Supplements for Longevity & Their Efficacy | Dr. Peter Attia

welcome to the huberman Lab podcast where we discuss science and science-based tools for everyday [Music] life I'm Andrew huberman and I'm a professor of neurobiology and Opthalmology at Stanford School of Medicine my guest today is Dr Peter AA Dr Peter AA is a medical doctor who did his training at Stanford University School of Medicine and John's Hopkins school of medicine Dr a 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 health span and lifespan Dr AA 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 and 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 known and what is not known about their ability to get into cells and any efficacy they may have for either longevity or health span Dr at 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 health span and or lifespan so by the end of today's episode you'll learn a lot about NAD you'll learn a lot about the biological pathway you'll learn a lot about the delivery routs the various supplements and why people think they may be useful why others perhaps even Dr AA and myself think they may not be useful for longevity you 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 rap amise and Metformin and whether or not fasting can improve longevity we get into that as well before we begin I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford it is however part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme I'd like to thank the sponsors of today's podcast our first sponsor is element element is an electrolyte drink that has everything you need and nothing you 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I like all the flavors if you'd like to try element you can go to drink element.com huberman to claim a free element sample pack with the purchase of any element drink mix again that's drink element.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 realtime 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 level steady without big spikes or crashes I first started using levels about 3 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 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currently ships to the USA Canada UK select countries in the EU and Australia again that's 8sleep.com huberman and now for my discussion about NAD and Longevity with Dr Peter AA Peter AA welcome how are you great to see you again great to be here again should we parse this NAD thing I think we should do you mind if I set up a little bit of a framework great so for people that want to live as long as possible I think fig 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 want to move appropriately and often enough so get enough Zone 2 cardio do your resistance training keep nerve to muscle connection strong avoid the sorts of things that would lead to falling and being immobile eat right there's a whole category of things there we're not going to talk about today although we might touch on a bit and know your genetics and make some good decisions on the basis of your genetics so the dos and don'ts the second category I would put under the umbrella of calories glucose insulin Etc that all kind of funnel in at least in my mind to mtor mamalian Target of rapamycin a molecule that's robustly expressed during development and essentially all cells of the body and then across the lifespan tapers off during puberty especially well let's say infancy through puberty cells are expressing so much 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 time stamp as opposed to the verb but I would argue as a developmental neurobiologist by training that it's one of the most rapid phases of Aging of our entire lifespan look at a picture of you when you were five look at a picture of you when you were eight versus 15 you look very different and your size is robustly different by the way I just did this exercise because 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 of her birth so we have a picture of her every single year holding a clock that says 356 at 3:56 p.m. because that's when she was born and I just went through and pulled each of the last 16 of them from the day she was born all the way up and you're right the biggest changes are actually in about the first 10 years 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 2 to three and 3 to four and four to five are ridiculous changes yeah I mean the brain the same brain has to learn an entirely new body every year in terms of how to move it limb length Etc so a lot of the so-called anti-aging or longevity approaches that fall under this umbrella relate to things like caloric restriction or taking drugs such as rapamycin and of course Maman Target of Ramin 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-call NAD pathway NR nmn NAD being the major players and we'll talk about some of the biochemical and enzymatic steps in between and then I suppose there's a fourth category which we could say is you know the do everything even the most esoteric of things category this is a rare category there are folks like Brian Johnson who spend a lot of time in this category specifically you know taking very high doses of polyphenols limiting their caloric intake to just early part of the day I think he eats dinner at 11:00 a.m. I don't know if it's still qualifies as dinner at 11:00 a.m. but his final bite of calories is I believe at 11:00 a.m. doing everything from red light to PRP platelet platelet rich plasma excuse me um and essentially the kitchen sink approach to longevity and aging did I miss any categories so I I I would frame it slightly differently because I I like categories to be more mey 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 want to do those things correctly or not correctly or do you want to do those things in a manner that promotes health or erodes Health right so again there's nobody listening to us who doesn't eat but again you can choose how much you eat and what you eat and when you eat there's nobody who's alive who isn't moving because Locomotion is life and the absence of life is the absence of locomotion but you can certainly choose to move very little you can choose to move a lot and you can choose to decide on how youve move you alluded to it already right you can you can move in a certain way that puts your Aerobic System in a zone that maximizes fat oxidation we call that zone two you can move at a level where you consume incredible amounts of oxygen at your maximum aerobic level you can choose to move in a manner that uses resistance and and gravity against you and all those sorts of things similarly we all have to sleep right Matt Walker would probably tell us the number of days you could go with sleep without sleep before you would literally perish 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 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 I'm just saying this is the way I think about it I would then say what are the molecules that I could take that specifically Target disease processes so I kind of think of like if we want to live longer and I described this I think in chapter 4 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 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 because that was a huge hit on mortality 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 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 sgt2 inhibitor or a glp1 Agonist and you will directly impact those things you could take uh a pcsk9 inhibitor or a Statin or bidic acid you will directly impact those disease processes you will delay the onset of those diseases and you will reduce the mortality associated with them then I would go to a third category that says are there exogenous molecules that you can take that don't Target a disease per se specifically but we're going to put them in a category called geroprotective which is they target Hallmarks and Pathways of Aging that you've described so we talk about all of these things that occur in an aging phenotype where we see more inflammation we see a greater abundance of senescent cells we see reduced 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 9 and 14 the number just keeps changing arbitrarily but it doesn't really matter we have these Central things that everybody would agree Define what an aging phenotype is 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 rapy so rapy targets a very specific Hallmark of aging and we can talk about what the experimental evidence is to suggest that that makes you live longer so I would sort of say those are the big three categories and then basically the fourth category you could just say is like how do you put them all together and how aggressive do you want to be in culminating those of course none of this touches on another area that I want to talk about that we won't talk about today which is like how does all that factor into kind of emotional health and happiness and 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 podcast on that topic right you've had Paul Con 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 because 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 mey um in that you know we talk about the behaviors um the exogenous molecules that Target diseases the exogenous molecules that Target uh aging aside from food what exogenous molecules do you take I take a few right so I take some that are disease specific right so I take a pcsk9 inhibitor I take bidic 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 and Juro protection which is rrap ayin and um and also the SG 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 canaga flosin in the interventions testing program the ITP which I am sure will talk about in the context of NAD as well what dosage of rapamycin do you take I take eight milligrams once a week for as long as I can tolerate it but that I usually have to take breaks why is that I get these vicious apus ulcers uh little mouth sores canker Source yes about 10% of people get them hm 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 rap AIS by virtue of the side effect by virtue of these miserable side effects 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 and the idea there is that you're limiting mtor you're causing your cells to grow less mature slower and and in that sense slowing down aging is that the idea 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 Ramy 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 a top Agy why would that suppress ccent 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 Ramy or its analoges for example ever alus um when you look at the administration of these molecules to organisms that are as close as possible to the species of Interest we 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 UK chariots caloric restriction and rap ay very important point right how do you feel when you're on rap ayon aside from the canker Source 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 um and maybe that's just a placebo effect 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 or happen to overeat a little bit just because is it going to collide with rapamycin's potential positive impact on slowing aging 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 cabin's dog aging study um which uh is is is going to 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 another trial in mammals and 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 want to 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 you really start to believe there's a signal there so now to be able to see this in a higher order mammal um and ultimately in companion dogs which is where Matt cabin is looking I think that's that's going to be really exciting and I've often said to my patients look in 2026 I'm either going to feel a lot more conviction about taking rapy and and prescribing it to some of my patients though again not most or I'm going to you know have a second look at this and say you know maybe maybe we just shouldn't be taking this right because I do think that the dogs study is going to be more telling um but again we'll have to wait and see what that shows without going off track too much my understanding is that the dog study was halted because of a lack of federal funding um is it continuing it is going to go on there's there's yeah it's so so initially there was kind of insufficient funding to do the study in an adequate way um and then it turned out there was a shortfall of about $2.5 million um to do the the study that really wanted to do and then actually a group of us raised that money for Matt and did that so great uh me and a so 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's what what did get pulled back by the NIH inexplicably and um 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 followup on this so yes unfortunately um until we can get more funding we're we're we're not going to be able to maybe do as much as we'd like to do and understand this which again when you look at some of the things that are funded it's hard to believe that there's not a more interesting question right now in biology than this drug that seems so promising why we wouldn't want to know you know if this is something we should all be taking is is kind of a mystery to me yeah I was on ni study sections for