ton of, we have just an overabundance of mouse data that are so reproducible and reproducible in really good mouse models.

As you know, I'm sure from your work, the model you choose matters, right? And in an ideal world, you want to use a mouse model that is not in bread, that is more closely related to what we care about, which is ourselves.

And so when you see many labs getting the same result over and over again, regardless of how they do it, you really start to believe there's a signal there. So now to be able to see this in a higher order mammal, and ultimately in companion dogs, which is where Matt Kaborlin is looking, I think that's, that's going to be really exciting.

And I've often said to my patients, look, in 2026, I'm either going to feel a lot more conviction about taking rapamycin and prescribing it to some of my patients, though again, not most, or I'm going to, you know, have a second look at this and say, you know, maybe, maybe we just shouldn't be taking this, right? Because I do think that the dog study is going to be more telling.

But again, we'll have to wait and see what that shows without going off track too much. My understanding is that the dog study was halted because of a lack of federal funding. Is it continuing? It is going to go on. There's, yeah, it's, so initially there was kind of insufficient funding to do the study in an adequate way.

And then it turned out there was a shortfall of about $2.5 million to do the study that Matt really wanted to do. And then actually a group of us raised that money for Matt and did that. So me and a few of my patients and a couple of other folks came together and put the money in to close the gap. But yes, there has been, what, what, what did get pulled back by the NIH inexplicably.

And in my view, totally incorrectly was the ongoing surveillance program, the funding for the ongoing surveillance program that would allow this type of work to continue and to allow greater follow-up on this. So yes, unfortunately, until we can get more funding, we're not going to be able to maybe do as much as we'd like to do and understand this.

Which again, when you look at some of the things that are funded, it's hard to believe that there's not a more interesting question right now in biology than this drug that seems so promising. Why we wouldn't want to know, you know, if this is something we should all be taking is kind of a mystery to me. Yeah, well, I was on in a study sections for many years reviewing grants. I've rotated off as a regular member a little over a year ago.

And I can tell you that the whole process is designed to be as targeted to the best and most exciting work possible. But there's a number of features now that make it such that it's largely the work that's already mostly completed. They get funded. You know, like how does that work? But anyway, we could have a whole other journal club discussion about funding. But I had to ask. I was curious. So hopefully that study will get completed. And thanks for raising those funds.

Let's talk about NAD. Yes. It's in essentially every cell of the body except red blood cells. Correct. You know, I don't even know if it's in red blood cells. My intuition is I've never looked to be honest with you, but given that red blood cells have a different metabolic pathway where they're purely glycolytic, they wouldn't have the need for it in the way that others would. But they might, right, because they still undergo redox potential. So it's possible NAD is in every single cell.

And it's generally thought to be associated with energy production and mitochondrial pathways in every single cell. Right. So NAD is, again, one of the most ubiquitous molecules in the body. And most of what it does. And I mean most, meaning like somewhere between five and 600 pathways of it, utilize NAD as a cofactor. Meaning that it's not consumed in a chemical reaction, but rather it serves as an electron shuttle. So NAD and NADH basically play catch with electrons.

And that's 99% of what NAD is doing in the body. And for that reason, NAD is so tightly regulated in the body. The levels of NAD in the cell are really tightly regulated. And that shouldn't be surprising. Just as glucose really tightly regulated, pH or hydrogen ion concentration really tightly regulated.

We as a species cannot survive outside of a very narrow band of pH, right. If it's below seven or above 7.8 on a zero to 14 scale, we die full stop. So similarly, NAD is managed across all ages and across all physiologic conditions in a super tight band. There's another place where NAD shows up and that shows up as a substrate, right. So cofactor means used coenzyme used but not consumed recycled. That's 99% of it.

A small fraction of it is used. And it's used by these things called certuans that consume NAD as an actual substrate in the process of DNA repair. And maybe we can go into this, but this is really where the story picks up. It's also as I recall where the story began. That's exactly right. It was some experiments where the certuans were mutated in one direction or the other, meaning gain a function or loss of function.

These days, people here are gain a function and they immediately think to pandemic related themes. But gain a function is a way of changing genes typically to augment a function. Increase its robustness or in some cases to rescue a phenotype where you have a knockout mouse that lacks a gene. So that's loss of function or a strain of yeast that lacks a gene.

And then you do the gain a function rescue experiment. You reintroduce the gene of interest. It's an important, we don't even call it a control. It's an important experiment in any case because loss of function will tell you a lot. But gain a function and loss of function, assuming that the results job tells you much, much more.

This is one of the major areas. I think this is very important to highlight where human genetics really struggles because you can get humans with a mutation in a particular pathway like the sonic hedgehog pathway. Somebody has hypomorphic for sonic hedgehog and they might actually lack a major tooth up middle because the role of sonic hedgehog at the midline and you can say, okay, well loss of function here. Here's the role of sonic hedgehog.

But the ideal experiment is to put the gene back in and then rescue that phenotype because as any logical mind can tell, there could be many things downstream of sonic hedgehog that could create the phenotype that you observe. But if you put sonic hedgehog back in, yes, that's still true, but you get more reassurance that that's the gene of interest. So with respect to Sir Tuen's, I recall they deleted the Sir Tuen's in ease.

Let's use another example of what the gold standard is here or what a great example is. So I recently did a podcast with Dina Dubal from UCSF on Clotho, which is an amazing scientific story.

And it's a great story because it shows how accidents can lead to great discoveries. So there was a researcher in Japan who was really interested in understanding hypertension, high blood pressure, and they had created a mouse model where they were trying to knock out certain sodium channels to see if they could perturb blood pressure.

And then there was this one strain of mouse with this one knockout that died really, really quickly and it developed like devastating neurogeneral disease and desired to died very quickly. And you know, like a good scientist, he didn't say, well, that sucks. I'm going to discard that one because it didn't give me what I wanted, which was the blood pressure change. And he kind of went and figured out what was going on.

And he figured out that there was a certain gene that he had hit that wasn't a sodium transporter. And instead was this other gene. He named it Clotho. So you had this one piece of evidence right now, which was if you knock out that gene, you kill an animal very quickly. Now that doesn't mean it's a longevity gene. You have to do the other experiment to your point.

You have to over express that gene and ask the question, do you live longer? And sure enough, when they over express that same gene that they had just knocked out and killed the mouse, the thing was living 15 to 20% longer. So it's both necessary and sufficient for extended, you can say, well, that's a longevity gene. As many of you know, I've been taking AG1 for more than 10 years now. So I'm delighted that they're sponsoring this podcast.

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So let's go to the Sir Two in story. So it goes back to the late 90s, Matt Cabrlin again. This is amazing. So you have this guy who's like the leading authority or one of the leading authorities on the work going on today with Rapa Mice, and along with one of his colleagues, David Sabatini and a few others. But when when Matt was a postdoc, he did an experiment in a strain of mice, pardon me, a strain of yeast. I think it was the W303 strain of yeast. And he over expressed Sir Two.

And lo and behold, the yeast lived longer. Now a year later, someone else in the same lab took a different strain of yeast and calorically restricted them. And they also lived longer. I forget the name of that. I forget what that strain was. It was something 316 was it was a different strain of yeast.

At that moment, again, this is about 25 years ago, a hypothesis emerged, which was we have two different strains of yeast. And in one of them, when you overexpress Sir Two, this gene, they live longer. And as other strain, if you calorically restrict them, they live longer. The understandable hypothesis was caloric restriction, which we had known was life extending is working through Sir Twoens.

That hypothesis sort of fell apart about four years later when Matt Cabralin, again, this time with Brian Kennedy, did another experiment in a different yet a third strain of yeast that allowed them to test hypothesis. Because there was a problem with the story I just told. When you took the 303 strain, this is the strain that when overexpressing Sir Two lived longer, if you took that strain and you calorically restricted them, no change. That's odd.

Even more odd is when you took the 316 strain, and this is the strain that lived longer with CR, if you overexpress Sir Two, no change. So right off the bat, the story didn't make sense. But it was further solidified that that story didn't make sense. When Brian and Matt published in 2004, and yet a different strain, got him blanking on the name, it's like B-Y-4742, these don't matter.

If you calorically restricted them, they lived longer. If you overexpress Sir Two, they lived longer. If you did both, they lived even longer. It was additive. Again, further suggesting that overexpressing of Sir Two and caloric restriction independently and separately extended lifespan. These are parallel pathways. They're parallel pathways.

For reasons that honestly escape me, Andrew, there are still people who maintain that the benefit of Sir Two and overexpressing is through the caloric restriction pathway and vice versa. And that's wrong. My reading of the literature, in addition to every person I have talked to on this who works in the space, including Matt Kabilin, who has done the most research on this, is that there is no evidence that caloric restriction and Sir Two ends operate through the same pathway.

And in that sense, I think there's relatively uniform agreement that caloric restriction extends life across the model systems we discussed. What have been humans? What about it specifically? Does the caloric restriction or should well, that experiment's never been done and never will be done. The joke I was trying to set up for is the one I'll make now, which is no one wants to be in the control experiment. That said, nobody wants to be in the treatment experiment either.

No one wants to be in the treatment group either because it requires eating so little. The joke is, you probably will live longer and it will feel even worse. Chloric restriction, which by the way, there are real debates about whether it will extend life in humans because it will clearly, I shouldn't say clearly, I think it would be a very safe bet that severe caloric restriction will absolutely reduce the risk of most chronic diseases.

I think there's very good reason to believe that if an individual constitutively consumed 25% fewer calories than they were meant to eat, their risk of cardiovascular disease, cancer, Alzheimer's disease would go down. The problem is what things go up. What does that do to your immune system? What does that do with respect to sarcopenia? What does that do to your risk of falling? Yeah, frailty. You trade one set of diseases for another, it's not at all clear that lifespan goes up.

By the way, when you even look at some of the animal literature where they're using different strains of mice that are not in bread and they don't put them in hermetically sealed situations, they don't live longer. So it's not always the case that caloric restriction extends life and therefore, well, it's safe to say caloric restriction probably reduces the onset of chronic disease that might not translate to an all-cause mortality benefit based on those downsides.

But all of that said, I think the whole stature and story got off to an incorrect start where it basically locked on to the CR story, which was, hey, we've got this thing CR that we've known since... Chloric restriction.

Right, chloric restriction. We've got this thing, which for 50 years, we've known has a signal that really says it's life extending and we've got this yeast where it works and this other yeast where a sirtoon activation works. Oh, it's got to be sort of... But again, if you go through the story in detail, as I just did, there's no evidence whatsoever that sirtoons have anything to do with chloric restriction and vice versa.

It's incredibly interesting because I think when you look at cell biology and you see these parallel pathways, when you see these effects of experiments where changing sirtoons or changing caloric restriction independently increase lifespan, combine the two, you get this. What appears to be a synergistic effect, but it's, as you pointed out, an additive effect.

It's like a pretty straightforward experiment to do. You could just do an occlusion, right? You could then put back in the sirtoon or adjust calories and see whether or not you get the effectively whether the math is corrected. Yeah. So, now none of this gets to the question you raised yet. That's all prologue, right? That's like, where did this story come up?

