Dr. Peter Attia
Appearances
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So if you can't regulate yourself, it's very difficult to regulate the do's and don'ts. But even absent just length of life stuff, it impacts quality of life, which is this idea of healthspan as well.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I guess that's just my slightly different way to frame it, but it's a little bit more MISI in that we talk about the behaviors, the exogenous molecules that target diseases, the exogenous molecules that target aging.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I take a few, right? So I take some that are disease-specific, right? So I take a PCSK9 inhibitor, I take bampidoic 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 risrapamycin. And also the SGLT2 inhibitor, I think, is probably just broadly geroprotective.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And we can even talk about that a little bit in terms of the success of one of those molecules called kanagaflozin in the interventions testing program, the ITP, which I am sure we'll talk about in the context of NAD as well.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I take eight milligrams once a week for as long as I can tolerate it, but I usually have to take breaks. Why is that? I get these vicious aphthous ulcers, little mouth sores. Canker sores. Yes. About 10% of people get them. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
By virtue of these miserable side effects. Interesting. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Yeah. I mean, you know, 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 sort of looking at the molecular explanation for why RAPA works, although I find that to be quite convincing.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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, were the species of interest.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
It's very important to understand there are only two interventions, full stop, that have ever extended life across those four categories of eukaryotes. Caloric restriction. And rapamycin. Very important point, right?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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, I've never heard... 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, and maybe that's just a placebo effect.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Yeah, that's a good question, Andrew. I don't know. I don't think we know. We do know that there's one other really important readout we're waiting for, which is Matt Kaberlin'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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And again, I think those two will be really interesting, right? Because we have a ton of, we have just an overabundance of mouse data that are so reproducible and reproducible in really good mouse models. As you know, I'm sure from your work, the model you choose matters, right? In an ideal world, you want to use a mouse model that is
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
you know, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So now to be able to see this in a higher order mammal and ultimately in companion dogs, which is where Matt Caberlin is looking, I think that's gonna be really exciting. And I've often said to my patients, look, in 2026, I'm either gonna feel a lot more conviction about taking rapamycin and prescribing it to some of my patients, though, again, not most,
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
It is going to go on. Initially, there was insufficient funding to do the study in an adequate way. Then it turned out there was a shortfall of about $2.5 million. um, to do the, the study that Matt really wanted to do. And then actually a group of us raised that money for Matt and did that.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So, uh, me and a few of my patients and a couple of other folks came together and put the money in to close the gap. But yes, there has been, um, what, what, what, what did get pulled back by the NIH inexplicably and, um,
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Why we wouldn't want to know if this is something we should all be taking is kind of a mystery to me.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. It's possible NAD is in every single cell.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 500 and 600 pathways of it, utilize NAD as a cofactor. Meaning that it's not consumed in a chemical reaction, but rather it serves as an electron shuttle. So NAD and NADH basically play catch with electrons.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
If it's below 7 or above 7.8 on a 0 to 14 scale, we die, full stop. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. Yeah. And maybe we can go into this, but this is really where the story picks up.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 Dina Duval from UCSF on clotho, which is an amazing scientific story. And it's a great story because it shows how accidents can lead to great discoveries, right?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And then there was this one strain of mouse with this one knockout that died really, really quickly. And it developed like 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And he kind of went and figured out what was going on. And he figured out that there was a certain gene that he had hit that wasn't a sodium transporter and instead was this other gene. He named it clotho. So you had this one piece of evidence right now, which was if you knock out that gene, you kill an animal very quickly. Now, that doesn't mean it's a longevity gene.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Yeah, so that's how you can say, well, that's a longevity gene.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So let's go to the Sirtuin story. So it goes back to the late 90s. Matt Cabral, and again, this is amazing, right? So you have this guy who's like 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 yeast.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I think it was the W303 strain of yeast. And he overexpressed Sirtu. And lo and behold, the yeast lived longer. Now, a year later, someone else in the same lab took a different strain of yeast and calorically restricted them, and they also lived longer. I forget the name of that. I forget what that strain was. It was something 316. It was a different strain of yeast.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
That hypothesis sort of fell apart about four years later when Matt Caberlin, again, this time with Brian Kennedy, did another experiment in a different, yet a third strain of yeast that allowed them to test hypothesis because there was a problem with the story I just told.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 overexpressed SIR2, they lived longer. If you did both, they lived even longer. It was additive.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Again, further suggesting that overexpression of SIR2 and caloric restriction independently and separately extended lifespan. These are parallel pathways. They're parallel pathways. For reasons that honestly escape me, Andrew, there are still people who maintain that the benefit of sirtuin overexpression is through the caloric restriction pathway and vice versa. And that's wrong.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