many years reviewing grants I rotated off as a regular member a little over a year ago and I can tell you that the whole process is designed to be as um targeted to the best and most exciting work possible but there's a number of features now that make it such that it's largely the work that's already mostly completed that gets funded you even go like how's that work but anyway we could have a whole other Journal Club discussion about funding but I I had to ask I was curious hope hopefully that um uh that study will get completed and thanks for raising those funds let's talk about NAD yes it's in essentially every cell of the body except red blood cells correct you know I 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 Redux potential so it's possible NAD is in every single cell yeah and it's generally thought to be associated with energy production and mitochondrial Pathways in every single cell right so NAD is again one of the most ubiquitous molecules in the body and most of what it does and I mean most meaning like somewhere between five and 600 Pathways of it utilize NAD as a co-actor meaning that it's not consumed in a chemical reaction but rather it serves as an electron shutle 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 0 to 14 scale we die full stop um so similarly NAD is managed across all ages and across all physiologic uh uh uh conditions in a super tight band there's another place where NAD shows up and that shows up as a substrate right so co-actor means used co-enzyme used but not consumed recycled that's 99% of it a small fraction of it is used and it's used by these things called cerin that consume NAD as an actual substrate in the process of DNA repair and maybe we can go into this but this is really where the story picks up it's also as I recall where the story began that's exactly it was some experiments where the cerin 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 phena type where you have a knockout mouse that lacks a gene so that's loss of function or a Trin 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 y um but gain of function and loss of function assuming that the results J 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 in the middle because the role of Sonic hedgehog at the midline and you could say okay well loss of function here here's the role of Sonic Hedgehog but the ideal experiment is to put the gene back in and then rescue that phenotype because as any logical mind can tell there could be many things Downstream of Sonic Hedgehog that could create the phenotype that you observe but if you put Sonic Hedgehog back in yes that's still true but you get more reassurance that that's the gene of Interest so with respect to cerin as I recall they deleted the cerin 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 dubal from UCSF on clotho which is an amazing scientific story and it's a great story because it shows how accidents can lead to great discoveries right so there was a a researcher in Japan who was really interested in understanding hypertension high blood pressure and they had created a mouse model where they were trying to knock out certain sodium channels to see if they could perturb blood pressure and then there was this one strain of mouse with this one knockout that died really really quickly and it developed like devastating neurogen disease and died very quickly and you know like a good scientist he didn't say well that sucks I'm going to discard that one CU it didn't give me what I wanted which was the blood pressure change and he kind of went and figured out what was going on and he figured out that there was a certain Gene that he had hit that wasn't a sodium transporter and instead was this other Gene he named it clotho so 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 so it's both necessary and sufficient for extended how you can say well that's a longevity Gene as many of you know I've been taking ag1 for more than 10 years now so I'm delighted that they're sponsoring this podcast 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 new nutrition is but here's what 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 AG one once and often twice every day is that it ensures I get all of those vitamins minerals probiotics Etc 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 well-being related to mental health and physical health if you'd like to try ag1 you can go to drink a1.com huberman to claim a special offer they'll give you five free travel packs with your order plus a year supply of vitamin D3 K2 again that's drink a1.com huberman so let's go to the ceran story so it goes back to the late 90s Matt cllin 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 Rapa and along with one of his colleagues David satini and a few others um but when when Matt was a post dog he did an experiment in a strain of mice uh pardon me a strain of yeast I think it was a w303 strain of yeast and he overexpressed sir two 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 sir 2 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 cerin that hypothesis sort of fell apart about four years later when Matt cabin again this time with Brian Kennedy did another experiment in a yet a third strain of yeast that allowed them to test hypothesis because there was a problem with the story I just told when you took the 303 strain this is the strain that when overexpressing sir two lived longer if you took that strain and you calorically 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 if you overexpress sir to 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 you know these don't matter if you calorically restricted them they lived longer if you overexpress sir two they lived longer if you did both they lived even longer it was additive again further suggesting that 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 ceran overexpression is through the caloric restriction pathway and vice versa and that's wrong my reading of the literature in addition to every person I have talked to on this who works in the space including Matt cin who has done the most research on this is that there is no evidence that caloric restriction and cerin 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 what about in humans what what about it specifically that experiment's never been done and never will be done the joke I was trying to set up for is the one I'll make now which is no one wants to be in the control experiment um that said nobody want want treatment experiment either you got me you got me you beat me to the punch uh no one wants to be in the treatment group either because it requires eating so little yeah you know it just the the yeah the joke is the joke is you probably will live longer and it will feel even worse like it's just it's yeah 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 fra 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 um uh 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 uh situations they don't live longer so it's not always the case that caloric restriction extends life and therefore well 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 holster in 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 restrict right clor restri we've got this thing which you know for 50 years we've known has a signal that really says it's life extending and we've got this yeast where it works and this other yeast where ceran activation works oh it's got to be St but again if you if you go through the story in detail as I just did there's no evidence whatsoever that cerin have anything to do with chloric restriction and vice versa it's incredibly interesting because I think when you look at cell biology and you see these parallel pathways when you see these effects of experiments where changing cerin or changing caloric restriction independently increased lifespan combine the two you get this what appears to be a synergistic effect but it's as you pointed out an additive effect seems like a pretty straightforward experiment to do you could just do an occlusion right you could then put back in the cerin OR adjust calories and see whether or not you get the effectively whether the math is corrected yeah you know so um 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 cerin are truly um a factor that drives longevity how can you activate them right how do you activate a ceran 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 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' be much more confident it works in US yeah making a fly mutant dropa mutant that overexpresses cin a worm cigance mutant that overexpresses cins that's a pretty quick experiment to do because of this short generation time of those species right now Mouse it's a longer experiment but I'm guessing all of those experiments have been done yeah and the only one that I can find that has demonstrated a survival Advantage is one particular transgenic Mouse experiment that overexpressed uh CT 6 and it did indeed for the male mice increase lifespan by 10 to 15% so this is one transgenic Mouse model that overexpressed CER six and those mice the male mice lived 10 to 15% longer the female mice did not we should probably clarify what a transgenic Mouse is I talked about knockout mice that's when a gene or genes in some cases is deleted from The genome so it's null it does not express that Gene the gain of function would be to put back that Gene in that would be a Knockin 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 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 it overexpresses C to in 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 CER six CT six yeah so every cell in the body that normally would Express C six would Express more 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 I'm guessing unless they made it clear that it was tissue specific that it's whole body so we're talking about it when Peter says transgenic Mouse he's talking about a mouse that has this trans Gene that causes it to express more cer2 in6 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 right so again just a summarize that that's 2012 we have this one transgenic Mouse you put CT six you over Express search six 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 Meyer 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 CT you are going to live longer that tends to be completely independent of caloric restriction that's the single thing I can say with the greatest confidence and there is at least one trans genic strain of mice that if you get it to overexpress a different C CT six but again they're these are homologues throughout the species so we don't have to get I don't think we need to get wrapped up in CT 2 versus C six um you will at least make the male mice live longer but not the females what sorts of things are Downstream of cerin and that question translated to normal English is what is changing as a consequence of increasing the cerin 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 senent cells I I'm just throwing out possibilities actually you've hit two of the big three right off the top right so we believe that when cerin are activated they're improving mitochondrial biogenesis um they are um uh in increasing DNA repair so that's probably the biggest one by the way that's sort of what brings us to um um the um the NAD story um and also reducing uh 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 siness and cells uh you increase mitochondrial biogenesis and you increase DNA repair those would be all great things to do and we think that Sans are probably doing all of them 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 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 chandelle and Tim Ferris so the four of us just took a trip to Easter Island to see the birthplace of Rapa so it's kind of like vacation SL science Journey a nerdy vacation 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 nonlinear so it's not just that cancer goes up with age it goes up like that um and I said I'll offer two hypotheses which is more compelling is it simply that as we're aging uh DNA replication again taking a step back for the listener uh cancer is a genetic disease meaning uh by definition it is uh sort of the canonical problem with cancer is a genetic mutation that leads to two properties of a cell the inability the cell to uh rep uh to control replication so it interrupts cell signaling so cell replicate but then don't know when to stop and then the introduction of the capacity to spread this property called metastasis those are the two Hallmarks of cancer so 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 and the truth of it is we didn't come up with an answer but it's probably all of the above so it's probably that as we are aging we are undergoing more DNA damage 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 to repair DNA and 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 ceran needs to repair DNA and that substrate is NAD so again remember the outside I said like there's two big categories to think about NAD most of what NAD is doing is operating as a co-actor 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 cerin 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 a substrate to repair