But then the question becomes, well, if you believe that sirtoons are truly a factor that drives longevity, how can you activate them? Right? How do you activate a sirtoon? So, we have to now simultaneously start to hold things true in parallel that may or may not be true. So, we want to then ask the question, do we believe that what we saw in yeast, which I think is the only reproducible finding I can draw?

Meaning this is a reproducible finding. In many, but not all strains of yeast, if you overexpress sirtoons, the yeast will live longer. So, let's park that in the parking lot as a very likely statement. You would then say, well, if it does it in yeast, does it do it in flies, does it do it in worms, does it do it in mammals? You want to be able to check those three boxes, because again, that's a billion years of evolution.

So, if something works across a billion years, we'd be much more confident it works in us. Yeah, making a fly mutant, just off a mutant, that overexpresses sirtoons, a worm, c-elegant mutant, that overexpresses sirtoons, that's a pretty quick experiment to do. But because of this short generation time of those species, mouse, it's a longer experiment, but I'm guessing all of those experiments have been done.

Yeah, and the only one that I can find that has demonstrated a survival advantage is one particular transgenic mouse experiment that overexpressed sirtoons, and it did indeed for the male mice increase lifespan by 10 to 15%. So, this is one transgenic mouse model that overexpressed sirtoons, and those mice, the male mice lived 10 to 15% longer, the female mice did not.

We should probably clarify what a transgenic mouse is. I talked about knockout mice, that's when a gene or genes, in some cases, is deleted from the genome. So, it's null, it does not express that gene. The gain of function would be to put back that gene in, that would be a knock-in mouse. So, in that case, you still get some normal expression of the gene from the endogenous genome, but now you have a transgen that's inserted there.

And there are all sorts of important intricacies that relate to this, for instance, where the transgenic is inserted. If it's down the stream of an enhancer, that's muscle-specific, then you can get a mouse that overexpressed sirtoons just in muscle, you can get it ubiquitously expressed. There are a number of different ways that this can happen. I'm assuming this was ubiquitous expression of, you said, Sirts 6.

Sirts 6. So, every cell in the body that normally would express Sirts 6 would express more Sirts 6. I don't remember, Andrew, to be honest with you, if you go back and look at the paper, I don't know if it was muscle-specific or whole-body-specific. I'm guessing, unless they made it clear that it was tissue-specific, that it's whole-body.

So, we're talking about it when Peter says, Transgenic mouse, he's talking about a mouse that has this transgen that causes it to express more Sirts 2 and 6 than it ordinarily would. And let's assume, although we don't know this for sure, that the other genes in this mouse are functioning as they would normally. So, again, just to summarize that, that's 2012. We have this one transgenic mouse. You put Sirts 6. You overexpress Sirts 6.

And all of a sudden, the males were living 10% longer. Again, to be clear, the females didn't experience a difference. And that's not uncommon or unheard of in longevity research. There generally are sex-specific differences. And you always have to read the fine print. The first thing I always look at in a study, when I see a difference in sexes, or frankly, any difference in longevity, but it's always great when they parse them out by sexes, is how long did the controls live?

But I went back and actually looked at the Kaplan-Mire curves on that exact study. And yes, indeed, I think that's a real effect. So, let's take stock of now two pieces of information that I think we could say is probably true. It is probably true that in a handful of strains of yeast, if you overexpress Sirts, you are going to live longer.

That tends to be completely independent of caloric restriction. That's the single thing I can say with the greatest confidence. And there is at least one transgenic strain of mice that if you get it to overexpress a different Sirts 6, but again, these are homologues throughout the species. So we don't think we need to get wrapped up in Sirts 2 versus Sirts 6. You will at least make the male mice live longer, but not the females.

What sorts of things are downstream of Sirts 2? And that question translated to normal English is, what is changing as a consequence of increasing the Sirts 2? And could it be, for instance, well, unlikely based on what we already know about caloric restriction and the fact that they are independent parallel pathways? What is it something related to glucose metabolism? Is it something related to clearance of sentencing cells? I mean, I'm just throwing out possibilities here.

Actually, you've hit two of the big three right off the top, right? So we believe that when Sirts 2ans are activated, they're improving mitochondrial biogenesis. So that's probably the biggest one. And by the way, that's sort of what brings us to the NAD story. And also reducing sasps, right? So the soluble products of senescent cells. So, so in other words, those are all three good things, right?

Tamptown on senescent cells, you increase mitochondrial biogenesis, and you increase DNA repair. Those would be all great things to do. And we think that Sirts 2ans are probably doing all of them. This business of DNA repair and reducing, you know, fragmentation or mutations to DNA that are naturally occurring has been a hot idea in the field of aging for a long time. Is that because when X-rays became popular or post nuclear fallout that people showed accelerated signs of aging?

How did we get from DNA mutation to accelerated aging? Well, I mean, I think we know that as we age, it's just a stochastic process, right? Like given the ubiquity of DNA replication and the fidelity of the system, which is high, very high, but not perfect, there's going to be mistakes.

Actually, this is an interesting question. So in 2016, I went to Easter Island with David Sabatini and Nav Chendelle and Tim Ferriss. So the four of us just took a trip to Easter Island to see the birthplace of Rapamyson. So it was kind of like vacation slash science journey. That's a nerdy thing.

It was awesome. And, you know, so just picture hiking around this incredible island, just talking about science all day, but this was an interesting question that I posed to nav and to David, which was, why do we see such a clear and present association with cancer as we age? And why is it so nonlinear? It's not just that cancer goes up with age. It goes up like that. And I said, I'll offer two hypotheses, which is more compelling.

Is it simply that as we're aging DNA replication, again, taking a step back for the listener, cancer is a genetic disease, meaning by definition, it is sort of the canonical problem with cancer is a genetic mutation that leads to two properties of a cell. The inability to sell to to control replication. So it interrupts cell signaling. So cells replicate, but then don't know when to stop.

And then the introduction of the capacity to spread this property called metastases. Those are the two hallmarks of cancer. So we know that that only happens in the context of genetic mutations. But why does this happen later in life and not at the beginning of life with very few exceptions?

And so the question is, is it because over time mutations compound? Is it because there are more mutations as we age? Or is there a third issue, which is, all of those things are happening normally, and they're no more abundant when you're 80 than when you're 20, but your immune system can't detect them as well.

The truth of it is we didn't come up with an answer, but it's probably all of the above. So it's probably that as we're aging, we are undergoing more DNA damage. And, or at a minimum, the DNA damage we're undergoing is less amenable to repair. And that's part of the thesis here. Part of the thesis here is as we're aging, we are less and less able to repair DNA.

And one of the arguments that put forth, although we're not quite ready for this part of the story yet, but I'll just say it now and we'll come back to it is we don't have enough of the substrate that the Sir 2 in needs to repair DNA and that substrate is NAD. So again, remember the outside I said, like there's two big categories to think about NAD. Most of what NAD is doing is operating as a cofactor for electron shuttling.

That's the NAD NADH electron transport electronic set, blah, blah, blah, blah, blah. Okay. Not consuming NAD, just using it to pass electrons back and forth. But then over here we have this other category where we use NAD as a substrate. It gets broken down. And that's what the Sir 2 in is doing to repair DNA.

Okay, so if that's true and if NAD levels are declining with age, it's a logical conclusion that should we give more NAD, right? If you're running out of substrate to repair DNA and DNA repair is an important way to thwart aging, it all makes sense.

So we'll keep that over there. But before we do, I want to come back to one other story, which is the story of Sir 2 and activators. So what's the most famous Sir 2 and activator of all time? What is the heavyweight champion of Sir 2 and activators that has taken up 99% of the bandwidth in this space? It's a lovely little chemical called Resvera Troll.

Okay, so Resvera Troll, which gained a lot of fame and notoriety because it happens to be found in trace elements in the skin of grapes and therefore shows up in wine, gained a lot of notoriety about 20 years ago when one lab doing one experiment, somehow was able to convince some people, including a very large pharma company, that Resvera Troll increased lifespan.

So the thesis was, Resvera Troll activates Sir 2 and, Sir 2 and activation is important because of all the things we just said, right? It improves mitochondrial biogenesis, it suppresses senescent cells and enhances DNA repair. So if you have something that is such a potent activator of Sir 2 and you give it to a mouse, that mouse should live longer. Now, lots of experiments were done that couldn't find that. But one experiment was done, but it was an interesting experiment.

I've discussed this at least on two podcasts, including one with Rich Miller, who runs the ITP, the interventions testing program, which later tested Resvera Troll and found that it did categorically nothing. In this one experiment that worked, the investigators took a bizarre mouse model where they force-fetted an enormously high-fat diet. And in doing so, they created such an abundance of fatty liver that the livers of these mice encroached the chest, the thoracic cavity of the mice.

And the mouse died prematurely because they couldn't breathe. And in that particular mouse model, Resvera Troll rescued the mice. So again, let's just assume that all of that is correct, and it's possible that there were even errors there. But let's just assume that's correct. Let's assume... So this is Resvera Troll delivered orally in the food. Yes, very high doses. Megadoses. The equivalent of barrels of grape. Exactly. Like doses so high you could...

If you recall, we're both an age that's old enough to remember this. There was this period of time when people thought this was the explanation to the French paradox. Why, on average, the French live longer when they consume so much wine, and the answer was it's got to be the Resvera Troll. It turns out that's not true at all, because you would need to be drinking your body weight in wine a day to get the doses of Resvera Troll that were needed to be drinking.

So you could never need to produce this effect. But for whatever reason, there wasn't effect, which is if the thing that was going to kill you was your liver being so full of fat that it... And shot up into your chest so you couldn't breathe, which I've never seen a human, no matter how bad their fatty liver has been, where that's been the case. But if that's the problem you're going to face, it's possible, at least based on this one mouse experiment that you are going to live longer.

But again, it turned out that there was no other replication of this in mouse models that matter. And that always comes back to the ITP, the Interventions Testing Program, which is the most robust tool we have scientifically to measure these exogenous molecules. So the ITP is an NIA-funded program that runs out of three independent labs. And by independent, I mean they're each doing the experiments independently, but they're in sync with doing the experiment, but they're doing it in triplicate.

So you have three labs, three great labs doing the experiments in triplicate. And when they did the Resvera Troll experiment, and they did it in combination with the people who found the result of that study. So they consulted these people and said, what dose should we give? And they said, do this, do this, do this. And they did it, and nothing. There was no effective Resvera Troll. And that result has been consistent across the board.

So that's also a very important part of the story, which was, if Resvera Troll was a sirtoon activator, and I don't know if it really is, it clearly has no effect on lifespan with the one little asterisk that says, unless your body weight is 50% fatty liver, then maybe it does. I'd like to take a quick break to let you know that the Hubertman Lab team has launched a new podcast with host, Dr. Andy Galpin.

Andy is an expert in exercise science and human performance, and has long been a fan favorite on the Hubertman Lab podcast. This new podcast is called Perform with Dr. Andy Galpin. And it dives into topics such as how to build muscle and strength, how to improve your cardiovascular health, and how to optimize recovery and sleep for performance and much more. Andy is an absolutely fantastic educator and true expert on all things human performance.

I know you'll thoroughly enjoy his new podcast and learn a ton of useful knowledge from it. So please check it out and give it a subscribe wherever you're watching or listening to podcasts now. Again, the podcast is called Perform with Dr. Andy Galpin. So let's see. Let's just take stock of where we are in the story. We've got the whole yeast sir two in situation, which is at least in some yeast, sir two and over expression lives longer.

