Huberman LabSupplements for Longevity & Their Efficacy | Dr. Peter Attia
EVERY SPOKEN WORD
150 min read · 30,016 words- 0:00 – 2:31
Dr. Peter Attia, NAD Pathway
- AHAndrew Huberman
(uptempo music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Peter Attia. Dr. Peter Attia is a medical doctor who did his training at Stanford University School of Medicine and Johns Hopkins School of Medicine. Dr. Attia is one of the world's most trusted voices on the topics of healthspan and lifespan, and with good reason. He is known to systematically review the research literature, the clinical trials, and he maintains an avid clinical practice. So when it comes to the topic of whether or not a particular molecule, or supplement, or prescription drug is indeed something that we should be thinking about and perhaps even taking in order to improve our healthspan and lifespan, Dr. Attia is the person that I choose to sit down with and discuss it. So, today, we are going to discuss the so-called NAD pathway. This is a pathway that's received a lot of attention in recent years as a potential target for improving lifespan, that is for living longer. Today, we discuss the various molecules in this pathway and the various approaches to increasing NAD, which is the end target goal of anyone that's trying to augment the NAD pathway, so to speak. So for instance, we talk about taking NR versus NMN versus direct infusions or even orally taking NAD, and we compare them in terms of both what's known and what is not known about their ability to get into cells and any efficacy they may have for either longevity or healthspan. Dr. Attia and I compare and contrast the literature on this, again, both research and clinical literature, and we discuss whether or not he or I take NAD, NMN, or NR, and if so or if not, the reasons for that. We also each go through our own supplement regimen, which of course reflects what we do believe can potentially have an effect on healthspan and/or lifespan. So by the end of today's episode, you'll learn a lot about NAD. You'll learn a lot about the biological pathway. You'll learn a lot about the delivery routes, the various supplements and why people think they may be useful, why others, perhaps even Dr. Attia and myself, think they may not be useful for longevity. You'll have to listen to find out what the answer is there. I should also mention that we give somewhat of an overview or a framework for thinking about approaches to longevity. So if you're interested in things like rapamycin, metformin, and whether or not fasting can improve longevity, we get into that as
- 2:31 – 6:38
Sponsors: LMNT, Levels & Eight Sleep
- AHAndrew Huberman
well. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes, sodium, magnesium, and potassium, in the correct ratios, but no sugar. Now, proper hydration is critical for the optimal functioning of all the cells in your body, and that's especially true for the neurons, the nerve cells. In fact, we know that even a slight degree of dehydration can diminish both cognitive and physical performance. So to make sure that I'm getting proper hydration and electrolytes, I personally dissolve one packet of LMNT in about 16 to 32 ounces of water when I first wake up in the morning, and I drink that or sip that across the first half-hour of the day or so. And then I also make it a point to drink another packet of LMNT dissolved in an equal amount of water, so 16 to 32 ounces, at some other point during the day, and maybe even a third if I'm exercising and/or sweating a lot. I should mention that LMNT tastes absolutely delicious. My favorite flavor is watermelon, although I also confess I like the raspberry flavor, the citrus flavor. Basically, I like all the flavors. If you'd like to try LMNT, you can go to drinklmnt.com/huberman to claim a free LMNT sample pack with the purchase of any LMNT drink mix. Again, that's drinklmnt.com/huberman to claim a free sample pack. Today's episode is also brought to us by Levels. Levels is a program that lets you see how different foods impact your health by giving you real-time feedback on your diet using a continuous glucose monitor. One of the most important factors in both short- and long-term health is your body's ability to manage blood glucose. To maintain optimal energy and focus throughout the day, you want to keep your blood glucose levels steady without big spikes or crashes. I first started using Levels about three years ago as a way to try and understand how different foods impacted my blood glucose levels, and it's proven incredibly useful for determining what food choices I should make, when best to eat certain foods, especially around things like workouts, and when and what to eat relative to when I go to sleep in order to allow for the best possible night's sleep and stable blood sugar throughout the night and when I wake up in the morning. So if you're interested in learning more about Levels and trying a CGM yourself, go to levels.link/huberman. Levels recently launched a new CGM sensor that's even smaller and has even better tracking than their previous version. Right now, they're also offering an additional two free months of membership. Again, that's levels.link, spelled L-I-N-K, /huberman to try the new sensor and two free months of membership. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep-tracking capacity. Now, I've spoken many times before on this podcast about the critical need for us to get adequate amounts of quality sleep each night. One of the best ways to ensure a great night's sleep is to control the temperature of your sleeping environment, and that's because in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees. And in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees. Eight Sleep makes it incredibly easy to control the temperature of your sleeping environment by allowing you to program the temperature of your mattress cover at the beginning, middle, and end of the night. I've been sleeping on an Eight Sleep mattress cover for well over three years now, and it has completely transformed my sleep for the better. Eight Sleep recently launched their newest generation pod cover, the Pod 4 Ultra. The Pod 4 Ultra has improved cooling and heating capacity, higher-fidelity sleep-tracking technology, and it also has snoring detection that, remarkably, will automatically lift your head a few degrees to improve your airflow and stop your snoring. If you'd like to try an Eight Sleep mattress cover, you can go to eightsleep.com/huberman to save $350 off their Pod 4 Ultra. Eight Sleep currently ships to the USA, Canada, UK, select countries in the EU, and Australia. Again, that's eightsleep.com/huberman. And now for my discussion about NAD and longevity with Dr. Peter Attia.
- 6:38 – 17:22
Categories of Longevity Approaches
- AHAndrew Huberman
Peter Attia, welcome.
- PAPeter Attia
How are you?
- AHAndrew Huberman
Great to see you again.
- PAPeter Attia
Great to be here again.
- AHAndrew Huberman
Should we parse this NAD thing?
- PAPeter Attia
(laughs)
- AHAndrew Huberman
(laughs)
- PAPeter Attia
I think we should.
- AHAndrew Huberman
Do you mind if I set up a little bit of a framework? Great. So for people that want to live as long as possible, I figure there are at least four categories of approaches, broadly speaking. The first, I'll just call the dos and don'ts. You've talked a lot about these. Your book Outlive beautifully covered these, and I tend to regurgitate some of what you say on this podcast. Namely, you wanna move appropriately and often enough, so get enough zone 2 cardio, do your resistance training, keep nerve to muscle connections strong. Avoid the sorts of things that would lead to falling and being immobile. Eat right. There's a whole category of things there we're not gonna talk about today, although we might touch on a bit. And know your genetics and make some good decisions on the basis of your genetics. So the dos and don'ts. The second category I would put under the umbrella of calories, glucose, insulin, et cetera, that all kind of funnel in, at least in my mind, to mTOR, mammalian target of rapamycin, a molecule that's robustly expressed during development in essentially all cells of the body, and then across the lifespan tapers off. During puberty especially, well, let's say infancy through puberty, cells are expressing so much mTOR and they're growing like crazy, and we often associate that early stage of life as youth, not aging, because we think of it as a, kind of a timestamp as opposed to the verb, but I would argue, as a developmental neurobiologist by training, that it's one of the most rapid phases of aging of our entire lifespan. Look at a picture of you when you were five, look at a picture of you when you were eight versus 15, you look very different and your size is robustly different.
