Dr. Peter Attia: Supplements for Longevity & Their Efficacy

Andrew Huberman:
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 healthspan 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 healthspan 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 end target goal of anyone that's trying to augment the NAD pathway, so to speak. So for instance, we talk about taking NR versus NMN 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 healthspan. 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, NMN, 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 healthspan 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'll 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 LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes, sodium, magnesium, and potassium in the correct ratios, but no sugar. Now, proper hydration is critical for the optimal functioning of all the cells in your body, and that's especially true for the neurons, the nerve cells. In fact, we know that even a slight degree of dehydration can diminish both cognitive and physical performance. So to make sure that I'm getting proper hydration and electrolytes, I personally dissolve one packet of LMNT in about 16 to 32 ounces of water when I first wake up in the morning and I drink that or sip that across the first half hour of the day or so. And then I also make it a point to drink another packet of LMNT dissolved in an equal amount of water, so 16 to 32 ounces, at some other point during the day, and maybe even a third if I'm exercising and/or sweating a lot. I should mention that LMNT tastes absolutely delicious. My favorite flavor is watermelon, although I also confess I like the raspberry flavor, the citrus flavor. Basically, I like all the flavors. If you'd like to try LMNT, you can go to drinklmnt.com/huberman to claim a free LMNT sample pack with the purchase of any LMNT drink mix. Again, that's drinklmnt.com/huberman to claim a free sample pack. Today's episode is also brought to us by Levels. Levels is a program that lets you see how different foods impact your health by giving you real-time feedback on your diet using a continuous glucose monitor. One of the most important factors in both short and long-term health is your body's ability to manage blood glucose. To maintain optimal energy and focus throughout the day, you want to keep your blood glucose levels steady without big spikes or crashes. I first started using Levels about three years ago as a way to try and understand how different foods impacted my blood glucose levels, and it's proven incredibly useful for determining what food choices I should make, when best to eat certain foods, especially around things like workouts, and when and what to eat relative to when I go to sleep in order to allow for the best possible night's sleep and stable blood sugar throughout the night and when I wake up in the morning. So if you're interested in learning more about Levels and trying a CGM yourself, go to levels.link/huberman. Levels recently launched a new CGM sensor that's even smaller and has even better tracking than their previous version. Right now, they're also offering an additional two free months of membership. Again, that's levels.link, spelled L-I-N-K, /huberman to try the new sensor and two free months of membership. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. Now, I've spoken many times before on this podcast about the critical need for us to get adequate amounts of quality sleep each night. One of the best ways to ensure a great night's sleep is to control the temperature of your sleeping environment. And that's because in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees. And in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees. Eight Sleep makes it incredibly easy to control the temperature of your sleeping environment by allowing you to program the temperature of your mattress cover at the beginning, middle, and end of the night. I've been sleeping on an Eight Sleep mattress cover for well over three years now, and it has completely transformed my sleep for the better. Eight Sleep recently launched their newest generation pod cover, the Pod 4 Ultra. The Pod 4 Ultra has improved cooling and heating capacity, higher fidelity sleep tracking technology, and it also has snoring detection that remarkably will automatically lift your head a few degrees to improve your airflow and stop your snoring. If you'd like to try an Eight Sleep mattress cover, you can go to eightsleep.com/huberman to save $350 off their Pod 4 Ultra. Eight Sleep currently ships to the USA, Canada, UK, select countries in the EU, and Australia. Again, that's eightsleep.com/huberman. And now for my discussion about NAD and longevity with Dr. Peter Attia. Peter Attia, welcome.

Dr. Peter Attia:
How are you?

Andrew Huberman:
Great to see you again.

Dr. Peter Attia:
Great to be here again.

Andrew Huberman:
Should we parse this NAD thing?

Dr. Peter Attia:
I think we should.

Andrew Huberman:
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, so get enough zone two 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, et cetera, that all kind of funnel in, at least in my mind, to mTOR, mammalian target of rapamycin. A molecule that's robustly expressed during development in 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 mTOR, 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 timestamp 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 size is robustly different.

Dr. Peter Attia:
By the way, I just did this exercise because my daughter, 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 3:56 at 3:56 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, 14 and 15, 15 and 16 becomes incrementally less and less and less. Whereas going from two to three and three to four and four to five are ridiculous changes.

Andrew Huberman:
Yeah. The same brain has to learn an entirely new body every year-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... in terms of how to move it, limb length, et cetera. So a lot of the so-called anti-aging or longevity approaches that fall under this umbrella relate to things like caloric restriction or taking drugs such as rapamycin. And of course, mammalian target of rapamycin is the target of rapamycin, duh, 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 the do everything, even the most esoteric of things category. This is a rarer category. There are folks like Bryan Johnson who spend a lot of time in this category specifically, taking very high doses of polyphenols, limiting their caloric intake to just early part of the day. I think he eats dinner at 11:00 a.m. I don't know if it still qualifies as dinner at 11:00 a.m., but his final bite of calories is, I believe, at 11:00 a.m. Doing everything from red light to PRP, platelet-rich plasma, excuse me, and essentially the kitchen sink approach to longevity and aging. Did I miss any categories?

Dr. Peter Attia:
So I would frame it slightly differently because I like categories to be more MECE, mutually exclusive, collectively exhaustive. So I don't know that I would formulate it that way, right? 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, right? So you have to eat. You have to sleep. You have to move. You just have a choice in 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, right? 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, and you can choose to decide on how you move. You alluded to it already, right? 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 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 without sleep before you would literally perish. But again, you have a lot of choices in 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 again, I'm not saying my framework is correct and 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 we want to live longer, and I describe this, I think, in chapter four of "Outlive," that turns out to be mathematically equivalent in the modern society to delaying the onset of chronic disease. Now, that 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, 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 the modern miracle of childbirth in this era. So now, for you and I to live longer, we basically have to delay the onset of cardiovascular disease, cerebrovascular 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 GLP-1 agonist, and you will directly impact those things. You could take a PCSK9 inhibitor or a statin or bempedoic 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 would 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 geroprotective, which is they target hallmarks and pathways of aging that you've described. So 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 describe as probably the most important nutrient sensing system in our body. So we have somewhere between nine 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, and can 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. So I would sort of say those are the big three categories. And then basically the fourth category you could just say is like 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 like how does all that factor into kind of emotional health and happiness and well-being, where none of this other stuff matters if you're kind of unhappy. And you've done so many podcasts on that topic, right? You've had Paul Conti on, 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 MECE, in that we talk about the behaviors, the exogenous molecules that target diseases, the exogenous molecules that target aging.

Andrew Huberman:
Aside from food, what exogenous molecules do you take?

Dr. Peter Attia:
I take a few, right? So I take some that are disease specific, right? So I take a PCSK9 inhibitor. I take bempedoic acid. I take an SGLT2 inhibitor. And then I take at least one that is purely just based on the belief of its capacity in geroprotection, which is rapamycin. And also the SGLT2 inhibitor, I think, is probably just broadly geroprotective, and we can even talk about that a little bit in terms of the success of one of those molecules called canagliflozin in the Interventions Testing Program, the ITP, which I am sure we'll talk about in the context of NAD as well.

Andrew Huberman:
What dosage of rapamycin do you take?

Dr. Peter Attia:
I take eight milligrams once a week for as long as I can tolerate it, but I usually have to take breaks.

Andrew Huberman:
Why is that?

Dr. Peter Attia:
I get these vicious aphthous ulcers, little mouth sores.

Andrew Huberman:
Canker sores.

Dr. Peter Attia:
Yes.

Andrew Huberman:
Ugh.

Dr. Peter Attia:
About 10% of people get them.

Andrew Huberman:
Hmm.

Dr. Peter Attia:
It's paradoxically the only biomarker we probably have. So I secretly rejoice in knowing that at least I'm getting a good batch of rapamycin.

Andrew Huberman:
By virtue of the side effect.

Dr. Peter Attia:
By virtue of these miserable side effects.

Andrew Huberman:
Interesting.

Dr. Peter Attia:
But so in reality, what it works out to is I'm probably on it for two months and then off it for a month, on it for two months, off it for a month, or thereabouts.