No evidence that that works through color restriction truly no evidence that's been known for 20 years now that paper was published in 2004. And that was a follow up to papers that had been published in 2002 to 1999, et cetera. You later on you'd have the 2012 transgenic mouse study. So now the question is okay. How do you activate sir two? How do you activate? Well, well, yeah. So more to the point, why don't we just give people NAD?

Okay. So again, the NAD story is NAD levels are declining with age in most issues. It appears most prevalent in the skin of all places. And I think we should come back to this because there's one interesting finding associated with augmenting NAD levels in the skin. And my thought is I wonder if it has to do with the fact that skin experiences the greatest decline in NAD. It's also interesting because keratinocytes and skin turn over every 28 days or so.

So you could imagine because it's a novel population of cells that they would have steady expression of sir two ends NAD. Then they simply die for whatever reason or that it starts off very high on day one of generation and tapers off quickly. But that's not the case. It sounds like you know on average skin over the course of your lifetime will see about a 60% reduction in NAD. Whereas other tissues and this is now based on you know animal studies, the brain might see a reduction by 15 to 20%.

And the same would be found even in humans looking at the blood. So if you just sample you know a whole blood in people at the age of 20, 30, 40, 50, 60, 70, 80, you're going to see about a 20% reduction in NAD. What about neurons? I mean, you've got the same set of central nervous system neurons your entire life. And of course some peripheral neurons as well. But there's some regeneration in the periphery. So we need to just got let's just talk about brain.

So unless you're talking about the olfactory bulb where you have constant turnover throughout the lifespan. You have the same hippocampal neurons except a small population. Same hippocampal neurons, cortical neurons, retinal neurons that you were born with. Are we observing NAD levels tapering off as we are? Animals yes, obviously in humans we're not doing that experiment. But yeah.

Now here's an interesting point in 2015 a study was published in PNAS that looked at NAD levels in whole blood over time. And it found indeed NAD levels were going down about 10 to 20% over four decades or so. But that same study said NADH levels were going up by the same amount explain the role of NADH for people. NADH is the electronic sector. So when you when you deal so let's maybe take a step back of like what how do we why are you and I sitting here talking and not dead?

Like because we have enough NAD right what's going on right so right you and I ate something at some point in the foreseeable past that contained chemical energy. So we ate something that was organic so it had so primarily fats and carbohydrates contain carbon carbon bonds and carbon hydrogen bonds.

And those bonds contain a ton of energy. But how do we liberate the energy? So we break it all down into these constitutive molecules namely glucose on the carbohydrate front and free fatty acids on the fat front. And then our bodies break those things down further into smaller molecules that get shuttled into the mitochondria where the lions share of our energy liberation comes from.

And what we do is we take that chemical energy that is stored in a carbon to carbon bond or a carbon to hydrogen bond. And we turn it into electrical energy. And people have heard this term it's called the electron transport chain. So there are these four complexes in the mitochondria. And there's an inner membrane and an outer membrane across which these mitochondrial these large mitochondrial complexes reside.

And what they're doing is they're building up a huge electron gradient by breaking them apart and taking the electrons and transferring them between NAD and NADH so that at the end they can do another trick which is transfer those electrons to a MP ADP and ultimately make ATP. The finished product is water and carbon dioxide. So we eat and we take that chemical energy and food.

We utilize oxygen in the mitochondria to make ATP carbon dioxide which we breathe out and water which we breathe and pee out. So what NAD and NADH are doing is playing an absolutely essential to life role in facilitating the transfer of chemical energy to electrical energy back to chemical energy.

ATP is just taking it from one chemical form in food to the electrical form as the intermediary in the mitochondria back to an electrical form of ATP. So you and I are walking around flush with ATP which as we sit here right now we're constantly firing off phosphates again now tearing the chemical energy back into electrical energy in a way we go. So yeah, this whole NAD, NADH thing is like, you know, it's essential to our existence as any form of respiration.

So my point, let's go back to the story. The story was NAD levels are going down as we age but NADH levels are going up suggesting that the total amount of NAD and NADH is the same and what's declining as we age should less be thought of as a reduction in NAD and should more be thought of as a reduction in what's called redox potential.

The ability to do what I just said. So when people say NAD levels decline with aging, the answer is yeah, but what's really declining as we age and this kind of comes back to what you said at the very, very outset like what's happening at the cellular level. I think what's happening is our mitochondria are not as good as we age and we have less redox potential.

And I would say a fair number of so-called anti-aging approaches are targeting the so-called reactive oxygen species, ROSs, which impede mitochondrial function essentially. This is an opportunity for me to call out the work that I think is at least intriguing, which is the work of a colleague by the name of Glenn Jeffrey at the University of College London.

He's been in the field of visual neuroscience for a very long time and a few years back he started doing some experiments on animals and now also two studies published on humans showing that exposing the age die so 40 and older to red light and near infrared light for a couple of minutes a few times a week can spare certain processes involved in vision, photo receptors.

How does this work? Well, the idea this isn't proven yet. The idea is that it's reducing reactive oxygen species and thereby improving mitochondrial function in what is perhaps the most metabolically active cell type in the entire body, not just the eye, which are the photo receptors.

So it's an intriguing set of studies. Again, we don't have all the mechanisms worked out, but it brings us around again to this idea that mitochondria are vitally important for the functioning of cells, things that impede the function of mitochondria can either reduce the output of end or kill cells. And so anything that can improve redox can potentially keep a cell around longer functioning better.

So when I hear about the role of NAD in this pathway, I think like most people I think, okay, well, then I should just take more NAD and maybe I will age more slowly where I will replace some NAD that's missing as I age in whatever cell type turns out that might not be so straightforward. I mean, I don't want to jump to supplementation just yet, but if we are to back up from NAD a little bit and look at the pathway leading to NAD, it's NR, NMN, and NAD will spell these out in a moment.

And this sort of competition that's out there in the market is around either infusing or in some cases ingesting NAD directly, taking NMN, which is the precursor to NAD orally, I haven't heard of anybody infusing it, or taking oral form NR, which is the precursors to NMN. And my understanding is that NMN is simply NR minus a phosphate group.

Yeah, and I'll take a step back from this first to say the following again, let because this topic is so confusing, I think it's just worth reminding everybody of what we now, everything we've said and where it brings us. So I'm not going to repeat the whole Sir-Tuan thing. Let's just leave that alone. Because everything we're on right now is upstream of Sir-Tuan's.

Yeah, it's basically like once you establish that we think Sir-Tuan's matter, even though they don't work through Chloric restriction, and that's about the single most obvious thing I can say, they might still matter, even though we don't have things that we figured out can activate Sir-Tuan's like Rysvera Troll, we don't seem to have things that we can give you that activates Sir-Tuan's.

We're now onto the next part of the story, which is, okay, Sir-Tuan's matter, they don't seem to matter, we think Sir-Tuan's matter because of a few of these over expression experiments. And we're making a big leap that, because they matter in yeast, they're going to matter in us. That's a huge leap for which there's zero evidence. Right, and I'm only leaping further to this discussion about how to increase NAD because I know that's in the back of people's minds.

That's right. We're not going to double click here just yet. I just want to frame that up. Because ultimately, that's where we are headed in terms of people making decisions as to whether or not they should take NR or take NMN. Yeah, and they're reusing NAD or none of the above. And the reason I'm being such a hard-ass about this Andrew is I spend so much time fielding questions on this that I realize we just have to talk about this and explore.

It's just in the most detailed fashion possible so that people understand why. Right. Because it is just too easy, right? There's this great quote by JFK that I'm going to paraphrase that is basically people enjoy the comfort of opinion with this.

The comfort of opinion without the discomfort of thought. Right. So we need to sort of this is this a podcast to get people to think and understand the entire history of this field so that they can actually make an informed decision about a supplement that I'm going to argue has very little scientific basis for its justification.

I would say scientific justification for longevity. I'll go on record now saying that I take NMN and in some cases I will take NR and NMN and I observe this is just N of one self observational data. I observe a very clear positive effect, but I don't think it has anything to do with extending lifespan. And we should talk about both health span and lifespan benefits when we get to that part, but we're so to bring us up to where we are now where you are with should people be supplementing NAD.

We're basically at the point where we're taking a lot of leaps of faith and saying because NAD levels are going down and redox potential is going down, we believe supplementing NAD in one form or another makes sense. Before we do that, we should acknowledge something. Yes, NAD levels are going down, but we have no reason to believe that raising NAD levels will correct a problem.

In other words, if the body operates between this level and this level of NAD and if you go below this level, you die and you go above this level, you die. And levels as you age go like this, do we believe that raising NAD to this does anything? There's no evidence that says it does. So that's a leap of faith. It's okay to take leaps of faith. You just have to know you're taking a leap of faith. Okay, so leap of faith number one is the Sir Two and Thing.

Leap of faith number two is the Clure Constriction Thing. Leap of faith number three is this matters in our species, the species of interest. Leap of faith four is the whole Sir Two and Activator thing. And now this leap of faith is if we just increase NAD levels in us, it will produce a positive benefit. Okay, so now how do we do that? Now you get into the tactic.

Okay, there are three ways to do it, as you said. One is you can intravenously take NAD. By the way, you could probably also orally take NAD. It would just break down in the gut into its constitutive products and then probably reform. But for the purpose of how people actually do this, they intravenously get NAD because it's not orally bioavailable. Or as you said, they orally take two precursors, NR and NMN. My personal view on this is there's not really much of a difference in what you do.

In other words, at the end of the day, all of these things are generally going to increase NAD levels in the blood. So a couple of practical notes. I've taken NR in capsule form. I've taken NMN typically impoutored form where it put it sublingually under the tongue. My understanding is that... Have you done intravenous NAD? I sure have. Did you experience a NIS in flush?

No, I took NAD as an infusion. I've probably done it five or six times. And for the first ten minutes of the infusion, you feel like somebody stepping on your chest with a boot. Your legs cramp up, you feel nauseous. I did not take the anti-naugium med that was offered. I don't like taking things if I can avoid it. I just figured I'll just experience this.

It was very uncomfortable. To the point where you couldn't read a paper or a book, you just want to be left alone. You actually get a little bit irritable. This is awful. Every noise in the room is a bit too loud during that first ten minutes. By the way, do you know how many people have said to me that because of that experience, they know it must be doing something good?

To which I'm like, why don't you spread your legs? Let me kick you right in the nuts. That's going to feel even worse. Is that doing something good? The fact that something feels so awful shouldn't be used as an explanation for why it's doing good physiologically. I don't know what it was doing physiologically except making me feel miserable during the infusion. There are ways to adjust this even without the anti-naugium meds. For instance, you can slow the infusion.

That's the typical way. People will put it in over the course of several hours anywhere from three hours to it as brief as 30 minutes is kind of the record that I've heard about for four minutes. For the record that I've heard about for 500 milligrams of NAD. If you put a thousand milligrams in there, obviously it's more painful. Anyway, there are a bunch of practical considerations. You feel, now maybe it's placebo, but one feels quite good afterward.