- PAPeter Attia
By the way, I just did this exercise 'cause my daughter, her birth- her 16th birthday is around the corner, and, uh, we take a picture of her every single year at the minute of her birth. So we have a picture of her every single year holding a clock that says 3:56, at 3:56 PM 'cause that's when she was born, and I just went through and pulled each of the last 16 of them from the day she was born all the way up, and you're right, the biggest changes are actually in about the first 10 years. Um, you know, 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.
- AHAndrew Huberman
Yeah, I mean, the brain, the same brain has to learn an entirely new body every year-
- PAPeter Attia
Yeah.
- AHAndrew Huberman
... in terms of how to move it, limb length, et cetera. So a lot of the so-called anti-aging or longevity approaches that fall under this umbrella relate to things like caloric restriction or taking drugs such as rapamycin, and of course, mammalian target of rapamycin is the target of rapamycin, duh, in an effort to essentially remove excess insulin, blood glucose, and thereby reduce mTOR activity, so essentially slow cellular growth, and all that fits nicely into the logic that mTOR is associated not just with development, but with aging because development is aging. And then I would say there's a third category, and it's the one we are going to talk about today, which is targeting specific cellular pathways that some people have deemed potentially interesting for longevity, and the pathway that we're going to spend some time on is the so-called NAD pathway, NR, NMN, NAD being the major players, and we'll talk about some of the biochemical and enzymatic steps in between. And then I suppose there's a fourth category, which we could say is, you know, the do everything, even the most esoteric of things category, this is a rarer category. There are folks like Bryan Johnson who spend a lot of time in this category specifically, you know, taking very high doses of polyphenols, limiting their caloric intake to just early part of the day, I think he eats dinner at 11:00 AM. I don't know if it still qualifies as dinner at 11:00 AM, but his final bite of calories is, I believe, at 11:00 AM, doing everything from red light to PRP, platelet- platelet rich plasma, excuse me, um, and essentially the kitchen sink approach to longevity and aging. Did I miss any categories?
- PAPeter Attia
So I- I- I would frame it slightly differently because I- I like categories to be more MECE, mutually exclusive, collectively exhaustive. Um, so- so I- I don't- I don't know that I would formulate it that way, right? I might say, look, category one are sort of the essential behavioral things that you have no choice but to engage in whether you want to or not, right? So you have to eat, you have to sleep, you have to move, you just have a choice in do you wanna do those things correctly or not correctly, or do you wanna do those things in a manner that promotes health or erodes health, right? So again, there's nobody listening to us who doesn't eat, but again, you can choose how much you eat and what you eat and when you eat. There's nobody who's alive who isn't moving because locomotion is life and the absence of life is the absence of locomotion, but you can certainly choose to move very little, you can choose to move a lot, and you can choose to decide on how you move. You alluded to it already, right? You can- you can move in a certain way that puts your aerobic system in a zone that maximizes fat oxidation, we call that zone 2. You can move at a level where you consume incredible amounts of oxygen at your maximum aerobic level, you can choose to move in a manner that uses resistance and- and gravity against you and all those sorts of things.... similarly, we all have to sleep, right? Matt Walker would probably tell us the number of days you could go with sleep, without sleep before you would literally perish. Um, 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, um, s- sort of what are the molecules that you would exogenously take to try to impact any of those systems. And maybe, then again, I'm not saying my framework is correct and yours isn't, I'm just saying this is the way I think about it. I would then say, what are the molecules that I could take that specifically target disease processes? So, uh, I kind of think of like if you want to live longer, and I described this I think in chapter four of Outlive, there's a, that's a, that turns out to be mathematically equivalent in the modern society to delaying the onset of chronic disease. Um, 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 and that, 'cause that was a huge hit on mortality.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
Um, and then you had to not get an infection or succumb to trauma. Um, and- and then maybe 150 years ago that was the case, but today most of those things are taken care of by antibiotics, sanitation, and, you know, the modern miracle of childbirth in the, in- in- in this era. So now for you and I to live longer, we basically have to delay the onset of cardiovascular disease, cerebrovascular disease, cancer, neurodegenerative disease, dementing diseases, and metabolic diseases. We have to delay the onset of those things. The longer we delay the onset, the longer we will live, full stop. So y- you can use everything that you talked about in the first category plays into that. But you also have this other category of where you can take molecules that specifically target those things. You can take metformin or an SGLT2 inhibitor or a GLP-1 agonist and you will directly impact those things. You could take, uh, a PCSK9 inhibitor or a statin or bempedoic acid. You will directly impact those disease processes. You will delay the onset of those diseases and you will reduce the mortality associated with them. Then I'm gonna 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 gonna put them in a category called geroprotective, which is they target hallmarks and pathways of aging that you've described. So we talk about all of these things that occur in an aging phenotype where we see more inflammation, we see a greater abundance of senescent cells, we see reduced, uh, nutrient sensing capacity of mTOR, which you described as the probably the most important nutrient sensing system in our body. Um, so, so we have, you know, 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 and can we use exogenous molecules to target those specifically? You gave one example, which I- I would argue is the single best example, which is rapamycin. So rapamycin targets a very specific hallmark of aging and we can talk about what the experimental evidence is to suggest that that makes you live longer. So I would sort of say those are the big three categories. And then basically the fourth category you could just say is like how do you put them all together and how aggressive do you want to be in culminating those? Of course, none of this touches on another area that I wanna 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- and well-being where, you know, none of, none of this other stuff matters if you're kind of unhappy. And so, so you have to... And- and you've done so many podcasts on that topic, right? You've had Paul Conti on where you kind of go through the understanding of ourselves and our minds and- 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 'cause the first bucket takes so much work. So if you can't regulate yourself, it's very difficult to regulate the- the dos and don'ts. But even absent just length of life stuff, it impacts quality of life, which is this idea of health span as well. So I guess that's just my slightly different way to frame it, but it's a little bit more messy, um, in that, you know, we talk about the behaviors, um, the exogenous molecules that target diseases, the exogenous molecules that target, uh, aging.
- 17:22 – 25:01
Peter’s Supplements; Rapamycin & Research Data
- AHAndrew Huberman
Aside from food, what exogenous molecules do you take?
- PAPeter Attia
I take a few, right? So I take some that are disease specific, right? So I take a PCSK9 inhibitor, I take bempedoic acid, uh, I take an SGLT2 inhibitor, um, and then I take at least one that is purely just, uh, based on the belief of its capacity in geroprotection, which is, is rapamycin. And, um, and also the SLG- the SGLT2 inhibitor I think is probably just broadly geroprotective. And we can even talk about that a little bit in terms of the success of one of those molecules called Canagliflozin and in the interventions testing program, the ITP, which I am sure we'll talk about in the context of NAD as well.
- AHAndrew Huberman
What dosage of rapamycin do you take?
- PAPeter Attia
I take eight milligrams once a week for as long as I can tolerate it, but that I usually have to take breaks.
- AHAndrew Huberman
Why is that?
- PAPeter Attia
I get these vicious aphthous ulcers, uh, little mouth sores.
- AHAndrew Huberman
Canker sores.
- PAPeter Attia
Yes.
- AHAndrew Huberman
Ugh.
- PAPeter Attia
About 10% of people get them.
- AHAndrew Huberman
Hmm.
- PAPeter Attia
It's paradoxically the only biomarker we probably have. So I- I secretly, uh, rejoice in knowing that at least I'm getting a good batch of rapamycin. (laughs)
- AHAndrew Huberman
By virtue of the side effect.
- PAPeter Attia
By virtue of these miserable side effects.
- AHAndrew Huberman
Interesting.