Andrew Huberman:
And the idea there is that you're limiting mTOR. You're Causing your cells to grow less, mature slower, and in that sense, slowing down aging. Is that the idea?

Dr. Peter Attia:
Yeah. And this will be an important theme today, right? It's like we can talk all day long about mechanisms and theoretical arguments for why it would work. And I think my conviction around taking rapamycin is less about looking at the molecular explanation for why rapa works, although I find that to be quite convincing, and why does the inhibition of mTOR stimulate autophagy? Why would that suppress senescent cells? But truthfully, my conviction around mTOR 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 rapamycin or its analogs, for example, everolimus, when you look at the administration of these molecules to organisms that are as close as possible to the species of interest. We're 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. No other molecule has done this. It's very important to understand there are only two interventions, full stop, that have ever extended life across those four categories of eukaryotes.

Andrew Huberman:
Caloric restriction.

Dr. Peter Attia:
And rapamycin. Very important point, right?

Andrew Huberman:
How do you feel when you're on rapamycin, aside from the canker sores?

Dr. Peter Attia:
Yeah, which 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. Actually, that's not true. 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.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
And maybe that's just a placebo effect.

Andrew Huberman:
Does it synergize with caloric restriction or collide with caloric excess? Meaning, if you're taking rapamycin, but you're slightly over your caloric needs, maybe you're trying to add a little bit of body weight-

Dr. Peter Attia:
Mm-hmm

Andrew Huberman:
... or happen to overeat a little bit just because, is it going to collide with rapamycin's potential positive impact on slowing aging?

Dr. Peter Attia:
Yeah, it'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 Kaeberlein'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 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? In an ideal world, you want to use a mouse model that is not inbred, 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-

Andrew Huberman:
Mm-hmm

Dr. Peter Attia:
... and ultimately in companion dogs, which is where Matt Kaeberlein is looking, I think 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 have a second look at this and say, 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.

Andrew Huberman:
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?

Dr. Peter Attia:
It is going to go on. So initially, there was insufficient funding to do the study in an adequate way. And then it turned out there was a shortfall of about two and a half million dollars 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.

Andrew Huberman:
Great.

Dr. Peter Attia:
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, 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 if this is something we should all be taking is kind of a mystery to me.

Andrew Huberman:
Yeah. Well, I was on NIH study sections for many years reviewing grants. I 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 that gets funded. You're going to go, "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.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
So hopefully that study will get completed, and thanks for raising those funds. Let's talk about NAD.

Dr. Peter Attia:
Yes.

Andrew Huberman:
It's in essentially every cell of the body except red blood cells, correct?

Dr. Peter Attia:
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. Because they still undergo redox potential. So it's possible NAD is in every single cell. Yeah.

Andrew Huberman:
And it's generally thought to be associated with energy production and mitochondrial pathways in every single cell.

Dr. Peter Attia:
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 six hundred 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 0 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 sirtuins 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.

Andrew Huberman:
It's also, as I recall, where the story began.

Dr. Peter Attia:
That's exactly right.

Andrew Huberman:
It was some experiments where the sirtuins were mutated in one direction or the other, meaning gain of function or loss of function. These days, people hear gain of function and they immediately think to pandemic-related themes. But gain of 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 of function rescue experiment. You reintroduce the gene of interest. It's an important-- I wouldn't even call it a control. It's an important experiment in any case, because loss of function will tell you a lot.

Dr. Peter Attia:
Yep.

Andrew Huberman:
But gain of function and loss of function, assuming that the results jibe, 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, I don't know, the sonic hedgehog pathway. Somebody is hypomorphic for sonic hedgehog, and they might actually lack a major tooth up the middle because the role of sonic hedgehog at the midline, and you could 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 sirtuins, as I recall, they deleted the sirtuins in the yeast.

Dr. Peter Attia:
Yeah. So 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 Dena Dubal from UCSF on Klotho.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
Which is an amazing scientific story.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
And it's a great story because it shows how accidents can lead to great discoveries, right?

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
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.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
And then there was this one strain of mouse with this one knockout that died really, really quickly, and it developed devastating neurodegenerative disease and died very quickly. And 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 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 Klotho.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
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 overexpress that gene and ask the question, do you live longer? And sure enough, when they overexpressed that same gene that they had just knocked out and killed the mouse, the thing was living 15% to 20% longer.

Andrew Huberman:
So it's both necessary and sufficient-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... for extended life.

Dr. Peter Attia:
So that's how you can say, "Well, that's a longevity gene."

Andrew Huberman:
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Dr. Peter Attia:
So let's go to the sirtuin story. So it goes back to the late '90s. Matt Kaeberlein again. This is amazing, right? So you have this guy who's the leading authority, or one of the leading authorities on the work going on today with rapamycin, along with one of his colleagues, David Sabatini, and a few others. But 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 overexpressed SIR2. 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 what that strain was. It was something 316. But 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 SIR2, this gene, they live longer, and in this 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 sirtuins. That hypothesis sort of fell apart about four years later when Matt Kaeberlein, again, this time with Brian Kennedy, did another experiment in 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 SIR2 lived longer, if you took that strain and you calorically restricted them, no change.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
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 SIR2, 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 in yet a different strain, God, I'm blanking on the name, it's like BY4742. These don't matter. If you calorically restricted them, they lived longer. If you overexpress SIR2, they lived longer. If you did both, they lived even longer. It was additive. Again, further suggesting that overexpression of SIR2 and caloric restriction independently and separately extended lifespan.

Andrew Huberman:
These are parallel pathways.

Dr. Peter Attia:
They're parallel pathways. For reasons that honestly escape me, Andrew, there are still people who maintain that the benefit of sirtuin overexpression is through the caloric restriction pathway, and vice versa.

Andrew Huberman:
And that's wrong.

Dr. Peter Attia:
My reading of the literature, in addition to every person I have talked to on this who works in the space, including Matt Kaeberlein, who has done the most research on this, is that there is no evidence that caloric restriction and sirtuins 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, right?

Andrew Huberman:
What about in humans?

Dr. Peter Attia:
What about it specifically?

Andrew Huberman:
Does it extend life?

Dr. Peter Attia:
Caloric restriction or sirtuin? Well, that experiment's never been done and never will be done. Yeah.

Andrew Huberman:
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-

Dr. Peter Attia:
I would argue no one wants to be in the treatment experiment either.

Andrew Huberman:
Oh, you got me. You beat me to the punch.

Dr. Peter Attia:
Yes.

Andrew Huberman:
No one wants to be in the treatment group either because it requires eating so little.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
The mere appearance of people-

Dr. Peter Attia:
The joke is you probably will live longer, and it will feel even worse. Caloric 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. Meaning, 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? Like this-

Andrew Huberman:
Yeah, frailty.

Dr. Peter Attia:
Yeah, exactly.

Andrew Huberman:
Yeah.

Dr. Peter Attia:
So you trade one set of diseases for another. It's not at all clear that lifespan goes up. And by the way, when you even look at some of the animal literature where they're using different strains of mice that are not inbred, 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, while 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 sirtuin story got off to an incorrect start, where it basically lopped on to the CR story, which was, "Hey, we've got this thing, CR, that we've known since-"

Andrew Huberman:
Caloric restriction.

Dr. Peter Attia:
Right. Caloric 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 sirtuin activation works. Oh, it's got to be-- But again, if you go through the story in detail, as I just did, there's no evidence whatsoever that sirtuins have anything to do with caloric restriction and vice versa.

Andrew Huberman:
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 sirtuins or changing caloric restriction independently increase lifespan, combine the two, you get what appears to be a synergistic effect, but it's, as you pointed out, an additive effect. It seems like a pretty straightforward experiment to do. You could just do an occlusion, right? You could-

Dr. Peter Attia:
Of course

Andrew Huberman:
... then put back in the sirtuin or adjust calories and see whether or not you get effectively whether the math is corrected.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
So-

Dr. Peter Attia:
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 sirtuins are truly a factor that drives longevity, how can you activate them, right? How do you activate a sirtuin? 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 sirtuins, 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.

Andrew Huberman:
Yeah. Making a fly mutant, Drosophila mutant that overexpresses sirtuins, a worm, C. elegans mutant that overexpresses sirtuins, that's a pretty quick experiment to do-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... because of the short generation time of those species.