As soon as the drip is done, you feel better than you did prior to the drip. How do you feel if you just receive an IV infusion of the same volume? That because I've received saline drips. You also feel pretty good. It's hard to disentangle these things. Typically, they'll put other things in the bag. Glue to thigh-own, some vitamin C. They tend to sell these as kits. I decided to try it. It seemed fine. I did it when traveling. Maybe I'm another one soon.

For me, the more typical way to try and increase NAD or whatever, because I don't know what it's doing exactly, but I like the effects of taking sublingual NMN. The single most, let's say salient to me, anecdotal data on taking sublingual NMN is that it makes my hair grow really fast. It makes my nails grow really fast. I do feel an increase in energy. I take it first thing in the morning. What dose? One and a half grams, 1500 milligrams.

By the way, the doses that they give mice in the studies where they're testing the efficacy are typically on the order of 500 to 1000 milligrams per kilogram. I'm 100 kilograms. Picture that the next time you're giving yourself some NAD or NR. I'm not even approaching that at all. It's clear to me, based on my read of the data, that NR can cross the cell membrane directly. Very easily, there's no obstacle to NR getting into cells. NMN cannot because of the exrophosphate group.

If you take it sublingually or you ingest it orally, it goes into the gut. The phosphate group is cleaved. Because of that, the argument is that if one were to compare the benefits of taking NR versus NMN, they're more data to support NR as a precursor to NAD, a more effective precursor to NAD than orally ingested NMN. But some people will say, well, I'll just take more NMN than I would NR. And then this gets into the realm of cost effectiveness.

It starts becoming a battle between commercial sources. I don't dispute that NR makes more sense as a precursor, especially at dosages of 300 to 600 milligrams versus 1500 milligrams. But I've opted to take sublingual NMN mostly based on cost. At the dosages, people recommend it is quite expensive. Imagine you had to take it at the mouse dosage. You'd be spending about 300 bucks a day. It's just not feasible. So I don't have a deep desire for my hair to grow faster or my nails to grow faster.

It's more the increase in energy effect. Now, I will say that sublingual NMN is also a bit of a laxative. So there are all these, and I say that somewhat chuckling, but some people say it makes them feel better. Well, is that because you're evacuating your bowels a few minutes or hours later and then you feel less bloated and you have more energy. That's very unclear.

I think what has not been done, as far as I know, is to compare early ingested NR at say 600 milligrams, a relatively high dose versus a gram of sublingual NMN, and then actually measure blood levels of NAD. If that experiment has been done and I'm not aware of it, I'm not aware of it, then forgive me. Maybe someone will put it in the show no captions.

But I guess this gets down to the question of how many people are taking oral NR or NNN men or are taking NAD infusions, which by the way are quite expensive. Anywhere from $300 to $1,000 a drip. That's pretty expensive. What benefits are they getting? Like what are they getting out of there? Like what are they getting? Is it an acute increase in NAD that causes them to live? What are we longer? I mean, we have no idea. So let's try to use data to answer the question.

This is exactly the thing that the ITP, the intervention's testing program, was designed to test. Again, if people are interested in this, they should go back and listen to my two discussions with Rich Miller, where we go through gory detail of every molecule that has gone through the ITP. The ITP is hands down the most rigorous tool we have for testing molecules in anything other than the species of interest, because we can't do these experiments in human.

We cannot test lifespan interventions in humans for the obvious reasons. So what is the next best thing? Well, it turns out it's doing it in a non-inbred mouse, in triplicate, in three institutions. Like you can't get more rigorous than this. The ITP has tested probably north of 50 molecules, meaning it has done the same experiment for 50 different molecules, and very few have extended lifespan. And the notable failure is NR. NR was tested.

And I believe it was tested at a very robust dose, either 500 or 1000 milligrams per kilogram, and there was no extension of life. There was no improvement in health span. There was no change. Megadose NR, placebo, same result. Conversely, let's consider some of the successes of the ITP, RAPA MISON.

When you give RAPA MISON, the first time they did it, because they had a hard time formulating the RAPA MISON, they weren't able to start it until the mice were like 21 months old, which is very old for mouse. It's like a 60-year-old mouse. And at that point, they almost aborted the experiment, because they were like, well, what's the point? Nothing is going to work when you start this late, including caloric restriction, by the way, although it has worked in one experiment.

But nevertheless, it worked. And when you gave RAPA that late in life, it still worked. Then they read the experiment and they gave it earlier. It worked. And then the HNAGA Flosen, as I mentioned, which is an SGLT2 inhibitor, it worked. A carbose, a drug that inhibits glucose absorption, worked, and interestingly didn't require weight loss.

But the treatment mice weren't any lighter than the non-treatment mice, which actually goes back to something you said at the very outset, which suggested that tight glycemic control independent of weight is a longevity benefit. The same was true with the SGLT2 inhibitor, KNAGA Flosen. SGLT2 inhibitors cause you to pee out more glucose. A carbose prevents you from absorbing in your gut.

So two different ways to regulate glucose, neither of those experiments resulted in a lower body weight for the mice, and yet they both lived longer. Again, there's something very important about regulating blood glucose. The other thing that worked is 17 alpha estradiol, and it only worked in male mice.

So again, suggesting that, well, we can come back to that. It's more than we want to get into at the moment. But the point here is there are very few molecules that have withstood the scrutiny of the ITP. It is a high-bar, metform and failed, by the way. And the ITP is specifically for offsetting aging. It is lifespan, but it also looks at some measures of health span. But it's primarily, it is the gold standard for lifespan.

Because my understanding is that there are some studies that have explored the role of supplemented NR, maybe NMN as well, but certainly supplemented NR, for sake of lowering inflammation to offset some of the negative effects of time zone shift, alcohol, and a few others listed here, overnutrition. Yes, so let's talk about that. So in 20, I don't remember what you were. It was somewhat recent. A study was published looking at NR with something called terrestrial bean.

So terrestrial bean is believed to be a seroton activator, like respiratory. It was a terrestrial, terrestrial, and it was a three-arm study in humans. Roughly 30 people per arm. So a decent sized study. So you take 100 people, more or less, with fatty liver disease.

And then you take a documentary with an MRI of the liver. So they're looking at hepatic fat in the liver by MR. And using this type of MRI, if your hepatic fat index is over 5%, that's a high enough degree of what's called stiototosis that you have fatty liver disease.

This is not a digital thing. It's an analog. There's a spectrum to this. So you start with just fat accumulating in the liver. But as more and more fat accumulates, you start to get inflammation that results in scarring and fibrosis. And ultimately you would get to cirrhosis. So just keep in mind the threshold at which we would say you're in the danger zone is once you hit 5%.

So this study randomizes people to either a placebo or a regular dose of this product or a double dose of the product. And I can't remember exactly how much is in the product. I think it's either 250 or 500. So then that would be what the regular group got of NR. And then the other group was getting 2x that. So it's either 250 and 500 or 500 and 1000. I don't recall.

They also looked at something called the they looked at many things right so they looked at all sorts of biomarkers. And the primary outcome for the study was did you see a reduction of this hepatic fat via the MRI. So what happened so they did the study and lo and behold, there was no difference. There was no difference in anything. Okay, so so at high dose at low dose, there was no difference in how much hepatic fat you had at the end of the study. There was no difference in body weight.

There was no difference in inflammatory markers. There was no difference in glycemic markers glucose levels liver function tests any of those things. So in that sense, it was a null study. But they did one sub analysis, which again, you have to be very careful of because a sub analysis is not a primary outcome.

But it's kind of a way to go and parse the data. And they did find one statistical, one statistically significant finding, which was if you limited the analysis to people who had a hepatic fat score below 27%. Remember I said, once you're above 5%, you're sort of you have fatty liver disease. Well, they had people anywhere from, you know, 10% to 40%. But if they looked at people who were below 27% in the low dose group, there was a statistically significant reduction in liver fat.

If it sounds like I'm machinating, I am. Let me say it again. If you limited the analysis to people who had below 27% on this hepatic fat index, the people who got the full dose had no difference. They averaged 20% at the beginning of the trial and 19% at the end, no statistically significant difference. The placebo group averaged 20% at the beginning, 20% at the end. But the single dose of the drug went from 20% to 15%, which was statistically significant.

It's not clear that that's clinically significant, which is a pretty consistent theme in this type of research. Never confuse statistical significance with clinical significance. If I gave you, if your blood pressure is 160 over 100, and I give you a drug that lowers it to 157 over 97, that could be statistically significant. If the variance is small enough between people in the study, it has no clinical significance. I haven't changed the course of your life.

That, to me, is one of the two big findings that people point to to say, aha, there was some benefit in fatty liver disease with this. But again, when you read the fine print, which I just vomited out to you, I don't think anybody is looking at that going, oh, we just found the solution to Natholdy. The second study that people point to a lot was 2021 or 2022. This came out of a group at WashU, I believe, and they looked at NMN, and they looked at glucose disposal.

So in this study, they asked the question, we're going to take two groups of people, you're going to get a placebo for a period of time, or you're going to get NMN for a period of time. And we're going to then do what's called a type of glucose challenge, where we look at how well you dispose of glucose with and without insulin infusion.

And in the placebo group, you would look at pre and post glucose, so pre and post placebo treatment, was there a difference in glucose disposal with no insulin? No. What about with insulin, where you would expect to see much more glucose disposal? No difference. But when you did that with the NMN group, there was a statistically significant increase in glucose disposal with insulin infusion, but it was quite small. In other words, it was clinically very insignificant.

Just to figure out how insignificant it was, I went back and actually looked at some of the red light data, because there's an interesting study that shines red light on a person's back and then does an oral glucose tolerance test. Yeah, and you can actually reduce post-prangial glucose by 8%.

Is that meaningful? Not really. I mean, not in this patient population, because these people were all prediabetic, and they had very high glucose. So it was against another example of something that statistically said anything, but not clinically significant.

And the same thing was true in this study. But again, people would probably point to these two studies, because they're in humans, and you had this one, if you squint and look really hard and take a subsets upset at the analysis on this one measurement, we saw a responsive hepatic fat going from 20 to 15%, which is still 3x above the threshold to have fatty liver disease.

And in this other study, you had this very, very modest reduction, pardon me, increase in glucose disposal. But I mean, there's a saying in my sort of mind, Andrew, which is like, if you have to resort to really interesting statistical machinations to see something, there probably isn't something very interesting there. Right. Right. I totally agree. And I think, you know, at this point, I'm questioning whether or not I'm wasting my money taking NMN or NR.

The reason I take NR is really for these anti-inflammation reported, purported effects. I just want to pay a little bit of attention to the whole commercial battle around this, because I think it's relevant. I mean, I think right now, as far as I know, the FDA has essentially said that NMN should not be sold as a supplement, but it is still being sold as a supplement. So there's a little bit of ignoring of the FDA's request. NR, as far as I know, is authorized for sale as a supplement.

So it's generally regarded as safe. It has an FDA designation of grass, which means it is not regulated. Generally recognized as safe. Right. And so that means anybody can sell it. The FDA will have no oversight. They're not telling you whether they're not going to put a stamp on it that says what they're selling is what it is. And you can't make a claim about it that isn't validated by some sort of study. So I honestly, I think the whole NMN and our debate is irrelevant.

