Dr. Peter Attia: Supplements for Longevity & Their Efficacy

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science

00:00:03.760 | and science-based tools for everyday life.

00:00:05.960 | I'm Andrew Huberman,

00:00:10.200 | and I'm a professor of neurobiology and ophthalmology

00:00:13.340 | at Stanford School of Medicine.

00:00:15.240 | My guest today is Dr. Peter Etia.

00:00:17.820 | Dr. Peter Etia is a medical doctor who did his training

00:00:20.760 | at Stanford University School of Medicine

00:00:22.960 | and Johns Hopkins School of Medicine.

00:00:25.320 | Dr. Etia is one of the world's most trusted voices

00:00:27.720 | on the topics of healthspan and lifespan,

00:00:30.000 | and with good reason.

00:00:31.120 | He is known to systematically review the research literature,

00:00:34.440 | the clinical trials,

00:00:35.560 | and he maintains an avid clinical practice.

00:00:38.320 | So when it comes to the topic

00:00:39.520 | of whether or not a particular molecule or supplement

00:00:42.120 | or prescription drug is indeed something

00:00:44.360 | that we should be thinking about

00:00:45.560 | and perhaps even taking

00:00:47.000 | in order to improve our healthspan and lifespan,

00:00:49.560 | Dr. Etia is the person that I choose

00:00:51.800 | to sit down with and discuss it.

00:00:53.720 | So today we are going to discuss the so-called NAD pathway,

00:00:57.700 | this is a pathway that's received a lot of attention

00:00:59.920 | in recent years as a potential target

00:01:02.240 | for improving lifespan, that is for living longer.

00:01:05.320 | Today, we discuss the various molecules in this pathway

00:01:08.200 | and the various approaches to increasing NAD,

00:01:11.360 | which is the end target goal of anyone that's trying

00:01:14.600 | to augment the NAD pathway, so to speak.

00:01:17.400 | So for instance, we talk about taking NR versus NMN

00:01:22.400 | versus direct infusions, or even orally taking NAD.

00:01:26.740 | And we compare them in terms of both what's known

00:01:30.200 | and what is not known about their ability to get into cells

00:01:33.640 | and any efficacy they may have

00:01:35.400 | for either longevity or healthspan.

00:01:38.200 | Dr. Etia and I compare and contrast the literature on this,

00:01:41.600 | again, both research and clinical literature,

00:01:43.600 | and we discuss whether or not he or I take NAD, NMN, or NR,

00:01:48.600 | and if so, or if not, the reasons for that.

00:01:52.920 | We also each go through our own supplement regimen,

00:01:55.900 | which of course reflects what we do believe

00:01:57.720 | can potentially have an effect

00:01:59.000 | on healthspan and/or lifespan.

00:02:01.240 | So by the end of today's episode,

00:02:02.640 | you'll learn a lot about NAD.

00:02:04.800 | You'll learn a lot about the biological pathway.

00:02:06.520 | You'll learn a lot about the delivery routes,

00:02:08.420 | the various supplements,

00:02:09.400 | and why people think they may be useful, why others,

00:02:12.260 | perhaps even Dr. Etia and myself,

00:02:14.200 | think they may not be useful for longevity.

00:02:16.640 | You'll have to listen to find out what the answer is there.

00:02:18.720 | I should also mention that we give somewhat of an overview

00:02:21.560 | or a framework for thinking about approaches to longevity.

00:02:24.920 | So if you're interested in things like rapamycin,

00:02:26.920 | metformin, and whether or not fasting can improve longevity,

00:02:29.840 | we get into that as well.

00:02:31.420 | Before we begin, I'd like to emphasize that this podcast

00:02:33.880 | is separate from my teaching and research roles at Stanford.

00:02:36.600 | It is, however, part of my desire and effort

00:02:38.760 | to bring zero cost to consumer information about science

00:02:41.400 | and science-related tools to the general public.

00:02:44.060 | In keeping with that theme,

00:02:45.160 | I'd like to thank the sponsors of today's podcast.

00:02:47.900 | Our first sponsor is Element.

00:02:49.760 | Element is an electrolyte drink

00:02:51.220 | that has everything you need and nothing you don't.

00:02:53.520 | That means the electrolytes,

00:02:54.800 | sodium, magnesium, and potassium in the correct ratios,

00:02:58.300 | but no sugar.

00:02:59.320 | Now, proper hydration is critical

00:03:00.800 | for the optimal functioning of all the cells in your body.

00:03:03.480 | And that's especially true for the neurons, the nerve cells.

00:03:06.820 | In fact, we know that even a slight degree of dehydration

00:03:09.160 | can diminish both cognitive and physical performance.

00:03:11.820 | So to make sure that I'm getting proper hydration

00:03:13.760 | and electrolytes,

00:03:14.900 | I personally dissolve one packet of Element

00:03:17.040 | in about 16 to 32 ounces of water

00:03:19.400 | when I first wake up in the morning,

00:03:20.600 | and I drink that or sip that

00:03:22.320 | across the first half hour of the day or so.

00:03:24.480 | And then I also make it a point

00:03:26.200 | to drink another packet of Element

00:03:27.720 | dissolved in an equal amount of water,

00:03:29.360 | so 16 to 32 ounces,

00:03:30.900 | at some other point during the day,

00:03:32.400 | and maybe even a third if I'm exercising

00:03:34.800 | and/or sweating a lot.

00:03:36.200 | I should mention that Element tastes absolutely delicious.

00:03:38.680 | My favorite flavor is watermelon,

00:03:40.400 | although I also confess I like the raspberry flavor,

00:03:43.040 | the citrus flavor.

00:03:43.920 | Basically, I like all the flavors.

00:03:45.580 | If you'd like to try Element,

00:03:46.720 | you can go to drinkelement.com/huberman

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00:03:51.600 | with the purchase of any Element drink mix.

00:03:53.560 | Again, that's drinkelement.com/huberman

00:03:56.740 | to claim a free sample pack.

00:03:58.480 | Today's episode is also brought to us by Levels.

00:04:01.560 | Levels is a program that lets you see

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00:05:17.900 | Now, I've spoken many times before on this podcast

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00:06:33.140 | And now for my discussion about NAD and longevity

00:06:36.500 | with Dr. Peter Attia.

00:06:38.180 | Peter Attia, welcome.

00:06:39.860 | - How are you?

00:06:40.820 | - Great to see you again.

00:06:42.040 | - Great to be here again.

00:06:43.540 | - Should we parse this NAD thing?

00:06:46.840 | - I think we should.

00:06:48.840 | - Do you mind if I set up a little bit of a framework?

00:06:52.560 | Great.

00:06:54.200 | So for people that want to live as long as possible,

00:06:57.920 | I figure there are at least four categories of approaches,

00:07:02.560 | broadly speaking.

00:07:03.480 | The first I'll just call the do's and don'ts.

00:07:06.700 | You've talked a lot about these,

00:07:07.920 | your book "Outlive" beautifully covered these,

00:07:11.380 | and I tend to regurgitate some of what you say

00:07:14.340 | on this podcast.

00:07:16.000 | Namely, you want to move appropriately and often enough,

00:07:20.080 | so get enough zone two cardio, do your resistance training,

00:07:23.640 | keep nerve to muscle connection strong,

00:07:25.920 | avoid the sorts of things that would lead to falling

00:07:29.500 | and being immobile, eat right.

00:07:33.060 | There's a whole category of things there

00:07:34.400 | we're not going to talk about today,

00:07:35.420 | although we might touch on a bit.

00:07:38.160 | And know your genetics and make some good decisions

00:07:43.000 | on the basis of your genetics.

00:07:45.300 | So the do's and don'ts.

00:07:46.540 | The second category I would put under the umbrella

00:07:52.300 | of calories, glucose, insulin, et cetera,

00:07:56.660 | that all kind of funnel in, at least in my mind,

00:07:59.060 | to mTOR, mammalian target of rapamycin,

00:08:02.280 | a molecule that's robustly expressed during development

00:08:06.660 | in essentially all cells of the body,

00:08:08.900 | and then across the lifespan tapers off.

00:08:11.400 | During puberty, especially,

00:08:14.180 | well, let's say infancy through puberty,

00:08:16.940 | cells are expressing so much mTOR,

00:08:19.580 | and they're growing like crazy.

00:08:21.140 | And we often associate that early stage of life

00:08:23.340 | as youth, not aging, because we think of it

00:08:27.940 | as a kind of a timestamp as opposed to the verb.

00:08:30.900 | But I would argue as a developmental neurobiologist

00:08:33.720 | by training that it's one of the most rapid phases

00:08:37.200 | of aging of our entire lifespan.

00:08:39.680 | Look at a picture of you when you were five,

00:08:41.040 | look at a picture of you when you were eight versus 15,

00:08:44.460 | you look very different and your size is robustly different.

00:08:49.360 | - By the way, I just did this exercise

00:08:50.800 | 'cause my daughter, her 16th birthday is around the corner.

00:08:55.340 | And we take a picture of her every single year

00:08:58.760 | at the minute of her birth.

00:09:00.680 | So we have a picture of her every single year

00:09:02.360 | holding a clock that says 3.56, at 3.56 PM,

00:09:06.200 | 'cause that's when she was born.

00:09:07.440 | And I just went through and pulled each of the last 16

00:09:11.100 | of them from the day she was born all the way up.

00:09:13.740 | And you're right, the biggest changes

00:09:16.600 | are actually in about the first 10 years.

00:09:18.760 | The difference between being 13 and 14,

00:09:22.520 | 14 and 15, 15 and 16 becomes incrementally less

00:09:24.920 | and less and less.

00:09:25.760 | Whereas going from two to three and three to four

00:09:27.840 | and four to five are ridiculous changes.

00:09:30.760 | - Yeah, I mean, the brain, the same brain

00:09:32.560 | has to learn an entirely new body every year

00:09:35.500 | in terms of how to move it, limb length, et cetera.

00:09:38.040 | So a lot of the so-called anti-aging or longevity approaches

00:09:44.200 | that fall under this umbrella relate to things

00:09:47.560 | like caloric restriction or taking drugs such as rapamycin.

00:09:52.000 | And of course, mammalian target of rapamycin

00:09:54.040 | is the target of rapamycin, duh.

00:09:58.320 | In an effort to essentially remove excess insulin,

00:10:02.840 | blood glucose, and thereby reduce mTOR activity.

00:10:07.840 | So essentially slow cellular growth.

00:10:11.680 | And all that fits nicely into the logic

00:10:13.560 | that mTOR is associated not just with development,

00:10:16.120 | but with aging because development is aging.

00:10:18.680 | And then I would say there's a third category

00:10:20.760 | and it's the one we are going to talk about today,

00:10:23.100 | which is targeting specific cellular pathways

00:10:27.160 | that some people have deemed potentially interesting

00:10:30.480 | for longevity.

00:10:31.920 | And the pathway that we're going to spend some time on

00:10:34.280 | is the so-called NAD pathway.

00:10:36.000 | NR, NMN, NAD being the major players.

00:10:39.200 | And we'll talk about some of the biochemical

00:10:40.920 | and enzymatic steps in between.

00:10:43.080 | And then I suppose there's a fourth category,

00:10:45.440 | which we could say is, you know, the do everything,

00:10:48.760 | even the most esoteric of things category.

00:10:52.040 | This is a rarer category.

00:10:54.720 | There are folks like Brian Johnson

00:10:56.120 | who spend a lot of time in this category specifically,

00:10:58.960 | you know, taking very high doses of polyphenols,

00:11:01.800 | limiting their caloric intake to just early part of the day.

00:11:05.200 | I think he eats dinner at 11 a.m.

00:11:06.820 | I don't know if it still qualifies as dinner at 11 a.m.,

00:11:09.400 | but his final bite of calories is I believe at 11 a.m.

00:11:13.760 | Doing everything from red light to PRP,

00:11:18.760 | platelet rich plasma, excuse me.

00:11:22.480 | And essentially the kitchen sink approach

00:11:25.840 | to longevity and aging.

00:11:28.240 | Did I miss any categories?