My reading of the literature, in addition to every person I have talked to on this who works in the space, including Matt Kaberlin, 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,
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
There's relatively uniform agreement that caloric restriction extends life across the model systems we discussed. What about in humans? What about it specifically? Does it extend life?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I think there's very good reason to believe that if an individual constitutively consumed 25% fewer calories than they were meant to eat, their risk of cardiovascular disease, cancer, Alzheimer's disease would go down. The problem is what things go up. What does that do to your immune system? What does that do with respect to sarcopenia? What does that do to your risk of falling? Yeah, frailty.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Yeah, exactly. 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 wild, like 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So it's not always the case that caloric restriction extends life. And therefore, well, it's safe to say caloric restriction probably reduces the onset of chronic disease that might not translate to an all-cause mortality benefit based on those downsides. But all of that said,
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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- Chloric restriction. Right. Chloric restriction. We've got this thing, which for 50 years we've known has a signal that really says it's life extending.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And we've got this yeast where it works and this other yeast where sirtuin activation works. Oh, it's got to be sore. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Now, none of this gets to the question you raised yet. That's just all, 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? How do you activate a sirtuin?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 the male mice lived 10% to 15% longer. The female mice did not.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I don't remember, Andrew, to be honest with you. I'd have to go back and look at the paper. I don't know if it was muscle specific or whole body specific.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Right. So again, just to summarize that, that's 2012. We have this one transgenic mouse. You put SIRT6, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. that tends to be completely independent of caloric restriction. That's the single thing I can say with the greatest confidence.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 we don't have to get, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Actually, you've hit two of the big three right off the top. We believe that when sirtuins are activated, they're improving mitochondrial biogenesis. They are increasing DNA repair. So that's probably the biggest one. And by the way, that's sort of what brings us to the NAD story. And also reducing SASPs, right? So the soluble products of senescent cells.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So in other words, those are all three good things, right? 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Well, I mean, I think we know that as we age, it's just a stochastic process, right? Like given the ubiquity of DNA replication and the fidelity of the system, which is high, very high, but not perfect, there's going to be mistakes. Actually, this is an interesting question. So in 2016, I went to Easter Island with David Sabatini and Nav Chendal and Tim Ferriss.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 slash science journey. That's a nerdy vacation. It was awesome. And so just picture hiking around this incredible island, just talking about science all day.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. And I said, I'll offer two hypotheses, which is more compelling.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Is it simply that as we're aging, DNA replication, again, taking a step back for the listener, cancer is a genetic disease. Meaning, by definition, it is sort of the canonical problem with cancer is a genetic mutation that leads to two properties of a cell. The inability of the cell to control replication. So it interrupts cell signaling. So cells replicate but then don't know when to stop.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And then... the introduction of the capacity to spread, this property called metastases. Those are the two hallmarks of cancer. So we know that that only happens in the context of genetic mutations, but why does this happen later in life and not at the beginning of life with very few exceptions? And so the question is, is it because over time mutations compound?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. And the truth of it is, we didn't come up with an answer, but it's probably all of the above.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Most of what NAD is doing is operating as a cofactor for electron shuttling. That's the NAD, NADH, electron transport, electron accept, blah, blah, blah, blah, blah. Okay, not consuming NAD, just using it to pass electrons back and forth. But then over here we have this other category where we use NAD as a substrate. It gets broken down, and that's what the sirtuins are doing to repair DNA.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So the thesis was resveratrol activates sirtuins. Sirtuin activation is important because of all the things we just said, right? 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. So this is resveratrol delivered orally? Yes. In the food? Yes. Very high doses. Mega doses. The equivalent of barrels of grapes.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Exactly, like 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, right? 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Turns out that's not true at all because yeah, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 gonna live longer.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And by independent, I mean they're each doing the experiments independently, but they're in sync with doing the experiment, but they're doing it in triplicate. So you have three labs, three great labs doing the experiments in triplicate. And when they did the resveratrol experiment, and they did it in combination with the people who found the result of that study.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So they consulted these people and said, what dose should we give? And they said, do this, do this, do this. And they did it and nothing. There was no effective resveratrol. And that result has been consistent across the board. So that's also a very important part of the story, which was
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. That paper was published in 2004.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
How do you activate sirtuins? Well, yeah. Or more to the point, why don't we just give people NADs? 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
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
thought is, I wonder if it has to do with the fact that skin experiences the greatest decline in NAD.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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...