I think it's just a commercial debate. I think it's literally just posturing about how can I carve out a different market? I don't think there's a scientific reason to favor one over the other. Well, you just answered the question I was going to ask, but I suppose the question therefore becomes, is there any benefit to taking either of them or say of lifespan?

There's one benefit I could find. There's one benefit I could find that I think is genuine. There are a few other really insignificant ones that fall into the category of goofy studies that cherry pick by data mining. Okay, so there's studies that like gave people NMN and looked at a shotgun approach of many different things like did it change LDL cholesterol, ACL, traditional triglycerides.

And the answer is, oh, look, there's a small decrease, but it was totally insignificant clinically, even if statistically significant. And oh, it increased your, you know, six minute walking test or whatever. And it's like a six minute walk test or whatever in people who are in their 20s is irrelevant. It had no change in VO2 max. It had no change in any meaningful metric of performance.

One test, one study I could find that actually had what looked like a signal to me. And it was a study that looked at skin cancer rates. And I can't remember if it was NR or NMN, but honestly, I don't think it matters because I think they're basically equivalent. Once just got a phosphate group on there, you might need to take a little bit more of the NMN versus NR, or maybe a lot more who knows in order to get the same increase in NAD is my understanding.

So this one study found somewhere between a 60 and 80% reduction in basal cell and squamous cell carcinomas. Now, I found no difference in melanomas. So again, you know this because you just did a podcast on this. Melanomas, the skin cancer that kills you, but that's not to say that, you know, squamous cell and basal cell carcinomas aren't problematic.

They can be very, you know, deforming. They can require pretty aggressive surgeries to address them. And so if indeed there is something that can reduce the risk of basal and squamous cell carcinomas, that may be a rationale for taking it. And I should say that basal and squamous cell carcinomas are very, very common.

They are very common and they are very clearly associated with sun exposure in a way that even melanoma is more complicated and has a genetic component and there are other things going on.

But squamous and basal cell carcinoma are very clearly related to sun exposure. As you said, they're quite common. And so, you know, personally, that's an experiment I would like to see repeated because if indeed N or NM, reduce the risk that significantly of squamous cell and basal cell carcinomas, I think you could make a case that if you're an individual who's at risk for those things, clearly I'm not right.

I've never had a sunburn in my life. I mean, I don't work outside. So it's like, it wouldn't matter to me. But there are a lot of people for whom either either their skin color makes them more susceptible or they're, you know, their past times or frankly, they're, their line of work makes them more susceptible.

You know, maybe there is a case to be made for it there. If you could, if you could literally take 60 to 80% of your risk away on squamous or basal cell carcinoma, that could matter. And by the way, I don't know if this is true, but you may recall at the outset, the outset, I said that when you look at all the tissues in the body where we see a reduction in NAD, do you remember what had the biggest reduction with skin?

So there's a part of me that wonders like, is the reason that the only place we see a really good signal potentially for NR and NMN supplementation is, is in a skin cancer? Although it's not melanoma, which is the one we'd really want to see. I mean, if this reduced the risk of melanoma, I would take it, right? Because even though I'm dark skinned, I'm still susceptible to melanoma.

So I just wonder, that could be true, true and unrelated, but that's, that's the first thought that crossed my mind when I came across that literature was, I wonder if the enormous reduction in tissue NAD in this particular tissue explains why maybe there is a benefit to it.

Assuming somebody is averse to feeling like they have an elephant stepping on their chest and they're going to pay $750 for it, AKA an NAD infusion once a week. And look, people may opt to do that, people with the disposable income could do that, drip it in slow or not feel nauseous, increase NAD with the hope, hope, hope that maybe it's going to extend your life. Most people considering supplementation to augment the NAD pathway are going to default to either taking in or or taking NMN.

By the way, just going back to the group that have decided that $1,000 for an NAD infusion and dripping it in over two hours is a good use of their time. What do you think would be the improvement in their lifespan if they spent that two hours exercising significantly greater? Interesting. All right. Just known. And less expensive. But yeah. You could also weight train for the first hour and then enjoy some food afterwards.

Lane Norton taught me that there are data showing that exercise in particular resistance training improves the rewarding properties of food makes food taste better.

We've all kind of intuitively experienced. So spend the first hour working out second hour eating. If you had an extra two hours a week to choose between paying $1,000 or $700 for an NAD infusion or, you know, lift weights for an hour, go for a half an hour walk and listen to your favorite podcast, like the Hubertman lab and then eat a meal for half an hour. Like I can just think of so many better ways to spend time and money. But anyway, let's not digress.

Well, I'm going to pull a little bit from marketing text here, but I trust these showing really? Yeah. Yeah. I do. Because they have citations to support them and we can include the citations. I can say these are these are not linchpin arguments for doing one thing or the other, but we already established the NR. And NMN are quite similar except for the presence of a phosphate group on NR that gets cleaved off.

So again, you might have a slight dose issue, but at the end of the day, you're giving NR. NR is freely taken up into cells. It turns into NAD. This is all a big sort of shell game of how do you get an AD up? And again, I think we've established and we can agree that there is an increase in NAD, at least in the blood and probably in the liver when you take exogenous NAD or precursor.

Or NR. Yeah, that's right. Yeah. Okay. So great. Well, then you took the words right out of the data I was going to refer to. That's right. Because I asked a few folks that helped develop some of the NR supplements. Like what are the data that support the use of NR for increasing NAD? And they say NR can cross the cell membrane directly and men cannot. Okay. But you can just cleave the phosphate group. Exactly.

And are they claim I'm not this is not my claim, but they claim that NR is quote unquote 25% more effective than NMN in raising whole blood NAD levels, but I'm guessing that's probably milligram for milligrams. Right. Okay. So then you just adjust the milligram dosage a little bit and so on. What's entirely unclear is what raising blood NAD translates to in terms of getting more NAD into cells.

I don't know that specifically cells like skeletal muscles, right. I think based on Josh Rebenoets' work. I also had Josh Rebenoets on the podcast to talk about this. And I trust Josh on this much more than I would trust any marketing material.

Because he doesn't have a dog in this fight, right. He just you know, he just does the work. And what Josh's research so which is basically NAD flux research has demonstrated that look, the liver is probably the place of greatest uptake in addition to blood. And that's about all we know. Like it's not clear how much of this is getting into other cells. So I mean, that's the rest of it is just, you know, I think rearranging deck chairs on a Titanic as far as like how much does it really matter.

And again, I don't even think it's worth arguing about whether NMN or NR is more bioavailable because to your point, you can sort of adjust the dose. And I trust that whatever you're taking NR or NMN, you are getting some NR into the cells and that's being converted to NAD. But we still keep coming back to the jugular question. Does that matter does increasing intracellular NAD matter when the system is so tightly regulated.

So I think what you see is a lot of marketing material that tries to make the case that you can do it. Great. I'll grant you that you can do it. Does it matter? Does it matter in lifespan? The answer appears to be unambiguously no at this point. Does it matter in health span? I think that's what we're discussing. There's something so sticky about the longevity field. Just so sticky about this idea that one could take something and extend lifespan and people don't want to be in the control group.

So they're willing to invest significant amount of money to do it. Well, I mean, I think the bigger issue is like you can't do the longevity experiment in humans. And I'm sure that these companies that sell this. And I honestly, I don't follow this space. I don't know how many of these companies there are out there. I can name two because the, you know, five years ago, which was the last time I really dug into this.

I knew who the two dominant players were. For all I know there could be 20 companies today that are selling NR and NMN. They're probably about 30 to 50 prior to this FDA ruling. Okay. Which is kind of an interesting situation in its own right. You know what happened there was the supplement NMN suddenly. The FDA decided that it should not be sold over the counter anymore because there was a clinical trial initiated on NMN, which essentially makes NMN a drug for clinical testing.

And thereby can't be classified as a supplement any longer. That was the rationale as I understood it. But as with things like an acetylcystine, that was more of a lobbying effort though. Right. I don't think actually that was a scientific decision. I think that was more of a lobbying decision from a market protections from an IP protection standpoint. And this had happened prior for an acetylcystine.

Yeah. NAC, which some people take it's a meucolytic, actually a great decongestant. If you're congested and it increases glutathione, that's my understanding. And I believe somebody checked me and the decrease or increase glutathione. Increases glutathione. Is my understanding if I have that wrong someone will tell me quickly in the comments. My understanding is that in Europe, NAC might even be available by prescription.

In the US, you can still buy it over the counter, but a few years back, the FDA said, nope, can't sell NAC any longer. And there was a pushback lobby to keep it on the market. And you can still buy it on Amazon. The same thing has more or less happened with NMN. And certainly with NR. Although NR was never in question in terms of whether or not it should be sold as a supplement or not. Because as far as I know, there's no clinical trial on NR, at least not currently.

So there's a clinical trial on NMN, which classifies it as an experimental drug. And therefore the FDA said, nope, you can't sell it as a supplement. A few companies, major companies, pulled NMN from the market in the US. Many smaller companies just kind of watched and waited and continued to sell it. And I checked prior to the beginning of this episode and you can still buy it online. But of course, a lot of what we're saying today is kind of a why would you.

We're not really coming up with strong arguments for taking NMN, at least not in today's discussion. Yeah, I mean, again, I think the strongest argument I could make based on the data would be potentially on the, on the, on the Basil cell and Squat-Misal Carcinoma risk reduction if indeed those results are reproducible. That, again, that's, that would be justification. Again, for the right individual, wouldn't be a justification for me. But really the rest of it is.

Why, why do you need to do experiments on this if you're selling a supplement when you don't need to make claims to sell a supplement? Like if it's a drug, you have to have an indication. Can't sell a drug without rigorous trials that demonstrate both safety and efficacy. I do think it's pretty safe to say that I, I do think NR and NMN are probably safe. There has been some voice around the idea that NR could increase the risk of cancer.

Right, and the experts in this area, like Charles Brenner, have pushed back hard on that. Arguing that the studies were not done well is a, I recall. I, I think that's probably fair. I don't think there's been a well done study in this entire field is, is part of the problem, right? So, so, and that's probably too harsh a statement, but, but I, this is not a field that's like, you know, that's necessarily lending itself to the rigor that you would in, in, in pharmacotherapy.

And I, I think there are probably, you know, you mentioned Charles Brenner, like I think Charles does good work, right? And he works on many things, not just this. Yeah, and, and, and, and by the way, I don't, I don't think, I don't hear Charles out there saying that NR increases lifespan.

No, in fact, I don't want to quote him at all, but I think he would argue that Sir Twins, NR, NMN, should not logically or practically be linked to efforts to extend lifespan, but that there are some interesting positive effects of augmenting NR as a means to increase NAD, for sake of anti-inflammation and some of these other effects that we've been discussing.

Yeah, that's my understanding of his position as well, is that I think he firmly agrees with what I laid down at the outset of this, which is, there's no meaningful logical connection between the relationship of Sir Twins, Choloric Restriction and NR. That's, that's just a, that's a shell game that is empty. And, and you're right. I mean, I think part of the reason why I think there's much better research going on with rapamycin is that there's really no commercial interest in rapamycin.

Like nobody's going to make money selling rapamycin. Because it's so cheap. Well, yeah, and it's actually not cheap, but it's a drug that is off patent. So this is a drug that was approved by the FDA 25 years ago. So generic forms are inexpensive enough that no leave it or not they're not. This is the irony of it is generic. So rapamyun is the brand drug that was initially approved in 1999. And today, if you go and buy rapamycin, you're going to not buy rapamyun.