Dr. Peter Attia:
Right.

Andrew Huberman:
Now, a mouse, it's a longer experiment, but I'm guessing all of those experiments have been done.

Dr. Peter Attia:
Yeah, and the only one that I can find that has demonstrated a survival advantage is one particular transgenic mouse experiment that overexpressed SIRT6, and it did indeed, for the male mice, increase lifespan by 10 to 15%. So this is one transgenic mouse model that overexpressed SIRT6, and those mice, the male mice, lived 10 to 15% longer. The female mice did not.

Andrew Huberman:
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 transgene that's inserted there. And there are all sorts of important intricacies that relate to this. For instance, where the transgene is inserted. If it's downstream of an enhancer that's muscle specific, then you can get a mouse that overexpresses sirtuins 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 SIRT6?

Dr. Peter Attia:
SIRT6, yeah.

Andrew Huberman:
So every cell in the body that normally would express SIRT6 would express more SIRT6.

Dr. Peter Attia:
I don't remember, Andrew, to be honest with you. I'd have to go back and look at the paper.

Andrew Huberman:
Okay.

Dr. Peter Attia:
I don't know if it was muscle specific or whole body specific.

Andrew Huberman:
I'm guessing unless they made it clear that it was tissue specific, that it's whole body. So we're talking about when Peter says transgenic mouse, he's talking about a mouse that has this transgene that causes it to express more SIRT6 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.

Dr. Peter Attia:
Right. So again, just to summarize that, that's 2012. We have this one transgenic mouse. You overexpress SIRT6, 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-Meier 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 SIRT, you are going to live longer.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
That tends to be completely independent of caloric restriction. That's the single thing I can say with the greatest confidence.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
And there is at least one transgenic strain of mice that if you get it to overexpress a different SIRT, SIRT6, but again, these are homologues throughout the species, so I don't think we need to get wrapped up in SIRT2 versus SIRT6. You will at least make the male mice live longer, but not the females.

Andrew Huberman:
What sorts of things are downstream of sirtuins? And that question translated to normal English is what is changing as a consequence-

Dr. Peter Attia:
Yeah. Why is this happening?

Andrew Huberman:
... of increasing-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... the sirtuin? 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, but is it something related to glucose metabolism? Is it something related to clearance of senescent cells? I'm just throwing out possibilities here.

Dr. Peter Attia:
Actually, you've hit two of the big three right off the top. So we believe that when sirtuins are activated, they're improving mitochondrial biogenesis. They are increasing DNA repair.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
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, so the soluble products of senescent cells. So in other words, those are all three good things. So you tamp down on senescent cells, you increase mitochondrial biogenesis, and you increase DNA repair. Those would be all great things to do, and we think that sirtuins are probably doing all of them.

Andrew Huberman:
This business of DNA repair and reducing 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?

Dr. Peter Attia:
Well, I think we know that as we age, it's just a stochastic process. 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 Chandel and Tim Ferriss. So the four of us just took a trip to Easter Island to see the birthplace of rapamycin. So it was kind of like vacation/science journey.

Andrew Huberman:
That's a nerdy vacation.

Dr. Peter Attia:
It was awesome. 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? So it's not just that cancer goes up with age, it goes up like that.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
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 the canonical problem with cancer is a genetic mutation that leads to two properties of a cell, the inability of the cell 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 metastasis. 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?

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
And 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 are aging, we are undergoing more DNA damage, 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 sirtuin needs to repair DNA, and that substrate is NAD. So again, remember at the outset, I said, look, 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, electron accept, ba ba ba ba ba. 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 sirtuins are 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 sirtuin activators. So what's the most famous sirtuin activator of all time? What is the heavyweight champion of sirtuin activators that has taken up 99% of the bandwidth in this space? It's a lovely little chemical called resveratrol. Okay, so resveratrol, 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 resveratrol increased lifespan So the thesis was resveratrol activates sirtuins. Sirtuin activation is important because of all the things we just said. It improves mitochondrial biogenesis, it suppresses senescent cells, and it enhances DNA repair. So if you have something that is such a potent activator of sirtuins 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 resveratrol and found that it did categorically nothing. In this one experiment that worked, the investigators took a bizarre mouse model where they force-fed it 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. So the mouse died prematurely because they couldn't breathe. And in that particular mouse model, resveratrol 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-

Andrew Huberman:
So this is resveratrol delivered orally?

Dr. Peter Attia:
Yes.

Andrew Huberman:
In the food?

Dr. Peter Attia:
Yes.

Andrew Huberman:
Very high doses.

Dr. Peter Attia:
Mega doses.

Andrew Huberman:
The equivalent of barrels of grape skin.

Dr. Peter Attia:
Exactly. Doses so high you could-- If you recall, we're both of 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, do the French live longer when they consume so much wine? And the answer was it's got to be the resveratrol. 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 resveratrol that were needed to produce this effect. But for whatever reason, there was an effect, which is if the thing that was going to kill you was your liver being so full of fat that it 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 great labs doing the experiments in triplicate, and when they did the resveratrol 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." And they did it, and nothing. There was no effect of resveratrol. And that result has been consistent across the board. So that's also a very important part of the story, which was if resveratrol was a sirtuin 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.

Andrew Huberman:
I'd like to take a quick break to let you know that the Huberman 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 Huberman 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.

Dr. Peter Attia:
So let's see. Let's just take stock of where we are in this story. We've got the whole yeast sirtuin situation, which is at least in some yeast, sirtuin overexpression lives longer. No evidence that that works through caloric restriction. Truly no evidence. That's been known for 20 years now.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
That paper was published in 2004, and that was a follow-up to papers that had been published in 2002, 1999, et cetera. Later on, you'd have the 2012 transgenic mouse study. So now the question is, okay-

Andrew Huberman:
How do you activate sirtuins?

Dr. Peter Attia:
How do you activate sirtuins?

Andrew Huberman:
Right.

Dr. Peter Attia:
Or 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 tissues. 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.

Andrew Huberman:
It's also interesting because keratinocytes in 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 sirtuins and NAD, then they simply die for whatever reason, or that it starts off very high on day one of generation, then tapers off quickly. But That's not the case, it sounds like.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
You know?

Dr. Peter Attia:
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 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 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.

Andrew Huberman:
What about neurons? You've got the same set of central nervous system neurons your entire life, and of course, some peripheral neurons as well.

Dr. Peter Attia:
Yeah, that's about it.

Andrew Huberman:
But there's some regeneration in the periphery-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... so 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 age?

Dr. Peter Attia:
In 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.

Andrew Huberman:
Explain the role of NADH for people.

Dr. Peter Attia:
NADH is the electron acceptor.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
So let's maybe take a step back of why are you and I sitting here talking and not dead?

Andrew Huberman:
Because we have enough NAD.

Dr. Peter Attia:
Right. What's going on, right?

Andrew Huberman:
Right.

Dr. Peter Attia:
You and I ate something at some point in the foreseeable past that contained chemical energy. So we ate something that was organic.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
So primarily fats and carbohydrates contain carbon–carbon bonds and carbon–hydrogen bonds.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
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 lion's 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 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 AMP, ADP, and ultimately make ATP. The finished product is water and carbon dioxide. So we eat, and we take that chemical energy in 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 turning the chemical energy back into electrical energy, and away we go. So yeah, this whole NAD, NADH thing it's as central 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.

Andrew Huberman:
And I would say a fair number of so-called anti-aging approaches are targeting the so-called reactive oxygen species, ROS-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... 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 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 aged eye, 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.

Dr. Peter Attia:
Mm.

Andrew Huberman:
Photoreceptors. How does this work? Well, 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 photoreceptors.

Dr. Peter Attia:
Mm.

Andrew Huberman:
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 and/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, or I will replace some NAD that's missing as I age in whatever cell type." Turns out that might not be so straightforward, right? I don't want to jump to supplementation just yet.

Dr. Peter Attia:
Yep.

Andrew Huberman:
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. We'll spell these out in a moment. And the 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 precursor to NMN. My understanding is that NMN is simply NR minus a phosphate group.

Dr. Peter Attia:
Yeah. And I'll take a step back from this first to say the following. Again, because this topic is so confusing, I think it's just worth reminding everybody of everything we've said and where it brings us, right?