DNA and DNA repair is an important way to thwart a 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 ceru and activators so what's the most famous ceran activator of all time what is the heavyweight champion of ceran activators that has taken up 99% of the bandwidth in this space it's a lovely little chemical called RIS veratrol okay so Resveratrol which gained a lot of Fame and notoriety because it happens to be found in Trace element 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 RIS veratrol increased lifespan so the thesis was RIS veratrol activates cerin cerin activation is important because of all the things we just said right it improves mitochondrial biogenesis it suppresses ccent cells and it and enhances DNA repair so if you have something that is such a potent activator of cerin and you give it to a mouse that Mouse should live longer now lots of experiments were done that couldn't find that but one experiment was done but it was 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 ratol and found that it did uh 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 and in doing so they created such an abundance of fatty liver that the livers of these mice um uh 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 RIS veratrol 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 resveratol delivered orally yes in the food yes very high doses Mega doses the equivalent of barrels of grape exactly like doses so high you could there 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 do the French live longer when they consume so much wine and the answer was it's got to be the ratol turns out that's not true at all because yeah you would need to be drinking your body weight and wine a day to get the doses of RIS veratrol 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 were 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 intervention testing program which is the most robust tool we have scientifically to measure these exogenous molecules so the ITP is an ni 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 RIS veratrol experiment and they did it in combination with the people who found the result of that study so they consulted these people and said what dose should we give and they said do this do this do this and they did it and nothing there was no effective RIS veratrol and that result has been consistent across the board so that's also a very important part of the story which was if RIS veratrol was a ceru an activator and I don't know if it really is it clearly has no effect on lifespan with the one little asterisk that says unless your body weight is 50% fatty liver then maybe it does I'd like to take a quick break to let you know that the 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 hubman 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 sleep for performance and much more Andy is an absolutely fantastic educator and true expert on all things Human Performance I know you'll thoroughly enjoy his new podcast and learn a ton of useful Knowledge from it so please check it out and give it a subscribe wherever you're watching or listening to podcasts now again the podcast is called perform with Dr Andy Galpin so let's see let's just take stock of where we are in the story we got the whole yeast ceran situation which is at least in some East ceru an 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 and that was a follow-up to papers that had been published in 2002 20 1999 Etc um you later on you'd have the 2012 transgenic Mouse study um so now the question is okay how do you activate certu how do you activate well well yeah so so so or or more to the point why don't we just give people NAD okay so the 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 because there's one interesting finding associated with augmenting NAD levels in the skin and my thought is I wonder if it has to do with the fact that skin experiences the greatest decline in NAD it's also interesting because catino sites 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 cerin 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 yeah you know on average skin over the course of your lifetime will see about a 60% reduction in NAD whereas other tissues and this is now based on you know animal studies the brain might see a reduction by 15 to 20% and the same would be found even in humans looking at the blood so if you just sample you know uh whole blood in people at the age of 20 30 40 50 60 70 80 you're going to see about a 20% reduction in NAD what about neurons I mean you've got the same set of central nervous system neurons your entire life and of course some peripheral neurons as well but there's some regeneration in the periphery so we need to let's just talk about brain so unless you're talking about the old factory bulb where you have constant turnover throughout the lifespan you have the same hippocampal neurons except a small population same hipocampal neurons cortical neurons retinal neurons that you were born with are we observing NAD levels tapering off as we 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 explain the role of nadh for people nadh is the um electron acceptor so when you when you the so let's maybe take a step back like what how do we why are you and I sitting here talking and not dead like because we have enough NAD right right what's going on right so right you and I ate something at some point in the foreseeable past that contained chemical energy so we ate something that was organic so it had um 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 energy so we break it all down into these constitutive molecules namely glucose on the carbohydrate front and free fatty acids on the fat front and then our bodies break those things down further into smaller molecules that get shuttled into the mitochondria where the Lion's Share of our energy Liberation comes from and what we do is we take that chemical energy that is stored in a carbon to carbon Bond or a carbon to hydrogen bond and we turn it into elect electrical energy and people have heard this term it's called the electron transport chain so there are these four complexes in the mitochondria and there's an inner membrane in an outer membrane across which these mitochondrial uh uh these large mitochondrial complexes reside and what they're doing is they're building up a huge electron gradient by 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 M ADP and ultimately make ATP the finished product is water and carbon dioxide so we eat and we take that chemical energy and food we utilize oxygen in the mitochondria to make ATP carbon dioxide which we breathe out and water which we breathe and pee out so what NAD and nadh are doing is playing an absolutely essential to life role in facilitating the transfer of chemical energy to electrical energy back to chemical energy ATP is just taking it from one chemical form in food to the electrical form as the intermediary in the mitochondria back to an electrical form of ATP so you and I are walking around flush with ATP which as we sit here right now we're constantly firing off phosphates again now turning the chemical energy back into electrical energy and away we go so yeah this this whole NAD nadh thing is like you know it's as Central to our existence as any form of respiration so my point let's go back to the story the story was NAD levels are going down as we age but nadh levels are going up suggesting that the total amount of NAD and nadh is the same and what's declining as we age should less be thought of as a reduction in NAD and should more be thought of as a reduction in what's called Redux potential the ability to do what I just said so when people say NAD levels decline with aging the answer is yeah but what's really declining as we age and this kind of comes back to what you said at the very very outset like what's happening at the cellular level I think what's happening is our mitochondria are not as good as we age and we have less Redux potential and I would say a fair number of so-called anti-aging approaches are targeting the so-called reactive oxygen species Ross's which impede mitochondrial function essentially uh this is an opportunity for me to call out the work that I think is at least intriguing which is uh the work of a colleague by the name of Glenn Jeffrey at the University of College London he's been in the field of visual Neuroscience for a very long time and a few years back he started doing some experiments on animals and now also two studies published on humans showing that exposing the Aged eye so 40 and older to red light and near infrared light for a couple minutes a few times a week can spare certain processes involved in Vision photo receptors how does this work well the idea this isn't proven yet the idea is that it's reducing reactive oxygen species and thereby improving mitochondrial function in what is perhaps the most metabolically active cell type in the entire body not just the eye which are the photo receptors so it's an intriguing set of studies again we don't have all the mechanisms worked out but it brings us around again to this idea that mitochondria are vitally important for the functioning of cells things that impede the function of mitochondria can either reduce the output of Andor kill cells and so anything that can improve Redux can potentially keep a cell around longer functioning better so when I hear about the role of NAD in this pathway I think like most people I think okay well then I should just take more anad 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 but if we are to back up from NAD a little bit and look at the pathway leading to NAD it's NR nmn and NAD we'll spell these out in a moment and the sort of competition that's out there in the market is around either infusing or in some cases ingesting NAD directly taking nmn which is the precursor to NAD orally I haven't heard of anybody infusing it or taking oral form NR which is the precursor to nmn my understanding is that nmn is simply NR minus a phosphate group yeah and and I'll take a step back from this first to say the following again let because this topic is so confusing I think it's just worth reminding everybody of what we now everything we've said and where it brings us right so I'm not going to repeat the whole ceran thing let's just leave that alone because everything we're on right now is Upstream of cin yeah it's basically like once you establish that we think cerin 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 cerin like RIS veratrol we don't seem to have things that we can give you that activate cerin we're now on to the next part of the story which is okay cerin matter they don't seem to matter we think cin 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 going to matter in us that's a huge leap for which there's zero evidence right and I'm only leaping further to this discussion about how to increase NAD because I know that's in the back of people's minds we're not we're not going to double click here just yet I just want to frame that up 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 NAD or none of the above and the reason I'm being such a hard ass about this Andrew is I spend so much time Fielding questions on this that I realize we just have to talk about this and excor it just in the most detailed fashion possible so that people understand why because it is just too easy right there's this great quote by JFK that I'm going to paraphrase that is basically people Ure 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 I I would say scientific justification for longevity I'll I'll go on record now saying that I take nmn and in some cases I will take NR and nmn and I observe this is just n of one self- observational data I observe a very clear positive effect but I don't think it has anything to do with extending lifespan and and we should talk about both Health span and lifespan benefits when we get to that part but we're so to bring us up to where we are now where you are with should people be supplementing NAD we're 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 Redux 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 ceran thing leap of faith number two is the ceric 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 ceran 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 were 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 it would just break down in the gut into its constitutive products um and then probably reform but for the purpose of how people actually do this they intravenously get NAD because it's not orally bioavailable or as you said they orally take two precursors NR and nmn my personal view on this is there's not really much of a difference in what you do in other words at the end of the day all of these things are generally going to increase NAD levels in the blood so a couple of um kind of practical notes I've taken NR in capsule form I've taken nmn typically in powdered form where I put it sublingually under the tongue my understanding is that have you done intravenous NAD I sure have and um and did you experience nasin flush no I I took NAD in a um as an infusion I probably done it five or six times and for the first 10 minutes of the infusion you feel like somebody stepping