- PAPeter Attia
But- but so- 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.
- AHAndrew Huberman
And the idea there is that you're limiting mTOR, you're-... causing your cells to grow less, mature slower, and in that sense, slowing down aging. Is that the idea?
- PAPeter Attia
Yeah. I mean, y- 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, um, sort of looking at the molecular explanation for why rapa works, although I find that to be quite convincing, and why does the inhibition of mTOR stimulate autophagy, why would that suppress senescent cells? But truthfully, my conviction around mTOR is far more based on the experimental data, um, something that is actually sorely lacking in the NAD story, which we'll discuss. So, the experimental data are far more convincing, right? Which is when you look at the administration of rapamycin or its analogues, for example, everolimus, um, when you look at the administration of these molecules to organisms that are as close as possible to the species of interest, or the species of interest, um, so looking at mammals such as, um, mice, um, and small primates, um, 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, um, you see something that you don't see for a single other molecule, which is uniform life extension. No other molecule has done this. It's very important to understand. There are only two interventions, full stop, that have ever extended life across those four categories of eukaryotes.
- AHAndrew Huberman
Caloric restriction.
- PAPeter Attia
And rapamycin. Very important point, right?
- AHAndrew Huberman
How do you feel when you're on rapamycin, aside from the canker sores?
- PAPeter Attia
Yeah, which fortunately aren't that frequent. You, I, I don't feel anything, and the very few of my patients who take it, because I, I, maybe 10% of my patients also take it, um, I've never heard... Actually, that's not true. I've probably heard two people say they feel better on it, but, you know, I don't know what to make of that. Maybe they do.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
Um, and maybe that's just a placebo effect.
- AHAndrew Huberman
Does it synergize with caloric restriction or collide with caloric excess? Meaning if you're taking rapamycin, but you're slightly over your caloric needs, maybe you're trying to add a little bit of body weight-
- PAPeter Attia
Mm-hmm.
- AHAndrew Huberman
... or you happen to overeat a little bit just because, is it going to collide with rapamycin's potential positive impact on slowing aging?
- PAPeter Attia
Yeah, it's a good question, Andrew. I don't, I don't know. I don't think we know. Uh, we do know that there's one other really important readout we're waiting for, which is, um, Matt Kaeberlen's dog aging study, um, which, uh, is, is, is gonna be an exciting readout in 2026. Um, we're also waiting for another readout out of the University of San Antonio looking at another, um, a- another trial in mammals. And, uh, again, I think those two will be really interesting, right? Um, 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. Um, you know, as you know, I'm sure, from your work, um, the model you choose matters, right? And, and sort of you, you, you know, in an ideal world, you wanna use a mouse model that is, um, you know, not inbred, that is more closely related to the, what we care about, which is ourselves. And, and so when you see many labs getting the same result over and over again, regardless of how they do it, you really start to believe there's a signal there. So now to be able to see this in a higher order mammal, um-
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
... and ultimately in companion dogs, which is where Matt Kaeberlen is looking, I think that's, 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, "or I'm gonna, you know, have a second look at this and say, 'You know, maybe, maybe we just shouldn't be taking this,'" right? Because I do think that the dog study is gonna be more telling. Um, but again, we'll have to wait and see what that shows.
- 25:01 – 30:35
NAD Pathway: Energy & DNA Repair; Knock-Out & Knock-In, Klotho
- AHAndrew Huberman
talk about NAD.
- PAPeter Attia
Yes.
- AHAndrew Huberman
It's in essentially every cell of the body except red blood cells, correct?
- PAPeter Attia
You know, I-I don't even know if it's in red blood cells. My intuition is, I- I- I've never looked, to be honest with you, but given that red blood cells, um, have a different metabolic pathway, right, where they're purely glycolytic, I don't... They wouldn't have the need for it in the way that others would. But they might, right? Because they still undergo redox potential. So it's possible NAD is in every single cell, yeah.
- AHAndrew Huberman
And it's generally thought to be associated with energy production and mitochondrial pathways in every single cell.
- PAPeter Attia
Right. So NAD is, again, one of the most ubiquitous molecules in the body. And most of what it does, and I mean most meaning, like, somewhere between five and 600 pathways of it utilize NAD as a cofactor, meaning that it's not consumed in a chemical reaction, but rather it serves as an electron shuttle. So NAD and NADH basically play catch with electrons, and that's 99% of what NAD is doing in the body. And for that reason, NAD is so tightly regulated in the body. The levels of NAD in the cell are really tightly regulated, and that shouldn't be surprising, just as glucose, really tightly regulated. pH, or hydrogen ion concentration, really tightly regulated. We as a species cannot survive outside of a very narrow band of, uh, pH, right? If it's below seven or above 7.8 on a zero to 14 scale, we die, full stop. Um, so similarly, NAD is managed across all ages and across all physiologic, uh, uh, uh, c- conditions in a super tight band. There's another, uh, 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 n- 99% of it. A small fraction of it is used, and it's used by these things called sirtuins that consume NAD as an actual substrate in the process of DNA repair. And maybe we can go into this, but this is really where the story picks up.
- AHAndrew Huberman
It's also, as I recall, where the story began.
- PAPeter Attia
That's exactly right.
- AHAndrew Huberman
Right? It was some experiments where the sirtuins were mutated in one direction or the other, meaning gain-of-function or loss-of-function. These days, people hear "gain-of-function" and they immediately think to pandemic-related themes. But gain-of-function is a way of changing genes typically to, um, augment a function, increase its robustness, or in some cases, to rescue a phenotype where you have a knockout mouse that lacks a gene, so that's loss-of-function, or a strain of yeast that lacks a gene, and then you do the gain-of-function rescue experiment. You re- reintroduce the, the gene of interest. Um, it's an important... I wouldn't even call it a control. It's an important experiment in any case, because loss of function will tell you a lot-
- PAPeter Attia
Yeah.
- AHAndrew Huberman
... um, but gain-of-function and loss-of-function, assuming that the results jibe, uh, tells you much, much more. This is one of the major areas, I think this is very important to highlight, where human genetics really struggles, because you can get humans with a mutation in a particular pathway, like, I don't know, the Sonic Hedgehog pathway. There, somebody is hypomorphic for Sonic Hedgehog, and, you know, they might actually lack a, a major tooth up middle because the role of Sonic Hedgehog at the midline, and you could say, "Okay, well, loss-of-function here. Here's the role of Sonic Hedgehog." But the ideal experiment is to put the gene back in and then rescue that phenotype, because as any logical mind can tell, there could be many things downstream of Sonic Hedgehog that could create the phenotype that you observe. But if you put Sonic Hedgehog back in, yes, that's still true, but you get more reassurance that that's the gene of interest. So with respect to sirtuins, as I recall, they deleted the sirtuins in yeast.
- PAPeter Attia
Yeah. So, but let, let's use another example of what the gold standard is here, or what a great example is. So, so I recently did a podcast with Dina DuBail from UCSF on klotho-
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
... which is a, an amazing scientific story.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
And it's a great story because it shows how accidents can lead to great discoveries, right?