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
So I'm not going to repeat the whole sirtuin thing. Let's just leave that alone. But we-

Andrew Huberman:
Because everything we're on right now is upstream of sirtuins.

Dr. Peter Attia:
Yeah. It's basically like once you establish that we think sirtuins matter, even though they don't work through caloric 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've figured out can activate sirtuins, like resveratrol, we don't seem to have things that we can give you that activate sirtuins. We're now onto the next part of the story, which is, okay, sirtuins matter, they don't seem to matter. We think sirtuins matter because of a few of these overexpression experiments. And we're making a big leap that because they mattered in yeast, they're going to matter in us. That's a huge leap for which there's zero evidence.

Andrew Huberman:
Right. And I'm only leaping further to this discussion about how to increase NAD because-

Dr. Peter Attia:
That's right

Andrew Huberman:
... I know that's in the back of people's minds.

Dr. Peter Attia:
That's right.

Andrew Huberman:
We're not going to double-click here just yet. I just want to frame that up.

Dr. Peter Attia:
Right, so why are we doing this? Yeah.

Andrew Huberman:
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-

Dr. Peter Attia:
Yeah, and the reason I'm-

Andrew Huberman:
... or infuse NAD or none of the above.

Dr. Peter Attia:
And the reason I'm being such a hardass about this, Andrew, is I spend so much time fielding questions on this that I realize we just have to talk about this in the most detailed fashion possible-

Andrew Huberman:
I agree

Dr. Peter Attia:
... so that people understand why.

Andrew Huberman:
Right.

Dr. Peter Attia:
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 without the discomfort of thought. Right? So we need to-- this is 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.

Andrew Huberman:
I would say scientific justification for longevity. I'll go on record now saying that I take NMN.

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
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.

Dr. Peter Attia:
And we should talk about both health span and lifespan benefits when we get to that part. But 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. But 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 them 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 sirtuin thing. Leap of faith number two is the caloric restriction thing. Leap of faith number three is this matters in our species, the species of interest. Leap of faith four is the whole sirtuin 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-

Andrew Huberman:
Mm-hmm

Dr. Peter Attia:
... 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.

Andrew Huberman:
So a couple of kind of practical notes. I've taken NR in capsule form, I've taken NMN, typically in powdered form where I put it sublingually-

Dr. Peter Attia:
Mm-hmm

Andrew Huberman:
... under the tongue. My understanding is that-

Dr. Peter Attia:
Have you done intravenous NAD?

Andrew Huberman:
I sure have, and what I-

Dr. Peter Attia:
Did you experience a niacin flush?

Andrew Huberman:
No. I took NAD as an infusion. I've probably done it five or six times, and for the first 10 minutes of the infusion, you feel like somebody's stepping on your chest with a boot. Your legs cramp up. You feel nauseous. I did not take the anti-nausea 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.

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
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. You're like, "This is awful." Every noise in the room is a bit too loud during that first 10 minutes. And then-

Dr. Peter Attia:
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?

Andrew Huberman:
Oh my goodness.

Dr. Peter Attia:
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?" Like, the fact that something feels so awful shouldn't be used as an explanation for why it's doing good physiologically.

Andrew Huberman:
Right. 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-nausea meds. For instance, you can slow the infusion.

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
That's the typical way. People will put it in over the course of several hours, anywhere from three hours to as brief as 30 minutes is kind of the record that I've heard about for 500 milligrams of NAD. If you put 1,000 milligrams in there, obviously it's more painful and you have to... Anyway, there are a bunch of practical considerations. You feel, now maybe it's placebo, but one feels quite good afterward. So as soon as the drip is done, you feel better than you did prior to the drip.

Dr. Peter Attia:
How do you feel if you just receive an IV infusion of the same volume?

Andrew Huberman:
I've done that because I've received saline drips.

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
You also feel pretty good.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
It's hard to-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... disentangle these things. And typically they'll put other things in the bag, glutathione, some vitamin C. They tend to sell these as kits. I decided to try it.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
It seemed fine. I did it when traveling. I don't know, maybe I'm due for another one soon. But 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, and I do feel an increase in energy, and I take it first thing in the morning.

Dr. Peter Attia:
At what dose?

Andrew Huberman:
One and a half grams. 1,500 milligrams. So-

Dr. Peter Attia:
By the way, if you translate the doses that they give mice in the studies where they're testing the efficacy, are typically on the order of 500 to 1,000 milligrams per kilogram.

Andrew Huberman:
Whoa.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
I'm 100 kilograms.

Dr. Peter Attia:
Yep.

Andrew Huberman:
Whoa. Okay.

Dr. Peter Attia:
So picture that the next time you're giving yourself some NAD or NR.

Andrew Huberman:
I'm not even approaching that-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... at all. Well, it's clear to me, based on my read of the data, that NR can cross the cell membrane directly.

Dr. Peter Attia:
Directly, very easily. There's no obstacle to NR getting into cells.

Andrew Huberman:
Okay. And NMN cannot because of that extra phosphate group, so that if you take it sublingually or you ingest it orally, it goes into the gut, the phosphate group is cleaved, and because of that, the argument is that if one were to compare the benefits of taking NR versus NMN, there are 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.

Dr. Peter Attia:
It's just a commercial issue.

Andrew Huberman:
It starts becoming a battle between commercial sources and-

Dr. Peter Attia:
Yeah. This is-

Andrew Huberman:
And I don't dispute that NR makes more sense as a precursor, especially at dosages of 300 to 600 milligrams versus 1,500 milligrams, but I've opted to take sublingual NMN mostly based on cost. NR at the dosages people recommend is quite expensive.

Dr. Peter Attia:
Imagine you had to take it at the mouse doses.

Andrew Huberman:
Right.

Dr. Peter Attia:
You'd be spending about 300 bucks a day.

Andrew Huberman:
Right. It's not feasible. 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? It's very unclear. I think what has not been done, as far as I know, is to compare orally 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 note captions. But I guess this gets down to the question of how many people are taking oral NR or NMN, or are taking NAD infusions, which by the way, are quite expensive.

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
Anywhere from $300 to $1,000 a drip. That's pretty expensive.

Dr. Peter Attia:
Think about that.

Andrew Huberman:
What benefits are they getting?

Dr. Peter Attia:
Just think about that, right?

Andrew Huberman:
What are they getting out of this?

Dr. Peter Attia:
Yeah.

Andrew Huberman:
What are they getting? Is it an acute increase in NAD that what? That causes them to live, what? A week longer? We have no idea.

Dr. Peter Attia:
Well, so let's try to use data to answer the question, right? So this is exactly the thing that the ITP, the Interventions Testing Program, was designed to test. And 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. 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 a notable failure is NR.

Andrew Huberman:
Hmm.

Dr. Peter Attia:
NR was tested, and I believe it was tested at a very robust dose, either 500 or 1,000 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. Rapamycin. When you give rapamycin, the first time they did it, because they had a hard time formulating the rapamycin, they weren't able to start it until the mice were 21 months old, which is very old for a mouse. That'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 redid the experiment, and they gave it earlier. It worked. Canagliflozin, as I mentioned, which is an SGLT2 inhibitor, it worked. Acarbose, a drug that inhibits glucose absorption, worked, and interestingly, didn't require weight loss. So the thesis behind giving acarbose to the mice was, it's a caloric restriction mimetic, a CR mimetic, and it worked, 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, canagliflozin. SGLT2 inhibitors cause you to pee out more glucose. Acarbose prevents you from absorbing it 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. Metformin failed, by the way.

Andrew Huberman:
And the ITP is specifically for offsetting aging. Is that right?

Dr. Peter Attia:
It is lifespan, but it also looks at some measures of healthspan. But it is the gold standard for lifespan, yeah.

Andrew Huberman:
Because my understanding is that there are some studies that have explored the role of supplemented NR, maybe NMN as well-

Dr. Peter Attia:
Yep

Andrew Huberman:
... but certainly supplemented NR, for sake of lowering inflammation to offset some of the negative effects of time zone shift, alcohol. I have a few others listed here. Overnutrition.