00:11:29.600 | - So I would frame it slightly differently

00:11:34.440 | because I like categories to be more MESI,

00:11:37.680 | mutually exclusive, collectively exhaustive.

00:11:40.220 | So I don't know that I would formulate it that way, right?

00:11:45.160 | I might say, look, category one are sort of

00:11:48.680 | the essential behavioral things that you have no choice

00:11:53.220 | but to engage in whether you want to or not, right?

00:11:55.760 | So you have to eat, you have to sleep, you have to move.

00:12:00.380 | You just have a choice and do you wanna do those things

00:12:03.680 | correctly or not correctly?

00:12:04.900 | Or do you wanna do those things in a manner

00:12:06.680 | that promotes health or erodes health, right?

00:12:09.920 | So again, there's nobody listening to us who doesn't eat,

00:12:12.960 | but again, you can choose how much you eat

00:12:15.180 | and what you eat and when you eat.

00:12:17.360 | There's nobody who's alive who isn't moving

00:12:19.680 | because locomotion is life and the absence of life

00:12:22.480 | is the absence of locomotion.

00:12:24.240 | But you can certainly choose to move very little.

00:12:26.640 | You can choose to move a lot.

00:12:27.800 | And you can choose to decide on how you move.

00:12:29.440 | You alluded to it already, right?

00:12:30.600 | You can move in a certain way that puts your aerobic system

00:12:34.760 | in a zone that maximizes fat oxidation.

00:12:36.960 | We call that zone two.

00:12:37.880 | You can move at a level where you consume

00:12:39.560 | incredible amounts of oxygen at your maximum aerobic level.

00:12:42.480 | You can choose to move in a manner that uses resistance

00:12:46.000 | and gravity against you and all those sorts of things.

00:12:49.120 | Similarly, we all have to sleep, right?

00:12:50.700 | Matt Walker would probably tell us the number of days

00:12:53.320 | you could go without sleep before you would literally perish.

00:12:57.000 | But again, you have a lot of choices in how you do it.

00:12:58.960 | So anyway, I agree, that's kind of category one,

00:13:00.880 | but that's kind of the way I would frame it.

00:13:02.760 | And then I would put in category two,

00:13:05.500 | sort of what are the molecules that you would

00:13:10.720 | exogenously take to try to impact any of those systems?

00:13:15.560 | And maybe, and again, I'm not saying my framework

00:13:17.600 | is correct and yours isn't.

00:13:18.640 | I'm just saying this is the way I think about it.

00:13:20.400 | I would then say, what are the molecules that I could take

00:13:23.480 | that specifically target disease processes?

00:13:26.800 | So I kind of think of like, if you want to live longer,

00:13:31.760 | and I described this, I think, in chapter four of Outlive,

00:13:34.600 | that turns out to be mathematically equivalent

00:13:37.880 | in the modern society to delaying

00:13:40.080 | the onset of chronic disease.

00:13:42.280 | Now, that wasn't true 100 years ago.

00:13:43.800 | 100 years ago, if you wanted to live longer,

00:13:46.120 | a few things had to be true.

00:13:47.100 | You couldn't die during childbirth,

00:13:49.080 | 'cause that was a huge hit on mortality.

00:13:52.460 | And then you had to not get an infection

00:13:56.480 | or succumb to trauma.

00:13:57.880 | And then maybe 150 years ago, that was the case.

00:14:01.840 | But today, most of those things are taken care of

00:14:04.840 | by antibiotics, sanitation, and the modern miracle

00:14:09.000 | of childbirth in this era.

00:14:12.000 | So now, for you and I to live longer,

00:14:14.400 | we basically have to delay the onset

00:14:16.360 | of cardiovascular disease, cerebrovascular disease,

00:14:18.960 | cancer, neurodegenerative disease,

00:14:21.000 | dementing diseases, and metabolic diseases.

00:14:23.600 | We have to delay the onset of those things.

00:14:25.680 | The longer we delay the onset,

00:14:27.260 | the longer we will live full stop.

00:14:29.360 | So you can use everything that you talked about

00:14:31.840 | in the first category plays into that.

00:14:34.000 | But you also have this other category

00:14:35.400 | of where you can take molecules

00:14:36.900 | that specifically target those things.

00:14:39.440 | You can take metformin, or an SGLT2 inhibitor,

00:14:43.040 | or a GLP-1 agonist,

00:14:44.760 | and you will directly impact those things.

00:14:47.280 | You could take a PCSK9 inhibitor,

00:14:50.560 | or a statin, or a bempedoic acid.

00:14:52.620 | You will directly impact those disease processes.

00:14:55.880 | You will delay the onset of those diseases,

00:14:57.560 | and you will reduce the mortality associated with them.

00:15:00.920 | Then I'm gonna go to a third category that says,

00:15:03.320 | are there exogenous molecules that you can take

00:15:06.920 | that don't target a disease per se, specifically,

00:15:10.440 | but we're gonna put them in a category

00:15:12.200 | called geroprotective,

00:15:14.120 | which is they target hallmarks and pathways of aging

00:15:17.280 | that you've described.

00:15:18.560 | So we talk about all of these things that occur

00:15:21.600 | in an aging phenotype, where we see more inflammation.

00:15:25.400 | We see a greater abundance of senescent cells.

00:15:28.660 | We see reduced nutrient sensing capacity of mTOR,

00:15:33.080 | which you described as the,

00:15:35.160 | probably the most important nutrient sensing system

00:15:38.080 | in our body.

00:15:38.920 | So we have these, somewhere between nine and 14,

00:15:43.200 | the number just keeps changing arbitrarily,

00:15:45.040 | but it doesn't really matter.

00:15:45.900 | We have these central things that everybody would agree

00:15:48.840 | define what an aging phenotype is,

00:15:51.480 | and can we use exogenous molecules

00:15:54.200 | to target those specifically?

00:15:55.880 | You gave one example,

00:15:57.240 | which I would argue is the single best example,

00:15:59.400 | which is rapamycin.

00:16:00.780 | So rapamycin targets a very specific hallmark of aging,

00:16:04.660 | and we can talk about what the experimental evidence is

00:16:08.280 | to suggest that that makes you live longer.

00:16:10.680 | So I would sort of say those are the big three categories.

00:16:13.800 | And then basically, the fourth category,

00:16:16.680 | you could just say is like,

00:16:17.720 | how do you put them all together?

00:16:19.000 | And how aggressive do you wanna be in culminating those?

00:16:21.680 | Of course, none of this touches on another area

00:16:24.040 | that I wanna talk about that we won't talk about today,

00:16:25.820 | which is like, how does all that factor

00:16:26.880 | into kind of emotional health and happiness and wellbeing,

00:16:30.320 | where none of this other stuff matters

00:16:33.040 | if you're kind of unhappy.

00:16:34.320 | And so you have to,

00:16:35.700 | and you've done so many podcasts on that topic, right?

00:16:37.780 | You've had Paul Conti on where you kind of go through

00:16:40.180 | the understanding of ourselves and our minds,

00:16:42.060 | and why that's also a very important part of it,

00:16:44.740 | because it actually does impact how long you live.

00:16:47.300 | Because if that piece isn't working,

00:16:49.340 | it's very difficult to regulate the first bucket,

00:16:52.180 | 'cause the first bucket takes so much work.

00:16:54.260 | So if you can't regulate yourself,

00:16:57.060 | it's very difficult to regulate the do's and don'ts.

00:17:01.100 | But even absent just length of life stuff,

00:17:03.740 | it impacts quality of life,

00:17:05.020 | which is this idea of healthspan as well.

00:17:07.260 | So I guess that's just my slightly different way

00:17:10.740 | to frame it, but it's a little bit more Meesey,

00:17:13.420 | in that we talk about the behaviors,

00:17:15.640 | the exogenous molecules that target diseases,

00:17:18.900 | the exogenous molecules that target aging.

00:17:21.720 | - Aside from food, what exogenous molecules do you take?

00:17:27.660 | - I take a few, right?

00:17:30.500 | So I take some that are disease specific, right?

00:17:33.180 | So I take a PCSK9 inhibitor, I take bempedoic acid,

00:17:36.660 | I take an SGLT2 inhibitor,

00:17:38.680 | and then I take at least one that is purely just

00:17:43.860 | based on the belief of its capacity and geroprotection,

00:17:46.660 | which is risrapamycin.

00:17:48.580 | And also the SGLT2 inhibitor,

00:17:52.020 | I think is probably just broadly geroprotective.

00:17:54.660 | And we can even talk about that a little bit

00:17:56.320 | in terms of the success of one of those molecules

00:17:59.700 | called canagaflozin in the interventions testing program,

00:18:03.100 | the ITP, which I am sure we'll talk about

00:18:05.340 | in the context of NAD as well.

00:18:07.440 | - What dosage of rapamycin do you take?

00:18:11.700 | - I take eight milligrams once a week

00:18:14.100 | for as long as I can tolerate it,

00:18:15.700 | but I usually have to take breaks.

00:18:17.820 | - Why is that?

00:18:18.660 | - I get these vicious apthos ulcers, little mouth sores.

00:18:23.220 | - Canker sores?

00:18:24.260 | - Yes.

00:18:25.100 | About 10% of people get them.

00:18:29.100 | It's paradoxically the only biomarker we probably have.

00:18:32.740 | So I secretly rejoice in knowing

00:18:35.740 | that at least I'm getting a good batch of rapamycin.

00:18:38.420 | - By virtue of the side effect.

00:18:39.260 | - By virtue of these miserable side effects.

00:18:40.980 | But so in reality, what it works out to

00:18:43.180 | is I'm probably on it for two months

00:18:44.820 | and then off it for a month,

00:18:46.220 | on it for two months, off it for a month, or thereabouts.

00:18:49.420 | - And the idea there is that you're limiting mTOR,

00:18:53.060 | you're causing your cells to grow less, mature slower,

00:18:58.060 | and in that sense, slowing down aging.

00:19:01.700 | Is that the idea?

00:19:03.100 | - Yeah, I mean, you know,

00:19:04.700 | and this will be an important theme today, right?

00:19:06.580 | It's like we can talk all day long about mechanisms

00:19:09.420 | and theoretical arguments for why it would work.

00:19:12.100 | And I think my conviction around taking rapamycin

00:19:15.380 | is less about sort of looking at the molecular explanation

00:19:20.380 | for why RAPA works,

00:19:23.380 | although I find that to be quite convincing.

00:19:25.300 | And why does the inhibition of mTOR stimulate autophagy?

00:19:29.260 | Why would that suppress senescent cells?

00:19:32.500 | But truthfully, my conviction around mTOR

00:19:34.340 | is far more based on the experimental data,

00:19:37.740 | something that is actually sorely lacking

00:19:39.460 | in the NAD story, which we'll discuss.

00:19:41.500 | So the experimental data are far more convincing, right?

00:19:44.260 | Which is when you look at the administration of rapamycin

00:19:49.260 | or its analogs, for example, Everolimus,

00:19:52.980 | when you look at the administration of these molecules

00:19:55.820 | to organisms that are as close as possible

00:19:59.300 | to the species of interest,

00:20:01.140 | we're the species of interest.

00:20:03.220 | So looking at mammals, such as mice and small primates,

00:20:08.220 | looking at fruit flies, looking at worms,

00:20:11.980 | and even looking at yeast,

00:20:13.020 | although that's so far from us that you would argue

00:20:15.260 | that's the least important.

00:20:17.140 | You see something that you don't see

00:20:18.380 | for a single other molecule,

00:20:20.500 | which is uniform life extension.

00:20:22.320 | No other molecule has done this.

00:20:25.140 | It's very important to understand

00:20:26.540 | there are only two interventions, full stop,

00:20:29.660 | that have ever extended life

00:20:31.520 | across those four categories of eukaryotes.

00:20:35.380 | - Caloric restriction.

00:20:36.660 | - And rapamycin.

00:20:37.620 | Very important point, right?

00:20:40.820 | - How do you feel when you're on rapamycin,

00:20:42.580 | aside from the canker sores?

00:20:44.220 | - Yeah, which fortunately aren't that frequent.