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
So there was a, uh, a researcher in Japan who was really interested in understanding hypertension, uh, 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.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
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, d- died very quickly. And, you know, like a good scientist, he didn't say, "Well, that sucks. I'm gonna discard that one 'cause it didn't give me what I wanted, which was the blood pressure change." And he kind of went and figured out what was going on, and he figured out that there was a certain gene that he had hit that wasn't a sodium transporter, and instead was this other gene. He named it klotho.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
So, so you had this one piece of evidence right now, which was, if you knock out that gene, you kill an animal very quickly. Now, that doesn't mean it's a longevity gene. You have to do the other experiment, to your point. You have to overexpress that gene and ask the question, "Do you live longer?" And sure enough, when they overexpressed that same gene that they had just knocked out and killed the mouse, the thing was living 15 to 20% longer.
- AHAndrew Huberman
So it's both necessary and sufficient for extended life.
- PAPeter Attia
Yeah. So that's how you can say, "Well, that's a longevity gene."
- 30:35 – 32:25
Sponsor: AG1
- PAPeter Attia
- AHAndrew Huberman
As many of you know, I've been taking AG1 for more than 10 years now, so I'm delighted that they're sponsoring this podcast. To be clear, I don't take AG1 because they're a sponsor. Rather, they are a sponsor because I take AG1. In fact, I take AG1 once and often twice every single day, and I've done that since starting way back in 2012. There is so much conflicting information out there nowadays about what proper nutrition is. But here's where there seems to be a general consensus on. Whether you're an omnivore, a carnivore, a vegetarian, or a vegan, I think it's generally agreed that you should get most of your food from unprocessed or minimally processed sources, which allows you to eat enough, but not overeat...... get plenty of vitamins and minerals, probiotics and micronutrients that we all need for physical and mental health. Now, I personally am an omnivore, and I strive to get most of my food from unprocessed or minimally processed sources. But the reason I still take AG1 once and often twice every day is that it ensures I get all of those vitamins, minerals, probiotics, et cetera, but it also has adaptogens to help me cope with stress. It's basically a nutritional insurance policy meant to augment, not replace, quality food. So by drinking a serving of AG1 in the morning and again in the afternoon or evening, I cover all of my foundational nutritional needs. And I, like so many other people that take AG1, report feeling much better in a number of important ways, such as energy levels, digestion, sleep, and more. So while many supplements out there are really directed towards obtaining one specific outcome, AG1 is foundational nutrition designed to support all aspects of wellbeing related to mental health and physical health. If you'd like to try AG1, you can go to drinkag1.com/huberman to claim a special offer. They'll give you five free travel packs with your order, plus a year's supply of vitamin D3 K2. Again, that's drinkag1.com/huberman.
- PAPeter Attia
So let's
- 32:25 – 38:56
Yeast, Sirtuins, Caloric Restriction & Lifespan
- PAPeter Attia
go to the sirtuin story. So it goes back to the late '90s. Matt Kaeberlein again. This is amazing, right? So you have this guy who's, like, the leading authority or one of the leading authorities on the, on the work going on today with rapamycin, along with one of his colleagues, David Sabatini, and a few others. Um, but when, when Matt was a post-doc, he did an experiment in a strain of mice, uh, pardon me, a strain of yeast. I think it was the W303 strain of yeast. And he overexpressed SIR2. Um, 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. Um, I forget the name of that... I forget what that strain was. It was something 316. Was it... But it was a different strain of yeast. At that moment, again this is about 25 years ago, a hypothesis emerged, which was we have two different strains of yeast, and in one of them, when you overexpress SIR2, this gene, they live longer, and in this other strain, if you calorically restrict them, they live longer. The understandable hypothesis was caloric restriction, which we had known was life-extending, is working through sirtuins. That hypothesis sort of fell apart about four years later when Matt Kaeberlein again, this time with Brian Kennedy, did another experiment in a different, yet a third strain of yeast that allowed them to test hypotheses, because there was a problem with the story I just told. When you took the 303 strain, this is the strain that when overexpressing SIR2 lived longer, if you took that strain and you calorically, calorically restricted them, no change.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
That's odd. Even more odd is when you took the 316 strain, and this is the strain that lived longer with CR. If you overexpressed SIR2, no change. So right off the bat, the story didn't make sense. But it was further solidified that that story didn't make sense when Brian and Matt published in 2004 in yet a different strain. God, I'm blanking on the name. It's like, uh, B-BY4742. Like, um, you know, n- 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. Again, further suggesting that overexpression of SIR2 and caloric restriction independently and separately extended lifespan.
- AHAndrew Huberman
These are parallel pathways.
- PAPeter Attia
They're parallel pathways. For reasons that honestly escape me, Andrew, there are still people who maintain that the benefit of sirtuin overexpression is through the caloric restriction pathway and vice versa.
- AHAndrew Huberman
And that's wrong.
- PAPeter Attia
My reading of the literature, in addition to every person I have talked to on this who works in the space, including Matt Kaeberlein, who has done the most research on this, is that there is no evidence that caloric restriction and sirtuins operate through the same pathway. And in that sense, I think there's, there's relatively uniform agreement that caloric restriction extends life across the model systems we discussed, right?
- AHAndrew Huberman
What about in humans?
- PAPeter Attia
What, what about it specifically?
- AHAndrew Huberman
Does it extend life?
- PAPeter Attia
Caloric restriction or sirt- Well, that experiment's never been done and never will be done, but, uh...
- AHAndrew Huberman
Uh, the, the joke I was trying to set up for is the one I'll make now, which is no one wants to be in the control experiment.
- PAPeter Attia
(laughs)
- AHAndrew Huberman
Um, that said, nobody wants-
- PAPeter Attia
I would argue no one wants to be in the treatment experiment either. (laughs)
- AHAndrew Huberman
Oh, you got me. You got me. Uh, you beat me to the punch.
- PAPeter Attia
Yes, yes.
- AHAndrew Huberman
Uh, no one wants to be in the treatment group either because of, it requires eating so little.
- PAPeter Attia
Yeah.
- AHAndrew Huberman
You know, it just... The, the...
- PAPeter Attia
Yeah, the joke is-
- AHAndrew Huberman
Just mere appearance of people-
- PAPeter Attia
The joke is you probably will live longer, and it will feel even worse. Like, it's just-
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
It's, yeah. Uh, caloric restriction, which by the way, there are real debates about whether it will extend life in humans, because it will clearly... I shouldn't say clearly. I think it would be a very safe bet that severe caloric restriction will absolutely reduce the risk of most chronic diseases, meaning I, I have, I think there's very good reason to believe that if an individual constitutively consumed 25% fewer calories than they were meant to eat, their risk of cardiovascular disease, cancer, Alzheimer's disease, would go down. The problem is what things go up. What does that do to your immune system? What does that do with respect to sarcopenia? What does that do to your risk of falling? Like, this-
- AHAndrew Huberman
Yeah, frailty.
- PAPeter Attia
Yeah, exactly.
- AHAndrew Huberman
Yeah.
- PAPeter Attia
So you trade one set of diseases for another. It's not at all clear that lifespan goes up. And by the way, when you even look at some of the wild, um, uh, like, the, 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, uh, situations, they don't live longer. So it's not always the case that caloric restriction extends life.And therefore, while, um, it's safe to say caloric restriction probably reduces the onset of chronic disease, that might not translate to an all-cause mortality benefit based on those downsides. But all of that said, I think the whole sirtuin story got off to an incorrect start where it basically lopped onto the CR story, which was, "Hey, we've got this thing CR that we've known since-"
- AHAndrew Huberman
Caloric restriction.
- 38:56 – 43:42
Sirtuins, Transgenic Mice, Gender & Lifespan
- AHAndrew Huberman
So, um-
- PAPeter Attia
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?