Dr. Peter Attia:
Yeah. So let's talk about that. So, in 20-- I don't remember what year it was. It was somewhat recent. A study was published looking at NR with something called pterostilbene. So pterostilbene is believed to be a sirtuin activator like resveratrol. So a commercially available product called Basis, and it was tested. It was a three-arm study in humans. Roughly 30 people per arm, so decent size study, right? This is a big study. So you take 100 people, more or less, with fatty liver disease. Now, this was documented 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 steatosis that you have fatty liver disease. Now, of course, this is not a digital thing. It's an analog, right? 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 the back of your mind, the threshold at which we would say you're in the danger zone is once you hit 5%. So this study randomized 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 1,000. I don't recall. They looked at many things, right? So they looked at all sorts of biomarkers. And the primary outcome for this 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 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 a way to go and parse the data. And they did find 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 have fatty liver disease. Well, they had people anywhere from 10% to 40%.

Andrew Huberman:
Wow.

Dr. Peter Attia:
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 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. So again, 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've just found the solution to NAFLD." The second study that people point to a lot was 2021 or 2022. This came out of a group at Wash U, 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-

Andrew Huberman:
Mm-hmm

Dr. Peter Attia:
... 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-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. And just to sort of figure out how insignificant it was, I went back and actually looked at some of the red light data.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
Because there's an interesting study that shines red light on a person's back and then does an oral glucose tolerance test.

Andrew Huberman:
Oh, yeah.

Dr. Peter Attia:
Yeah, and you can actually reduce postprandial glucose by 8%.

Andrew Huberman:
Is that meaningful?

Dr. Peter Attia:
Not really. Not in this patient population, because these people were all pre-diabetic, and they had very high glucose. So it was another example of something that was statistically significant but not clinically significant. And the same thing was true in this study, right? 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 sub-sub-subset of 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 modest increase in glucose disposal. But there's a saying in my mind, Andrew, which is, if you have to resort to really interesting statistical machinations to see something, there probably isn't something very interesting there.

Andrew Huberman:
Right. I totally agree. And I think, at this point, I'm questioning whether or not I'm wasting my money taking NMN or NR.

Dr. Peter Attia:
Well, let me tell you one positive thing about this.

Andrew Huberman:
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 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.

Dr. Peter Attia:
Yeah. So it's generally regarded as safe. It has an FDA designation of GRAS, which means it is not regulated.

Andrew Huberman:
Generally recognized as safe.

Dr. Peter Attia:
Right. And so that means anybody can sell it. The FDA will have no oversight. 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 honestly, Andrew, I think the whole NMN, NR debate is irrelevant.

Andrew Huberman:
Hmm.

Dr. Peter Attia:
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.

Andrew Huberman:
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-

Dr. Peter Attia:
Okay. So-

Andrew Huberman:
... for sake of lifespan and/or healthspan?

Dr. Peter Attia:
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 gave people NMN and looked at a shotgun approach of many different things, like did it change LDL cholesterol, HDL cholesterol, 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 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 with-- 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.

Andrew Huberman:
It's 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.

Dr. Peter Attia:
So this one study found somewhere between a 60 and 80% reduction in basal cell and squamous cell carcinomas. Now, it found no difference in melanomas. So again, you know this because you just did a podcast on this. Melanoma is the skin cancer that kills you, but that's not to say that squamous cell and basal cell carcinomas aren't problematic. They can be very 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.

Andrew Huberman:
And I should say that basal and squamous cell carcinomas are very, very common.

Dr. Peter Attia:
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 personally, that's an experiment I would like to see repeated, because if indeed NR and/or NMN 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?

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
I've never had a sunburn in my life. I don't work outside, so it wouldn't matter to me, but there are a lot of people for whom either their skin color makes them more susceptible or their pastimes or frankly, their line of work makes them more susceptible. Maybe there is a case to be made for it there.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
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, 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? It was skin. So there's a part of me that wonders, is the reason that the only place we see a really good signal potentially for NR and NMN supplementation is in a skin cancer?

Andrew Huberman:
Mm.

Dr. Peter Attia:
Although it's not melanoma, which is the one we'd really want to see. If this reduced the risk of melanoma, I would take it, right?

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
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 the first thought that crossed my mind when I came across that literature was, hmm, I wonder if the enormous reduction in tissue NAD in this particular tissue explains why maybe there is a benefit to it.

Andrew Huberman:
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 a disposable income could do that, drip it in slower, 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 NR or taking NMN.

Dr. Peter Attia:
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?

Andrew Huberman:
Significantly greater.

Dr. Peter Attia:
Interesting. All right. Just noted. And less expensive, but yeah.

Andrew Huberman:
Right. You could also weight train for the first hour and then enjoy some food afterwards.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
Layne Norton taught me that there are data showing that exercise, in particular, resistance training, improves the rewarding properties of food, makes food taste better, which we've all kind of intuitively experienced. So you spend the first hour working out-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... second hour eating.

Dr. Peter Attia:
If you had an extra two hours a week-

Andrew Huberman:
Right

Dr. Peter Attia:
... to choose between paying 1,000 bucks or 700 bucks for an NAD infusion or lift weights for an hour, go for a half an hour walk, and listen to your favorite podcast, like the Huberman Lab, and then eat a meal for a half an hour. I can just think of so many better ways to spend time and money. But anyway, let's move on. Not digress.

Andrew Huberman:
Okay. Well, I'm going to pull a little bit from marketing text here, but I trust these. Showing-

Dr. Peter Attia:
Really?

Andrew Huberman:
Yeah.

Dr. Peter Attia:
Okay.

Andrew Huberman:
Yeah, I do, because they have citations to support them, and we can include the citations.

Dr. Peter Attia:
Okay.

Andrew Huberman:
I'm not going to say these are not linchpin arguments for doing one thing or the other, but we already established that NR and NMN are quite similar, except for the presence of a phosphate group on NR that gets cleaved off.

Dr. Peter Attia:
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. So this is all a big sort of shell game of how do you get NAD 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 a precursor. Let's pause at that.

Andrew Huberman:
Or NR.

Dr. Peter Attia:
Yeah. That's what I mean-

Andrew Huberman:
Yeah

Dr. Peter Attia:
... a precursor.

Andrew Huberman:
Yeah, okay.

Dr. Peter Attia:
So.

Andrew Huberman:
Great. Well, then you took the words right out of the-

Dr. Peter Attia:
That's right

Andrew Huberman:
... data I was going to refer to.

Dr. Peter Attia:
That's right.

Andrew Huberman:
Because I asked a few folks that helped develop some of the NR supplements, what are the data-

Dr. Peter Attia:
Yep

Andrew Huberman:
... that support the use of NR for increasing NAD?

Dr. Peter Attia:
And I-

Andrew Huberman:
And they say, "NR can cross the cell membrane directly-

Dr. Peter Attia:
That's right

Andrew Huberman:
... NMN cannot." Okay, but-

Dr. Peter Attia:
Yep. Doesn't matter

Andrew Huberman:
... you can just cleave the phosphate group.

Dr. Peter Attia:
Because NMN-

Andrew Huberman:
Yeah, right. Exactly.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
NR, this is not my claim, but they claim that NR is "25% more effective than NMN in raising whole blood NAD levels." But I'm guessing that's-

Dr. Peter Attia:
That's probably dose to dose

Andrew Huberman:
... milligram to milligram.

Dr. Peter Attia:
Exactly.

Andrew Huberman:
Right. Okay.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
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 that's really-

Dr. Peter Attia:
Specifically cells like skeletal muscles, right? I think based on Josh Rabinowitz's work, and I also had Josh Rabinowitz on the podcast to talk about this, and I trust Josh on this much more than I would trust any marketing material-

Andrew Huberman:
Sure

Dr. Peter Attia:
... because he doesn't have a dog in this fight, right? He just does the work. And, what Josh's research showed, which is basically NAD flux research, has demonstrated that, look, the liver is probably the place of greatest uptake-

Andrew Huberman:
Mm

Dr. Peter Attia:
... in addition to blood, and that's about all we know. It's not clear how much of this is getting into other cells. So, the rest of it is just I think rearranging deckchairs on a Titanic as far as 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.

Andrew Huberman:
Right. 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 amounts of money to do it.

Dr. Peter Attia:
Well, I think the bigger issue is you can't do the longevity experiment in humans, and I'm sure that these companies that sell this, and 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 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. I don't know any of them.