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
you know, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Explain the role of NADH for people. NADH is the electron acceptor. So let's maybe take a step back. Why are you and I sitting here talking and not dead? Because we have enough NAD. Right, right. What's going on, right? So you and I ate something at some point in the foreseeable past that contained chemical energy. So we ate something that was organic. So it had...
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So primarily fats and carbohydrates contain carbon-carbon bonds and carbon-hydrogen bonds. And those bonds contain a ton of energy. But how do we liberate the energy? So we break it all down into these constitutive molecules, namely glucose on the carbohydrate front and free fatty acids on the fat front.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And people have heard this term, it's called the electron transport chain. So there are these four complexes in the mitochondria. And there's an inner membrane and an outer membrane across which these mitochondrial, these large mitochondrial complexes reside.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So yeah, this whole NAD, NADH thing is like, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 what we now, everything we've said and where it brings us, right? So I'm not going to repeat the whole sirtuin thing. Let's just leave that alone.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 figured out can activate sirtuins, like resveratrol, we don't seem to have things that we can give you that activate sirtuins.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. Right.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And the reason I'm being such a hard ass about this, Andrew, is- I spend so much time fielding questions on this that I realize we just have to talk about this in the most detailed fashion possible so that people understand why. Because it is just too easy.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So we need to sort of, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And we should talk about both healthspan and lifespan benefits when we get to that part. But...
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 were 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
It would just break down in the gut into its constitutive products and then probably reform. But for the purpose of how people actually do this, they intravenously get NAD because it's not orally bioavailable. Or as you said, they orally take two precursors, NR and NMN. My personal view on this is there's not really much of a difference in what you do.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
In other words, at the end of the day, all of these things are generally going to increase NAD levels in the blood.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
My understanding is that- Have you done intravenous NAD? I sure have. Did you experience a niacin flush?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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? Oh, my goodness. 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?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Like the fact that something feels so awful shouldn't be used as an explanation for why it's doing good physiologically.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. Whoa. Yeah. I'm 100 kilograms. Yep. Well, okay. So picture that the next time you're giving yourself some NAD or NR.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Imagine you had to take it at the mouse doses, right?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. What is the next best thing? Well, it turns out it's doing it in a non-inbred mouse in triplicate in three institutions.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
You can't get more rigorous than this. The ITP has tested probably north of 50 molecules, meaning it has done the same experiment for 50 different molecules, and very few have extended lifespan. And the notable failure is NR. NR was tested, and I believe it was tested at a very robust dose, either 500 or 1,000 milligrams per kilogram, and there was no extension of life.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 like 21 months old, which is very old for a mouse.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 gonna 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Then they redid the experiment and they gave it earlier. It worked. Kanagaflozin, 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
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Acarbose prevents you from absorbing in your gut. So two different ways to regulate glucose. Neither of those experiments resulted in a lower body weight for the mice, and yet they both lived longer. Again, there's something very important about regulating blood glucose. The other thing that worked is 17 alpha estradiol, and it only worked in male mice.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So again, suggesting that, well, we can come back to that. It's more than we want to get into at the moment. But the point here is there are very few molecules that have withstood the scrutiny of the ITP. It's a high bar. Metformin failed, by the way. And the ITP is specifically for offsetting aging. Is that right? It is lifespan, but it also looks at some measures of healthspan.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
But it's primarily, it is the gold standard for lifespan. Yeah.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 terastilbene. So terastilbene is believed to be a sirtuin activator, like resveratrol. So commercially available product called BASIS, and it was tested. It was a three-arm study in humans. roughly 30 people per arm.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So just keeping back 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 also looked at something called the, they looked at many things, right? So they looked at all sorts of biomarkers. And the primary outcome for the study was, did you see a reduction of this hepatic fat via the MRI? So what happened?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So they did the study and lo and behold, there was no difference. There was no difference in anything. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