You're going to probably buy generic cirrolemus or rapamycin. And yet it's surprisingly quite expensive. Now, it's not enormously expensive because you're not taking much of it, but it's about five bucks a milligram. That's pretty expensive. So if you're taking eight milligrams a week, that's 40 bucks a week. It's probably what I spend on rapamycin. That ain't cheap relative to, you know, and it's cheaper than some things I take.

But it's not cheap. But the point is like nobody has a commercial interest in rapamycin. Right. It's sort of in a relevant drug. It's, but the interest is scientific. Right. And the commercial interest is in what we call rapologs, which are analogs of rapamycin that are being investigated by a number of companies to look at new indications.

For example, immunity, immune function. Right. So rapamycin historically is thought of as an immune suppressant because that's the context in which it was approved for patients undergoing organ transplantation.

But, you know, I think Joan Mannock and Lloyd Klickstein, when they published that paper in 2014 using everrolemus where they took a group of 65-year-olds and randomized them to either a placebo or different doses and dosing schedules of everrolemus found enhanced immunity in response to an influenza vaccine.

Which again, was for me, that was the turning point. Right. That's when rapamycin went from something that was interesting based on the first ITP in 2009 to maybe we should be taking this in 2014. So between 2009 and 2014, I was kind of looking at the curiosity of rapamycin and saying, well, cool that it worked in mice. I don't think humans should ever consider this to that study, which was like, wait a minute, something's different.

If you take rapamycin as a human at least every day, it seems to suppress your immune system. But if you just pulse it once a week as they did in that study, it seems to improve immune function. Which again, means it's an immune modulator. It can go up or down on the immune system. That was really the hypothesis that emerged from that experiment.

And so now the question is, could you design drugs that are more specific to M4 complex-1, which rapamycin is not, but you can get around that by dosing it intermittently? And then of course, is it a drug that has efficacy in terms of other things that can be tested in humans that are not longevity? Because you can't test lifespan in humans, obviously. Right. You're 50, right? 50 or so?

51. You seem to be vigorous. You take great care of yourself. How much do you think taking rapamycin for how many years have you been taking it? Six. Has contributed to your current state or vigor? Zero idea. This is my opportunity to ask about your belief or lack of belief in biological aging tests. Because if somebody is going to experiment with any or all of these things, they may want to evaluate whether or not their biological age is changing.

And there are a number of these tests available. And people love this stuff. Love them. I mean, who wouldn't want to see that they are 51 years old, but their biological age is 37? I just did a movement test the other day. So it's a very fancy camera system where you've got a million cameras on you. And you go through this whole exercise. How high can you jump? How far can you throw? Like it was awesome. And then it gives you a movement age. Andrew, I was 22. I believe it.

I should be amazing. Do you actually think I moved like a 22-year-old? Are you freaking kidding me? I bet you if I went and did that again tomorrow, I'd come back at 31 or something. There is so much nonsense in this type of testing. It is just, you know, look, there's probably something to be said.

If I do that and I come out at 22 as I did versus 92, I would grant you that if you took 150-year-olds and you put them through a movement test, the ones that really, really are struggling will come out older and the ones that really, really are doing great are going to come out younger. So great. I guess it's not. I guess I move reasonably well for a 51-year-old.

But it's simply impossible to believe that I can do today what I could do when I was 22 with respect to movement and strength and power, which is what that was assessing. You're doing a lot of jumping, single leg jump here, do all this kind of stuff. Balance testing, all sorts of things. And I guess I would say the gold standard for any of these biologic aging tests has to be the following. What is a better predictor of remaining years of life, chronologic age or biologic age?

That's to me the most important standard. So how old are you chronologically? I turned 49 in six weeks. Okay. So I'm sure your listeners will not like to hear this because they would probably hope and believe that you are immortal. But some might want to hear that I'm going to be taken out soon. But let's just grant your mortality as a given. Based just on your chronologic age, an actuary would come up with a pretty decent prediction of how long you're going to live.

Now I would argue that that's a crude assumption because it doesn't take into account the fact that you're metabolically healthy, that you do all of the things that you do. Just based on the fact that you are a man who is 49 years old and who doesn't smoke those three things would give me if I were an actuary, a very good prediction of your life expectancy. And because I'm not an actuary, I don't know the exact number, but my guess is it would be predicted at this point at another 37 years.

Okay. I bought that chart my life in weeks. In fact, I bought two of them for reasons that are uninteresting. But I've watched that chart fill. Not quite what you predicted, but I put my estimated lifespan to be 95. Great. That's fine. The little lines on the side of how much vigor I felt from just overall wellness, completely subjective of zero being completely cratered near death to 10. That's what I've ever felt. But you do that you make that note every how often.

Okay. So what I did is from 10 to 15, I felt blank. And then in my 20s, I actually didn't feel so great because I was working 80 hour weeks commonly. You can ask my former lab technicians. I was just talking to Fengwin recently. I mean, I used to work to collapse, not healthy.

80 hour a week, maybe 100 hours occasionally, maybe 70, maybe back to 40, but just too much work, not enough sleep, nutrition, not great, not just not doing the right things, but just gave my 20s to being in lab, basically. And a lot of my 30s as well. So I would say from 40 to 45, my vigor was higher than in my 30s. And then now I track, I would say about every two months, I'll start filling in that line. And it's adjusted for by stressors and adjusted for by positive things in life.

And the goal for me is to figure out what are the behavioral tools and other things I can do or take that are going to keep the vigor as high as possible. Vigor well being internal peace, etc. All of that combined, kind of what I'm calling wellness in this very subjective measure, as high as possible, as I transition to my 50s, my 60s, 70s and 80s.

And I'm guessing that I'm going to have to do many more things in my 80s and 90s in order to maintain a similar, hopefully, level of vigor and well being than I do now. And the question is will I be able to? Yeah, maybe, maybe. I might take a slightly different, different angle on that. But let me go back and make one point and then we'll come back to this point, which is actually really interesting.

Because I think the chart is great. I think the chart, more than any supplement for longevity gives you a, or gives one a visual perspective of where they sit in this long arc. And I don't think the brain is very good at anchoring us to the notion that we are mortal. Because if we think about that for even a few moments too long, it makes us anxious. And I think we are very good at avoiding that reality. Yeah. Well, it's, it's, as you said, it's very difficult to contemplate finitude.

So I actually want to talk about that because I think it's so interesting. But I just want to make this point about the actual point, right? So let's just say actuarially your expectation is 40 years more at this point because you're 49, you're a male and you don't smoke. So we believe you have somewhere between 35 and 40 more years of life predicted on the basis of your biological age. That's it. That's all I got.

You're going to live to whatever 88 to 91 or something. I'm making that up. But that's like, okay, I better get cracking on some stuff. So now let's pretend you went and did a biologic age test. Okay. So let's say you did that. And let's say it came back and said you're 25. So if I had a 25 year old male, non-smoker in front of me, what's his life expectancy? Well, it's about 60 to 65 years.

Does that mean that you and Drew have 60 to 65 more years of life based on a fact that your biologic clock says you're 25? Do you believe that? No, no way. No, of course not. Now, this would be an easy thing to test, not in humans, but you could do it in mice. Right? Interesting that to my knowledge, that experiment hasn't been done.

So right out of the gate, when I look at people talking about their biologic age, you know, well, I'm actually 60 years old chronologically, but my biologic age is 35. My response is who cares truthfully? Like, is that a good thing? Yes, probably. But is it is it is it tangibly, measurably meaningful like to have a biologic age of 35 versus 40 versus 30 if you're 60? I don't think I think we're applying a very false level of precision to something that might only need to be directionally true.

Secondly, we don't really yet understand the biologic noise in that measurement, right? So there are lots of things that we measure that are really noisy. So if I measured your, I don't know, let's think of something that's very biologically noisy, your triglyceride level, like your triglycerides are pretty noisy unless I do something very important, which is standardized by how long it's been sent down.

How long it's been since your last meal? Like, if you ask me right now what my trig are, I have no earthly idea because, you know, I probably ate three hours ago, like, and I don't even remember what I ate, how much fat was in it, how much carbohydrate was it, I have no idea.

So the only way you could really get a triglyceride measurement and put any weight to it is if you've been fasting for eight to 12 hours, then we can at least say, hey, a triglyceride level of 50 milligrams per deciliter is excellent. Whereas a triglyceride level of 120 milligrams per deciliter is lousy. But if you measured my trig today and they were, meaning at this moment and they were 150, that could be totally reasonable, even though at fasting levels I'm at 50.

So we know that because we know exactly what goes into the triglyceride measurement. But when you look at a biologic clock that takes into account your glucose level, your vitamin D level, your epigenetic marker here or there, those are very noisy things. So how do I know when I measure it in you now versus when I measure it in you a year from now, I captured you in the exact same space? I mean, I don't. So it's for that reason that I just have a very hard time putting any stock in this.

Now, does that mean that in the future we won't find some benefit in this? I think we probably will. I do think of all the things that go into it, probably the epigenetic part of it would be the most interesting. But again, what most people don't understand is sort of a dirty little secret is how difficult it is to measure the, and to sequence the epigeno.

So to my knowledge, none of the companies that are doing this, I may be incorrect on this, by the way, but the last time I looked, which was about a year ago, not a single company was correctly sequencing the epigeno on these things. So they were not able to accurately say what they were giving you an average representation of your methylation, but they weren't going base pair by base pair and actually sequencing this the way we would sequence the genome.

So again, he just so much noise in this system. And I just think it creates a little bit of a distraction for people truthfully. Do you avoid going through the non, let's just say the non traditional scanner at the airport, the one that might use higher levels of radiation.

And I think about how many flights you take as a source of radiation. Let's just keep this all in context. So the NRC recommends that a human being, or at least an American, should expose themselves to less than 50 milli seaverts of radiation a year. Okay, so what that number doesn't mean anything to somebody. So let me give people a sense of what that means. So how many milli seaverts of radiation do you and I receive because we both live at sea level.

And just ambient radiation living at sea level is one milli seaver to year. Okay, so we just shoot up 2% of our annual allocation. What if you moved to Colorado. Now you're a mile up. That increases you from one to two milli seaverts a year. Okay, what if you had a CT scan of your chest, a CT angiogram. Well, depends on where you got it done. If you got it done at a really good place with a fast scanner and great software, probably 3 milli seaverts a year.

If you got it done at a place that sort of average might be 10 to 15 milli seaverts pardon me, per scan. Now here's what's really interesting. By the way, I'm totally fascinated by this question, which is how much radiation is too much. A Dexascan, by the way, you can't even measure how many milli seaverts you're getting. So a Dexascan is like less radiation than a cross country flight. So it's super, super, super low, less than an x-ray or anything like that.

People who work in nuclear plants, I'm told, I haven't looked at the primary data on this, but I've talked to people who incessently do this. So it's possible I'm a little bit off on this, but I'm told that these people are at 10 times that level of radiation exposure and sometimes higher. So they're not getting 50. They might be getting like 500 milli seaverts a year. And yet interestingly, they're not at an increased risk for cancer. I'm not sure what to make of that.