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
But then the question becomes, well, if you believe that sirtuins are truly, um, a factor that drives longevity, how can you activate them, right?
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
How do you activate a sirtuin? So, we have to now simultaneously start to hold things true in parallel that may or may not be true. So we, we, we want to then ask the question, do we believe that what we saw in yeast, which I think is the only reproducible finding I can draw, meaning this is a reproducible finding. In many but not all strains of yeast, if you overexpress sirtuins, the yeast will live longer. So let's park that in the parking lot as a very likely statement. You would then say, "Well, if it does it in yeast, does it do it in flies? Does it do it in worms? Does it do it in mammals?" You, you wanna 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.
- AHAndrew Huberman
Yeah, making a fly mutant, Drosophila mutant, that overexpresses sirtuins, a worm, C. elegans mutant, that overexpresses sirtuins, that's a pretty quick experiment to do.
- PAPeter Attia
Yeah.
- AHAndrew Huberman
Because of this short generation time of those species.
- PAPeter Attia
Right.
- AHAndrew Huberman
Now, a mouse, it's a longer experiment, but I'm guessing all of those experiments have been done.
- PAPeter Attia
Yeah, and the only one that I can find that has demonstrated a survival advantage is one particular transgenic mouse experiment that overexpressed, uh, SIRT6. And it did indeed for the male mice increase lifespan by 10 to 15%. So this is one transgenic mouse model that overexpressed SIRT6, and those mice, the male mice lived 10 to 15% longer. The female mice did not.
- AHAndrew Huberman
We should probably clarify what a transgenic mouse is. I talked about knockout mice. That's when a gene or genes in some cases is deleted from the genome. So it's null, it does not express that gene. The gain of function would be to put back that gene in, that would be a knock-in mouse. So in that case, you still get some normal expression of the gene from the endogenous genome, but now you have a trans gene that's inserted there. And there are all sorts of important intricacies that relate to this. For instance, where the trans gene is inserted. If it's, you know, downstream of, of an enhancer that's muscle specific, then you can get a mouse that overexpresses sirtuins just in muscle. You can get it ubiquitously expressed. There are a number of different ways that this can happen. I'm assuming this was ubiquitous expression of, you said SIRT6?
- PAPeter Attia
SIRT6, yeah.
- AHAndrew Huberman
So every cell in the body that normally would express SIRT6 would express more SIRT6.
- PAPeter Attia
I, I don't remember, Andrew, to be honest with you. I'd have to go back and look at the paper.
- AHAndrew Huberman
Okay.
- PAPeter Attia
I don't know if it was muscle specific or whole body specific. Um-
- AHAndrew Huberman
I'm guessing unless they made it clear that it was tissue specific that it's, uh, whole body. So we're talking about it when Peter says transgenic mouse, he's talking about a mouse that has this trans gene that causes it to express more SIRT2 and 6 than it ordinarily would. And let's assume, although we don't know this for sure, that the other genes in this mouse are functioning as they would normally.
- PAPeter Attia
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. Um, and that's not uncommon or unheard of in longevity research. There generally are sex specific differences, and you always have to read the fine print. The first thing I always look at in a study when I see a difference in sexes or frankly any difference in longevity, but it's always great when they parse them out by sexes, is how long did the controls live? But I went back and actually looked at the Kaplan-Meier curves on that exact study. And yes, indeed, I think that's a real effect. Um, 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.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
That tends to be completely independent of caloric restriction. That's the single thing I can say with the greatest confidence.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
And there is at least one transgenic strain of mice that if you get it to overexpress a different SIRT, SIRT6, but again they're, these are homologs throughout the species, so we don't have to get, I don't think we need to get wrapped up in SIRT2 versus SIRT6. Um, you will at least make the male mice live longer, but not the females.
- 43:42 – 53:31
DNA Repair, Sirtuins, Cancer; Resveratrol
- AHAndrew Huberman
... what sorts of things are downstream of sirtuins? And that question translated to normal English is, what is changing as a consequence-
- PAPeter Attia
Yeah, why is this happening?
- AHAndrew Huberman
... of increasing-
- PAPeter Attia
Yeah.
- AHAndrew Huberman
... the sirtuin, could it be, for instance, well, unlikely based on what we already know about caloric restriction and the fact that they are independent parallel pathways, but is it something related to glucose metabolism? Is it something related to, um, clearance of senescent cells? I mean, I'm just throwing out-
- PAPeter Attia
Yeah, yeah.
- AHAndrew Huberman
... possibilities here.
- PAPeter Attia
Actually you've hit two of the big three right off the top, right? So, w-we believe that when sirtuins are activated they're improving mitochondrial biogenesis, um, they are, um, uh, in- increasing DNA repair.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
So that's probably the biggest one, and by the way, that's sort of what brings us to, um, um, the, um, the NAD story. Um, and also reducing SASPS, right, so the soluble products of senescent cells. So, so tamp- so in other words those are all three good things, right? So you tamp down on senescent cells, uh, 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.
- AHAndrew Huberman
This business of DNA repair and reducing, um, you know, fragmentation or mutations to DNA that are naturally occurring has been a hot idea in the field of aging for a long time. Is that because when x-rays became popular or, um, post-nuclear fallout that people showed accelerated signs of aging? I mean, how did we get from DNA mutation to accelerated aging? Like w-
- PAPeter Attia
Well, I mean, I think we, 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. Um, actually this is an interesting question. So in 2016, I went to Easter Island with David Sabatini and Nav Chandel and Tim Ferriss. So the four of us just took a trip to Easter Island to see the birthplace of rapamycin. So it was kind of like s- vacation/science journey.
- AHAndrew Huberman
That's a nerdy vacation.
- PAPeter Attia
It was awesome. And, um, you know, so just picture hiking around this incredible island just talking about science all day, but this was an interesting question that I posed to Nav and to David which was, "Why do we see such a clear and present association with cancer, uh, as we age, and why is it so non-linear?" So it's not just that cancer goes up with age, it goes up like that.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
Um, and I said, "I'll offer two hypotheses, which is more compelling? Is it simply that as we're aging, uh, DNA replication..." A-a-again, taking a step back for the listener, uh, cancer is a genetic disease, meaning, uh, by definition i-it is, uh, 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, uh, rep, uh, to control replication, so it interrupts cell signaling so cells replicate but then don't know when to stop, and then the introduction of the capacity to spread, th-this property called metastasis. Those are the two hallmarks of cancer. So, 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, and so the question is, is it because over time mutations compound? Is it because there are more mutations as we age? Or is there a third issue which is, um, 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?