There was no difference in glycemic markers, glucose levels, liver function tests, any of those things. So in that sense, it was a null study, but they did one sub analysis, which again, you have to be very careful of because a sub analysis is not a primary outcome, but it's kind of a way to go and parse the data.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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%. But if they looked at people who were below 27%, in the low dose group, there was a statistically significant reduction in liver fat.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
But the single dose of the drug went from 20% to 15%, which was statistically significant. It's not clear that that's clinically significant, which is a pretty consistent theme in this type of research. Never confuse statistical significance with clinical significance. If I gave you, if your blood pressure is 160 over 100,
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
But again, when you read the fine print, which I just vomited out to you, I don't think anybody is looking at that going, oh, we just found the solution to 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,
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
We're going to take two groups of people. You're going to get a placebo for a period of time or you're going to get NMN for a period of time. And we're going to then do what's called a type of glucose challenge where we look at how well you dispose of glucose with and without insulin infusion. And in the placebo group, you would look at pre and post glucose.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So pre and post placebo treatment, was there a difference in glucose disposal with no insulin? No. What about with insulin where you would expect to see much more glucose disposal? No difference. But when you did that with the NMN group, there was a statistically significant increase in glucose disposal with insulin infusion, but it was quite small.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. Because there's an interesting study that shines red light on a person's back and then does an oral glucose tolerance test. Yeah. And you can actually reduce like postprandial glucose by 8%. Is that meaningful? Not really.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I mean, not in this patient population because these people were all pre-diabetic and they had very high glucose. So- It was, again, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 response of hepatic fat going from 20% to 15%. which is still 3X above the threshold to have fatty liver disease. And in this other study, you had this very, very modest reduction, pardon me, increase in glucose disposal.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
But I mean, there's a saying in my sort of mind, Andrew, which is like, if you have to resort to really interesting statistical machinations to see something, there probably isn't something very interesting there. Right.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So it's generally regarded as safe. It has an FDA designation of grass, which means it is not regulated. Generally recognized as safe. Right. And so that means anybody can sell it. The FDA will have no oversight. They're not telling you whether – they're not going to put a stamp on it that says what they're selling is what it is.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 NMNNR debate is irrelevant. Yeah. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
There's one benefit I could find. There's one benefit I could find that I think is genuineness. There are a few other really insignificant ones that fall into the category of goofy studies that cherry pick by data mining. Okay. So there's studies that like gave people NMN and looked at a shotgun approach of many different things. Like did it change LDL cholesterol, HDL cholesterol, triglycerides?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 p.m. because that's when she was born.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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, you know, squamous cell and basal cell carcinomas aren't problematic. They can be very, you know, deforming.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And so, you know, 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? Like I've never had a sunburn in my life.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I don't work outside, so it's like, it wouldn't matter to me, but there are a lot of people for whom either 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. If you could literally take 60 to 80% of your risk away on squamous or basal cell carcinoma, that could matter.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And by the way, I don't know if this is true, but you may recall at the outset, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So there's a part of me that wonders, like, is the reason that the only place we see a really good signal potentially for NR and NMN supplementation is in a skin cancer? Although it's not melanoma, which is the one we'd really want to see. I mean, if this reduced the risk of melanoma, I would take it, right? Because even though I'm dark skinned, I'm still susceptible to melanoma.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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, I wonder if the enormous reduction in tissue NAD in this particular tissue explains why maybe there is a benefit to it.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
By the way, just going back to the group that have decided that $1,000 for an NAD infusion and dripping it in over two hours is a good use of their time. What do you think would be the improvement in their lifespan if they spent that two hours exercising? Significantly greater. Interesting. All right. And less expensive, but yeah.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
If you had an extra two hours a week to choose between paying $1,000 or $700 for an NADU 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 half an hour. I can just think of so many better ways to spend time and money. But anyway, let's not digress.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I don't know that that's really- Specifically cells like skeletal muscles, right? I think based on Josh Rabinowitz's work, 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. Sure. Because he doesn't have a dog in this fight, right? He just does the work.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