on your chest with a boot your legs cramp up you feel nauseous I did not take the anti-nausea Med that was offered I don't like taking things if I can avoid it I just figured I'll just experience this it was very uncomfortable MH to the point where you couldn't read a paper or a book you just you just want to be left alone you actually get a little bit irritable you're like this is awful you know every noise in the room is a bit too loud during that first 10 minutes and then 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 to which I'm like why don't you spread your legs let me kick you right in the nuts that's going to feel even worse is that doing something good like the fact that something feels so awful shouldn't be used as an explanation for why it's doing good physiologically right I don't know what it was doing physiologically except making me feel miserable during the infusion there are ways to adjust this even without the anti nausea meds for instance you can slow the infusion um that's the typical way people will put it in over the course of several hours anywhere from 3 hours to as brief as 30 minutes is kind of the record that I've heard about for 500 milligrams of NAD if you put 1,000 milligrams in there obviously it's more painful and you have to anyway there are a bunch of practical considerations you feel now maybe it's Placebo but one feels quite good afterward so as soon as the drip is done you feel better than you did prior to the drip how do you feel if you just receive an IV infusion of the same volume I've done that because I've received saline drips um you also feel pretty good yeah um it's hard to disentangle these things um and typically they'll put other things in the bag glutathione some vitamin C you know they tend to sell these as kits I just decided to try it it it seemed fine I did it when traveling I don't know maybe I'm due for another one soon but for me the more typical way to try and increase NAD or whatever because I don't know what it's doing exactly but I like the effects of taking sublingual nmn the single most let's say Salient to me uh anecdotal data on taking sublingual nmn is that it makes my hair grow really fast it makes my nails grow really fast and I do feel an increase in energy and I take it first thing in the morning morning um and what dose one and a half gram 1500 milligrams so by by the way if you translate you know the the doses that they give mice in the studies where they're testing the efficacy um are typically on the order of 500 to 1,000 milligrams per kilogram whoa yeah I'm 100 kilograms yep whoa okay so picture that the next time you're giving yourself some NAD or NR I'm not even approaching that yeah um at all well it's clear to me um based on my read of the data that NR can cross the cell membrane directly directly very easily there's no obstacle to NR getting into cells okay and nmn cannot because of that extra phosphate group so that if you take it sublingually or you ingest it orally it goes into the gut the phosphate group is clean and because of that the argument is that if one were to compare the benefits of taking NR versus nmn they're more data to support NR as a precursor to NAD a more effective precursor to NAD than orally ingested nmn but some people will say well I'll just take more nmn than I would NR and then this gets into the realm of Cost effectiven commercial starts becoming a battle between commercial sources 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 and are at the dosages people recommend is quite expensive imagine you had to take it at the mouse doses right you'd be spending about 300 bucks a day 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 to grow faster or my nails to grow faster it's more the increase in energy effect now I will say that sublingual nmn is also a bit of a laxative so there 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 early and ingested NR at say 600 milligram a relatively high dose versus a gram of sublingual nmn and then actually measure blood levels of NAD if that experiment has been done and I'm not aware of it I'm not aware of it then forgive me maybe someone we'll put in the show note captions but I guess this gets down to the question of how many people are taking oral NR or n and Men or are taking NAD infusions which by the way are quite expensive mhm anywhere from $300 to $1,000 a drip that's pretty expensive what benefits are they getting what are they getting out of this like what are they getting 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 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 noninbred mouse in triplicate in three institutions like you can't get more rigorous than this the ITP has tested probably north of 50 molecules meaning it has done the same experiment for 50 different molecules and very few have extended lifespan and the notable failure is NR NR was tested and I believe it was tested at a very robust dose either 500 or 1,000 milligrams per kilogram and there was no extension of life there was no improvement in health span there was no change megad do NR Placebo same result conversely let's consider some of the successes of the ITP rap a when you give rap a the first time they did it because they had a hard time formulating the Rapa they weren't able to started 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 going to work when you start this late including caloric restriction by the way although it has worked in one experiment but nevertheless it worked and when you gave Raa that late in life it still worked then they redid the experiment and they gave it earlier it worked kagaoan 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 th pis behind giving a carbos to the mice was it's a caloric restriction mimetic a CR mimetic and it worked but then 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 canaga floen sglt2 Inhibitors cause you to pee out more glucose a carbos vents 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 beta sorry 17 Alpha estradiol and it only worked in male mice so again suggesting that um well we can come back to that it's more than we want to get into at the moment but Point here is there are very molecules that have withstood the scrutiny of the ITP it it is it's a high bar met foran failed by the way for and the ITP is specifically for offsetting aging is that right it is it is lifespan but it also looks at some measures of Health span but it's it's primarily it is the gold standard for lifespan yeah because my understanding is that there are some studies that have explored the role of supplemented NR maybe nmn as well but certainly supplemented NR for sake of lowering inflam to offset some of the negative effects of time zone shift alcohol um I have a few others listed here um overnutrition 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 teras Bean so tertill Bean is believed to be a ceran activator like RIS veratrol so 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 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 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 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 therosis so just keep in back of your mind the Threshold at which we would say you're you're in the you're get you're in the danger zone is once you hit 5% so this study randomize people to either uh a placebo or a regular dose of this product or a double dose of the product and I can't remember exactly how much is in the product I think it's either 250 or 500 so then that would be what the regular group got of NR and then the other group was getting 2x that so it's either 250 and 500 or 500 and a th000 I don't recall um they also looked at something called the um 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 lowd dose there was no difference in how much hepatic fat you had at the end of the 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 H but they did one subanalysis which again you have to be very careful of because a subanalysis is not a primary outcome but it's kind of a way to go and parse the data and they did find one statistically 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% wow but if they looked at people who were below 27% in the lowd do group there was a statistically significant reduction in liver fat if it sounds like I'm masting 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 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 Naf D the second study that people point to a lot was 2021 or 2022 um this came out of a group at washu I believe and they looked at nmn and they looked at glucose disposal so in this study they asked the question um 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 um we're going to then do what's called a a a type of glucose challenge 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 glucose 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 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 I mean not in this not in this patient population because these people were all pre-diabetic 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 would probably point to these St two studies because they're Inhumans 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 you know a result a response of hepatic fat going from 20 to 15% which is still 3x above the threshold to hepati liver disease and in this other study you had this you know very very modest reduction pardon me increase in glucose disposal but I mean like we're you know there's a saying in my in my sort of Mind Andrew which is like if you have to resort to really interesting statistical machinations to see something there probably isn't something very interesting there right right I totally agree and I think you know at this point I'm questioning whether or not I'm wasting my money taking NN or I take NR is really for these anti-inflammation um reported purported effects um I just want to pay a little bit of attention to the whole commercial battle around this because I think it's relevant I mean I think right now as far as I know the FDA has essentially said that nmn should not be sold as a supplement but it is still being sold as a supplement so there's a little bit of a ignoring of the and of the fda's request NR as far as I know is authorized for sale as a supplement yeah 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 um 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 um and they you can't make a claim about it that isn't validated by some sort of study so um I honestly Andrew I think the whole nnnr debate is irrelevant I I think it's just a commercial debate I think it's literally just posturing about how can I carve out a different Market I don't think there's a scientific reason to favor one over the other well you just answered the question I was going to ask but I suppose the question therefore becomes is there any benefit to taking either of them for sake of lifespan there's one benefit I could find there's one benefit I could find that I think is genuine there are a few other really insignificant ones that fall into the category of goofy studies that cherry pick by data mining okay so 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 and the answer is oh look there's a small decrease but it was totally insignificant clinically even if stati Ally significant and oh it increased your you know six-minute walking test or whatever and it's like a six-minute walk test or whatever in people who were in their 20s is irrelevant it had no change in V2 Max it had no change in any meaningful metric of performance one test one study I could find that actually had what looked like a signal to me and it was a study that looked at skin cancer rates um 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 um once just got a phosphate group on there you might need to take a little bit more of the nmn versus NR or maybe a lot more who knows in order to get the same increase in NAD is my understanding so this one study found somewhere between a 60 and 80% reduction in basil cell and squa cell carcinomas I found no difference in melanomas so again you know this because you just did a podcast on this melanomas the skin cancer that kills you but that's not to say that you know squa cell and basil cell carcinomas aren't problematic they can be very uh you know deforming uh they can require pretty aggressive surgeries to address them and so if indeed there is something that can reduce the risk of basil and squel carcinomas that may be a rationale for taking it and I should say that basil and Squam Cel carcinomas are very very common they are very common and they are very clearly associated with sun exposure a way that even melanoma is more complicated and has a genetic component and there are other things going on but squamous and basil cell carcinoma are very clearly related to sun exposure uh as you said they're quite common and so you know personally that's an experiment I would like to see repeated because if indeed um NR and/or nmn reduce the risk that significantly of sell and basal so 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 I mean I I don't work outside so it's like it wouldn't matter to me but there are a lot of people for whom either either their skin color makes them more susceptible or their their um you