00:20:46.620 | I don't feel anything,

00:20:47.700 | and the very few of my patients who take it,

00:20:50.140 | because maybe 10% of my patients also take it,

00:20:54.060 | I've never heard, actually, that's not true.

00:20:56.020 | I've probably heard two people say they feel better on it,

00:20:58.380 | but I don't know what to make of that.

00:21:00.180 | Maybe they do, and maybe that's just a placebo effect.

00:21:03.100 | - Does it synergize with caloric restriction

00:21:05.540 | or collide with caloric excess?

00:21:07.860 | Meaning if you're taking rapamycin,

00:21:09.980 | but you're slightly over your caloric needs,

00:21:12.820 | maybe you're trying to add a little bit of body weight

00:21:15.080 | or happen to overeat a little bit just because,

00:21:17.820 | is it going to collide with rapamycin's potential

00:21:21.700 | positive impact on slowing aging?

00:21:24.500 | - Yeah, that's a good question, Andrew.

00:21:25.580 | I don't know.

00:21:26.820 | I don't think we know.

00:21:28.540 | We do know that there's one other really important readout

00:21:31.340 | we're waiting for,

00:21:32.180 | which is Matt Kaberlin's dog aging study,

00:21:35.920 | which is gonna be an exciting readout in 2026.

00:21:41.820 | We're also waiting for another readout

00:21:43.980 | out of the University of San Antonio,

00:21:45.700 | looking at another trial in mammals.

00:21:50.460 | And again, I think those two

00:21:52.460 | will be really interesting, right?

00:21:54.600 | Because we have a ton of,

00:21:56.140 | we have just an overabundance of mouse data

00:21:58.560 | that are so reproducible,

00:22:00.140 | and reproducible in really good mouse models.

00:22:02.660 | As you know, I'm sure from your work,

00:22:06.380 | the model you choose matters, right?

00:22:08.380 | And sort of you, in an ideal world,

00:22:11.020 | you wanna use a mouse model that is not inbred,

00:22:16.020 | that is more closely related to what we care about,

00:22:19.780 | which is ourselves.

00:22:21.100 | And so when you see many labs getting the same result

00:22:24.900 | over and over again,

00:22:26.260 | regardless of how they do it,

00:22:28.340 | you really start to believe there's a signal there.

00:22:30.300 | So now to be able to see this in a higher order mammal,

00:22:33.100 | and ultimately in companion dogs,

00:22:35.580 | which is where Matt Kaberlin is looking,

00:22:37.960 | I think that's gonna be really exciting.

00:22:40.260 | And I've often said to my patients,

00:22:41.580 | "Look, in 2026, I'm either gonna feel

00:22:44.100 | "a lot more conviction about taking rapamycin

00:22:47.020 | "and prescribing it to some of my patients,"

00:22:49.340 | though, again, not most,

00:22:50.900 | "or I'm gonna have a second look at this and say,

00:22:54.180 | "maybe we just shouldn't be taking this," right?

00:22:57.300 | 'Cause I do think that the dog study

00:22:58.860 | is gonna be more telling.

00:23:00.720 | But again, we'll have to wait and see what that shows.

00:23:04.700 | - Without going off track too much,

00:23:06.760 | my understanding is that the dog study was halted

00:23:08.940 | because of a lack of federal funding.

00:23:11.460 | Is it continuing?

00:23:12.540 | - It is going to go on.

00:23:13.980 | There's, yeah, it's...

00:23:15.820 | So initially, there was kind of insufficient funding

00:23:19.140 | to do the study in an adequate way.

00:23:21.400 | And then it turned out there was a shortfall

00:23:24.580 | of about $2.5 million to do the study

00:23:28.140 | that Matt really wanted to do.

00:23:29.620 | And then, actually, a group of us

00:23:31.060 | raised that money for Matt and did that.

00:23:32.900 | So me and a few of my patients

00:23:35.860 | and a couple of other folks came together

00:23:37.820 | and put the money in to close the gap.

00:23:40.140 | But yes, there has been...

00:23:42.500 | What did get pulled back by the NIH inexplicably

00:23:46.500 | and, in my view, totally incorrectly

00:23:51.380 | was the ongoing surveillance program,

00:23:53.880 | the funding for the ongoing surveillance program

00:23:55.760 | that would allow this type of work to continue

00:23:58.440 | and to allow greater follow-up on this.

00:24:00.340 | So yes, unfortunately, until we can get more funding,

00:24:04.920 | we're not gonna be able to maybe do as much

00:24:06.660 | as we'd like to do and understand this.

00:24:08.700 | Which, again, when you look at some of the things

00:24:10.820 | that are funded, it's hard to believe

00:24:13.260 | that there's not a more interesting question right now

00:24:15.380 | in biology than this drug that seems so promising.

00:24:18.500 | Why we wouldn't want to know

00:24:20.780 | if this is something we should all be taking

00:24:22.380 | is kind of a mystery to me.

00:24:24.500 | - Yeah, I was on NIH study sections for many years

00:24:27.420 | reviewing grants.

00:24:28.260 | I rotated off as a regular member a little over a year ago.

00:24:33.260 | And I can tell you that the whole process

00:24:35.260 | is designed to be as targeted to the best

00:24:39.700 | and most exciting work possible.

00:24:41.180 | But there's a number of features now that make it such

00:24:43.620 | that it's largely the work that's already mostly completed

00:24:48.220 | that gets funded.

00:24:49.060 | You don't even know, like, how does that work?

00:24:50.580 | But anyway, we could have a whole other

00:24:52.260 | journal club discussion about funding,

00:24:53.720 | but I had to ask, I was curious.

00:24:55.340 | So hopefully that study will get completed

00:24:59.020 | and thanks for raising those funds.

00:25:00.940 | Let's talk about NAD.

00:25:02.100 | - Yes.

00:25:03.420 | - It's in essentially every cell of the body

00:25:05.080 | except red blood cells, correct?

00:25:08.220 | - You know, I don't even know if it's in red blood cells.

00:25:10.780 | My intuition is, I've never looked to be honest with you,

00:25:13.740 | but given that red blood cells

00:25:15.500 | have a different metabolic pathway, right,

00:25:18.180 | where they're purely glycolytic,

00:25:19.860 | they wouldn't have the need for it

00:25:21.100 | in the way that others would, but they might, right?

00:25:22.980 | 'Cause they still undergo redox potential.

00:25:24.380 | So it's possible NAD is in every single cell, yeah.

00:25:27.240 | - And it's generally thought to be associated

00:25:29.580 | with energy production and mitochondrial pathways

00:25:32.140 | in every single cell.

00:25:34.460 | - Right, so NAD is, again,

00:25:38.100 | one of the most ubiquitous molecules in the body

00:25:40.820 | and most of what it does, and I mean most,

00:25:45.060 | meaning like somewhere between five and 600 pathways of it,

00:25:48.940 | utilize NAD as a cofactor,

00:25:52.100 | meaning that it's not consumed in a chemical reaction,

00:25:55.740 | but rather it serves as an electron shuttle.

00:25:59.180 | So NAD and NADH basically play catch with electrons.

00:26:04.980 | And that's 99% of what NAD is doing in the body.

00:26:09.740 | And for that reason, NAD is so tightly regulated

00:26:14.740 | in the body.

00:26:16.160 | The levels of NAD in the cell are really tightly regulated.

00:26:20.940 | And that shouldn't be surprising.

00:26:22.540 | Just as glucose, really tightly regulated.

00:26:25.860 | pH or hydrogen ion concentration, really tightly regulated.

00:26:30.780 | We as a species cannot survive

00:26:33.140 | outside of a very narrow band of pH, right?

00:26:38.020 | If it's below seven or above 7.8 on a zero to 14 scale,

00:26:42.920 | we die, full stop.

00:26:45.140 | So similarly, NAD is managed across all ages

00:26:49.020 | and across all physiologic conditions in a super tight band.

00:26:54.020 | There's another place where NAD shows up,

00:26:57.920 | and that shows up as a substrate, right?

00:26:59.740 | So cofactor means used coenzyme,

00:27:02.900 | used but not consumed, recycled.

00:27:05.100 | That's 99% of it.

00:27:07.100 | A small fraction of it is used.

00:27:09.820 | And it's used by these things called sirtuins

00:27:12.940 | that consume NAD as an actual substrate

00:27:16.840 | in the process of DNA repair.

00:27:19.940 | And maybe we can go into this,

00:27:22.260 | but this is really where the story picks up.

00:27:25.500 | - It's also, as I recall, where the story began.

00:27:27.700 | - That's exactly right.

00:27:28.520 | It was some experiments where the sirtuins were mutated

00:27:33.000 | in one direction or the other,

00:27:34.520 | meaning gain of function or loss of function.

00:27:36.680 | These days, people hear gain of function

00:27:38.600 | and they immediately think to pandemic-related themes.

00:27:41.240 | But gain of function is a way of changing genes,

00:27:44.500 | typically to augment a function, increase its robustness,

00:27:49.500 | or in some cases to rescue a phenotype

00:27:52.520 | where you have a knockout mouse that lacks a gene,

00:27:55.320 | so that's loss of function,

00:27:57.480 | or a strain of yeast that lacks a gene,

00:28:00.400 | and then you do the gain of function rescue experiment.

00:28:03.080 | You reintroduce the gene of interest.

00:28:06.400 | It's an important, I wouldn't even call it a control.

00:28:08.520 | It's an important experiment in any case

00:28:10.400 | because loss of function will tell you a lot.

00:28:13.900 | But gain of function and loss of function,

00:28:16.380 | assuming that the results jive, tells you much, much more.

00:28:20.200 | This is one of the major areas,

00:28:22.120 | I think this is very important to highlight,

00:28:24.200 | where human genetics really struggles

00:28:27.600 | because you can get humans with a mutation

00:28:31.000 | in a particular pathway,

00:28:32.360 | like I don't know, the sonic hedgehog pathway.

00:28:34.560 | Somebody is hypomorphic for sonic hedgehog

00:28:36.760 | and they might actually lack a major tooth up middle

00:28:40.780 | because the role of sonic hedgehog at the midline,

00:28:43.580 | and you could say, okay, well, loss of function here,

00:28:45.160 | here's the role of sonic hedgehog.

00:28:46.520 | But the ideal experiment is to put the gene back in

00:28:49.360 | and then rescue that phenotype

00:28:50.640 | because as any logical mind can tell,

00:28:55.560 | there could be many things downstream of sonic hedgehog

00:28:58.440 | that could create the phenotype that you observe.

00:29:00.660 | But if you put sonic hedgehog back in,

00:29:02.680 | yes, that's still true,

00:29:03.600 | but you get more reassurance

00:29:05.000 | that that's the gene of interest.

00:29:06.800 | So with respect to sirtuins,

00:29:08.960 | as I recall, they deleted the sirtuins in yeast.

00:29:11.800 | - Let's use another example

00:29:12.960 | of what the gold standard is here

00:29:14.300 | or what a great example is.

00:29:15.640 | So I recently did a podcast with Dina Dubal

00:29:17.960 | from UCSF on clotho, which is an amazing scientific story.

00:29:22.000 | And it's a great story because it shows

00:29:23.760 | how accidents can lead to great discoveries, right?

00:29:26.180 | So there was a researcher in Japan

00:29:28.400 | who was really interested in understanding hypertension,

00:29:31.280 | high blood pressure, and they had created a mouse model

00:29:33.760 | where they were trying to knock out certain sodium channels

00:29:36.580 | to see if they could perturb blood pressure.

00:29:39.240 | And then there was this one strain of mouse

00:29:42.400 | with this one knockout that died really, really quickly.

00:29:45.800 | And it developed like devastating neurodegenerative disease

00:29:47.920 | and died very quickly.

00:29:49.960 | And like a good scientist, he didn't say,

00:29:52.080 | well, that sucks, I'm gonna discard that one

00:29:53.880 | 'cause it didn't give me what I wanted,

00:29:55.220 | which was the blood pressure change.

00:29:56.440 | And he kind of went and figured out what was going on.

00:29:58.100 | And he figured out that there was a certain gene

00:30:00.080 | that he had hit that wasn't a sodium transporter

00:30:03.000 | and instead was this other gene.