Andrew Huberman:
There were probably about 30 to 50 prior to this FDA ruling-

Dr. Peter Attia:
Okay

Andrew Huberman:
... which is kind of an interesting situation in its own right.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
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 N-acetylcysteine-

Dr. Peter Attia:
That was more of a lobbying effort, though-

Andrew Huberman:
Right

Dr. Peter Attia:
... I think.

Andrew Huberman:
Right.

Dr. Peter Attia:
I don't think actually that was a scientific decision. I think that was more of a lobbying decision-

Andrew Huberman:
Right

Dr. Peter Attia:
... from an IP protection standpoint.

Andrew Huberman:
Right. And this had happened prior for N-acetylcysteine-

Dr. Peter Attia:
Yep

Andrew Huberman:
... NAC, which some people take. It's a mucolytic.

Dr. Peter Attia:
Yep.

Andrew Huberman:
It's actually a great decongestant-

Dr. Peter Attia:
Yep

Andrew Huberman:
... if you're congested, and it increases glutathione. That's my understanding. And I believe, somebody check me on this-

Dr. Peter Attia:
Does it decrease or increase glutathione?

Andrew Huberman:
Increases glutathione-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... is my understanding.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
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-

Dr. Peter Attia:
Mm

Andrew Huberman:
... 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.

Dr. Peter Attia:
Yeah. Again, I think the strongest argument I could make based on the data would be potentially on the basal cell and squamous cell carcinoma risk reduction, if indeed those results are reproducible.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
Again, that would be justification, again, for the right individual. Wouldn't be a justification for me, might be a justification for somebody. But really the rest of it is, 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? If it's a drug, you have to have an indication. You can't sell a drug without rigorous trials that demonstrate both safety and efficacy. I do think NR and NMN are probably safe. There has been some-

Andrew Huberman:
Mm-hmm

Dr. Peter Attia:
... voice around the idea that NR could increase the risk of cancer.

Andrew Huberman:
Right. And the experts in this area, like Charles Brenner, have pushed back hard on that.

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
Arguing that the studies were not done well, as I recall.

Dr. Peter Attia:
I think that's probably fair. I don't think there's been a well-done study in this entire field is part of the problem, right? And that's probably too harsh a statement, but this is not a field that's necessarily lending itself to the rigor that you would in pharmacotherapy. And you mentioned Charles Brenner, I think Charles does good work.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
Right?

Andrew Huberman:
And he works on many things, not just this.

Dr. Peter Attia:
Yeah. And by the way, I don't hear Charles out there saying that NR increases lifespan.

Andrew Huberman:
No. In fact, I don't want to quote him at all, but I think he would argue that sirtuins, 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.

Dr. Peter Attia:
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 is no meaningful, logical connection between the relationship of sirtuins, caloric restriction, and NR. That's a shell game that is empty. And you're right. 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. Nobody's going to make money selling rapamycin.

Andrew Huberman:
Because it's so cheap?

Dr. Peter Attia:
Well, yeah, and it's actually not cheap, but it's a drug that is off patent.

Andrew Huberman:
Oh, okay.

Dr. Peter Attia:
So this is a drug that was approved by the FDA 25 years ago.

Andrew Huberman:
So generic forms are inexpensive enough that no big-

Dr. Peter Attia:
Believe it or not, they're not. This is the irony of it. So Rapamune is the brand drug that was initially approved in 1999, and today, if you go and buy rapamycin, you're going to not buy Rapamune, you're going to probably buy generic sirolimus 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-

Andrew Huberman:
Yeah

Dr. Peter Attia:
... is probably what I spend on rapamycin. That ain't cheap.

Andrew Huberman:
No.

Dr. Peter Attia:
I mean, it's cheaper than some things I take, but it's not cheap. But the point is nobody has a commercial interest in rapamycin, right? It's sort of an irrelevant drug. But the interest is scientific, right? And the commercial interest is in what we call rapalogs, 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 I think Joan Mannick and Lloyd Clickstein, when they published that paper in 2014 using everolimus, where they took a group of 65-year-olds and randomized them to either a placebo or different doses and dosing schedules of everolimus, found an enhanced immunity in response to an influenza vaccine. Which again, 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."

Andrew Huberman:
Yeah.

Dr. Peter Attia:
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 mTOR 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.

Andrew Huberman:
Right. You're 50, right? 50 years old?

Dr. Peter Attia:
51.

Andrew Huberman:
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?

Dr. Peter Attia:
Six.

Andrew Huberman:
Has contributed to your current state or vigor?

Dr. Peter Attia:
Zero idea.

Andrew Huberman:
This is my opportunity to ask about your belief or lack of belief in biological aging tests. Because if somebody's 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.

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
And people love this stuff.

Dr. Peter Attia:
Love them.

Andrew Huberman:
They love them. Who wouldn't want to see that they are 51 years old, but their biological age is 37?

Dr. Peter Attia:
I just did a movement test the other day. So it's a very fancy camera system where it's got a million cameras on you, and you go through this whole exercise. How high can you jump? How far can you throw? It was awesome. And then it gives you a movement age.

Andrew Huberman:
Hmm.

Dr. Peter Attia:
Andrew, I was 22.

Andrew Huberman:
I believe it.

Dr. Peter Attia:
I should feel amazing. Do you actually think I move like a 22-year-old? Are you freaking kidding me?

Andrew Huberman:
No, you look-

Dr. Peter Attia:
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. Look, there's probably something to be said if I do that and I come out at 22 as I did versus 92.

Andrew Huberman:
Sure.

Dr. Peter Attia:
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 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.

Andrew Huberman:
Right.

Dr. Peter Attia:
So how old are you chronologically?

Andrew Huberman:
I turn 49 in six weeks.

Dr. Peter Attia:
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-

Andrew Huberman:
Some might want to hear that I'm going to be taken out soon.

Dr. Peter Attia:
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. But 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.

Andrew Huberman:
Okay. Well, I bought that chart, my life in weeks.

Dr. Peter Attia:
Yes.

Andrew Huberman:
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.

Dr. Peter Attia:
Great. That's fine.

Andrew Huberman:
And then I have little lines on the side-

Dr. Peter Attia:
Mm-hmm

Andrew Huberman:
... of how much vigor I felt, and just overall wellness, completely subjective, of zero being completely cratered, near death, to 10, as best I've ever felt.

Dr. Peter Attia:
But you make that note every how often?

Andrew Huberman:
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 Fong Lynn recently, and 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. 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.

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
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, wellbeing, internal peace, et cetera, 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 wellbeing than I do now. And the question is-

Dr. Peter Attia:
Maybe

Andrew Huberman:
... will I be able to?

Dr. Peter Attia:
Yeah, maybe. I might take a slightly 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-

Andrew Huberman:
Yeah, the chart

Dr. Peter Attia:
... really interesting.

Andrew Huberman:
Yeah.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
Because I think the chart is great.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
I think the chart, more than any supplement for longevity, 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.

Dr. Peter Attia:
Yeah. Well, 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 actuarial point. 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 biologic age.

Andrew Huberman:
That's it? That's all I got?

Dr. Peter Attia:
Yeah, because you're going to live to, whatever, 88 to 91 or something. I'm making that up. But that's okay.

Andrew Huberman:
I better get cracking on some stuff.

Dr. Peter Attia:
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, Andrew, have 60 to 65 more years of life based on a fact that your biologic clock says you're 25? Do you believe that?

Andrew Huberman:
No. No way.

Dr. Peter Attia:
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, "Well, I'm actually 60 years old chronologically, but my biologic age is 35," my response is, "Who cares?" truthfully. Is that a good thing? Yes, probably. But is it tangibly, measurably meaningful to have a biologic age of 35 versus 40 versus 30 if you're 60? 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. Your triglycerides are pretty noisy unless I do something very important, which is standardize it by how long it's been since your last meal. If you ask me right now what my trigs are, I have no earthly idea because I probably ate three hours ago, and I don't even remember what I ate, how much fat was in it, how much carbohydrate was in 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 8 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 trigs today, 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 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 as sort of a dirty little secret is how difficult it is to measure and to sequence the epigenome, right? 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 epigenome on these things.

Andrew Huberman:
Hmm.