know their pastimes or or frankly their their their line of work makes them more susceptible you know maybe there is a case to be made for it there if if you could if you could literally take 60 to 80% of your risk away on S Mr basell carcoma that could matter and by the way I don't know if this is true but you you may recall at the outset the outset I said that when you look at all the tissues in the body where we see a reduction in NAD do you remember what had the biggest reduction it was skin so there's a part of me that wonders like is the reason that the only place we see a really good signal potentially for NR and nmn supplementation is is in a skin cancer although it's not melanoma which is the one we'd really want to see I mean if this reduce the risk of melanoma I would take it right because even though I'm dark skinned I'm still susceptible to melanoma um so I just wonder that could be true true and unrelated but that's that's the first thought that crossed my mind when I came across that literature was hm I wonder if the enormous reduction in uh tissue NAD in this particular tissue explains why maybe there is a benefit to it assuming somebody is averse to feeling like they have an elephant stepping on their chest and they're going to pay $750 for it AKA and NAD infusion once a week and look people may opt to do that with the disposable income could do that drip it in slower not feel nauseous increase NAD with the hope hope hope that maybe it's going to extend your life most people considering supplementation to augment the NAD pathway are going to default to either taking INR or taking nmn by the way just going back to the group that have decided that $1,000 for an NAD infusion and dripping it in over two hours is a good use of their time what do you think would be the Improvement in their lifp if they spent that 2 hours exercising significantly greater interesting all right just just not and and less expensive but yeah right you could also weight train for the first hour and then enjoy some food afterwards Lane Norton taught me that there are data showing that exercise in particular resistance training improves the rewarding properties of food makes food taste better which we've all kind of intuitively experienced so you spend the first hour working out hour eating if you had an extra two hours a week to choose between paying a th000 bucks or 700 bucks for an Adu infusion or you know uh lift weights for an hour go for a half an hour walk and listen to your favorite podcast uh like the huberman lab and then eat a meal for half an hour like I can just think of so many better ways to spend time uh and money but anyway let's let's not digress okay well I'm going to pull a little bit from marketing text here but I trust these showing really yeah yeah I do because they have citations to support them and we can include the citations these are not um I'm not going to say these are these are not Lynch pin Arguments for doing one thing or the other but we already established that NR and nmn are quite similar except for the presence of a phosphate group on NR that gets cleaved off 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 and again I think we've established and we can we can agree that that there is an increase in NAD at least in the blood and probably in the liver when you take exogenous NAD or precursor let's yeah that's right so great well then you took the words right out of the the data I was going to refer to that's right because I asked a few folks that help develop some of the NR supplements like what are the data yep that support the use of NR for increasing n and they say NR can cross the cell membrane directly NN cannot okay but you can just CLE the phosphate group right exactly um NR they claim I'm not this is not my claim but they claim that NR is quote unquote 25% more effective than NN in raising whole blood NAD levels but I'm guessing that's milligram for milligram right okay so then you just adjust the milligram dosage a little bit and so on what's entirely unclear is what raising blood NAD translates to in terms of getting more NAD into cells I don't know that that's specifically cells like skeletal muscles right I think based on Josh Rabinowitz his work I also had Josh Rabinowitz on the podcast to talk about this um and I trust Josh on this um much more than I would trust any marketing material um because he doesn't have a dog in this fight right right he just you know he just does the work and um what Josh's research soed which is basically NAD flux research has demonstrated that look the liver is probably the place of greatest uptake uh in addition to blood and that's about all we know like it's not clear how much of this is getting into other cells um 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 and again I don't even think it's worth arguing about whether nmn or NR is more bioavailable because to your point you can sort of adjust the dose and I trust that whatever you're taking NR or nmn you are getting some NR into the cells and that's being converted to NAD but we still keep coming back to the jugular question does that matter does increasing intracellular NAD matter when the system is so tightly regulated so I think what you see is a lot of marketing material that tries to make the case that you can do it great I'll grant you that you can do it does it matter does it matter in lifespan the answer appears to be unambiguously no at this point does it matter in health span I think that's what we're discussing right there's something um so sticky about the longevity field just so sticky about this idea that one could take something and extend lifespan and people don't want to be in the control group so they're willing to invest significant amounts of money to do it 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 the space I don't know how many of these companies there are out there I can name two because the you know five years ago which was the last time I really dug into this I knew who the two dominant players were for all I know there could be 20 companies today that are selling NR and NN I don't know they're probably about 30 to 50 prior to this FDA ruling okay which is kind of an interesting situation in its own right yeah you know what happened there was the supplement nmn suddenly the FDA decided that it should not be sold over the counter um anymore because there was a clinical trial initiated on nmn which essentially makes nmn a drug for clinical testing and thereby can't be classified as a supplement any longer that was the rationale As I understood it but as with things like anical cysteine that was more of a lobbying effort though I think I I don't think actually that was a scientific decision I think that was more of a lobbying decision um from a from a market protection from an IP protection standpoint and this had happened prior for netal cysteine Knack which some people take it's a mucolytic it's actually a great decongestant yep if uh you're congested and it increases glutathione that's my understanding and I believe somebody checked me on does it decrease or increase glutathione increases glutathione is my understanding if I have that wrong someone will tell me quickly in the comments my understanding is that in Europe Knack might even be available by prescription in the US you can still buy it over the counter but a few years back the FDA said nope can't sell Knack any longer and there was a push back lobby to keep it on the market and you can still buy it on Amazon the same thing has more or less happened with nmn and certainly with NR although NR was never in question in terms of whether or not it should be sold as a supplement or not because as far as I know there's no clinical trial on nnr at least not currently so there's a clinical trial on nmn which classifies it as an experimental drug and therefore the FDA said nope you can't sell it as a supplement a few companies major companies pulled NN from the market in the US many smaller companies just kind of watched and waited and continued to sell it and I checked prior to the beginning this episode and you can still buy it online but of course a lot of what we're saying today is kind of a why would you um we're not really coming up with strong arguments um for taking nmn um at least not in today's discussion yeah I mean again I think the strongest argument I could make based on the data would be potentially on the um on the on the basil cell and squa cell carcinoma uh risk reduction if indeed those results are reproducible um that again that's that would be justification again for the right individual wouldn't be a justification for me might be a justification for somebody um but really the rest of it is um why why do you need to do experiments on this if you're selling a supplement when you don't need to make claims to sell a supplement like if it's a drug you have to have an indication you can't sell a drug without rigorous trials that demonstrate both safety and efficacy um I do think it's pretty safe to say that I I I do think NR and nmn are probably um there has been some voice around the idea that NR could increase the risk of cancer right and the experts in this area like Charles brener have pushed back hard on that arguing that the studies were not done well is as I recall I I think that's probably fair I don't think there's been a well done study in this entire field is is part of the problem right um so so and then that's probably too harsh a statement but but this is not a field that's like you know that's necessarily lending itself to the rigor that you would in in in pharmacotherapy and I I I think there are probably you know you mentioned Charles brener like I think Charles does good work right um and he works on many things not just this yeah and and and and by the way I don't I don't think I don't hear Charles out there saying that NR increases lifespan No in fact I don't want to quote him um at all but I think he would argue that sirtuin NR and a men should not logically or practically be linked to to efforts to extend lifespan but that there are some interesting positive effects of augmenting NR as a means to increase NAD for sake of anti-inflammation and some of these other effects that we've been discussing yeah that's my understanding of his position as well is that I I think he firmly agrees with what I laid down at the outset of this which is there's no meaningful logical connection between the relationship of uh ceran caloric restriction and NR that's that's just a that's a shell game that is empty um and and you're right I mean I think part of the reason why I think there's much better research going on with rap ay is that there's really no commercial interest in Rapa like nobody's going to make money selling Rapa because it's so cheap well yeah and it's actually not cheap but it's a drug that is off- patent right so this is a drug that was approved by the FDA 25 years ago so generic forms are inexpensive enough that no believe it or not they're not this is the irony of it is is generic so rap immune is the brand drug um that was initially uh uh 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 uh ceramus or rapamycin and yet it's surprisingly quite expensive now it's not enormously expensive because you're not taking much of it but it's about five bucks a milligram that's pretty expensive so if you're taking 8 milligrams a week that's 40 bucks a week is probably what I spend on Rapa and that ain't cheap no relative to you know and it's cheaper than some things I take but it's not cheap um but the point is like nobody has a commercial interest in rapy right it's sort of an irrelevant drug it's but the interest is scientific right and and and the commercial interest is in what we call rapalogs which are analoges of Rapa and that are being um investigated by a number of companies to to look at new indications for example immunity immune function right so rapy historically is thought of as an immune suppressant because that's the context in which it was approved for patients uh undergoing organ transplantation um but you know I think Joan manik um and Lloyd klickstein when they published that paper in 2014 using everolimus where they took a group of 65y olds and randomize 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 right that's when Rapa went from something that was interesting based on the first ITP in 2009 to maybe we should be taking this in 2014 so between 2009 and 2014 I was kind of looking at the curios of rapy and saying well cool that it worked in mice I don't think humans should ever consider this to that study which was like wait a minute something's different if you take rapamycin as a human at least every day it seems to suppress your immune system but if you just pulse it once a week as they did in that study it seems to improve immune function which again means it's an immune modulator it can go up or down on the immune system that was really the the hypothesis that emerged from that experiment um and so now the question is could you design drugs that are more specific to empor complex one which ramyon is not but you can get around that by dosing it intermittently um and then of course you know is it a drug that has efficacy in in terms of other um other