00:30:04.360 | He named it clotho.

00:30:06.080 | So you had this one piece of evidence right now,

00:30:09.120 | which was if you knock out that gene,

00:30:11.720 | you kill an animal very quickly.

00:30:13.600 | Now that doesn't mean it's a longevity gene.

00:30:15.520 | You have to do the other experiment to your point.

00:30:17.880 | You have to overexpress that gene and ask the question,

00:30:21.000 | do you live longer?

00:30:22.280 | And sure enough, when they overexpress that same gene

00:30:25.120 | that they had just knocked out and killed the mouse,

00:30:27.380 | the thing was living 15 to 20% longer.

00:30:29.680 | - So it's both necessary and sufficient for extended life.

00:30:32.720 | - Yeah, so that's how you can say,

00:30:33.540 | well, that's a longevity gene.

00:30:35.240 | - As many of you know, I've been taking AG1

00:30:37.440 | for more than 10 years now.

00:30:39.000 | So I'm delighted that they're sponsoring this podcast.

00:30:41.480 | To be clear, I don't take AG1 because they're a sponsor,

00:30:44.240 | rather they are a sponsor because I take AG1.

00:30:47.340 | In fact, I take AG1 once and often twice every single day,

00:30:50.760 | and I've done that since starting way back in 2012.

00:30:54.480 | There is so much conflicting information out there nowadays

00:30:57.040 | about what proper nutrition is.

00:30:59.220 | But here's what there seems to be a general consensus on.

00:31:02.200 | Whether you're an omnivore, a carnivore,

00:31:04.560 | a vegetarian or a vegan,

00:31:06.240 | I think it's generally agreed

00:31:07.440 | that you should get most of your food

00:31:08.960 | from unprocessed or minimally processed sources,

00:31:11.960 | which allows you to eat enough, but not overeat,

00:31:14.480 | get plenty of vitamins and minerals,

00:31:16.040 | probiotics and micronutrients

00:31:18.080 | that we all need for physical and mental health.

00:31:20.500 | Now, I personally am an omnivore,

00:31:22.300 | and I strive to get most of my food

00:31:23.840 | from unprocessed or minimally processed sources.

00:31:26.640 | But the reason I still take AG1 once

00:31:28.600 | and often twice every day,

00:31:30.320 | is that it ensures I get all of those vitamins,

00:31:32.820 | minerals, probiotics, et cetera,

00:31:34.960 | but it also has adaptogens to help me cope with stress.

00:31:37.800 | It's basically a nutritional insurance policy

00:31:40.060 | meant to augment, not replace quality food.

00:31:42.760 | So by drinking a serving of AG1 in the morning,

00:31:45.000 | and again in the afternoon or evening,

00:31:47.040 | I cover all of my foundational nutritional needs.

00:31:49.760 | And I, like so many other people that take AG1,

00:31:52.360 | report feeling much better in a number of important ways,

00:31:55.400 | such as energy levels, digestion, sleep, and more.

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00:31:59.960 | are really directed towards obtaining one specific outcome,

00:32:03.120 | AG1 is foundational nutrition

00:32:04.880 | designed to support all aspects of wellbeing

00:32:07.040 | related to mental health and physical health.

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00:32:10.960 | you can go to drinkag1.com/huberman

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00:32:20.560 | Again, that's drinkag1.com/huberman.

00:32:24.760 | - So let's go to the sirtuin story.

00:32:25.980 | So it goes back to the late nineties.

00:32:28.480 | Matt Kaeberlin again, this is amazing, right?

00:32:30.540 | So you have this guy who's like the leading authority

00:32:33.200 | or one of the leading authorities

00:32:34.280 | on the work going on today with rapamycin,

00:32:37.200 | along with one of his colleagues,

00:32:38.600 | David Sabatini and a few others.

00:32:40.380 | But when Matt was a postdoc,

00:32:43.120 | he did an experiment in a strain of mice,

00:32:46.480 | pardon me, a strain of yeast.

00:32:47.320 | I think it was the W3O3 strain of yeast.

00:32:50.280 | And he over-expressed SIR2.

00:32:54.100 | And lo and behold, the yeast lived longer.

00:32:58.500 | Now, a year later, someone else in the same lab

00:33:02.920 | took a different strain of yeast

00:33:05.680 | and calorically restricted them,

00:33:08.960 | and they also lived longer.

00:33:10.560 | I forget the name of that.

00:33:12.800 | I forget what that strain was.

00:33:14.080 | It was something 316 was it,

00:33:16.780 | but it was a different strain of yeast.

00:33:18.760 | At that moment, again, this is about 25 years ago,

00:33:22.040 | a hypothesis emerged,

00:33:23.720 | which was we have two different strains of yeast.

00:33:26.220 | And in one of them, when you over-express SIR2,

00:33:31.480 | this gene, they live longer.

00:33:33.760 | And in this other strain,

00:33:34.600 | if you calorically restrict them, they live longer.

00:33:38.080 | The understandable hypothesis was caloric restriction,

00:33:41.960 | which we had known was life-extending,

00:33:44.560 | is working through sirtuins.

00:33:46.200 | That hypothesis sort of fell apart about four years later

00:33:50.820 | when Matt Kaberlin, again, this time with Brian Kennedy,

00:33:54.560 | did another experiment in a different,

00:33:58.200 | yet a third strain of yeast

00:34:00.160 | that allowed them to test hypothesis,

00:34:02.520 | because there was a problem with the story I just told.

00:34:06.600 | When you took the 303 strain,

00:34:09.800 | this is the strain that when over-expressing SIR2

00:34:13.480 | lived longer, if you took that strain

00:34:15.200 | and you calorically restricted them, no change.

00:34:18.620 | That's odd.

00:34:20.800 | Even more odd is when you took the 316 strain,

00:34:24.880 | and this is the strain that lived longer with CR.

00:34:27.640 | If you over-express SIR2, no change.

00:34:31.420 | So right off the bat, the story didn't make sense,

00:34:34.040 | but it was further solidified

00:34:35.560 | that that story didn't make sense

00:34:37.320 | when Brian and Matt published in 2004

00:34:40.160 | in yet a different strain.

00:34:41.720 | God, I'm blanking on the name.

00:34:42.700 | It's like BY4742, like, you know, these don't matter.

00:34:47.700 | If you calorically restricted them, they lived longer.

00:34:52.040 | If you over-express SIR2, they lived longer.

00:34:54.960 | If you did both, they lived even longer.

00:34:57.720 | It was additive.

00:34:59.260 | Again, further suggesting that over-expression of SIR2

00:35:03.620 | and caloric restriction independently

00:35:06.660 | and separately extended lifespan.

00:35:08.980 | These are parallel pathways.

00:35:10.580 | They're parallel pathways.

00:35:11.900 | For reasons that honestly escape me, Andrew,

00:35:15.580 | there are still people who maintain

00:35:18.280 | that the benefit of SIR2 and over-expression

00:35:23.280 | is through the caloric restriction pathway and vice versa.

00:35:26.540 | And that's wrong.

00:35:27.420 | My reading of the literature,

00:35:30.220 | in addition to every person I have talked to on this

00:35:32.960 | who works in the space, including Matt Kaberlin,

00:35:35.980 | who has done the most research on this,

00:35:38.340 | is that there is no evidence that caloric restriction

00:35:41.380 | and sirtuins operate through the same pathway.

00:35:43.740 | And in that sense, I think there's relatively

00:35:47.540 | uniform agreement that caloric restriction extends life

00:35:50.660 | across the model systems we discussed.

00:35:52.700 | - What about in humans?

00:35:54.620 | - What about it specifically?

00:35:56.020 | - Does it extend life?

00:35:57.580 | - Well, that experiment's never been done

00:35:59.060 | and never will be done.

00:36:00.380 | - The joke I was trying to set up for

00:36:01.700 | is the one I'll make now,

00:36:02.540 | which is no one wants to be in the control experiment.

00:36:05.820 | That said, nobody wants to be in the--

00:36:06.660 | - I would argue nobody wants to be

00:36:07.860 | in the treatment experiment either.

00:36:08.700 | - Oh, you got me, you got me.

00:36:10.100 | You beat me to the punch.

00:36:11.660 | No one wants to be in the treatment group either

00:36:13.580 | because it requires eating so little.

00:36:15.940 | It just, the mere appearance of people--

00:36:20.180 | - The joke is you probably will live longer

00:36:22.380 | and it will feel even worse.

00:36:23.700 | Like it's just, it's, yeah.

00:36:25.580 | Caloric restriction, which by the way,

00:36:27.620 | there are real debates about whether

00:36:29.180 | it will extend life in humans

00:36:31.620 | because it will clearly, I shouldn't say clearly.

00:36:35.180 | I think it would be a very safe bet

00:36:37.140 | that severe caloric restriction

00:36:39.060 | will absolutely reduce the risk of most chronic diseases.

00:36:43.540 | Meaning I have, I think there's very good reason

00:36:46.100 | to believe that if an individual

00:36:47.700 | constitutively consumed 25% fewer calories

00:36:51.380 | than they were meant to eat,

00:36:52.840 | their risk of cardiovascular disease,

00:36:55.460 | cancer, Alzheimer's disease would go down.

00:36:58.100 | The problem is what things go up.

00:37:01.240 | What does that do to your immune system?

00:37:03.220 | What does that do with respect to sarcopenia?

00:37:05.620 | What does that do to your risk of falling?

00:37:07.140 | - Yeah, frailty.

00:37:07.980 | - Yeah, exactly.

00:37:08.860 | So you trade one set of diseases for another,

00:37:11.820 | it's not at all clear that lifespan goes up.

00:37:14.580 | And by the way, when you even look at some of the wild,

00:37:18.580 | like some of the animal literature

00:37:21.100 | where they're using different strains of mice

00:37:22.860 | that are not inbred and they don't put them

00:37:25.160 | in hermetically sealed situations, they don't live longer.

00:37:28.960 | So it's not always the case that caloric restriction

00:37:31.580 | extends life.

00:37:32.820 | And therefore, well, it's safe to say caloric restriction

00:37:36.940 | probably reduces the onset of chronic disease

00:37:39.940 | that might not translate to an all-cause mortality benefit

00:37:42.800 | based on those downsides.

00:37:44.820 | But all of that said, I think the holster two in story

00:37:48.460 | got off to an incorrect start where it basically

00:37:52.940 | lopped on to the CR story, which was,

00:37:55.260 | hey, we've got this thing CR that we've known since--

00:37:57.260 | - Caloric restriction.

00:37:58.100 | - Right, caloric restriction.

00:37:58.940 | We've got this thing, which for 50 years,

00:38:00.980 | we've known has a signal that really says

00:38:04.100 | it's life extending.

00:38:05.460 | And we've got this yeast where it works

00:38:07.380 | and this other yeast where sirtuin activation works.

00:38:09.300 | Oh, it's gotta be sore.

00:38:10.320 | But again, if you go through the story in detail,

00:38:12.740 | as I just did, there's no evidence whatsoever

00:38:16.560 | that sirtuins have anything to do with caloric restriction

00:38:18.780 | and vice versa.

00:38:19.620 | - It's incredibly interesting because I think

00:38:23.800 | when you look at cell biology

00:38:25.300 | and you see these parallel pathways,

00:38:27.500 | when you see these effects of experiments

00:38:29.100 | where changing sirtuins or changing caloric restriction

00:38:33.340 | independently increase lifespan, combine the two,

00:38:36.140 | you get this, what appears to be a synergistic effect,

00:38:38.920 | but it's, as you pointed out, an additive effect.

00:38:41.940 | It's like a pretty straightforward experiment to do.

00:38:44.540 | You could just do an occlusion, right?

00:38:46.860 | You could then put back in the sirtuin

00:38:49.780 | or adjust calories and see whether or not you get the,

00:38:52.500 | effectively, whether the math is corrected, you know?

00:38:55.980 | So--

00:38:57.460 | - Now, none of this gets to the question you raised yet.

00:38:59.820 | That's just all, that's all prologue, right?

00:39:02.680 | That's like, where did this story come up?