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
And the truth of it is we didn't come up with an answer, but it's probably all of the above. So it's probably that as we're aging we are undergoing more DNA damage and, um, 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 in one of the arguments that put forth although we have, we're not quite ready for this part of the story yet but I'll just say it now and we'll come back to it is, we don't have enough of the substrate that the sirtuin needs to repair DNA and that substrate is NAD. So again remember at the outset I said, "Look, there's two big categories to think about NAD." Most of what NAD is doing is operating as a cofactor for electron shuttling. That's the NAD, NADH, electron transport, electron accept, 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. 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 wanna come back to one other story which is the story of sirtuin activators. So what's the most famous sirtuin activator of all time? What is the heavyweight champion of sirtuin activators that has taken up 99% of the bandwidth in this space? It's a lovely little chemical called resveratrol. Okay, so resveratrol which gained a lot of fame and notoriety because it happens to be found in trace elements in the, uh, skin of grapes and therefore shows up in wine, uh, gained a lot of notoriety about 20 years ago when one lab doing one experiment somehow was able to convince some people including, uh, a very large pharma company that resveratrol increased lifespan.So, the thesis was resveratrol activates sirtuins. Sirtuin activation is important because of all the things we just said, right? It improves mitochondrial biogenesis, it suppresses senescent cells, and it- and enhances DNA repair. So, if you have something that is such a potent activator of sirtuins and you give it to a mouse, that mouse should live longer. Now, lots of experiments were done, they couldn't find that. But one experiment was done, but it was a- it was an interesting experiment. I've discussed this at least on two podcasts, including one with Rich Miller who runs the ITP, the Interventions Testing Program, which later tested resveratrol and found that it did categorically nothing. In this one experiment that worked, the investigators took a bizarre mouse model where they force fed it, uh, an enormously high fat diet.
- AHAndrew Huberman
Mm.
- PAPeter Attia
And in doing so, they created such an abundance of fatty liver that the livers of these mice, um, encroached the chest, the thoracic cavity of the mice. So, the mouse died prematurely because they couldn't breathe. And in that particular mouse model, resveratrol rescued the mice. So again, let's just assume that all of that is correct, and it's possible that there were even errors there, but let's just assume that's correct. Let's assume-
- AHAndrew Huberman
So, this is resveratrol delivered orally?
- PAPeter Attia
Yes.
- AHAndrew Huberman
In the food?
- PAPeter Attia
Yes.
- AHAndrew Huberman
Very high doses?
- PAPeter Attia
Megadoses.
- AHAndrew Huberman
The equivalent of barrels of grape skin.
- PAPeter Attia
E-exactly. Like, doses so high you could... There were, you know, 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, did the French live longer when they consume so much wine? And the answer was it's got to be the resveratrol. Turns out that's not true at all because, 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. 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, um, 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- if that's the problem you're going to face, it's possible, at least based on this one mouse experiment, that you are going to live longer. But again, it turned out that there was no other replication of this in mouse models that matter, and that always comes back to the ITP, the Interventions Testing Program, which is the most robust tool we have scientifically to measure these exogenous molecules. So, the ITP is an NIA-funded program that runs out of three independent labs. And by independent, I mean they're each doing the experiments independently, but they're- 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, um, when they did the resveratrol experiment, and they did it in combination with the people who found the result of that study. So, they consulted these people and said, "What dose should we give?" And they said, "Do this, do this, do this," and they did it and nothing. There was no effect of resveratrol. And that result has been consistent across the board. So, that's also a very important part of the story, which was if resveratrol was a sirtuin activator, and I don't know if it really is, it clearly has no effect on lifespan with the one little asterisk that says unless your body weight is 50% fatty liver, then maybe it does.
- 53:31 – 54:18
Perform with Dr. Andy Galpin Podcast
- AHAndrew Huberman
I'd like to take a quick break to let you know that the Huberman Lab team has launched a new podcast with host Dr. Andy Galpin. Andy is an expert in exercise science and human performance and has long been a fan favorite on the Huberman Lab podcast. This new podcast is called Perform with Dr. Andy Galpin, and it dives into topics such as how to build muscle and strength, how to improve your cardiovascular health, and how to optimize recovery and sleep for performance, and much more. Andy is an absolutely fantastic educator and true expert on all things human performance. I know you'll thoroughly enjoy his new podcast and learn a ton of useful knowledge from it, so please check it out and give it a subscribe wherever you're watching or listening to podcasts now. Again, the podcast is called Perform with Dr. Andy
- 54:18 – 1:02:17
NAD & NADH, Reactive Oxygen Species (ROS), Mitochondrial Health
- AHAndrew Huberman
Galpin.
- PAPeter Attia
So, let's see. Let's just take stock of where we are in the story. We 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.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
That paper was published in 2004, and that was a follow-up to papers that had been published in 2002, 1999, et cetera. Um, you... Later on, you'd have the 2012 transgenic mouse study, um... So, now the question is, okay-
- AHAndrew Huberman
How do you activate sirtuins?
- PAPeter Attia
How do you activate sirtuins?
- AHAndrew Huberman
Right.
- PAPeter Attia
Well, well, yeah. So- so- so... Or more to the point, why don't we just give people NAD? Okay, so again, the NAD story is NAD levels are declining with age in most tissues. Um, it appears most prevalent in the skin, of all places. And I think we should come back to this, 'cause there's one interesting finding associated with augmenting NAD levels in the skin, and my thought is, I wonder if it has to do with the fact that skin experiences the greatest decline in NAD.
- AHAndrew Huberman
It's also interesting because keratinocytes in skin turn over every 28 days or so, so you could imagine because it's a novel population of cells, that they would have steady expression of sirtuins and NAD, then they simply die for whatever reason, or that it starts off very high on day one of generation, then tapers off quickly. But-That's not the case, it sounds like. You know-
- PAPeter Attia
Yeah. On average, skin, over the course of your lifetime, will see about a 60% reduction in NAD, whereas other tissues, and this is now based on, you know, animal studies, the brain might see a reduction by 15 to 20%, and the same would be found even in humans looking at the blood. So if you just sample, you know, uh, whole blood in people at the age of 20, 30, 40, 50, 60, 70, 80, you're gonna see about a 20% reduction in NAD.
- AHAndrew Huberman
What about neurons? I mean, you've got the same set of central nervous system neurons your entire life, and of course some peripheral neurons as well, but-
- PAPeter Attia
Yeah, that's about it.
- AHAndrew Huberman
... there's some regeneration in the periphery.
- PAPeter Attia
Yeah.
- AHAndrew Huberman
So we need to
- NANarrator
Yeah.
- AHAndrew Huberman
... let's just talk about brain. So unless you're talking about the olfactory bulb where you have constant turnover throughout the lifespan, you have the same hippocampal neurons, except a small population, same hippocampal neurons, cortical neurons, retinal neurons that you were born with. Are we observing NAD levels tapering off as we age?
- PAPeter Attia
In animals, yes. Obviously, in humans, we're not doing that experiment, but yeah. Now, here's an interesting point. In 2015, a study was published in PNAS that looked at NAD levels in whole blood over time, and it found indeed NAD levels were going down about 10 to 20% over four decades or so. But that same study said NADH levels were going up by the same amount.
- AHAndrew Huberman
Explain the role of NADH for people.
- PAPeter Attia
NADH is the, um, electronic sector.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
So when you, when you... The e- So let's maybe take a step back of like what- how do we- why are you and I sitting here talking and not dead? Like...
- AHAndrew Huberman
'Cause we have enough NAD.
- PAPeter Attia
Right, right.
- AHAndrew Huberman
(laughs)
- PAPeter Attia
Like what's going on, right?
- AHAndrew Huberman
Right.
- PAPeter Attia
So you and I ate something at some point in the foreseeable past that contained chemical energy. So we ate something that was organic.
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
So it had, um... So primarily fats and carbohydrates contain carbon-carbon bonds and carbon-hydrogen bonds.
- 1:02:17 – 1:11:33
NAD vs NR vs NMN Supplementation; IV & Oral Routes
- AHAndrew Huberman
So when I hear about the role of NAD in this pathway, I think like most people, I think, "Okay, well then, I should just take more NAD and maybe I will age more slowly, or I will replace some NAD that's missing as I age in whatever cell type." Turns out that might not be so straightforward, right? I mean, I don't want to jump to supplementation just yet-
- PAPeter Attia
Yep.