What Josh's research showed, which is basically NAD flux research, has demonstrated that, look, the liver is probably the place of greatest uptake in addition to blood, and that's about all we know. It's not clear how much of this is getting into other cells.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So, I mean, that's, the rest of it is just, you know, I think rearranging deck chairs on a Titanic as far as like, how much does it really matter? And again, I don't even think it's worth arguing about whether NMN or NR is more bioavailable because to your point, you can sort of adjust the dose.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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? I think what you see is a lot of marketing material that tries to make the case that you can do it. Great.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 healthspan? I think that's what we're discussing.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Well, I mean I think the bigger issue is like you can't do the longevity experiment in humans. And I'm sure that these companies that sell this – and I honestly – I don't follow this space. I don't know how many of these companies there are out there. I can name two because five years ago, which was the last time I really dug into this, I knew who the two dominant players were.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
For all I know, there could be 20 companies today that are selling NR and NMN. I don't know any of them.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I don't think actually that was a scientific decision. I think that was more of a lobbying decision from an IP protection standpoint.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Yeah. I mean, 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. 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 –
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Why do you need to do experiments on this if you're selling a supplement when you don't need to make claims to sell a supplement? Like if it's a drug, you have to have an indication. You can't sell a drug without rigorous trials that demonstrate both safety and efficacy. I do think it's pretty safe to say that I do think NR and NMN are probably safe.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
There has been some voice around the idea that NR could increase the risk of cancer.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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? So – and that's probably too harsh a statement. But this is not a field that's like – That's necessarily lending itself to the rigor that you would in pharmacotherapy. And I think there are probably – you mentioned Charles Brenner.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Like I think Charles does good work, right? And he works on many things, not just this. Yeah. And by the way, I don't think – I don't hear Charles out there saying that NR increases lifespan.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I mean, I think part of the reason why I think there's much better research going on with rapamycin is that there's really no commercial interest in rapamycin. Like nobody's going to make money selling rapamycin. Because it's so cheap? Well, yeah. And it's actually not cheap, but it's a drug that is off-patent. So this is a drug that was approved by the FDA 25 years ago.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So generic forms are inexpensive enough that nobody- Believe it or not, they're not. This is the irony of it, is generic. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 is probably what I spend on rapamycin. That ain't cheap relative to, you know, and it's cheaper than some things I take, but it's not cheap.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
But the point is, like, nobody has a commercial interest in rapamycin. It's sort of an irrelevant drug, but the interest is scientific. 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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Rapamycin historically is thought of as an immune suppressant because that's the context in which it was approved for patients undergoing organ transplantation.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
But I think Joan Manick 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 was, for me, that was the turning point. That's when rapamycin went from
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
something that was interesting based on the first ITP in 2009 to maybe we should be taking this in 2014. So between 2009 and 2014, I was kind of looking at the curiosity of rapamycin and saying, well, cool that it worked in mice. I don't think humans should ever consider this to that study, which was like, wait a minute, something's different.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
drugs that are more specific to mTOR complex one, which rapamycin is not, but you can get around that by dosing it intermittently. And then of course, you know, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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, I was 22. I believe it. I mean, I should feel amazing. Do you actually think I move like a 22-year-old? I mean, are you freaking kidding me?
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I bet you if I went and did that again tomorrow, I'd come back at 31 or something. There is so much nonsense in this type of testing. It is just, you know, look... there's probably something to be said if I do that and I come out at 22 as I did versus 92. I would grant you that if you took 150 year olds and you put them through a movement test,
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
The ones that really, really are struggling will come out older. And the ones that really, really are doing great are going to come out younger. So great. I guess it's nice. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
You're doing a lot of jumping, single leg jump here, do all this kind of stuff. Balance testing, all sorts of things. I guess I would say the gold standard for any of these biologic aging tests has to be the following. What is a better predictor of remaining years of life, chronologic age or biologic age? That's, to me, the most important standard. So how old are you chronologically?