00:39:05.380 | But then the question becomes, well,

00:39:07.740 | if you believe that sirtuins are truly

00:39:10.940 | a factor that drives longevity,

00:39:14.820 | how can you activate them, right?

00:39:17.060 | How do you activate a sirtuin?

00:39:19.820 | So we have to now simultaneously start to hold things true

00:39:24.020 | in parallel that may or may not be true.

00:39:26.380 | So we want to then ask the question,

00:39:29.180 | do we believe that what we saw in yeast,

00:39:32.500 | which I think is the only reproducible finding I can draw,

00:39:37.220 | meaning this is a reproducible finding,

00:39:39.140 | in many but not all strains of yeast,

00:39:41.940 | if you overexpress sirtuins, the yeast will live longer.

00:39:46.300 | So let's park that in the parking lot

00:39:48.580 | as a very likely statement.

00:39:52.400 | You would then say, well, if it does it in yeast,

00:39:54.500 | does it do it in flies?

00:39:55.800 | Does it do it in worms?

00:39:57.000 | Does it do it in mammals?

00:39:58.000 | You want to be able to check those three boxes,

00:40:00.440 | because again, that's a billion years of evolution.

00:40:02.760 | So if something works across a billion years,

00:40:05.000 | we'd be much more confident it works in us.

00:40:06.880 | - Yeah, making a fly mutant, Drosophila mutant

00:40:09.760 | that overexpresses sirtuins,

00:40:11.960 | a worm C. elegans mutant that overexpresses sirtuins,

00:40:14.840 | that's a pretty quick experiment to do

00:40:17.360 | because of this short generation time of those species.

00:40:20.400 | Now, a mouse, it's a longer experiment,

00:40:22.960 | but I'm guessing all of those experiments have been done.

00:40:25.200 | - Yeah, and the only one that I can find

00:40:28.320 | that has demonstrated a survival advantage

00:40:31.260 | is one particular transgenic mouse experiment

00:40:35.340 | that overexpressed SIRT6,

00:40:39.720 | and it did indeed, for the male mice,

00:40:44.720 | increase lifespan by 10 to 15%.

00:40:48.760 | So this is one transgenic mouse model

00:40:51.600 | that overexpressed SIRT6,

00:40:53.640 | and the male mice lived 10 to 15% longer.

00:40:56.840 | The female mice did not.

00:40:58.320 | - We should probably clarify what a transgenic mouse is.

00:41:00.920 | I talked about knockout mice.

00:41:02.500 | That's when a gene, or genes in some cases,

00:41:05.280 | is deleted from the genome.

00:41:08.280 | So it's null, it does not express that gene.

00:41:11.040 | The gain of function would be to put back that gene in.

00:41:13.840 | That would be a knock-in mouse.

00:41:16.060 | So in that case, you still get some normal expression

00:41:19.280 | of the gene from the endogenous genome,

00:41:21.100 | but now you have a transgene that's inserted there.

00:41:23.420 | And there are all sorts of important intricacies

00:41:26.540 | that relate to this.

00:41:27.580 | For instance, where the transgene is inserted.

00:41:29.900 | If it's downstream of an enhancer that's muscle-specific,

00:41:33.500 | then you can get a mouse

00:41:35.660 | that overexpresses SIRT2 and it's just in muscle.

00:41:38.020 | You can get it ubiquitously expressed.

00:41:40.540 | There are a number of different ways that this can happen.

00:41:42.220 | I'm assuming this was ubiquitous expression of,

00:41:45.620 | you said SIRT6?

00:41:46.780 | - SIRT6, yeah.

00:41:47.620 | - So every cell in the body

00:41:48.980 | that normally would express SIRT6

00:41:50.580 | would express more SIRT6.

00:41:52.140 | - I don't remember, Andrew, to be honest with you.

00:41:53.820 | I'd have to go back and look at the paper.

00:41:54.900 | I don't know if it was muscle-specific

00:41:56.340 | or whole body-specific.

00:41:57.780 | - I'm guessing unless they made it clear

00:41:59.920 | that it was tissue-specific, that it's whole body.

00:42:03.140 | So we're talking about it,

00:42:04.240 | when Peter says transgenic mouse,

00:42:05.860 | he's talking about a mouse that has this transgene

00:42:08.140 | that causes it to express more SIRT2 and SIRT6

00:42:10.420 | than it ordinarily would.

00:42:11.820 | And let's assume, although we don't know this for sure,

00:42:14.680 | that the other genes in this mouse

00:42:17.160 | are functioning as they would normally.

00:42:19.140 | - Right.

00:42:20.100 | So again, just to summarize that, that's 2012.

00:42:23.140 | We have this one transgenic mouse.

00:42:25.780 | You put SIRT6, you overexpress SIRT6,

00:42:28.460 | and all of a sudden, the males were living 10% longer.

00:42:31.300 | Again, to be clear,

00:42:32.140 | the females didn't experience a difference.

00:42:34.520 | And that's not uncommon or unheard of in longevity research.

00:42:38.740 | There generally are sex-specific differences,

00:42:41.380 | and you always have to read the fine print.

00:42:43.400 | The first thing I always look at in a study,

00:42:46.180 | when I see a difference in sexes,

00:42:49.100 | or frankly, any difference in longevity,

00:42:51.740 | but it's always great when they parse them out by sexes,

00:42:53.740 | is how long did the controls live?

00:42:56.260 | But I went back and actually looked

00:42:57.860 | at the Kaplan-Meier curves on that exact study.

00:43:00.780 | And yes, indeed, I think that's a real effect.

00:43:03.080 | So let's take stock of now two pieces of information

00:43:07.340 | that I think we could say is probably true.

00:43:09.820 | It is probably true that in a handful of strains of yeast,

00:43:14.120 | if you overexpress SIRT, you are going to live longer.

00:43:19.120 | That tends to be completely independent

00:43:21.240 | of caloric restriction.

00:43:22.200 | That's the single thing I can say

00:43:23.680 | with the greatest confidence.

00:43:25.120 | And there is at least one transgenic strain of mice

00:43:29.280 | that if you get it to overexpress, a different SIRT6,

00:43:32.400 | but again, these are homologs throughout the species,

00:43:34.720 | so I don't think we need to get wrapped up

00:43:36.520 | in SIRT2 versus SIRT6.

00:43:38.840 | You will at least make the male mice live longer,

00:43:41.020 | but not the females.

00:43:42.740 | - What sorts of things are downstream of SIRT2-ins?

00:43:46.340 | And that question translated to normal English

00:43:49.280 | is what is changing as a consequence

00:43:52.780 | of increasing the SIRT2-in?

00:43:55.060 | Could it be, for instance, well,

00:43:57.340 | unlikely based on what we already know

00:43:58.900 | about caloric restriction and the fact

00:44:00.260 | that they are independent parallel pathways,

00:44:02.800 | but is it something related to glucose metabolism?

00:44:05.500 | Is it something related to clearance of senescent cells?

00:44:09.160 | I mean, I'm just throwing out possibilities here.

00:44:10.660 | - Actually, you've hit two of the big three

00:44:12.020 | right off the top, right?

00:44:13.140 | So we believe that when SIRT2-ins are activated,

00:44:16.700 | they're improving mitochondrial biogenesis.

00:44:19.140 | They are increasing DNA repair.

00:44:25.500 | So that's probably the biggest one.

00:44:27.140 | And by the way, that's sort of what brings us

00:44:28.620 | to the NAD story.

00:44:34.220 | And also reducing SASPs, right?

00:44:36.660 | So the soluble products of senescent cells.

00:44:38.860 | So in other words, those are all three good things, right?

00:44:41.460 | So you tamp down on senescent cells,

00:44:44.740 | you increase mitochondrial biogenesis,

00:44:46.900 | and you increase DNA repair.

00:44:48.700 | Those would be all great things to do,

00:44:50.340 | and we think that SIRT2-ins are probably doing all of them.

00:44:53.940 | - This business of DNA repair and reducing, you know,

00:44:58.940 | fragmentation or mutations to DNA

00:45:01.740 | that are naturally occurring has been a hot idea

00:45:04.900 | in the field of aging for a long time.

00:45:07.180 | Is that because when x-rays became popular

00:45:11.460 | or post-nuclear fallout

00:45:15.100 | that people showed accelerated signs of aging?

00:45:19.140 | I mean, how did we get from DNA mutation

00:45:23.100 | to accelerated aging?

00:45:24.740 | - Well, I mean, I think we know that as we age,

00:45:29.020 | it's just a stochastic process, right?

00:45:30.900 | Like given the ubiquity of DNA replication

00:45:34.620 | and the fidelity of the system,

00:45:36.180 | which is high, very high, but not perfect,

00:45:39.620 | there's going to be mistakes.

00:45:41.500 | Actually, this is an interesting question.

00:45:42.780 | So in 2016, I went to Easter Island

00:45:46.420 | with David Sabatini and Nav Chandel and Tim Ferriss.

00:45:49.900 | So the four of us just took a trip to Easter Island

00:45:51.780 | to see the birthplace of rapamycin.

00:45:53.540 | So it was kind of like vacation slash science journey.

00:45:56.820 | - That's a nerdy vacation.

00:45:57.780 | - It was awesome.

00:45:59.500 | And so just picture hiking around this incredible island,

00:46:03.060 | just talking about science all day.

00:46:04.740 | But this was an interesting question

00:46:06.180 | that I posed to Nav and to David,

00:46:10.100 | which was, why do we see such a clear

00:46:14.100 | and present association with cancer as we age?

00:46:18.860 | And why is it so non-linear?

00:46:20.740 | So it's not just that cancer goes up with age,

00:46:23.100 | it goes up like that.

00:46:24.580 | And I said, I'll offer two hypotheses,

00:46:28.820 | which is more compelling.

00:46:30.460 | Is it simply that as we're aging, DNA replication,

00:46:35.460 | again, taking a step back for the listener,

00:46:38.020 | cancer is a genetic disease.

00:46:39.860 | Meaning by definition, it is sort of the canonical problem

00:46:44.860 | with cancer is a genetic mutation

00:46:47.380 | that leads to two properties of a cell,

00:46:49.900 | the inability of the cell to control replication.

00:46:54.660 | So it interrupts cell signaling.

00:46:56.580 | So cells replicate, but then don't know when to stop.

00:46:59.020 | And then the introduction of the capacity to spread,

00:47:02.220 | this property called metastasis.

00:47:03.980 | Those are the two hallmarks of cancer.

00:47:05.940 | So we know that that only happens

00:47:07.940 | in the context of genetic mutations,

00:47:09.900 | but why does this happen later in life

00:47:12.340 | and not at the beginning of life with very few exceptions?

00:47:14.700 | And so the question is,

00:47:16.180 | is it because over time mutations compound?

00:47:19.580 | Is it because there are more mutations as we age?

00:47:22.420 | Or is there a third issue, which is all of those things

00:47:26.500 | are happening normally, and they're no more abundant

00:47:29.020 | when you're 80 than when you're 20,

00:47:31.620 | but your immune system can't detect them as well.

00:47:34.740 | And the truth of it is we didn't come up with an answer,

00:47:36.860 | but it's probably all of the above.

00:47:39.020 | So it's probably that as we're aging,

00:47:41.260 | we are undergoing more DNA damage,

00:47:43.660 | and or at a minimum, the DNA damage we're undergoing

00:47:47.980 | is less amenable to repair.

00:47:49.860 | And that's part of the thesis here.

00:47:51.780 | Part of the thesis here is as we're aging,

00:47:55.120 | we are less and less able to repair DNA.

00:47:59.300 | And one of the arguments that put forth,

00:48:01.260 | although we're not quite ready for this part of the story

00:48:03.260 | yet, but I'll just say it now and we'll come back to it,

00:48:05.060 | is we don't have enough of the substrate

00:48:08.060 | that the sirtuin needs to repair DNA,

00:48:10.060 | and that substrate is NAD.

00:48:12.220 | So again, remember at the outset I said,

00:48:13.700 | look, there's two big categories to think about NAD.

00:48:16.860 | Most of what NAD is doing is operating as a cofactor

00:48:20.380 | for electron shuttling.