But it suggests to me that we probably don't need to worry about things like airport scanners and flights. In fact, even if you look at pilots who do constant flights across the poles, because you're going to get the most radiation going over the pole, to my knowledge, there's no convincing data that suggests those people are at an increased risk of cancer either. And they're obviously at the upper end of what a civilian would experience in terms of radiation.

So I'm not convinced that that's something we should be stressed about. I think you just relieved a lot of people some unnecessary concern. I want to go back to what you were saying earlier about what you need to do in your 90s versus what you're doing now. So you said you think that in your 80s and 90s, you're going to have to work harder to preserve the vitality that you have now. Yeah, grip strength, jumping, cognitive function.

I mean, I've got very good genes in terms of longevity on one side of my family. Pretty good on the other, although not as robust. I mean, if I just look historically. Yeah, who knows, right? I mean, but my sense is that I'll live to be 95 if, you know, barring, you know, bullet bus or cancer. So I would say that yes, you're going to have to work hard in that last decade of life to preserve those things. But I think it's the work we do now that sets the stage for that.

It's the foundational work that we do in this period of our lives. You know, you and I are only a couple years apart. But I think this is the critical decade. It's in your 50s to your 60s and in your 60s to your 70s that I think is the deciding time. 50s to 70s. Yeah, 50s to 70s. So what is it about this window that you and I are just entering now and why is it so important? I think it's important because we're getting to that point where aging does start to show up.

Like I think if you and I are being brutally honest, like we're kind of half the men we used to be. And and and again, that just means like, look, like a night of poor sleep shows up more, right? When you were working in the lab as hard as you were describing it, you could probably walk through walls when you were exhausted. Yeah, a short nap would reset me near completely. Yeah. I got more colds and flus in that time because I wasn't taking such good care. But then again, I was indoors more.

So it's an imperfect experiment, but you're right. I think that as I've approached 50, I need to do more. You need to do more self care. You need to be more mindful of what you're eating, how you're sleeping, how you're recovering from those workouts. Because we still do hard workouts, but recovery plays a greater role. And others were just not quite as resilient as we used to be. You know, I was telling somebody the other day they asked me about my residency.

I don't think I'm being hyperbolic when I say this. I couldn't do one month of what I did for five years. I really couldn't do it. I don't think I don't think there's any. There's no way I could go back to that level of sleep deprivation for a month, let alone five years. So, you know, that's just a fact of aging, I think. So, but what we have to do during this period of time is build up as much physiologic reserve as possible.

And so, the important thing is we, you know, we have to stay in the game because compounding makes such a difference. Right? So, you know, we're still young enough that we can actually put on muscle mass. Now, that's not always going to be the case. It's going to be very difficult to add muscle mass when you're in your mid to late 70s. It's doable, but it's very, very difficult.

So, instead, we want to be putting on as much muscle mass as we can and increasing or at least maintaining strength as much as we can. Again, probably increasing it is unlikely. Clearly, we're not increasing power as we age. Right? Andy Gelpin has talked a lot about this. The atrophy of the type two muscle fibers, the two A muscle fibers, really start to atrophy in your 20s and 30s.

So, I know I don't have a fraction of the power that I used to have, and I know that because my vertical jump is literally half what it was when I was a teenager. Mine was never very good. So, I... It doesn't matter how good it was. My point is like, if you know what your vertical jump was at 18, 19, 20, and then you do it today, I mean, it's literally 50%. And that's one of the purest tests of power. So, power is going down, strength is going down, but not as much.

So, muscle mass is actually not, because remember, that's the order in which you lose things. Right? You're going to lose power, strength, and size of muscle. But again, size still matters. It's still a glucose sink, all these other things. But what we don't want to do is, you know, be out of the game. Right? What we don't want to do is injure ourselves and get a setback that becomes very difficult to recover from.

Because, you know, when you're our age, if you're inactive for months at a time, it's going to be two to one or three to one ratio of inactivity to activity to get it back. What about energy? Sorry to interrupt, but since we've been talking about molecules and energetic pathways, what about energy? Just that, get up and go, let's just say after a decent night, sleep, seven and a half hours, making up same time more or less, you know, 6.37 am probably for you or me.

And why is it that as we get older, we have less energy. Our mutual good friend, the late Ben Barris, used to ask about this. He used to say, he called me Andy. He was like, Andy, why do I have so much less energy? I was like, I don't know. I don't know. It's a great question. Unfortunately, he died of pancreatic cancer. So there may have been other things going on, but that was prior to the cancer, at least as far as I know.

You know, it's a very interesting question. Why do we have less energy? And I don't think anyone's ever been able to answer that question. No, and when you have kids, you're going to be even more starkly confronted with that. Because actually it's one of the things I am most amazed by when I look at my kids, especially the youngest ones, the boys who are seven and 10 is what I just described as spontaneous outbursts of energy.

Like, their inability to sit still, their kinetic desire to just like they will like if we're I remember once we were kind of walking through a mall and we're walking through the mall, they are sprinting ahead of us, sprinting back, sprinting ahead of us, sprinting back. Like, imagine if you and I were walking through the mall and I just started running ahead and running back, you'd be so sore the next day. But it's like it just wouldn't occur to me to ever run unless being chased.

Like it's just, I mean, like we now live a life like I think our ancestors did, which was, you know, if we're not deliberately in the business of moving for a reason, like you're exercising, you're going for a walk for the sake of going for a walk. You just wouldn't, it wouldn't occur to you go and expend energy for no reason. And yet kids do this. It's amazing. And look, it's going to go down by the time you're a teenager, like just going from being, you know, sort of 10 to 18.

There's probably a significant reduction in spontaneous outbursts of energy, let alone where we are now. And it's a great question. Maybe it's NAD. I mean, I don't know. Maybe, although up until now we've been talking about all these ways to try and increase NAD in the bloodstream and hopefully in cells and I don't know, I take my NMN and my NR and I feel a little bit of a boost in energy.

But I can't say that it's so significant that I feel like I can sprint back and forth just spontaneously. Again, it's just so hard for me to imagine that any supplement or any drug, including rapamycin, which I think is the most promising, neuroprotective drug we have, I just can't imagine that those things even compare to what good sleep, good exercise and good nutrition do for your energy levels and vitality.

And the reality of it is all three of those things are hard to do, you know, especially if you're an adult, like especially if you have a real life, you know, you've got kids, you've got a job, which is presumably many people listening to us right now. Like there's very few people listening to us right now whose only purpose in life is to take care of their health. Everybody's got something else they have to do, which means you have competing interests for how do you take care of yourself.

So to sleep is not easy, right? Like we all are busy as hell. We don't want to have to stop what we're doing to undergo a nighttime routine to put ourselves in the right headspace to be able to sleep, do all the things necessary. We give ourselves that eight hours in bed to hopefully get seven, seven and a half hours of sleep. Even people like me who like exercise, I know you like exercise. It still is a sacrifice in terms of time.

And for many people, certainly for me, food is the hardest of these all right. If I left my own devices, I eat for-confruit loops all day. Like I love fruit loops, right?

Interesting. By way of contrast, the food part is easy for me. I like healthy food and- I like healthy food. I just like all food. I like food. I don't like unhealthy food. I've weaned myself off. I never really liked it that much. I mean, I like a great tasting slice of pizza or ice cream every once in a while, but I much prefer meat, fish, chicken, eggs, fruits, vegetables, rice, oatmeal. I just like that stuff.

I'm more or no that way, I suppose. But on the topic of exercise as it relates to vigor and longevity, I'm intrigued by how some forms of exercise give us more energy, especially the same day, and how some forms of exercise or even timing of exercise tends to pleat us.

Because I think one of your major calls to the public has been to move more for sake of their health span and lifespan. But because of the time investment that it takes to work out in a jam or to go for a run or a ruck, I think some people think, well, that's a lot of time.

But if it gives you more energy and more focus to do other things, well, then it's great. So it's not just about living longer. It's absolutely being able to do more. And I've noticed I don't have any science to back this up, but I'd love someone to run a test on this. That if I complete my workout before 9 a.m., even if I have to start it while I'm a little bit fatigued, I have more energy all day long.

But that if I initiate that workout, say mid to late morning, I'm pretty tired in the afternoon. It's like I give everything I have to that workout. And so it becomes a little bit defeating since I'm not a professional athlete or even an amateur athlete. I'm working out for health span, lifespan. But I want to do exercise that gives me more life during my waking hours. I think somebody should study this.

And I'm convinced that it has something to do with the change in body temperature that occurs across the day and the additional change in body temperature that occurs as a consequence of exercise. That's my hypothesis. Do you notice a seasonal change in that? Do you experience it more or less than one season or the other?

I haven't thought about it that much, but not so much. Not so much. And I wonder whether folks like our friend, Jocke Willink, are able to do so much. He has so much bigger that guy. In part, because he basically exercises at the just after the lowest temperature phase of the circadian rhythm and uses exercise presumably to drive himself out of that and get that, you know, temperature increase.

That's the consequence of waking, but in his case, he's waking up so early for 30 is when he starts those workouts. So it's something for people that play with it's something that I don't think gets discussed enough, which is yes, you should exercise due resistance training, do cardiovascular training, but play with the timing of those and see how at a given intensity. It impacts your energy levels for the remainder of the day. I think that's I think it's an important metric that.

Again, I just don't see a lot of attention to because I think if people could experience the increase in energy that is the consequence of working out at the right intensity in the right way at the right times for them. They'd be much more apt to do it. It wouldn't feel like this. Like spending money on something that sure will make you live longer, but then you're depleted and you can't do cognitive work.

There's something pretty impressive about the fact that as far as I know, the last three, let's just call them. I don't want to call anyone out specifically major pillars of the high level administration at Stanford School of Medicine to my knowledge were all 5 a.m. runners. There's something about early morning exercise and my good friend Eddie Chang is the chair of neurosurgery at UCSF. He's been on this podcast known since we were seven years old.

He's an early morning exercise or and then he's got tons of energy all day. What about the reverse causality there? Do you think it's possible that they're they have a whole they have a system of high energy that makes Jaco who he is or makes. You know, these people who they are and as a result of that they they they're able to work out five clock in the morning.

I don't doubt it. I just have noticed that in the few times in my life where I've kicked my own butt to get out and start working out really early. I have more energy all day long. Sometimes I still require a brief nap, but it's a pretty striking effect as compared to you know the 10 a.m. workout effect.

So I've started setting a standard of trying to get my workout done before 9 a.m. So anyway, it's something for people to play with because the more energy to live in your waking hours perhaps not longer, but certainly have more energy in terms of output. I think is a significant and undervalued parameter.

Let's quickly return to supplements. We I think are converging on an answer about N R N M N N N A D, which is you don't take them correct. I take N R N N N N with not a lot of religious adherence. I should say if I ran out, I might not buy it for a while and the only observed effect for me is this accelerated hair growth, which is a pain in the butt frankly because it just means I have to get my hair cut more often. I'm not trying to grow my hair faster, but okay.

What are some other supplements if any that you take that are peripheral to this pathway or separate from this pathway. Rappamysin is a prescription drug only right so are there any over the counter things that you take that you would place into the lifespan category. Maybe they touch into health span as well. I'm happy to list off what I do, but what are your let's just say top five at least. Well, I don't I don't take that many so at top five would be a pretty exhaustive list.