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I turned 49 in six weeks. Okay. So I'm sure your listeners will not like to hear this because they would probably hope and believe that you are immortal. Some might want to hear that I'm going to be taken out soon. Yeah. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 really interesting.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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, right? So let's just say actuarially your expectation is 40 years more at this point because you're 49, you're a male, and you don't smoke.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So we believe you have somewhere between 35 and 40 more years of life. predicted on the basis of your biologic age. That's it? That's all I got? You're going to live to whatever, 88 to 91 or something. I'm making that up, but that's like, okay.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Do you believe that? No way. No, of course not. Now, this would be an easy thing to test, not in humans, but you could do it in mice. Interesting that, to my knowledge, that experiment hasn't been done. 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. Um, my response is who cares truthfully?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Like, is that a good thing? Yes, probably. But does it, is it, is it, is it tangibly measurably meaningful like to have a biologic age of 35 versus 40 versus 30 if you're 60? I don't think, I think we're, 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?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So there are lots of things that we measure that are really noisy. So if I measured your, I don't know, let's think of something that's very biologically noisy, your triglyceride level. Like your triglycerides are pretty noisy unless I do something very important, which is standardize it by how long it's been since your last meal.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Like if you ask me right now what my trigs are, I have no earthly idea because, you know, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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?
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I mean, I don't. So it's for that reason that I just have a very hard time putting any stock in this. Now, does that mean that in the future we won't find some benefit in this? I think we probably will. I do think of all the things that go into it, probably the epigenetic part of it would be the most interesting, but again,
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
what most people don't understand is sort of a dirty little secret is how difficult it is to measure the, and to sequence the 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So they were not able to accurately say what, they were giving you an average representation of your methylation, but they weren't going base pair by base pair and actually sequencing this the way we would sequence the genome. So again, it's so much noise in this system. And I just think it creates a little bit of a distraction for people, truthfully.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So I would frame it slightly differently because I like categories to be more MISI, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
A DEXA scan, by the way, you can't even measure how many millisieverts you're getting. So a DEXA scan is like less radiation than a cross-country flight. So it's super, super, super low, less than an X-ray or anything like that. People who work in nuclear plants, I'm told, I haven't looked at the primary data on this, but I've talked to people who incessantly do this.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. They're not getting 50, they might be getting like 500 millisieverts a year. Yet interestingly, they're not at an increased risk for cancer. I'm not sure what to make of that.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
It's in your 50s to your 60s and in your 60s to your 70s that I think is the deciding time. 50s to 70s. 50s to 60s. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Like I think if you and I are being brutally honest, like we're kind of half the men we used to be. And again, that just means like, look, like a night of poor sleep. shows up more, right? When you were working in the lab, as hard as you were describing it, you could probably walk through walls when you were exhausted.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
You need to do more self-care. You need to be more mindful of what you're eating, how you're sleeping, how you're recovering from those workouts, because we still do hard workouts, but recovery plays a greater role. In other words, we're just not quite as resilient as we used to be. I was telling somebody the other day, they asked me about my residency.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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, right? Now, that's not always gonna be the case. It's gonna be very difficult to add muscle mass when you're in your mid to late 70s. It's doable, but it's very, very difficult.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So instead, we wanna 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 2 muscle fibers, the 2A muscle fibers, really start to atrophy in your 20s and 30s.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And it doesn't matter how good it was. My point is like, if you know what your vertical jump was at 18, 19, 20, and then you do it today, I mean, it's literally 50%. And that's one of the purest tests of power. So power'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?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
You're going to lose power, strength, and size of muscle. But again, size still matters. It's still a glucose sink, all these other things. But what we don't want to do is, you know, be out of the game, right? What we don't want to do is injure ourselves and get a setback that becomes very difficult to recover from.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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. What about energy?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 7 and 10, is what I just describe as spontaneous outbursts of energy.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
like their inability to sit still, their kinetic desire to just, like they will, like if we're, I remember once we were kind of walking through a mall and we're walking through the mall, they are sprinting ahead of us, sprinting back, sprinting ahead of us, sprinting back. Like imagine if you and I were walking through the mall and I just started running ahead and running back.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
You'd be so sore the next day. But it's like, it just wouldn't occur to me to ever run unless being chased, right? Like, it's just, I mean, like, we now live a life like I think our ancestors did, which was, you know, if we're not deliberately in the business of moving for a reason, like you're exercising, you're going for a walk for the sake of going for a walk, like...