00:48:22.540 | That's the NAD, NADH, electron transport,

00:48:24.960 | electron accept, blah, blah, blah, blah, blah.

00:48:26.480 | Okay, not consuming NAD,

00:48:28.480 | just using it to pass electrons back and forth.

00:48:30.680 | But then over here, we have this other category

00:48:32.240 | where we use NAD as a substrate, it gets broken down,

00:48:36.080 | and that's what the sirtuins are doing to repair DNA.

00:48:38.800 | Okay, so if that's true,

00:48:41.600 | and if NAD levels are declining with age,

00:48:45.280 | it's a logical conclusion that should we give more NAD?

00:48:50.280 | If you're running out of substrate to repair DNA,

00:48:53.720 | and DNA repair is an important way to thwart aging,

00:48:57.440 | it all makes sense.

00:48:58.800 | So we'll keep that over there.

00:48:59.640 | But before we do, I wanna come back to one other story,

00:49:02.240 | which is the story of sirtuin activators.

00:49:05.180 | So what's the most famous sirtuin activator of all time?

00:49:08.760 | What is the heavyweight champion of sirtuin activators

00:49:12.120 | that has taken up 99% of the bandwidth in this space?

00:49:16.680 | It's a lovely little chemical called resveratrol.

00:49:19.800 | Okay, so resveratrol,

00:49:22.360 | which gained a lot of fame and notoriety

00:49:24.840 | because it happens to be found in trace elements

00:49:27.100 | in the skin of grapes, and therefore shows up in wine,

00:49:31.440 | gained a lot of notoriety about 20 years ago

00:49:34.840 | when one lab doing one experiment

00:49:38.320 | somehow was able to convince some people,

00:49:41.440 | including a very large pharma company,

00:49:44.520 | that resveratrol increased lifespan.

00:49:49.400 | So the thesis was, resveratrol activates sirtuins.

00:49:54.000 | Sirtuin activation is important

00:49:55.760 | because of all the things we just said, right?

00:49:57.480 | It improves mitochondrial biogenesis,

00:50:00.280 | it suppresses senescent cells,

00:50:02.880 | and it enhances DNA repair.

00:50:06.520 | So if you have something

00:50:07.840 | that is such a potent activator of sirtuins

00:50:10.160 | and you give it to a mouse, that mouse should live longer.

00:50:13.640 | Now, lots of experiments were done that couldn't find that.

00:50:17.800 | But one experiment was done,

00:50:20.400 | but it was an interesting experiment.

00:50:22.400 | I've discussed this at least on two podcasts,

00:50:24.700 | including one with Rich Miller,

00:50:26.280 | who runs the ITP, the Interventions Testing Program,

00:50:28.600 | which later tested resveratrol

00:50:30.200 | and found that it did categorically nothing.

00:50:33.120 | In this one experiment that worked,

00:50:34.920 | the investigators took a bizarre mouse model

00:50:38.420 | where they force-fed it an enormously high-fat diet.

00:50:43.320 | And in doing so,

00:50:44.800 | they created such an abundance of fatty liver

00:50:48.840 | that the livers of these mice encroached the chest,

00:50:53.840 | the thoracic cavity of the mice.

00:50:55.580 | So the mouse died prematurely because they couldn't breathe.

00:51:00.580 | And in that particular mouse model,

00:51:04.800 | resveratrol rescued the mice.

00:51:07.360 | So again, let's just assume that all of that is correct.

00:51:11.640 | And it's possible that there were even errors there,

00:51:13.400 | but let's just assume that's correct.

00:51:14.680 | Let's assume.

00:51:15.520 | - So this is resveratrol delivered orally in the food?

00:51:18.920 | - Yes.

00:51:19.760 | - Very high doses.

00:51:20.640 | - Mega doses.

00:51:21.840 | - The equivalent of barrels of grape skin.

00:51:23.840 | - Exactly, like doses so high you could...

00:51:26.960 | If you recall,

00:51:27.880 | we're both of an age that's old enough to remember this.

00:51:30.360 | There was this period of time when people thought

00:51:32.280 | this was the explanation to the French paradox, right?

00:51:35.080 | Why on average do the French live longer

00:51:37.080 | when they consume so much wine?

00:51:38.500 | And the answer was, it's got to be the resveratrol.

00:51:40.440 | It turns out that's not true at all

00:51:42.020 | because yeah, you would need to be drinking your body weight

00:51:44.760 | and wine a day to get the doses of resveratrol

00:51:47.680 | that were needed to produce this effect.

00:51:50.220 | But for whatever reason, there was an effect,

00:51:53.400 | which is if the thing that was going to kill you

00:51:56.400 | was your liver being so full of fat

00:51:59.120 | that it shot up into your chest so you couldn't breathe,

00:52:04.120 | which I've never seen a human,

00:52:05.760 | no matter how bad their fatty liver has been,

00:52:07.640 | where that's been the case.

00:52:08.760 | But if that's the problem you're going to face,

00:52:12.300 | it's possible at least based on this one mouse experiment

00:52:15.180 | that you are gonna live longer.

00:52:17.180 | But again, it turned out

00:52:18.220 | that there was no other replication of this

00:52:21.100 | in mouse models that matter.

00:52:23.860 | And that always comes back to the ITP,

00:52:25.900 | the Interventions Testing Program,

00:52:27.780 | which is the most robust tool we have scientifically

00:52:32.180 | to measure these exogenous molecules.

00:52:34.860 | So the ITP is an NIA funded program

00:52:38.100 | that runs out of three independent labs.

00:52:40.400 | And by independent,

00:52:41.240 | I mean they're each doing the experiments independently,

00:52:42.720 | but they're in sync with doing the experiment,

00:52:45.680 | but they're doing it in triplicate.

00:52:47.440 | So you have three labs,

00:52:48.680 | three great labs doing the experiments in triplicate.

00:52:52.020 | And when they did the resveratrol experiment,

00:52:55.920 | and they did it in combination with the people

00:52:58.800 | who found the result of that study.

00:53:01.040 | So they consulted these people and said,

00:53:03.080 | "What dose should we give?"

00:53:04.280 | And they said, "Do this, do this, do this."

00:53:06.280 | And they did it and nothing.

00:53:07.920 | There was no effective resveratrol.

00:53:09.640 | And that result has been consistent across the board.

00:53:13.820 | So that's also a very important part of the story,

00:53:15.860 | which was if resveratrol was a SIRTU inactivator,

00:53:20.120 | and I don't know if it really is,

00:53:21.960 | it clearly has no effect on lifespan

00:53:24.320 | with the one little asterisk that says,

00:53:26.400 | "Unless your body weight is 50% fatty liver."

00:53:30.000 | Then maybe it does.

00:53:31.800 | - I'd like to take a quick break to let you know

00:53:33.520 | that the Huberman Lab team has launched a new podcast

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00:54:06.840 | and learn a ton of useful knowledge from it.

00:54:09.480 | So please check it out and give it a subscribe

00:54:12.060 | wherever you're watching or listening to podcasts now.

00:54:14.840 | Again, the podcast is called Perform with Dr. Andy Galpin.

00:54:19.280 | - So let's see, let's just take stock

00:54:20.680 | of where we are in the story.

00:54:22.200 | We've got the whole yeast SIRTU in situation,

00:54:24.720 | which is at least in some yeast,

00:54:27.280 | SIRTU in overexpression lives longer.

00:54:30.400 | No evidence that that works through caloric restriction.

00:54:32.680 | Truly no evidence.

00:54:33.720 | That's been known for 20 years now.

00:54:36.040 | That paper was published in 2004.

00:54:38.880 | And that was a follow up to papers

00:54:40.400 | that had been published in 2002 to 1999, et cetera.

00:54:43.520 | Later on, you'd have the 2012 transgenic mouse study.

00:54:50.180 | So now the question is, okay.

00:54:54.560 | - How do you activate SIRTU?

00:54:55.720 | - How do you activate SIRTU?

00:54:56.560 | Well, yeah, so, or more to the point,

00:54:59.800 | why don't we just give people NAD?

00:55:02.240 | Okay, so again, the NAD story is,

00:55:06.120 | NAD levels are declining with age in most tissues.

00:55:11.120 | It appears most prevalent in the skin of all places.

00:55:17.480 | And I think we should come back to this

00:55:18.600 | 'cause there's one interesting finding

00:55:20.760 | associated with augmenting NAD levels in the skin.

00:55:24.800 | And my thought is, I wonder if it has to do

00:55:28.760 | with the fact that skin experiences

00:55:30.660 | the greatest decline in NAD.

00:55:32.980 | - It's also interesting because keratinocytes in skin

00:55:36.080 | turn over every 28 days or so.

00:55:38.880 | So you could imagine,

00:55:39.780 | because it's a novel population of cells,

00:55:41.840 | that they would have steady expression of SIRTUins and NAD.

00:55:46.840 | Then they simply die for whatever reason,

00:55:50.440 | or that it starts off very high on day one of generation

00:55:52.840 | then tapers off quickly.

00:55:53.960 | But that's not the case.

00:55:55.880 | It sounds like, you know.

00:55:57.440 | - On average, skin over the course of your lifetime

00:56:00.160 | will see about a 60% reduction in NAD.

00:56:03.480 | Whereas other tissues,

00:56:05.440 | and this is now based on animal studies,

00:56:07.880 | the brain might see a reduction by 15 to 20%.

00:56:11.640 | And the same would be found

00:56:12.840 | even in humans looking at the blood.

00:56:14.600 | So if you just sample whole blood in people

00:56:19.040 | at the age of 20, 30, 40, 50, 60, 70, 80,

00:56:21.120 | you're gonna see about a 20% reduction in NAD.

00:56:24.040 | - What about neurons?

00:56:25.000 | I mean, you've got the same set

00:56:26.000 | of central nervous system neurons your entire life.

00:56:28.920 | And of course, some peripheral neurons as well,

00:56:30.640 | but there's some regeneration in the periphery.

00:56:32.660 | So we need to discuss, let's just talk about brain.

00:56:34.760 | So unless you're talking about the olfactory bulb,

00:56:36.480 | where you have constant turnover throughout the lifespan,

00:56:39.040 | you have the same hippocampal neurons,

00:56:41.880 | except a small population.

00:56:43.040 | Same hippocampal neurons, cortical neurons, retinal neurons

00:56:45.680 | that you were born with.

00:56:47.220 | Are we observing NAD levels tapering off as we age?

00:56:49.920 | - In animals, yes.

00:56:50.800 | Obviously in humans, we're not doing that experiment.

00:56:52.840 | But yeah.

00:56:53.680 | Now, here's an interesting point.

00:56:56.400 | In 2015, a study was published in PNAS

00:57:00.600 | that looked at NAD levels in whole blood over time.

00:57:05.080 | And it found indeed, NAD levels were going down

00:57:07.840 | about 10 to 20% over four decades or so.

00:57:12.200 | But that same study said NADH levels

00:57:14.480 | were going up by the same amount.

00:57:16.260 | - Explain the role of NADH for people.

00:57:18.240 | - NADH is the electron acceptor.

00:57:22.800 | So when you, so let's maybe take a step back

00:57:26.040 | and like, how do we, why are you and I sitting here talking

00:57:29.720 | and not dead?

00:57:30.840 | - Like, 'cause we have enough NAD.

00:57:32.520 | - Right, right.

00:57:33.340 | What's going on, right?

00:57:34.180 | So you and I ate something at some point

00:57:37.600 | in the foreseeable past that contained chemical energy.

00:57:42.360 | So we ate something that was organic.

00:57:45.240 | So it had, so primarily fats and carbohydrates

00:57:49.240 | contain carbon-carbon bonds and carbon-hydrogen bonds.

00:57:52.040 | And those bonds contain a ton of energy.

00:57:54.960 | But how do we liberate the energy?

00:57:57.040 | So we break it all down into these constitutive molecules,

00:57:59.960 | namely glucose on the carbohydrate front

00:58:02.600 | and free fatty acids on the fat front.