I think the other supplements that I take I do take EPA and DHA in the form of liquid or capsule, visual capsules not because I have an affection for capsule over liquid. It's just going to increase my compliance if I take I've done both and I noticed when I was taking liquid because you're storing it in the fridge. It's just one more step removed than I was just less likely to remember to take it twice a day.

I take a fair acumen and there's some reasonable evidence in MCI patients that they're a human improves cognitive function. So I think there's a relatively low downside to the hypothesis that fair acumen may preserve cognitive function again I don't I don't I wouldn't put that in the category of like beat the table for it right I think it's just you know reasonable evidence.

I take I do take vitamin D because interestingly despite the fact that I'm outside every day without supplemental vitamin D my levels are surprisingly low. How much do you take I take 5,000 I you and that takes me from kind of a level of 30 ish to a level of 50 ish. And there's you know there's a lot of debate about how high vitamin D levels should be that's a whole separate podcast we could you know waste time on that and 10 years.

Yeah, my appetite to talk about that one let me think what else do I take I sure I do take methyl folate and methyl B12. And again the rational there is I do think there's some evidence that elevated levels of homocysteine are bad in and of themselves so there's no denying the fact that elevated levels of homocysteine are associated with bad things that's unambiguously clear meaning there's an association between badness and homocysteine what's not clear is it causal.

And there's definitely one mechanism you can point to although again mechanisms are what they are we just spent how many hours talking about mechanisms that theoretically make sense that never pan out. But mechanistically homocysteine will inhibit the clearance of something called symmetric an asymmetric dimethylarginine if you heard of these things sdma and a dma.

And sdma regulate nitric oxide synthase and homocysteine impairs their clearance and therefore when you have high levels of homocysteine it it results ultimately an impaired nitric oxide synthase and therefore low and no more nitric oxide. So this has been proposed as at least one mechanism by which homocysteine might negatively impact vascular disease.

So and we also know by the way that a dma and sdma are cleared by the kidneys and therefore this might this is also proposed as one of the mechanisms by which impaired kidney function is is impacts vascular health because that's a known right if you if your kidneys don't work well your risk of car heart disease goes way up.

So this is now proposed as a link between what we observe with homocysteine and impaired renal function. So we know that if you take methyl folate and methyl B12 you're going to lower homocysteine that's abundantly clear. So the thinking is that that might actually lower a dma sdma and raise nitric oxide synthase again relatively low cost low risk you know thing to take at modest doses.

So there's probably some evidence that over supplementing vitamin B is problematic, especially B6. So I don't care for all nerve damage exactly. So I don't supplement B6 I'm just taking a bit of folate and methyl B12. Let me think what else do I take because I do take a couple other things. Magnesium L3 and 8 and ashwaganda for sleep. I take slow mag which is just a magnesium chloride slow releasing version of magnesium and I take methyl I've heard me I take magnesium oxide.

So I take magnesium in three forms. So I'm a I'm a I'm a long magnesium your carpet modeling. Yeah, I'm big on magnesium right great for bowel function great for I mean I don't know the last time I had a cramp in my life you know it's been years since I've had a cramp despite exercising in a really hot place like Austin, Texas where I'm sweating like there's no tomorrow.

Whether you call it a supplement or not I take I take like electrolytes I take element which I should disclose I'm an investor in that company. So I drink an element today I take creatine monohydrate five grams a day I take AG most mornings. Oh and I take pendulum the probiotic got it.

As far as I know there's no other probiotic that has any meaningful effect on the body outside of pendulum right pendulum is the because if you buy the argument that a probiotic for your gut needs to have anaerobic bacteria in it there's no value in giving you aerobic bacteria.

You have to have something anaerobic so acrimansia which works through the GLP one buterate pathway is anaerobic and pendulum is the only company that can make it I have no affiliation with this company I think you should have the CEO calling cut cliff on your show she's an actual scientist and she's fantastic and

it's a really interesting story how they kind of develop this and how difficult it is to actually make an anaerobic bacteria and so this is kind of an odd company because it's a supplement company but they have to basically adhere to farma gmp conditions to make it because of the anaerobic vats that you have to use infused with nitrogen to be able to make an anaerobic bacteria so anyway so I take three of their products I take something called glucose control I take polyphenol and I take acrimansia.

Okay, I think that's the list. Okay, yeah, I'll try and move through my list pretty quickly I may miss one or two things and I may will put the list someplace online and fill in any gaps. I definitely take AG, AG1 you know that by typical ad read up doing it since 2012 that's true take one or two servings a day three if I'm traveling and I'll generally do that first thing in the morning or

in the evening. For me it's really about capping off the vitamin minerals that I might be lacking in my diet and also the whole adaptogen business I think and polyphenols and I'm very interested in pendulum because part of the reason I take AG1 is for the gut health aspect I think just

bowel movements are more where I'd want them I mean it sounds kind of weird to talk about but you just feel better when your gut motility is right I feel like it adjusts my gut motility so it's neither too fast nor too slow. So that's first and foremost. I take a quality fish oil either the one that AG makes or Carlson's in liquid form has that lemon flavoring and I make sure I get above one

gram per day of EPA so that's usually a tablespoon sometimes two tablespoons. I make sure that I get enough D3 typically from the dropper 5,000 I you per day approximately sometimes 3000 sometimes 7,000 I can play around that and I test my blood levels. I take a lot of the protein I take, methyl B12 and I also take Tonga Ali so I take one capsule of that in the early part of the day that has lowered my sex hormone running globulin freeing up a bit more testosterone.

And I take a couple of green tea capsules in the morning I drink your Ramote that's more of a stimulatory fact and I take the NMN in powder form sometimes NR as well and again if I run out of that I tend to go long periods of time without I use element as an electrolyte so people are probably noticing this is all pretty basic I take my case 10 grams of creatine monohydrate per day sometimes forget to take it that's why I take 10 grams I'll sometimes miss a day.

And I certainly feel the effects of that in the gym because of the greater water volume in the muscles but there are a lot of data on creatine monohydrate per sake of either maintaining or offsetting some of the cognitive dysfunction associated with sleep deprivation maybe aging altitude and some other things as well.

And then for a few months I was playing around with let's say nicotine gums I stopped doing that first of all I was dipping it and I ended up lifting for an entire episode of the Lexington podcast and I only realized later so I stopped taking it also because it gave me a kind of a tick and cough when I wasn't chewing it and then I felt like I needed to chew it and it's a little too stimulatory for me. Before sleep I take magnesium 3 and 8 really bullish on magnesium as well.

Apigenin 50 milligrams which is essentially came a mile extract and the in and occasionally I'll take 900 milligrams in a citol also or instead kind of mix those up and around and then I use a quality way protein as a protein replacement that kind of thing. And I've played around with various things like she legit and you know sometimes get the sense that it's having an effect but then I'll stop taking it for long periods of time.

You know there are very few things that I've stayed with for long periods of time and I basically just described what those are. You know if ever someone were to design a supplement that would provide more energy all day long that wasn't caffeine I'd probably look to that but I ingest caffeine in the form of your raw material coffee.

I've played around with caffeine tablets you know taking you know 50 milligrams of caffeine in tablet form I mentioned that only because it has a distinctly different feel than ingesting caffeine through liquid form. And I don't know why that is in fact there's a very well known podcaster who drinks peppermint tea and takes caffeine tablets as a way to I don't know drink peppermint tea which sounds very nice and mellow but also get the stimulant effect.

So anyway that's pretty much it and then I do a lot of things as I know you do mainly based on suggestions you've made about getting zone to cardio, rocking, weight vest walks and hikes. Three times a week resistance training three times a week cardiovascular training one long one medium one short and I try and hit the sauna and the cold once a week and yeah that's pretty much it.

I think there are a bunch of other supplements that are really interesting and kind of fun to play with if one wants to like 600 milligrams of alpha GPC or 900 milligrams of alpha GPC in a double espresso prior to a workout you feel different it's a stimulant.

But I don't like to do that too often because of the increase in TMAO that occurs and then you have to take 600 milligrams of garlic to offset that increase and you start getting if we believe TMAO matters right if you believe TMAO matters and okay great even better I'll maybe skip the garlic so things like that I prefer to just eat garlic anyway.

So there are a bunch of things like that that are kind of fun to play with as pre workouts but yeah that's the core supplement regimen and it's the one I've stuck with for gosh. At least 10 years or in the case of AG you're more than you know more than that so. I should say because any discussion around supplements I think it's going to you know have people picking up their ears to okay this is like a sales pitch or something I absolutely want to go on record.

The things you choose to do and not do are going to have much greater effect on your health span and lifespan that is the behavioral things in particular sleep exercise nutrition sunlight etc.

than any one supplement that you're going to take so I do view supplements I think through the appropriate lens which is that they are indeed a supplement they are not necessary many of them are simply sufficient to serve as an insurance policy or to augment mental and physical health maybe longevity in ways that make it worthwhile given my disposable income that I want to devote to supplements but I don't think you need them.

Yeah I'll go even more extreme on that statement everything we have talked about on this podcast today whether it be NR NAD NMN Thericumin magnesium this supplement that supplement all of that stuff while potentially mattering I would put in the category of was the Titanic serving lobster or steak.

I like steak more than lobster that's a relative discussion exercise sleep nutrition emotional health is the question of what was the heading of the Titanic okay so I just want people to understand the magnitude of what we're talking about how you eat how you sleep how you train and how you take care of your mental health is the equivalent of what direction was the Titanic going with respect to the Titanic.

All this supplement bullshit that we just talked about is equivalent to where they serving lobster or were they serving steak and was the band playing this song or that song I'm not saying those things don't matter but just put them in the context of the direction the Titanic is going. Okay so I completely agree with you exercise sleep nutrition and emotional health not listed in any particular order Peter and I both completely agree those are the critical for. Before we close.

NR NMN NAD. And NAD in particular how do we view this is it a pathway that we should be focusing on in terms of supplementation or infusions for sake of extending our life my answer on that is no.

Yeah I would say the same you know I don't remember who said this but someone maybe it was naseem to lab said don't tell me what you think show me what's in your portfolio like meaning people who pontificate about this stock versus that stock he's kind of like assuming it was him that said this is like okay I don't care what you're telling me tell me what you own that's going to show me your conviction.

So through that lens look I'll show you my conviction on exercise I'll show you what I do I'll show you my conviction on sleep this is what I do I'll show you my conviction on all these other things. I mean I don't take these supplements full stop I don't take them because I can't afford it's not that I can't afford them it's not that there any inconvenience to me to take them I.

Passionately do not believe they do anything for me and why would I waste time money anything on something that I really don't believe makes a difference now again I am always happy to be proven wrong and I am very happy to say that two years from now five years from now we can be doing this exercise again and in the presence of new information maybe I'm not taking rap and my son and maybe I am fist following you know nr and mn possible I will I will reserve the right to change.

My mind for the rest of my life in the presence of new data but as it stands today I do not take these supplements and I have no foreseeable plan to do so until information changes. Great thank you for that clear stance and the willingness to change it in light of new data Peter so good to sit down with you again and talk science talk health.

And in this case talk about the supplements that we're not going to take in addition to the ones that we do take we will do this again sometime very soon hopefully in Austin would love that. Thanks Peter thanks man.

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