Dr. Peter Attia:
So they were not able to accurately say. 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 a genome. So again, it's so much noise in this system, and I just think it creates a little bit of a distraction for people, truthfully.

Andrew Huberman:
Do you avoid going through the non-traditional scanner at the airport, the one that might use higher levels of radiation? No.

Dr. Peter Attia:
No.

Andrew Huberman:
Do you think about how many flights you take as a-

Dr. Peter Attia:
No

Andrew Huberman:
... source of radiation?

Dr. Peter Attia:
No.

Andrew Huberman:
Do you-

Dr. Peter Attia:
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 millisieverts of radiation a year. Okay, so that number doesn't mean anything to somebody, so let me give people a sense of what that means. So how many millisieverts of radiation do you and I receive because we both live at sea level? So just ambient radiation, living at sea level is one millisievert a year. Okay, so we just chewed 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 millisieverts a year. Okay. What if you had a CT scan of your chest, a CT angiogram? Well, it 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 three millisieverts a year. If you got it done at a place that's sort of average, might be 10 to 15 millisieverts, 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 DEXA scan, by the way, you can't even measure how many millisieverts you're getting. So a DEXA scan is less radiation than a cross-country flight. So it's 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 incessantly 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 millisieverts a year. And yet interestingly, they're not at an increased risk for cancer. Now, 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.

Andrew Huberman:
Well, I think you just relieved a lot of people of some unnecessary concern.

Dr. Peter Attia:
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.

Andrew Huberman:
Yeah. Grip strength, jumping, cognitive function. 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. If I just look historically.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
Yeah. Who knows, right? But my sense is that I'll live to be 95 if, barring, a bullet, bus, or cancer.

Dr. Peter Attia:
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 and I are only a couple of 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.

Andrew Huberman:
50s to 70s.

Dr. Peter Attia:
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.

Andrew Huberman:
Mm.

Dr. Peter Attia:
I think if you and I are being brutally honest, we're kind of half the men we used to be. And again, that just means like, look, 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.

Andrew Huberman:
Yeah. A short nap would reset me near completely.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
I got more colds and flus in that time because I wasn't taking such good care of, but then again, I was indoors more, so it's an imperfect experiment, but you're right.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
I think that as I've approached 50, I need to do more.

Dr. Peter Attia:
You need to do more self-care.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
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. In other words, we're just not quite as resilient as we used to be.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
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. There's no way I could go back to that level of sleep deprivation for a month, let alone five years. So, that's just a fact of aging, I think. 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 have to stay in the game because compounding makes such a difference, right? So, 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 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 Galpin has talked a lot about this, the atrophy of the type two muscle fibers. The 2A 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. I mean, I measured this.

Andrew Huberman:
Well, mine was never very good, so I-

Dr. Peter Attia:
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, it's literally 50%, and that's one of the purest tests of power. So power's going down, strength is going down, but not as much. 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 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.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
Because 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.

Andrew Huberman:
What about energy? Sorry to interrupt.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
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's sleep-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... seven and a half hours, waking up same time, more or less, 6:30, 7:00 a.m. 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?" And I was like, "I don't know. It's a great question." Now, unfortunately, he died of pancreatic cancer.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
So there may have been other things going on, but that was prior to the cancer, at least as far as I 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.

Dr. Peter Attia:
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.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
Like, their inability to sit still, their kinetic desire to just-- I remember once we were 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.

Andrew Huberman:
You'd be so sore the next day.

Dr. Peter Attia:
But it just wouldn't occur to me to ever run unless being chased, right? Like, we now live a life like I think our ancestors did, which was, 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, 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 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.

Andrew Huberman:
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 these days.

Dr. Peter Attia:
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 geroprotective 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.

Andrew Huberman:
Yeah, they do.

Dr. Peter Attia:
Especially if you're an adult. Like, especially if you have a real life. 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, 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.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
And for many people, certainly for me, food is the hardest of these all, right? If left to my own devices, I'd eat freaking Froot Loops all day. Like, I love Froot Loops, right?

Andrew Huberman:
Interesting. By way of contrast, the food part is easy for me. I like healthy food and-

Dr. Peter Attia:
Oh, I like healthy food. I just like all food.

Andrew Huberman:
Okay.

Dr. Peter Attia:
There's nothing I don't like.

Andrew Huberman:
Yeah, I don't like unhealthy food.

Dr. Peter Attia:
Oh, I do.

Andrew Huberman:
I've weaned myself off it. I never really liked it that much. 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.

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
I'm a weirdo 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 deplete us. Because I think one of your major sort of calls to the public has been to move more-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... for sake of their health span and lifespan. But because of the time investment that it takes to work out in a gym 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 about-

Dr. Peter Attia:
Absolutely

Andrew Huberman:
... 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 9:00 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-

Dr. Peter Attia:
Mm

Andrew Huberman:
... 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.

Dr. Peter Attia:
Do you notice a seasonal change in that? Do you experience it more or less in one season or the other?

Andrew Huberman:
I haven't thought about it that much, but not so much. Not so much. And I wonder whether folks like our friend Jocko Willink are able to do so much. He has so much vigor-

Dr. Peter Attia:
Mm-hmm

Andrew Huberman:
... that guy, in part because he basically exercises at just after the lowest temperature phase of the circadian rhythm, and he uses exercise-

Dr. Peter Attia:
Mm

Andrew Huberman:
... presumably to drive himself out of that and get that temperature increase that's the consequence of waking. But in his case, he's waking up so early, 4:30 is when he starts those workouts. So it's something for people to play with. It's something that I don't think gets discussed enough, which is, yes, you should exercise, do resistance training, do cardiovascular training, but play with the timing of those and see how-

Dr. Peter Attia:
Mm

Andrew Huberman:
... at a given intensity, it impacts your energy levels for the remainder of the day. 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 spending money on something that sure will make you live longer, but then you're depleted and you can't do cognitive work.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
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 5:00 a.m. runners. There's something about early morning exercise. And my good friend Eddie Chang, who's the chair of neurosurgery at UCSF, he's been on this podcast. I've known him since we were seven years old. He's an early morning exerciser, and then he's got tons of energy all day.

Dr. Peter Attia:
What about the reverse causality there?

Andrew Huberman:
Sure.

Dr. Peter Attia:
Do you think it's possible that they have a system of high energy that makes Jocko who he is or makes these people who they are?

Andrew Huberman:
I don't doubt it.

Dr. Peter Attia:
And as a result of that, they're able to work out five o'clock in the morning.

Andrew Huberman:
Yeah. 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 up and start working out really early, I have more energy all day long. Sometimes I still require-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... a brief nap, but it's a pretty striking effect as compared to the 10:00 a.m. workout effect.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
So I've started setting a standard of trying to get my workout done before 9:00 a.m.

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
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. So let's quickly return to supplements. We, I think are converging on an answer about NR, NMN, and NAD, which is you don't take them.

Dr. Peter Attia:
Correct.

Andrew Huberman:
I take NR and NMN 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? Rapamycin is a prescription drug only, right?

Dr. Peter Attia:
Mm-hmm.

Andrew Huberman:
So are there any over-the-counter things that you take that you would place into the lifespan category? Maybe they touch into healthspan as well. I'm happy to list off what I do, but what are your, let's just say top five, at least?

Dr. Peter Attia:
Well, I don't take that many, so top five would be a pretty exhaustive list. I think the other supplements that I take, I do take EPA and DHA.

Andrew Huberman:
In the form of liquid or capsule fish oil?

Dr. Peter Attia:
Capsules. Not because I have an affection for capsule over liquid. It's just going to increase my compliance. I've done both, and I've noticed when I was taking liquid, because you're storing it in the fridge, it's just one more step removed, and I was just less likely to remember to take it twice a day. I take theracumin, and there's some reasonable evidence in MCI patients that theracumin improves cognitive function. So I think there's a relatively low downside to the hypothesis that theracumin may preserve cognitive function. Again, I wouldn't put that in the category of beat the table for it, right? I think it's just reasonable evidence. 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.

Andrew Huberman:
How much do you take?

Dr. Peter Attia:
I take 5,000 IU.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
And that takes me from a level of 30-ish to a level of 50-ish.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
And there's a lot of debate about how high vitamin D levels should be. That's a whole separate podcast. We could waste time on that in 10 years.