00:58:04.920 | And then our bodies break those things down further

00:58:08.240 | into smaller molecules that get shuttled

00:58:10.840 | into the mitochondria where the lion's share

00:58:13.320 | of our energy liberation comes from.

00:58:15.640 | And what we do is we take that chemical energy

00:58:20.200 | that is stored in a carbon-to-carbon bond

00:58:23.000 | or a carbon-to-hydrogen bond,

00:58:24.760 | and we turn it into electrical energy.

00:58:27.200 | And people have heard this term,

00:58:28.400 | it's called the electron transport chain.

00:58:30.320 | So there are these four complexes in the mitochondria

00:58:32.960 | and there's an inner membrane and an outer membrane

00:58:35.160 | across which these large mitochondrial complexes reside.

00:58:40.160 | And what they're doing is they're building up

00:58:42.480 | a huge electron gradient by breaking them apart

00:58:47.320 | and taking the electrons and transferring them

00:58:49.440 | between NAD and NADH so that at the end,

00:58:52.720 | they can do another trick,

00:58:54.080 | which is transfer those electrons to a MP, ADP,

00:58:58.520 | and ultimately make ATP.

00:59:00.180 | The finished product is water and carbon dioxide.

00:59:04.600 | So we eat and we take that chemical energy and food,

00:59:08.600 | we utilize oxygen in the mitochondria to make ATP,

00:59:13.600 | carbon dioxide, which we breathe out,

00:59:15.460 | and water, which we breathe and pee out.

00:59:18.280 | So what NAD and NADH are doing

00:59:21.640 | is playing an absolutely essential-to-life role

00:59:25.660 | in facilitating the transfer of chemical energy

00:59:29.920 | to electrical energy back to chemical energy.

00:59:33.080 | ATP is just taking it from one chemical form in food

00:59:36.840 | to the electrical form as the intermediary

00:59:38.600 | in the mitochondria back to an electrical form of ATP.

00:59:42.240 | So you and I are walking around flush with ATP,

00:59:45.540 | which as we sit here right now,

00:59:47.280 | we're constantly firing off phosphates,

00:59:49.980 | again, now turning the chemical energy

00:59:51.920 | back into electrical energy and away we go.

00:59:53.980 | So yeah, this whole NAD, NADH thing is like,

00:59:58.980 | it's as central to our existence as any form of respiration.

01:00:02.580 | So my point, let's go back to the story.

01:00:04.280 | The story was NAD levels are going down as we age,

01:00:07.360 | but NADH levels are going up,

01:00:09.400 | suggesting that the total amount of NAD and NADH is the same

01:00:12.880 | and what's declining as we age

01:00:15.560 | should less be thought of as a reduction in NAD

01:00:18.920 | and should more be thought of as a reduction

01:00:21.000 | in what's called redox potential,

01:00:22.840 | the ability to do what I just said.

01:00:25.360 | So when people say NAD levels decline with aging,

01:00:29.000 | the answer is, yeah, but what's really declining as we age,

01:00:33.440 | and this kind of comes back to what you said

01:00:35.160 | at the very, very outset,

01:00:36.200 | like what's happening at the cellular level,

01:00:38.160 | I think what's happening is our mitochondria

01:00:39.960 | are not as good as we age and we have less redox potential.

01:00:43.200 | And I would say a fair number

01:00:45.080 | of so-called anti-aging approaches

01:00:48.100 | are targeting the so-called reactive oxygen species, ROSs,

01:00:53.100 | which impede mitochondrial function, essentially.

01:00:56.680 | This is an opportunity for me to call out the work

01:00:59.280 | that I think is at least intriguing,

01:01:00.960 | which is the work of a colleague by the name of Glenn Jeffery

01:01:04.600 | at the University of College London.

01:01:06.440 | He's been in the field of visual neuroscience

01:01:08.120 | for a very long time.

01:01:09.320 | And a few years back,

01:01:10.280 | he started doing some experiments on animals

01:01:12.540 | and now also two studies published on humans

01:01:15.920 | showing that exposing the aged eye, so 40 and older,

01:01:20.240 | to red light and near-infrared light for a couple minutes

01:01:25.000 | a few times a week can spare certain processes

01:01:30.000 | involved in vision, photoreceptors.

01:01:33.400 | How does this work?

01:01:34.240 | Well, the idea, this isn't proven yet,

01:01:36.080 | the idea is that it's reducing reactive oxygen species

01:01:40.560 | and thereby improving mitochondrial function

01:01:43.500 | in what is perhaps the most metabolically active cell type

01:01:47.140 | in the entire body, not just the eye,

01:01:50.100 | which are the photoreceptors.

01:01:51.940 | So it's an intriguing set of studies.

01:01:53.500 | Again, we don't have all the mechanisms worked out,

01:01:55.420 | but it brings us around again to this idea

01:01:59.220 | that mitochondria are vitally important

01:02:01.180 | for the functioning of cells.

01:02:02.180 | Things that impede the function of mitochondria

01:02:04.940 | can either reduce the output of and/or kill cells.

01:02:08.140 | And so anything that can improve redox

01:02:11.920 | can potentially keep a cell around longer,

01:02:15.960 | functioning better.

01:02:18.120 | So when I hear about the role of NAD in this pathway,

01:02:21.440 | I think like most people, I think, okay,

01:02:22.680 | well then I should just take more NAD

01:02:25.480 | and maybe I will age more slowly,

01:02:28.080 | or I will replace some NAD that's missing as I age

01:02:31.320 | in whatever cell type.

01:02:32.540 | Turns out that might not be so straightforward, right?

01:02:35.920 | I mean, I don't want to jump to supplementation just yet.

01:02:38.040 | - Yeah.

01:02:38.880 | - But if we are to back up from NAD a little bit

01:02:41.680 | and look at the pathway leading to NAD,

01:02:44.080 | it's NR, NMN, and NAD, we'll spell these out in a moment.

01:02:49.080 | And this sort of competition that's out there in the market

01:02:54.180 | is around either infusing,

01:02:58.860 | or in some cases, ingesting NAD directly,

01:03:01.740 | taking NMN, which is the precursor to NAD orally,

01:03:08.200 | I haven't heard of anybody infusing it,

01:03:09.800 | or taking oral form NR, which is the precursors to NMN.

01:03:14.800 | My understanding is that NMN is simply NR

01:03:18.420 | minus a phosphate group.

01:03:19.960 | - Yeah, and I'll take a step back from this first

01:03:23.360 | to say the following.

01:03:24.520 | Again, because this topic is so confusing,

01:03:27.520 | I think it's just worth reminding everybody

01:03:29.840 | of what we now, everything we've said

01:03:32.000 | and where it brings us, right?

01:03:33.160 | So I'm not going to repeat the whole sirtuin thing,

01:03:35.260 | let's just leave that alone.

01:03:36.600 | - Because everything we're on right now

01:03:37.880 | is upstream of sirtuins.

01:03:39.280 | - Yeah, it's basically like once you establish

01:03:41.920 | that we think sirtuins matter,

01:03:44.000 | even though they don't work through caloric restriction,

01:03:46.140 | and that's about the single most obvious thing I can say,

01:03:49.320 | they might still matter,

01:03:50.840 | even though we don't have things that we figured out

01:03:53.360 | can activate sirtuins, like resveratrol,

01:03:55.480 | we don't seem to have things that we can give you

01:03:57.120 | that activates sirtuins,

01:03:58.440 | we're now onto the next part of the story,

01:04:00.800 | which is, okay, sirtuins matter,

01:04:04.240 | they don't seem to matter,

01:04:05.280 | we think sirtuins matter

01:04:06.480 | because of a few of these overexpression experiments,

01:04:09.920 | and we're making a big leap

01:04:12.120 | that because they mattered in yeast,

01:04:14.140 | they're going to matter in us,

01:04:15.840 | that's a huge leap for which there's zero evidence.

01:04:18.200 | - Right, and I'm only leaping further

01:04:20.320 | to this discussion about how to increase NAD

01:04:23.120 | because I know that's in the back of people's minds,

01:04:25.080 | we're not going to double click here just yet,

01:04:27.000 | I just want to frame that up

01:04:28.400 | because ultimately that's where we are headed

01:04:31.760 | in terms of people making decisions

01:04:34.840 | as to whether or not they should take NR,

01:04:36.960 | or take NMN, or use NAD, or none of the above.

01:04:40.760 | - And the reason I'm being such a hard-ass

01:04:42.320 | about this, Andrew,

01:04:43.400 | is I spend so much time fielding questions on this

01:04:47.120 | that I realize we just have to talk about this

01:04:49.320 | in excursion, in the most detailed fashion possible

01:04:53.720 | so that people understand why,

01:04:56.040 | because it is just too easy, right?

01:04:58.320 | There's this great quote by JFK

01:05:00.240 | that I'm going to paraphrase

01:05:01.280 | that is basically people enjoy the comfort of opinion

01:05:06.280 | without the discomfort of thought, right?

01:05:09.240 | So we need to sort of,

01:05:10.640 | this is a podcast to get people to think

01:05:13.080 | and understand the entire history of this field

01:05:15.760 | so that they can actually make an informed decision

01:05:18.440 | about a supplement that I'm going to argue

01:05:21.520 | has very little scientific basis for its justification.

01:05:25.960 | - I would say scientific justification for longevity.

01:05:29.600 | I'll go on record now saying that I take NMN,

01:05:34.040 | and in some cases I will take NR and NMN,

01:05:38.240 | and I observe,

01:05:40.120 | this is just N of one self-observational data,

01:05:43.480 | I observe a very clear positive effect,

01:05:46.760 | but I don't think it has anything to do

01:05:49.480 | with extending lifespan.

01:05:51.760 | - And we should talk about both healthspan

01:05:53.760 | and lifespan benefits when we get to that part,

01:05:56.000 | but to bring us up to where we are now,

01:05:58.960 | where you are with, should people be supplementing NAD,

01:06:03.000 | we're basically at the point

01:06:04.320 | where we're taking a lot of leaps of faith

01:06:06.720 | and saying, because NAD levels are going down

01:06:11.720 | and redox potential is going down,

01:06:14.720 | we believe supplementing NAD

01:06:16.640 | in one form or another makes sense.

01:06:18.680 | But before we do that, we should acknowledge something.

01:06:21.820 | Yes, NAD levels are going down,

01:06:24.440 | but we have no reason to believe

01:06:26.880 | that raising NAD levels will correct a problem.

01:06:30.300 | In other words, if the body operates

01:06:32.600 | between this level and this level of NAD,

01:06:35.840 | and if you go below this level, you die,

01:06:37.500 | and you go above this level, you die,

01:06:39.840 | and levels as you age go like this,

01:06:43.080 | do we believe that raising them to this does anything?

01:06:46.700 | There's no evidence that says it does.

01:06:48.880 | So that's a leap of faith.

01:06:50.360 | It's okay to take leaps of faith,

01:06:51.920 | you just have to know you're taking a leap of faith.

01:06:53.820 | Okay, so leap of faith number one is,

01:06:56.600 | the sirtuin thing.

01:06:57.440 | Leap of faith number two is the caloric restriction thing.

01:07:00.360 | Leap of faith number three is this matters in our species,

01:07:04.040 | the species of interest.

01:07:05.040 | Leap of faith four is the whole sirtuin activator thing.

01:07:08.880 | And now this leap of faith is,

01:07:10.980 | if we just increase NAD levels in us,

01:07:14.440 | it will produce a positive benefit.

01:07:16.600 | Okay, so now how do we do that?

01:07:18.480 | Now you get into the tactic.

01:07:20.120 | Okay, there were three ways to do it, as you said.

01:07:22.720 | One is you can intravenously take NAD.

01:07:25.760 | By the way, you could probably also orally take NAD.

01:07:29.000 | It would just break down in the gut

01:07:30.680 | into its constitutive products and then probably reform.

01:07:34.560 | But for the purpose of how people actually do this,

01:07:37.720 | they intravenously get NAD

01:07:39.480 | because it's not orally bioavailable.

01:07:41.640 | Or as you said, they orally take two precursors, NR and NMN.

01:07:46.640 | My personal view on this is,

01:07:49.040 | there's not really much of a difference in what you do.