things that can be tested in humans that are not longevity because you can't test lifespan in humans obviously right you're 50 right 50 years old 51 you seem to be vigorous you take great care of yourself how much do you think taking rap ayin for how many years have you been taking it six has contributed to your current state or Vigor zero idea this is my opportunity to ask about your belief or lack of belief in biological aging tests because if somebody's going to experiment with any or all of these things um they may want to evaluate whether or not they're biological ages is changing and there are a number of these tests available mhm um and people love this stuff love them they love them I mean who wouldn't want to see that they are 51 years old but their biological age is 37 I just did a movement test the other day so it's a it's a it's a very fancy camera system where you 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 like it was awesome and then it gives you a movement age Andrew I was 20 I believe it I mean I'm on I should be I should feel amazing do you actually think I move like a 22y old I mean are you freaking kidding me I bet you if I went and did that again tomorrow I'd come back at 31 or something there is so much nonsense in this type of testing it 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 sure I would I would grant you that if you took 150 year olds and you put them through a movement test the ones that really really are struggling will come out older and the ones that really really are doing great are going to come out younger so great I guess it's not I guess I move reasonably well for a 51y old but it's simply impossible to believe that I can do today what I could do when I was 22 with respect to movement and strength and power which is what that was assessing you're doing a lot of jumping single leg jump here do all this kind of stuff balance testing all sorts of things um and and and I guess I would say the gold standard for any of these biologic aging tests has to be the following what is a better predictor of remaining years of life chronologic age or biologic age that's to me the most important standard so how old are you chronologically I turned 49 in six weeks okay so um I'm sure your listeners will not like to hear this because they would probably hope and believe that you are Immortal but some might want to hear that I'm going to be taken out soon but uh let's let's just grant your mortality as a given um based just on your chronologic age an actuary would come up with a pretty decent prediction of how long you're going to live now I would argue that that's a crude assumption because it doesn't take into account the fact that you're metabolically healthy that you do all of the things that you do but just based on the fact that you are a man who is 49 years old and who doesn't smoke those three things would give me if I were an actuary a very good prediction of your life expectancy and because I'm not an actuary I don't know the exact number but my guess is it would be predicted at this point at another 37 years okay well I bought that chart my life in weeks yes in fact I bought two of them um for reasons that are uninteresting but I've watched that chart Phil um not quite what you predicted but I put my estimated lifespan to be 95 great that's fine and then I have little lines on the side MH of how much Vigor I felt from uh and just overall Wellness completely subjective of zero being like completely cratered near death to 10 like it's best I've ever felt but you do that you make that note every how often uh okay so what I did is you know from 10 to 15 I felt you know blank and then um in my 20s I actually didn't feel so great because I was I was working 80 hour weeks commonly you can ask my former lab technicians um I was just talking to Fong win recently and I mean I used to work to collapse not healthy you know 80 hour a week maybe 100 hours occasionally maybe 70 maybe back to 40 but just too much work not enough sleep s nutrition not great not just not doing the right things but just gave gave my 20s to being in in lab basically and a lot of my 30s as well so I would say from 40 to 45 my Vigor was higher than in my 30s MH and then now I track I would say about every two months I'll start filling in that line and it's adjusted for by stressors and adjusted for by positive things in life life and the goal for me is to figure out what are the behavioral tools and other things I can do or take that are going to keep the Vigor as high as possible Vigor well-being internal peace Etc all of that combined kind of what I'm calling Wellness in this very subjective uh measure as high as possible as I transition to my 50s my 60s 70s and 80s and I'm guessing that I'm going to have to do many more things in my 80s and 90s in order to maintain a simil hopefully level of vigor and well-being than I do now and the question is will I be able to yeah maybe maybe I I might take a slightly different different um um 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 yeah because I think the chart is great I think the chart um more than any supplement for longevity gives you a or gives one a visual perspective of where they sit in this long Arc and I don't think the brain is very good at anchoring us to the notion that we are mortal um because if we think about that for even a few moments too long it makes us anxious and I think we are very good at avoiding that reality yeah well it's it's it's um as you said it's very difficult to contemplate finitude um so I 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 um let's just say actuarially your expectation is 40 years more at this point because you're 49 you're a male and you don't smoke so we believe you have somewhere between 35 and 40 more years of life predicted on the basis of your biologic age that's it that's all I got you're going to live to whatever 88 to 91 or something I'm making that up but that's like okay I better get cracking on some stuff so now let's pretend you went and did a biologic age test okay so let's say you did that and let's say it came back and said you're 25 so if I had a 25-year-old male non-smoker in front of me what's his life expectancy well it's about 60 to 65 years does that mean that you Andrew have 60 to 65 more years of life based on a fact that your biologic clock says you're 25 do you believe that no no way no of course not now this would be an easy thing to test not in humans but you could do it in mice right interesting that to my knowledge that experiment hasn't been done so right out of the gate when I look at people talking about their biologic age you know well I'm I'm actually 60 years old you know chronologically but my biologic age is 35 um my response is who cares truth F 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 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 so there are lots of things that we measure that are really noisy so um 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 like if you ask me right now what my trigs are I have no earthly idea because you know I probably ate 3 hours ago like and I don't even remember what I ate how much fat was in it how much carbohydrate was in I have no idea so the only way you could really get a triglyceride measurement and put any weight to it is if you've been fasting for 8 to 12 hours then we can at least say hey a triglyceride level of 50 milligrams per deciliter is excellent whereas a triglyceride level of 120 milligrams per deciliter is lousy but if you measured my trigs today and they meaning at this moment and they were 150 that could be totally reasonable even though at fasting levels I'm at 50 so we know that because we know exactly what goes into the triglyceride measurement but when you look at a biologic clock that takes into account your glucose level your vitamin D level your epigenetic marker here or there those are very noisy things so how do I know when I measure it in you now versus when I measure it in you a year from now I captured you in the exact same space I mean I don't so it's for that reason that I just have a very hard time putting any stock in this um now does that mean that in the future we won't find some benefit in this I I I think we probably will um I do think of all the things that go into it probably the epigenetic part of it would be the most interesting but again what most people don't understand is sort of a dirty little secret is how difficult it is to measure the and to sequence The epig genome 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 epig genome on these things so they were not able to accurately say what they were giving you an average representation of your methylation but they weren't going base pair by base pair and actually sequencing this the way we would sequence The genome so so again it just it's so much noise in this system and um I I just think it creates a a little bit of a distraction for people truthfully do you avoid going through the um non uh let's just say the non-traditional scanner at the airport the one that might use higher levels of radiation no do you think about how many flights you take as a source of radiation no 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 MTS of radiation a year okay so what that number doesn't mean anything to somebody so let me give people a sense of what that means so how many mills of radiation do you and I receive because we both live at sea level so just ambient radiation living at sea level is one Miller 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 Ms a year okay what if you had a CT scan of your chest uh uh a CT angiogram well it depends on where you got it done if you got it done at a really good place with a fast scanner and great software probably three Mill certs a year if you got it done at a place that's sort of average might be 10 to 15 Mill cevers pardon me per scan um now here's what's really interesting uh by the way I'm I'm totally fascinated by this question which is how much radiation is too much um a dexa scan by the way you can't even measure how many Ms 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 xray or anything like that um people who work in uh in nuclear plants I'm told I haven't looked at the primary data on this but I've talked to people who incessantly do this so so it's possible I'm a little bit off on this but I'm told that these people are at 10 times that level of radiation exposure and sometimes higher so not they're not getting 50 they might be getting like 500 m seits a year and yet interestingly they're not in an increased risk for cancer I'm not sure what to make of that um 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 suggest those people are't an increased risk of cancer either and they're you know they're obviously at the upper end of what a civilian would experience in terms of radiation so um I just I'm not convinced that that's like that's something we should be stressed about I think you just relieved a lot of people of some unnecessary concern I want to go back to what you were saying earlier about what you need to do in your 90s versus what you're doing now so you said you think that in the in your 80s and 90s you're going to have to work harder to preserve the vitality that you have now yeah grip strength jumping cognitive function I mean I've got very good genes in terms of longevity on one side of my family pretty good on the other although not as robust I mean if I just look historically um yeah who who knows right I mean but my sense is that I'll live to be 95 if you know barring you know bullet Buster cancer so I would say that yes you're going to have to work hard in that last decade of life to preserve those things but I think it's the work we do now that sets the stage for that it's the foundational work that we do in this period of Our Lives you know you and I are only a couple years apart but I think this is the critical decade it's in your 50s to your 60s and in your 60s to your 70s that I think is is the deciding time 50s to 750s to yeah 50s to 70s so so what is it about this this window that you and I are just entering now and why is it so important um I think it's important because we're we're getting to that point where aging does start to show up like I think if if you and I are being brutally honest like we're we're kind of half the men we used to be um and and and and again that just means like look like a night of poor sleep shows up more right when you were working in the lab as hard as you were describing it you could probably walk through walls when you were exhausted yeah a short nap would reset me near completely yeah I I got more colds and flu in that time because I wasn't taking such good care but then again I was indoors more so it's an imperfect experiment but you're right I think that um as I've approached 50 I need to do more you need to do more self-care you need to be more mindful of what you're eating how you're sleeping how you're recovering from those workouts because we still do hard workouts but recovery plays a greater role in other words we're just not quite as resilient as we used to be you know I was telling somebody the other day they asked me about my residency I don't think being hyperbolic when I say