Andrew Huberman:
Great.

Dr. Peter Attia:
Yeah. My appetite to talk about that one. Let me think, what else do I take? Oh, I do take methylfolate and methyl B12. And again, the rationale 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, is it causal? Now, 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 and asymmetric dimethylarginine. Have you heard of these things, SDMA and ADMA? So ADMA and SDMA regulate nitric oxide synthase, and homocysteine impairs their clearance, and therefore, when you have high levels of homocysteine, it results ultimately in impaired nitric oxide synthase, and therefore lower nitric oxide. So this has been proposed as at least one mechanism by which homocysteine might negatively impact vascular disease. And we also know, by the way, that ADMA and SDMA are cleared by the kidneys, and therefore this is also proposed as one of the mechanisms by which impaired kidney function impacts vascular health. Because that's a known, right? If your kidneys don't work well, your risk of 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 methylfolate and methyl B12, you're going to lower homocysteine. That's abundantly clear. So the thinking is that that might actually lower ADMA, SDMA, and raise nitric oxide synthase. Again, relatively low cost, low risk thing to take at modest doses. There's probably some evidence that over-supplementing vitamin B is problematic, especially B6. So I don't-

Andrew Huberman:
Because of peripheral nerve damage?

Dr. Peter Attia:
Exactly.

Andrew Huberman:
Yeah.

Dr. Peter Attia:
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. Oh, I take magnesium L-threonate and ashwagandha for sleep.

Andrew Huberman:
Mm-hmm.

Dr. Peter Attia:
I take Slow-Mag, which is just a magnesium chloride slow-releasing version of magnesium, and I take magnesium oxide. So I take magnesium in three forms. So I'm long magnesium.

Andrew Huberman:
You're carpet bombing with magnesium.

Dr. Peter Attia:
Yeah. I'm big on magnesium, right?

Andrew Huberman:
Yeah.

Dr. Peter Attia:
Great for bowel function. I don't know the last time I had a cramp in my life. 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 electrolytes. I take LMNT, which I should disclose I'm an investor in that company. So I drink an LMNT a day. I take creatine monohydrate, five grams a day. I take AG most mornings. Oh, and I take Pendulum, the probiotic.

Andrew Huberman:
Got it.

Dr. Peter Attia:
Yep. As far as I know, there's no other probiotic that has any meaningful effect on the body outside of Pendulum, right? 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. So you have to have something anaerobic. So Akkermansia, which works through the GLP-1 butyrate pathway, is anaerobic, and Pendulum's the only company that can make it. I have no affiliation with this company. I think you should have the CEO, Colleen Cutcliffe, on your show. She's an actual scientist, and she's fantastic. And it's a really interesting story how they developed 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 pharma 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 Akkermansia.

Andrew Huberman:
Okay.

Dr. Peter Attia:
And I think that's the list.

Andrew Huberman:
Okay.

Dr. Peter Attia:
Yeah.

Andrew Huberman:
I'll try and move through my list pretty quickly. I may miss one or two things, and I don't know, maybe we'll put the list someplace online and fill in any gaps. I definitely take AG, AG1. That's my typical ad read. I've been doing it since 2012. That's true. I 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. 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-

Dr. Peter Attia:
Mm-hmm

Andrew Huberman:
... that has that lemon flavoring, and I make sure I get above one gram per day of EPA.

Dr. Peter Attia:
Yep.

Andrew Huberman:
So that's usually a tablespoon, sometimes two tablespoons. I make sure that I get enough D3, typically from the dropper, 5,000 IU per day approximately, sometimes 3,000, sometimes 7,000. I kind of play around that. And I test my blood levels. I also take methyl B12, and I also take tongkat ali, so I take one capsule of that in the early part of the day. That has lowered my sex hormone binding globulin, freeing up a bit more testosterone. That's why I like it. And I take a couple of green tea capsules in the morning.

Dr. Peter Attia:
Oh, yeah.

Andrew Huberman:
I drink yerba mate. That's more of a stimulatory effect, 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 LMNT-

Dr. Peter Attia:
Mm-hmm

Andrew Huberman:
... as an electrolyte. So people are probably noticing this is all pretty basic. I take, in my case, 10 grams of creatine monohydrate per day. I sometimes forget to take it. That's why I take 10 grams. I'll sometimes miss a day.

Dr. Peter Attia:
Okay.

Andrew Huberman:
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 for 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 lisping for an entire episode of the Lex Fridman podcast that 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.

Dr. Peter Attia:
Hmm.

Andrew Huberman:
And then I felt like I needed to chew it, and it's a little too stimulatory for me.

Dr. Peter Attia:
Hmm.

Andrew Huberman:
Before sleep, I take magnesium threonate. I'm really bullish on magnesium as well. Apigenin, 50 milligrams, which is essentially chamomile extract, and theanine. And occasionally I'll take 900 milligrams of inositol also.

Dr. Peter Attia:
Hmm.

Andrew Huberman:
Or instead, kind of mix those up and around. And then I use a quality whey protein as a protein replacement, that kind of thing. And I've played around with various things like shilajit, and I'll sometimes get the sense that it's having an effect. But then I'll stop taking it for long periods of time. There are very few things that I've stayed with for long periods of time, and I basically just described what those are. 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 yerba mate and coffee. I've played around with caffeine tablets, taking 50 milligrams of caffeine in tablet form. I mention that only because it has a distinctly different feel than ingesting caffeine through liquid form. It feels stronger, 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, oh, 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 two cardio, rucking, 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-

Dr. Peter Attia:
If we believe TMAO matters.

Andrew Huberman:
Right. If you believe TMAO matters and-

Dr. Peter Attia:
I don't.

Andrew Huberman:
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-

Dr. Peter Attia:
Yeah

Andrew Huberman:
... 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, more than that. So I should say, because any discussion around supplements, I think is going to have people pricking 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, et cetera, 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.

Dr. Peter Attia:
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, theracumin, 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? Look, 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 iceberg. All this supplement bullshit that we just talked about is equivalent to were 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.

Andrew Huberman:
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 four. 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

Dr. Peter Attia:
Yeah, I would say the same. I don't remember who said this, but someone, maybe it was Nassim Taleb, said, "Don't tell me what you think, show me what's in your portfolio." Meaning people who pontificate about this stock versus that stock, he's like, assuming it was him that said this, he's 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 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 they're 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 could be doing this exercise again, and in the presence of new information, maybe I'm not taking rapamycin and maybe I am fistfuling NR and NMN. Possible. 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.

Andrew Huberman:
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.

Dr. Peter Attia:
In Austin.

Andrew Huberman:
Would love that. Thanks, Peter.

Dr. Peter Attia:
Thanks, man.

Andrew Huberman:
Thank you for joining me today for my discussion with Dr. Peter Attia. If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel. In addition, please subscribe to the podcast on both Spotify and Apple. That's a terrific zero-cost way to support us. In addition, you can leave us up to a five-star review on either Spotify or Apple. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. If you have questions for me or comments about the podcast or topics or guests that you'd like me to consider for the Huberman Lab podcast, please put those in the comments section on YouTube. I do read all the comments. If you're not already following me on social media, I am Huberman Lab on all social media platforms. So that's Instagram, X, formerly known as Twitter, Threads, LinkedIn, and Facebook. And on all those platforms, I discuss science and science-related tools, some of which overlaps with the content of the Huberman Lab podcast, other of which is distinct from the content on the Huberman Lab podcast. So again, it's Huberman Lab on all social media platforms. And if you haven't already subscribed to our Neural Network Newsletter, our Neural Network Newsletter is a zero-cost monthly newsletter that includes what we call protocols in the form of brief one to three-page PDFs on everything from neuroplasticity and learning, to optimizing your sleep, to improving dopamine regulation, to foundational fitness protocol that includes both resistance training and cardiovascular training. It details sets and reps. All of that and more is completely zero cost. You simply go to hubermanlab.com, go to the Menu tab, scroll down to Newsletter, and provide your email. And I should point out that we do not share your email with anybody. Thank you once again for joining me for today's discussion, all about NAD and longevity with Dr. Peter Attia. And last but certainly not least, thank you for your interest in science.