- AHAndrew Huberman
... but if we are to back up from NAD a little bit and look at the pathway leading to NAD, it's NR, NMN, and NAD. We'll spell these out in a moment. And this sort of competition that's out there in the market is around either infusing or in some cases ingesting NAD directly, taking NMN, which is the precursor to NAD, orally, I haven't heard of anybody infusing it, or taking oral form NR, which is the precursors to NMN. My understanding is that NMN is simply NR minus a phosphate group.
- PAPeter Attia
Yeah. And, and I'll take a step back from this bef- first to say the following. Again, let... Because this topic is so confusing, I think it's just worth reminding everybody of what we now... everything we've said and where it brings us, right?
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
So I'm not gonna repeat the whole sirtuin thing. Let's just leave that alone. But we-
- AHAndrew Huberman
Because everything we're on right now is upstream of sirtuins.
- PAPeter Attia
Yeah. It's basically like once you establish that we think sirtuins matter, even though they don't work through caloric restriction, and that's about the single most obvious thing I can say-
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
... 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. 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. Um, and we're making a big leap that because they mattered in yeast, they're gonna matter in us. That's a huge leap for which there's zero evidence.
- AHAndrew Huberman
Right. And I'm only leaping further to this discussion about how to increase NAD because I know-
- PAPeter Attia
That's right.
- AHAndrew Huberman
... that's in the back of people's minds.
- PAPeter Attia
That's right.
- AHAndrew Huberman
We're not, we're not gonna double click here just yet. I just wanna frame that up-
- PAPeter Attia
Right. So why are we doing this? Yeah.
- AHAndrew Huberman
... because ultimately, ultimately that's where we are headed in terms of people making decisions as to whether or not they should take NR or take NMN-
- PAPeter Attia
Yeah. And the reason I'm being-
- AHAndrew Huberman
... or infuse NAD or none of the above.
- PAPeter Attia
And, 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 excorsi- uh, it just, uh, in the most detailed fashion possible-
- AHAndrew Huberman
I agree.
- PAPeter Attia
... so that people understand why-
- AHAndrew Huberman
Right.
- PAPeter Attia
... because it is just too easy, right? There's this great quote by JFK that I'm gonna paraphrase that is basically, "People endure, you know, enjoy the comfort of opinion without the discomfort of thought," right? So we need to sort of, this is, 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.
- AHAndrew Huberman
I would, I would say-
- PAPeter Attia
B-
- AHAndrew Huberman
... scientific justification for longevity. I'll, I'll go on record now saying that I take NMN-
- PAPeter Attia
Mm-hmm.
- AHAndrew Huberman
... and in some cases I will take NR and NMN and I observe, this is just N of one self observational data. I observe a very clear positive effect, but I don't think it has anything to do with extending lifespan.
- PAPeter Attia
And, and we should talk about both healthspan and lifespan benefits when we get to that part. But we're... So to bring us up to where we are now, where you are with should people be supplementing NAD, we're, we're basically at the point where we're taking a lot of leaps of faith and saying because NAD levels are going down and redox potential is going down, we believe supplementing NAD in one form or another makes sense. But before we do that, we should acknowledge something. Yes, NAD levels are going down, but we have no reason to believe that raising NAD levels will correct a problem. In other words, if the body operates between this level and this level of NAD, and if you go below this level you die, and you go above this level you die, and levels as you age go like this, do we believe that raising them to this does anything? We have... There's no evidence that says it does. So that's a leap of faith. It's okay to take leaps of faith. You just have to know you're taking a leap of faith. Okay, so leap of faith number one is the sirtuin thing. Leap of faith number two is the caloric restriction thing. Leap of faith number three is this matters in our species, the species of interest. Leap of faith four is, you know, the whole, uh, 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, how do we, how do we do that? Now you get into the tactic. Okay, there are three ways to do it, as you said. Um, one is you can intravenously take NAD. By the way, you could probably also orally take NAD. Uh, it would just break down in the gut into its constitutive products-
- 1:11:33 – 1:17:43
NR vs. NMN, Doses, Side Effects; Interventions Testing Program
- AHAndrew Huberman
Well, it's clear to me, um, based on my read of the data, that NR can cross the cell membrane directly.
- PAPeter Attia
Directly. Very easily. There's no obstacle to NR getting into cells.
- AHAndrew Huberman
Okay. And NMN cannot because of the extra phosphate group. So that if you take it sublingually or you ingest it orally, it goes into the gut, the phosphate group is cleaved, and because of that, the argument is that if one were to compare the benefits of taking NR versus NMN, there are more data to support NR as a precursor to NAD, a more effective precursor to NAD than orally ingested NMN. But some people will say, "Well, I'll just take more NMN than I would NR," and then this gets into the realm of cost effectiveness.
- PAPeter Attia
It's, it's, it's, it's just a commercial-
- AHAndrew Huberman
It starts-
- PAPeter Attia
... it's just a commercial issue.
- AHAndrew Huberman
... it starts becoming a battle between commercial sources-
- PAPeter Attia
Yeah, yeah, yeah, yeah.
- AHAndrew Huberman
... and, and, and I don't dispute that NR makes more sense as a precursor, especially at dosages of, you know, 300 to 600 milligrams versus 1500 milligrams, but I've opted to take sublingual NMN mostly based on cost. NR at the dosages people recommend is quite expensive.
- PAPeter Attia
Imagine you had to take it at the mouse doses.
- AHAndrew Huberman
Right.
- PAPeter Attia
You'd be spending about 300 bucks a day.
- AHAndrew Huberman
Right. It's just, it's not feasible. It's just not feasible. So, you know, I don't have a deep desire for my hair to grow faster or my nails to grow faster. It's more the increase in energy effect. Now, I will say that sublingual NMN is also a bit of a laxative. So (laughs) there are all these... And I say that, you know, somewhat chuckling, but, you know, some people say it makes them feel better. Well, is that because you're, you know, evacuating your bowels a few minutes or hours later and then you feel less bloated and you have more energy? You know, it's very unclear. I think what has not been done, as far as I know, is to compare orally ingested NR at, say, 600 milligrams, a relatively high dose, versus a gram of sublingual NMN, and then actually measure blood levels of NAD. If that experiment has been done and I'm not aware of it, or I'm not aware of it, then forgive me. Maybe someone will put it in the show note captions. But I guess this gets down to the question of how many people are taking oral NR or NMN, or are taking NAD infusions, which by the way are quite expensive.
- PAPeter Attia
Mm-hmm.
- AHAndrew Huberman
Anywhere from $300 to $1,000 a drip. That's pretty expensive.
- PAPeter Attia
Think about that.
- AHAndrew Huberman
What, what benefits are they getting?
- PAPeter Attia
Just, just, just think about that, right? Yeah, yeah, yeah, yeah.
- AHAndrew Huberman
Like, like, what are they getting out of this? Like, what are they getting?
- PAPeter Attia
Yeah, so-
- AHAndrew Huberman
Is it an acute increase in NAD that, that what?... that, that causes them to live, what, a week longer? I mean, we have no idea.