this I couldn't do one month of what I did for five years I really couldn't do it I don't think I I don't think there's any there's no way I could go back to that level of sleep deprivation for a month let alone five years so um you know that's just a fact of Aging I think so um but what we have to do during this period of time is build up as much physiologic Reserve as possible and so the the important thing is we you know we have to stay in the game because compounding makes such a difference right so you know we're still young enough that we can actually put on muscle mass now that's not always going to be the case it's going to be very difficult to add muscle mass when you're in your mid to late 70s it's doable but it's very very difficult so instead we want to be putting on as much muscle mass as we can and increasing or at least maintaining strength as much as we can uh again probably increasing it is unlikely clearly we're not increasing power as we age right Andy Galpin has talked a lot about this the atrophy of the type two muscle fibers the 2A muscle fibers really start to atrophy in your 20s and 30s so I know I don't have a fraction of the power that I used to have and I know that because my vertical jump is L literally half what it was when I was a teenager I was never mine was never very good so I it doesn't matter how good it was my point is like if you know what your vertical jump was at8 192 and then you do it today I mean it's literally 50% and that's one of the purest tests of power um so power's going down strength is going down but not as much muscle mass is actually not because remember that's the order in which you lose things right you're going to lose power strength and size of muscle um but again size still matters it's still a glucose sync all these other things um but what we don't want to do is you know be out of the game right what we don't want to do is injure ourselves and get a setback that becomes very difficult to recover from because you know when you're our age if you're inactive for months at a time it's it's going to be 2: one or 3:1 ratio of inactivity to activity to get it back um what about energy sorry to interrupt but since we've been talking about molecules and energetic Pathways what about energy just that get up and go let's just say after a decent night's sleep 7 and half hours um waking up same time more or less you know 6:30 7: a.m. probably for you or me and why is it that as we get older we have less energy our mutual good friend the late Ben Baris used to ask about this he used to say he called me Andy he was like Andy why do I have so much less energy I was like I don't know I don't know it's a great question now unfortunately he died of pancreatic cancer so there may have been other things going on but that was prior to the cancer at least as far as I know you know it's a very interesting question why do we have less energy and I don't think anyone's ever been able to answer that question no and when you have kids you're going to be even more starkly confronted with that because I actually it's one of the things I am most Amazed by when I look at my kids especially the youngest ones the boys who are seven and 10 is what I just describe as spontaneous outbursts of energy um like their inability to sit still their kinetic desire to just like they will like if we 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 like imagine if you and I were walking through the mall and I just started running ahead and running back you'd be so sore the next day but it's like it just wouldn't occur to me to ever run unless being chased right like it's just I mean like 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 you just wouldn't it wouldn't occur to you go and expend energy for no reason and yet kids do this it's amazing and um 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 um and it's a great question who maybe it's NAD I mean I don't know maybe although up until now we've been talking about all these ways to try and increase NAD in the bloodstream and hopefully in cells and I don't know I take my nmn and my NR and I feel a little bit of a boost in energy but I can't say that it's so significant that I feel like I can Sprint back and forth Just spontaneously these again it's just so hard for me to imagine that any supplement or any drug including rapy which I think is the most promising geroprotective drug we have I just can't imagine that those things even compare to what good sleep good exercise and good nutrition do for your energy levels and vitality and the reality of it is all three of those things are hard to do you know yeah they especially if you're an adult like especially if you have a real life you know you got kids you got a job which is presumably many people listening to us right now like there's very few people listening to us right now whose only purpose in life is to take care of their health everybody's got something else they have to do which means you have competing interests for how do you take care of yourself so to sleep is not easy right like we all are busy as hell we don't want to have to stop what we're doing to undergo 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 um even people like me who like exercise I know you like exercise um it still is a sacrifice in terms of time um and and and for many people certainly for me food is the hardest of these all right if left my own devices I'd eat freaking Froot Loops all day like I love fro Loops right interesting by way of contrast the food party is easy for me I like healthy food and oh I like healthy food I just like all food I like I don't like unhealthy food I've weaned myself off it I never really liked it that much I mean I like a great tasting slice of pizza or ice cream every once in a while but I much prefer meat fish chicken eggs fruits vegetables rice OB I just like that stuff I'm a weirdo that way I suppose but on the topic of exercise as it relates to Vigor and Longevity I'm intrigued by how some forms of exercise give us more energy especially the same day and how some forms of exercise or even timing of exercise tends to deplete us because I think one of your major um sort of calls to the public has been to move more yeah for sake of their health span and lifespan but because of the time investment that it takes to work out in a gym or to go for a run or a Ruck I think some people think well that's a lot of time but if it gives you more energy and more Focus to do other things well then it's great so it's not just about living longer it's about being able to do more and I've noticed I don't have any science to back this up but I'd love someone to run a test on this that if I complete my workout before 9:00 a.m. even if I have to start it while I'm a little bit fatigued I have more energy all day long but that if I initiate that workout say mid to late morning I'm pretty tired in the afternoon it's like I give everything I have to that workout and so it becomes a little bit defeating since I'm not a professional athlete or even an amateur athlete I'm working out for health span lifespan but I I want to do exercise that gives me more life during my waking hours I think somebody should study this and I'm convinced that it has something to do with the change in body temperature that occurs across the day and the additional change in body temperature that occurs as a consequence of exercise that's my hypothesis do you notice a seasonal change in that do you experience it more or less in one season or the other I haven't thought about it that much but not so much not so much and I wonder whether folks like our friend Joo willink are able to do so much he has so much Vigor that guy in part because he basically exercises at the just after the lowest temperature phase of the Circadian rhythm and use his exercise presumably to drive himself out of that and get that you know temperature increase that's the consequence of waking but in his case he's waking up so early 4:30 is when he starts those workouts so it's something for people to play with it's something that I don't think gets discussed enough which is yes you should exercise do resistance training do cardiovascular training but play with the timing of those and see how at a given intensity it impacts your energy levels for the remainder of the day I think that's I think it's an important metric that again I I just don't see a lot of attention to because I think if people could experience the increase in energy that is the consequence of working out at the right intensity in the right way at the right times for them they'd be much more apt to do it it wouldn't feel like this like spending money on something that sure will make you live longer but then you're depleted and you can't do cognitive work there's something pretty impressive about the fact that as far as I know the last three let's just call them I don't want to call anyone out specifically major pillars of the high level administration at Stanford school of medicine to my knowledge were all 5 am. Runners there's something about early morning exercise and my good friend Eddie Chang who's the chair of neurosurgery at ucss he's been on this podcast known him since we were 7 years old he's an early morning exerciser and then he's got tons of energy all day what about the reverse causality there do you think it's possible that they're they have a whole they have a system of high energy that makes Joo who he is or makes you know these people who they are and as a result of that they they they're able to work out 5 o' in the morning yeah I don't doubt it I just have noticed that in the few times in my life where I've kicked my own butt to get out and start working out really early I have more energy all day long sometimes I still require a brief nap but it's a pretty striking effect as compared to you know the 10: a.m. workout effect yeah so I've started setting a standard of trying to get my workout done before 9:00 a.m. so anyway something for people to play with because the more energy to live in your waking hours um perhaps not longer but um certainly have more energy in terms of output I think is a significant and undervalued parameter so let's let's quickly return to supplements we I think are converging on an answer about NR nmn and NAD which is you don't take them correct I take NR and nmn with not a lot of religious adherence I should say if I ran out I might not buy it for a while and the only observed effect for me is this accelerated hair growth which is a pain in the butt frankly cuz it just just means I have to get my hair cut more often I'm not trying to grow my hair faster but okay what are some other supplements if any that you take that are peripheral to this pathway or separate from this pathway Romy is a prescription drug only right so are there any over-the-counter things that you take that you would Place into the lifespan category maybe they touch into Health span as well I'm happy to list off what I do but um what are your let's just say top five at least well I don't I don't take that many so top five would be a pretty exhaustive list um 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 a an effection for capsule over liquid it's just going to increase my compliance if I take I've done both and I noticed when I was taking liquid because you're storing it in the fridge it's just it's just one more step removed and I was just less likely to remember to take it twice a day um I take uh thumin um and there's some reasonable evidence in MCI patients that thumin improves cognitive function um so I think there's a relatively low downside to the hypothesis that theum uh May uh preserve cognitive function um again I I don't I don't I don't I 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 um I take I do take vitamin D because interestingly despite the fact that I'm outside every day without supplemental vitamin D my levels are surprisingly low how much do you take I take 5,000 IU um and that takes me from kind of a level of 30ish to a level of 50ish mhm 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 in 10 years yeah my appetite to talk about that one uh let me think what else do I take because I sure oh I do take methyl folate and methyl B12 um and again the the the rationale there is um I do think there's some evidence that elevated levels of homosysteine are uh bad in and of themselves so there's no denying the fact that elevated levels of homosysteine are associated with bad things that's unambiguously clear meaning there's an association between Badness and homocysteine what's not clear is is it causal now there's definitely one mechanism you can point to although again mechanisms are what they are we just spent how many hours talking about mechanisms that theoretically make sense that never pan out but mechanistically homocysteine will um inhibit the clearance of something called symmetric uh and asymmetric dimethyl Arginine have you heard of these things sdma and adma so adma and sdma uh regulate nitric oxide synthes and homocystine impairs their clearance and therefore when you have high levels of homocystine it per it results ultimately an impaired nitric oxide synthes and therefore low lower nitric oxide so this has been proposed as at least