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
It wouldn't occur to you go and expend energy for no reason. And yet kids do this. It's amazing. And look, it's going to go down by the time you're a teenager. Like just going from being, you know, sort of 10 to 18, there's probably a significant reduction in spontaneous outbursts of energy, let alone where we are now. And it's a great question. Maybe it's NAD. I mean, I don't know.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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, is 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Especially if you're an adult, especially if you have a real life. You got kids, you got a job, which is presumably many people listening to us right now. 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 head space, 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,
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
It still is a sacrifice in terms of time. And for many people, certainly for me, food is the hardest of these all, right? If left to my own devices, I'd eat fricking Froot Loops all day.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
That's my hypothesis. Do you notice a seasonal change in that? Do you experience it more or less in one season or the other?
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 maybe, and again, I'm not saying my framework is correct and yours isn't.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
What about the reverse causality there? 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? And as a result of that, they're able to work out five o'clock in the morning.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Well, I don't... 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. In the form of liquid or capsule fish oil? Capsules. Not because I have an affection for capsule over liquid. It's just going to increase my compliance. I've done both.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
And I 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I'm just saying, this is the way I think about it. I would then say, what are the molecules that I could take that specifically target disease processes? So I kind of think of like, if you want to live longer, And I described this, I think, in chapter four of Outlive. That turns out to be mathematically equivalent in the modern society to delaying the onset of chronic disease.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 like beat the table for it, right? I think it's just, you know, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
How much do you take? I take 5,000 IU. And that takes me from kind of a level of 30-ish to a level of 50-ish. Mm-hmm. Um, and there's, you know, there's a lot of debate about how high vitamin D levels should be. That's a whole separate podcast. We could, you know, waste time on that in 10 years. Yeah. My appetite to talk about that one. Uh, let me think, what else do I take?
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Cause I sure, oh, I do take methylfolate and methyl B12. Um, and again, the, the, the rationale there is, um, 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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
But mechanistically, homocysteine will inhibit the clearance of something called symmetric and asymmetric dimethyl arginine. Have you heard of these things, SDMA and ADMA? So ADMA and SDMA regulate nitric oxide synthase.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 analysis.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
you know, thing to take at modest doses. I also, there's probably some evidence that over supplementing vitamin B is problematic, especially B6. So I don't think- Because of peripheral nerve damage. Exactly. So I don't supplement B6. I'm just taking a bit of folate and methyl B12. Let me think what else do I take? Because I do take a couple other things.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Oh, I take magnesium L3 and 8 and ashwagandha for sleep. I take slow mag, which is just a magnesium chloride, slow releasing version of magnesium. And I take methyl, pardon me, I take magnesium oxide. So I take magnesium in three forms. So I'm long magnesium. You're carpet bombing with magnesium. Yeah, I'm big on magnesium, right? Yeah. Great for bowel function.
Huberman Lab
Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
Great for – I mean 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 like electrolytes. I take Element, which I should disclose I'm an investor in that company. So I drink an Element a day.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I take creatine monohydrate, five grams a day. I take AG most mornings. Oh, and I take Pendulum, the probiotic. Got it. 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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So you have to have something anaerobic. So Ackermansia... 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...
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
It's a really interesting story how they kind of 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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
So anyway, so I take three of their products. I take something called glucose control. I take polyphenol and I take acromantia.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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?
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
I'm not saying those things don't matter, but just put them in the context of the direction the Titanic is going.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 kind of 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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
That's going to show me your conviction. So through that lens, look, I'll show you my conviction on exercise. I'll show you what I do. I'll show you my conviction on sleep. This is what I do. I'll show you my conviction on all these other things. I mean, I don't take these supplements. Full stop. I don't take them because I can't afford... It's not that I can't afford them.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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?
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
You could take a PCSK9 inhibitor or a statin or bempadoic 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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 fist-fulling 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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
But as it stands today, I do not take these supplements and I have no foreseeable plan to do so until information changes.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
We see a greater abundance of senescent cells. we see reduced nutrient sensing capacity of mTOR, which you described as probably the most important nutrient sensing system in our body. So we have these 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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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 wellbeing where, you know, none of this other stuff matters if you're kind of unhappy. And so you have to, and you've done so many podcasts on that topic, right?
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Dr. Peter Attia: Supplements for Longevity & Their Efficacy
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.