- PAPeter Attia
Well, so, so let's, let's try to use data to answer the question, right? So this is exactly the thing that the ITP, the Interventions Testing Program, was designed to test. And again, um, I, I would, I would... If people are interested in this, they should go back and listen to my two discussions with Rich Miller, where we go through gory detail of every molecule that has gone through the ITP. The ITP is hands down the most rigorous tool we have for testing molecules in anything other than the species of interest, because we can't do these experiments in human. We cannot test lifespan interventions in humans for the obvious reasons. So what is the next best thing? Well, it turns out, it's doing it in a non-inbred mouse in triplicate in three institutions. Like, you can't get more rigorous than this. The ITP has tested probably north of 50 molecules, meaning it has done the same experiment for 50 different molecules, and very few have extended lifespan. And a notable failure is NR.
- AHAndrew Huberman
Hmm.
- PAPeter Attia
NR was tested, and I believe it was tested at a very robust dose, either 500 or 1,000 milligrams per kilogram, and there was no extension of life. There was no improvement in healthspan. 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. 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. Then they d- redid the experiment and they gave it earlier. It worked. Uh, canagliflozin, as I mentioned, which is an SGLT2 inhibitor, it worked. Acarbose, a drug that inhibits glucose absorption, worked, and interestingly, didn't require weight loss. So the thesis behind giving acarbose to the mice was, it's a caloric restriction memetic, a CR memetic, and it worked, but then the, but the, but the treatment mice weren't any lighter than the non-treatment mice, which actually goes back to something you said at the very outset, which suggested that tight glycemic control independent of weight is a longevity benefit. The same was true with the SGLT2 inhibitor, canagliflozin. SGLT2 inhibitors cause you to pee out more glucose. Acarbose prevents you from absorbing it into 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-beta es- or seven, sorry, 17-alpha estradiol. And it only worked in male mice. So, uh, again, suggesting that, um... Well, eh, we can come back to that. It's m- more than we wanna get into at the moment.
- AHAndrew Huberman
Yeah.
- PAPeter Attia
But the point here is, there are very (laughs) few molecules that have withstood the scrutiny of the ITP. It, it is, it's a high bar. Metformin failed, by the way.
- AHAndrew Huberman
For... And the ITP is specifically for offsetting aging. Is that right?
- PAPeter Attia
It is, it is lifespan, but it also looks at some measures of healthspan. But it's, it's primarily, it is the gold standard for lifespan. Yeah.
- 1:17:43 – 1:25:17
Fatty Liver Disease & NR; NMN & Glucose; Clinical Significance
- PAPeter Attia
- AHAndrew Huberman
Because my understanding is that there are some studies that have explored the role of supplemented NR, maybe NMN as well-
- PAPeter Attia
Yeah.
- AHAndrew Huberman
... but certainly supplemented NR for sake of lowering inflammation to offset some of the negative effects of timezone shift, alcohol, um... I have a few others listed here. Um, overnutrition.
- PAPeter Attia
Yeah. So let's talk about that. So, so in 20... I don't remember what year it was. It was somewhat recent. Um, a study was published looking at NR with, uh, uh, something called pterostilbene. So pterostilbene is believed to be a sirtuin activator, like resveratrol. So a commercially available product called Basis, and it was tested. There was a, it was a three-arm study in humans. Um, roughly 30 people per arm. So decent-sized study, right? This is a big study. So you take 100 people, more or less, with fatty liver disease. Now, this was documented with, um, uh, an MRI of the liver. So, um, they're looking at, um, hepatic fat in the liver, um, by MR. And, um, using this type of MRI, if your hepatic fat index is over 5%, that's a high enough degree of what's called steatosis that you have fatty liver disease. Now, of course, this is not, um, this is not an, uh, a digital thing. It's an analog, right? There's a, there's a spectrum to this. So, so, you know, you start with just fat accumulating in the liver. But as more and more fat accumulates, you start to get inflammation that results in scarring and fibrosis, and ultimately, you would get to cirrhosis. So just keep in the back of your mind, the threshold at which we would say you're, you're in the, you're, you're, you're, you're in the danger zone is once you hit 5%. So this study randomized people to either, uh, a placebo or, uh, a regular dose of this product or a double dose of the product. And I can't remember exactly how much is in the product. I think it's either 250 or 500. So then, that would be what the regular group got of NR, and then the other group was getting 2X that. So it's either 250 and 500, or 500 and 1,000. I don't recall. Um, they also looked at something called the, um, th- they, they looked at many things, right? So they looked at all sorts of biomarkers. Um, and the primary outcome for the study was, did you see a reduction of this hepatic fat via the MRI?Um, so what happened? So they, they did the study and, uh, lo and behold, there was no difference. There was no difference in anything. Okay. So, so at high dose, at low dose, there was no difference in how much hepatic fat you had at the end of the study. There was no difference in body weight, there was no difference in inflammatory markers. There was no difference in glycemic markers, glucose levels, liver function tests, any of those things. So in that sense, it was a null study, uh, but they did one sub-analysis, which again, you have to be very careful of 'cause a sub-analysis is not a primary outcome, but it's, uh, kind of a, a way to go and parse the data. And they did find one statistically, uh, one statistically significant finding, which was if you limited the analysis to people who had a hepatic fat score below 27%, remember I said once you're above 5%, you're, you're sort of, you have fatty liver disease. Well, they had people anywhere from, you know, 10% to 40%.
- AHAndrew Huberman
Wow.
- PAPeter Attia
But if they looked at people who were below 27% in the low dose group, there was a statistically significant reduction in liver fat. Uh, if it sounds like I'm machinating, I am. Let me say it again. If you limited the analysis to people who had below 27% on this hepatic fat index, the people who got the full dose had no difference. They averaged 20% at the beginning of the trial and 19% at the end. No statistically significant difference. The placebo group averaged 20% at the beginning, 20% at the end, but the single dose of the drug went from 20% to 15%, which was statistically significant. It's not clear that that's clinically significant, which is a pretty consistent theme in this type of research. Never confuse statistical significance with clinical significance. If I gave you, if your blood pressure is 160 over 100 and I give you a drug that lowers it to 157 over 97, that could be statistically significant if the variance is small enough between people in the study, it has no clinical significance. I haven't changed the course of your life. So again, that to me is one of the f- one of the two big findings that people point to, to say, "Aha, there was some benefit in fatty liver disease with this." But again, when you read the fine print, which I just vomited out to you, I, I don't think anybody's looking at that going, "Oh, we, we just found the solution to, to NAFLD." The second study that people point to a lot was 2021 or 2022, um, 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, uh, we're gonna take two groups of people. You're gonna get a placebo for a period of time, or you're going to get NMN for a period of time. And, um, we're gonna then do what's called a, a gl- a type of glucose challenge-
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
... where we look at how well you dispose of glucose with and without insulin infusion. And in the, uh, placebo group, you would look at pre and post gluco- uh, so, so pre and post placebo treatment was there a difference in glucose disposal with no insulin? No. What about with insulin where you would expect to see much more glucose disposal? No difference. But when you did that with the NMN group, there was a statistically significant increase in glucose disposal with insulin infusion, but it was quite small. In other words, it was clinically very insignificant. And just to make, just to sort of figure out how insignificant it was, I went back and actually looked at some of the red light data-
- AHAndrew Huberman
Mm-hmm.
- PAPeter Attia
... 'cause there's an interesting study that shines red light on a person's back and then does an oral glucose tolerance test.
- AHAndrew Huberman
Oh, yeah.
- PAPeter Attia
Yeah. And you can actually reduce, like, postprandial glucose by 8%.
Episode duration: 2:30:41
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