one mechanism by which homosysteine might negatively impact um vascular disease uh so and we also know by the way that um adma and sdma are cleared by the kidneys and therefore this might this is also proposed as one of the mechanisms by which impaired kidney function is is um uh impacts vascular health because that's a known right if you if your kidneys don't work well your risk of heart disease goes way up so this is now proposed as a link between what we OB erve with homocysteine and impaired renal function so um we know that if you take methyl folate and uh uh methyl B12 you're going to lower homocysteine that's abundantly clear so the the thinking is that that might actually lower um adma sdma and raise nitri oxide synthes again relatively low cost lowrisk you know thing to take at modest doses I also there's probably some evidence that overs supplementing vitamin B is problematic especially B6 so I don't because of peripheral nerve damage exactly so I don't supplement B6 I'm just taking a bit of folate and and and methyl B12 let me think what else do I take because I do take a couple other things oh I take um magnesium L3 and8 and ashwagandha for Sleep um i' take slow mag which is just a a magnesium chloride slow relasing version of magnesium and I take methyl pardon me I take uh magnesium oxide so I take magnesium in three forms so I'm I'm I'm I'm long magnesium you're carpet bombing Mages I'm big on magnesium right great for bow function great for I mean I don't know the last time I had a cramp in my life you know it's been years since I've had a cramp despite exercising in a really hot place like Austin Texas where I'm sweating like there's no tomorrow um whether you call it a supplement or not I take uh I I take um uh like electrolytes I take a element um which I should disclose I'm an investor in that company um so I I drink an element a day I take creatine monohydrate five grams a day I take AG most mornings oh and I take pendulum the probiotic got it y as far as I know there's no other probiotic that has any meaningful effect on the body outside of pendulum right pendulum is the because CU if you buy the argument that a probiotic for your gut needs to have Anor robic bacteria in it there's no value in giving you aerobic bacteria so you have to have something anerobic so acrania which works through the um glp1 butyrate pathway is anerobic and pendulum is 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 um she's an actual scientist and she's fantastic and um um it's a really interesting story how they kind of developed this and how difficult it is to actually make an aerobic 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 anerobic Vats that you have to use infused with nitrogen to be able to make an Anor robic bacteria so anyway so I take three of their products I take something called glucose control I take polyphenol and I take acromania okay I think that's the list okay yeah I'll try and move through my list pretty quickly I may miss one or two things and I don't know maybe we'll put the list someplace online and fill in any gaps I definitely take AG ag1 you know I've my typical ad read I've been doing it since 2012 that's true uh take one or two servings a day three of I'm traveling and I'll generally do that first thing in the morning or in the evening um for me it's really about capping off the vitamin minerals that I might be lack lacking in my diet and also the whole adaptogen business I think and polyphenols and I'm a very interested in pendulum because part of the reason I take ag1 is for the gut health aspect I think just bowel movements are more where I'd want them I mean it sounds kind of uh weird to talk about but you just feel better when your gut motility is right I feel like it adjusts my gut motility so it's neither too fast nor too slow so that's first and foremost I take a quality fish oil either the one that AG makes or Carlson's in liquid form mhm that has that lemon flavoring and I make sure I get above one gram per day of EPA yep so that's usually a tablespoon sometimes two tablespoons I make sure that I get enough D3 typically from The Dropper 5,000 IU per day approxim sometimes 3,000 sometimes 7,000 I kind of play around that and I test my blood levels I also take methyl B12 and I also take Tonga Ali so I take one capsule of that in the early part of the day that has lowered my sex hormone binding globulin freeing up a bit more testosterone it's why I like it um and I take a couple of green tea capsules in the morning I drink yamate that's more of a stimulatory effect and I take the NM in powder form sometimes NR as well and again if I run out of that I tend to go long periods of time without I use element MH as an electrolyte so people are probably noticing this is all pretty basic I take in my case 10 grams of creatine monohydrate per day I sometimes forget to take it that's why I take 10 grams I'll sometimes miss a day okay um and I certainly feel the effects of that in the gym because of the greater water volume in the muscles but there are a lot of data on creatine monohydrate for sake of either maintain paining or offsetting some of the cognitive dysfunction associated with sleep deprivation maybe aging altitude and some other things as well and then for a few months I was playing around with let's say um nicotine gums I stopped doing that um first of all I was dipping it and I ended up lifing for uh an entire episode of The Lex Freedman podcast and I only realized later so I stopped taking it also because it gave me a kind of a tick and off when I wasn't chewing it and then I felt like I needed to chew it and it's a little too stimulatory for me um before sleep I take magnesium 3 and8 I'm really bullish on magnesium as well appenine 50 milligrams which is essentially chamomile extract and theanine and occasionally I'll take 900 milligrams in netl also um or instead I kind of mix those up and around and then I use a quality way protein as a protein replacement that kind of thing and I've played around with various things like Sheila G and you know sometimes get the sense that it's having an effect but then I'll stop taking it for long periods of time um you know there are very few things that I've stayed with for long periods of time and I basically just described what those are you know if ever someone were to design a supplement that would provide more energy all day long that wasn't caffeine I'd probably look to that but I ingest caffeine in the form of yerbamate and coffee I've played around with caffeine tablets you know taking you know 50 milligrams of caffeine in tablet form I mentioned that only because it has a distinctly different feel than ingesting caffeine through liquid form it feels stronger and I don't know why that is in fact I there's a very well-known podcaster who drinks peppermint tea and takes caffeine tablets as a way to uh I don't know drink peppermint tea which sounds very nice and mellow but also get the stimulant effect so anyway that's pretty much and then I do a lot of things as I know you do mainly based on suggestions you've made about getting zone two cardio rucking weight vest walks and Hikes three times a week resistance training three times a week cardiovascular training one long one medium one short and I try to hit the sauna and the cold once a week and um yeah that's pretty much it um I think there are a bunch of other supplements that are really interesting and kind of fun to play with if one wants to like 600 million Mig of alpha GPC or 900 milligrams of alpha GPC in a Double Espresso prior to a workout you feel different it's a stimulant but I don't like to do that too often because of the increase in tmao that occurs and then you have to take 600 milligrams of garlic to offset that increase and you start getting if we believe tmao matters right if you believe tmao matters and um okay great even better I'll maybe skip the garlic so things like that I prefer to just eat garlic anyway um so there are a bunch of things like that that are kind of fun to play with as pre-workouts but yeah that's the core um supplement regimen and it's the one I've stuck with for gosh at least 10 years or in the case of AG near more than you know more than that so I should say because any discussion around supplements I think it's going to you know have people pricking up their ears to okay this is like a sales pitch or something I absolutely want to go on record the things you choose to do and not do are going to have much greater effect on your healthspan and lifespan that is the behavioral things in particular sleep exercise nutrition sunlight Etc than any One supplement that you're going to take so I do view supplements I think through the appropriate lens which is that they are indeed a supplement they are not necessary many of them are simply sufficient to serve as an insurance policy or to augment mental and physical health maybe longevity uh in ways that make it worthwhile given my disposable income that I want to devote to supplements but I don't think you need them yeah I'll go even more extreme on that statement everything we have talked about on this podcast today whether it be NR NAD nmn thumin magnesium this supplement that supplement all of that stuff while potentially mattering I would put in the category of was the Titanic serving LOB Lobster or steak look I I like steak more than Lobster that's a relative discuss exercise sleep nutrition emotional health is the question of what was the heading of the Titanic okay so I just want people to understand the magnitude of what we're talking about how you eat how you sleep how you train and how you take care of your mental health is the equivalent of what Direction was the Titanic going with respect to the iceberg all this supplement that we just talked about is equivalent to were they serving Lobster or were they serving steak and was the band playing this song or that song I'm not saying those things don't matter but just put them in the context of the direction the Titanic is going okay so I completely agree with you exercise sleep nutrition and emotional health not listed in any particular order Peter and I both completely agree those are the critical four before we close nrnm NAD and NAD in particular how do we view this is it a pathway that we should be focusing on in terms of supplementation or infusions for sake of extending our life my answer on that is no yeah I would say the same you know I I don't remember who said this but someone maybe it was Nim TB said don't tell me what you think show me what's in your portfolio like meaning people who pontificate about this stock versus that stock he's kind of like assuming it was him that said this he's like okay I I don't care what you're telling me tell me what you own that's going to show me your conviction so through that lens look I'll show you my conviction on exercise I'll show you what I do I'll show you my conviction on sleep this is what I do I'll show you my conviction on all these other things I mean I don't take these supplements full stop I don't take them because I can't afford it's not that I can't afford them it's not that there're any inconvenience to me to take them I passionately do not believe they do anything for me and why would I waste time money anything on something that I really don't believe makes a difference now again I am always happy to be proven wrong and I am very happy to say that two years from now five years from now we could be doing this exercise again and in the presence of new information maybe I'm not taking rap ay and maybe I am fist fulling you know NR and nmn possible I will I will reserve the right to change my my mind for the rest of my life in the presence of new data but as it stands today I do not take these supplements and I have no foreseeable plan to do so until information changes great thank you for that clear stance and the willingness to change it in light of new data Peter so good to sit down with you again and talk science talk health and in this case talk about the supplements that we're not going to take in addition to the ones that we do take we will do this again sometime very soon hopefully in Austin would love that thanks Peter thanks man thank you for joining me today for my discussion with Dr Peter Atia if you're learning from Andor enjoying this podcast please subscribe to our YouTube channel in addition please subscribe to the podcast on both Spotify and apple that's a terrific zero cost way to support us in addition you can leave us up to a five-star review on either Spotify or apple please also check out the sponsors mentioned at the beginning and throughout today's episode that's the best way to support this podcast if you have questions for me or comments about the podcast or topics or guests that you'd like me to consider for the hubman Lab podcast please put those in the comment section on YouTube I do read all the comments if you're not already following me on social media I am hubman lab on all social media platforms so that's Instagram X formerly known as Twitter threads LinkedIn and Facebook and on all those platforms I discuss science and science 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certainly not least thank you for your interest in science [Music]