01:07:51.920 | In other words, at the end of the day,

01:07:54.680 | all of these things are generally going to increase

01:07:58.960 | NAD levels in the blood.

01:08:01.600 | - So a couple of kind of practical notes.

01:08:04.260 | I've taken NR in capsule form.

01:08:07.280 | I've taken NMN typically in powdered form

01:08:10.540 | where I put it sublingually under the tongue.

01:08:13.340 | My understanding is that--

01:08:14.180 | - Have you done intravenous NAD?

01:08:15.920 | - I sure have.

01:08:16.760 | - Did you experience a niacin flush?

01:08:19.980 | - No, I took NAD as an infusion.

01:08:24.980 | I've probably done it five or six times.

01:08:27.500 | And for the first 10 minutes of the infusion,

01:08:32.500 | you feel like somebody's stepping on your chest with a boot.

01:08:36.180 | Your legs cramp up, you feel nauseous.

01:08:38.880 | I did not take the anti-nausea med that was offered.

01:08:41.700 | I don't like taking things if I can avoid it.

01:08:43.500 | I just figured I'll just experience this.

01:08:46.060 | It was very uncomfortable

01:08:48.100 | to the point where you couldn't read a paper or a book.

01:08:50.940 | You just wanna be left alone.

01:08:52.460 | You actually get a little bit irritable.

01:08:53.940 | You're like, this is awful.

01:08:55.720 | Every noise in the room is a bit too loud

01:08:57.980 | during that first 10 minutes.

01:08:59.500 | And then--

01:09:00.340 | - By the way, do you know how many people have said to me

01:09:02.180 | that because of that experience,

01:09:04.040 | they know it must be doing something good?

01:09:05.620 | - Oh my goodness.

01:09:06.780 | - To which I'm like, why don't you spread your legs?

01:09:09.220 | Let me kick you right in the nuts.

01:09:11.220 | That's gonna feel even worse.

01:09:13.000 | Is that doing something good?

01:09:14.140 | Like the fact that something feels so awful

01:09:17.460 | shouldn't be used as an explanation

01:09:19.460 | for why it's doing good physiologically.

01:09:21.540 | - Right, I don't know what it was doing physiologically

01:09:23.620 | except making me feel miserable during the infusion.

01:09:26.060 | There are ways to adjust this

01:09:26.980 | even without the anti-nausea meds.

01:09:28.540 | For instance, you can slow the infusion.

01:09:32.260 | That's the typical way.

01:09:34.800 | People will put it in over the course of several hours,

01:09:37.060 | anywhere from three hours to as brief as 30 minutes

01:09:41.580 | is kind of the record that I've heard about

01:09:43.760 | for 500 milligrams of NAD.

01:09:47.220 | If you put 1000 milligrams in there,

01:09:48.740 | obviously it's more painful and you have to,

01:09:50.660 | anyway, there are a bunch of practical considerations.

01:09:53.520 | You feel, now maybe it's placebo,

01:09:56.540 | but one feels quite good afterward.

01:09:59.940 | So as soon as the drip is done,

01:10:02.340 | you feel better than you did prior to the drip.

01:10:05.940 | - How do you feel if you just receive an IV infusion

01:10:08.420 | of the same volume?

01:10:09.620 | - I've done that because I've received saline drips.

01:10:13.020 | You also feel pretty good.

01:10:15.140 | It's hard to disentangle these things.

01:10:17.700 | And typically they'll put other things in the bag,

01:10:21.020 | glutathione, some vitamin C.

01:10:23.540 | They tend to sell these as kits.

01:10:25.160 | I decided to try it.

01:10:26.540 | It seemed fine.

01:10:27.380 | I did it when traveling.

01:10:28.940 | I don't know, maybe I'm due for another one soon.

01:10:31.220 | But for me, the more typical way

01:10:32.700 | to try and increase NAD or whatever,

01:10:35.100 | because I don't know what it's doing exactly,

01:10:37.820 | but I like the effects of taking sublingual NMN.

01:10:40.660 | The single most, let's say salient to me,

01:10:44.940 | anecdotal data on taking sublingual NMN

01:10:48.140 | is that it makes my hair grow really fast.

01:10:50.500 | It makes my nails grow really fast.

01:10:52.100 | And I do feel an increase in energy.

01:10:54.260 | And I take it first thing in the morning.

01:10:56.780 | - And what dose?

01:10:57.620 | - One and a half grams, 1,500 milligrams.

01:11:01.080 | So-

01:11:01.920 | - By the way, if you translate the doses

01:11:04.580 | that they give mice in the studies

01:11:06.620 | where they're testing the efficacy

01:11:10.060 | are typically on the order of 500

01:11:14.300 | to 1,000 milligrams per kilogram.

01:11:17.120 | - Whoa.

01:11:20.340 | - Yeah.

01:11:21.160 | - I'm a hundred kilograms.

01:11:22.020 | - Yep.

01:11:23.660 | - Whoa, okay.

01:11:24.740 | - So picture that the next time

01:11:26.220 | you're giving yourself some NAD or NR.

01:11:29.900 | - I'm not even approaching that at all.

01:11:33.740 | Well, it's clear to me based on my read of the data

01:11:37.540 | that NR can cross the cell membrane directly.

01:11:41.220 | - Directly, very easily.

01:11:42.660 | There's no obstacle to NR getting into cells.

01:11:44.980 | - Okay.

01:11:45.820 | And NMN cannot because of the extra phosphate group.

01:11:49.180 | So that if you take it sublingually

01:11:50.620 | or you ingest it orally, it goes into the gut.

01:11:53.900 | The phosphate group is cleaved.

01:11:56.060 | And because of that, the argument is that

01:11:57.900 | if one were to compare the benefits of taking NR versus NMN,

01:12:02.740 | there are more data to support NR as a precursor to NAD,

01:12:06.940 | a more effective precursor to NAD than orally ingested NMN.

01:12:11.620 | But some people will say,

01:12:12.580 | "Well, I'll just take more NMN than I would NR."

01:12:14.900 | And then this gets into the realm of cost effectiveness.

01:12:18.620 | - It's just a commercial issue.

01:12:19.860 | - It starts becoming a battle between commercial sources.

01:12:22.540 | And I don't dispute that NR makes more sense as a precursor,

01:12:27.540 | especially at dosages of 300 to 600 milligrams

01:12:31.620 | versus 1,500 milligrams.

01:12:33.700 | But I've opted to take sublingual NMN

01:12:37.900 | mostly based on cost.

01:12:39.540 | NR at the dosages people recommend is quite expensive.

01:12:44.020 | - Imagine you had to take it at the mouse doses.

01:12:46.400 | - Right.

01:12:47.240 | - You'd be spending about 300 bucks a day.

01:12:48.900 | - Right. It's just, it's not feasible.

01:12:50.860 | It's just not feasible.

01:12:52.340 | So, you know, I don't have a deep desire

01:12:54.900 | for my hair to grow faster or my nails to grow faster.

01:12:57.760 | It's more the increase in energy effect.

01:13:00.520 | Now, I will say that sublingual NMN

01:13:02.960 | is also a bit of a laxative.

01:13:05.320 | So there are all these, and I say that, you know,

01:13:07.400 | somewhat chuckling, but, you know,

01:13:08.960 | some people say it makes them feel better.

01:13:10.940 | Well, is that because you're, you know,

01:13:12.860 | evacuating your bowels a few minutes or hours later

01:13:15.800 | and then you feel less bloated and you have more energy?

01:13:18.720 | You know, it's very unclear.

01:13:20.340 | I think what has not been done, as far as I know,

01:13:23.760 | is to compare orally ingested NR at say 600 milligrams,

01:13:27.680 | a relatively high dose, versus a gram of sublingual NMN,

01:13:32.680 | and then actually measure blood levels of NAD.

01:13:36.240 | If that experiment has been done and I'm not aware of it,

01:13:39.480 | I'm not aware of it, then forgive me.

01:13:41.120 | Maybe someone will put it in the show note captions.

01:13:42.880 | But I guess this gets down to the question

01:13:44.920 | of how many people are taking oral NR or NMN,

01:13:49.600 | or are taking NAD infusions,

01:13:52.240 | which by the way are quite expensive,

01:13:54.280 | anywhere from $300 to $1,000 a drip.

01:13:59.200 | That's pretty expensive.

01:14:01.000 | - Think about that.

01:14:01.840 | - What benefits are they getting?

01:14:02.680 | Like, what are they getting out of this?

01:14:04.200 | Like, what are they getting?

01:14:05.040 | Is it an acute increase in NAD that, that what?

01:14:08.060 | That causes them to live, what, a week longer?

01:14:10.440 | I mean, we have no idea.

01:14:12.320 | - So let's try to use data to answer the question, right?

01:14:15.340 | So this is exactly the thing that the ITP,

01:14:17.800 | the Interventions Testing Program, was designed to test.

01:14:21.300 | And again, I would, if people are interested in this,

01:14:25.300 | they should go back and listen to my two discussions

01:14:27.180 | with Rich Miller, where we go through gory detail

01:14:30.220 | of every molecule that has gone through the ITP.

01:14:33.060 | The ITP is hands down the most rigorous tool we have

01:14:37.660 | for testing molecules in anything other

01:14:40.140 | than the species of interest,

01:14:41.420 | because we can't do these experiments in human.

01:14:43.600 | We cannot test lifespan interventions in humans

01:14:46.500 | for the obvious reasons.

01:14:47.780 | So what is the next best thing?

01:14:49.460 | Well, it turns out it's doing it in a non-inbred mouse

01:14:53.440 | in triplicate in three institutions.

01:14:55.940 | Like, you can't get more rigorous than this.

01:14:58.460 | The ITP has tested probably north of 50 molecules,

01:15:03.260 | meaning it has done the same experiment

01:15:06.020 | for 50 different molecules,

01:15:08.420 | and very few have extended lifespan.

01:15:11.740 | And the notable failure is NR.

01:15:14.820 | NR was tested, and I believe it was tested

01:15:17.900 | at a very robust dose,

01:15:19.620 | either 500 or 1,000 milligrams per kilogram,

01:15:22.860 | and there was no extension of life.

01:15:25.600 | There was no improvement in healthspan.

01:15:28.000 | There was no change.

01:15:30.300 | Megadose NR, placebo, same result.

01:15:35.300 | Conversely, let's consider some of the successes

01:15:39.200 | of the ITP, rapamycin.

01:15:42.660 | When you give rapamycin, the first time they did it,

01:15:45.860 | because they had a hard time formulating the rapamycin,

01:15:48.180 | they weren't able to start it

01:15:49.260 | until the mice were like 21 months old,

01:15:51.440 | which is very old for a mouse.

01:15:52.740 | That's like a 60-year-old mouse.

01:15:54.740 | And at that point, they almost aborted the experiment

01:15:56.900 | because they were like, well, what's the point?

01:15:58.900 | Nothing is gonna work when you start this late,

01:16:00.840 | including caloric restriction, by the way,

01:16:02.780 | although it has worked in one experiment.

01:16:04.580 | But nevertheless, it worked.

01:16:05.780 | And when you gave RAPA that late in life, it still worked.

01:16:09.680 | Then they redid the experiment and they gave it earlier.

01:16:11.820 | It worked.

01:16:12.860 | Canagaflozin, as I mentioned, which is an SGLT2 inhibitor,

01:16:16.140 | it worked.

01:16:16.980 | Acarbose, a drug that inhibits glucose absorption, worked,

01:16:21.860 | and interestingly, didn't require weight loss.

01:16:24.140 | So the thesis behind giving Acarbose to the mice was,

01:16:27.860 | it's a caloric restriction memetic, a CR memetic,

01:16:31.100 | and it worked, but the treatment mice weren't any lighter

01:16:36.100 | than the non-treatment mice,

01:16:37.740 | which actually goes back to something you said

01:16:39.820 | at the very outset,

01:16:40.900 | which suggested that tight glycemic control,

01:16:43.660 | independent of weight, is a longevity benefit.

01:16:47.620 | The same was true with the SGLT2 inhibitor, Canagaflozin.

01:16:50.580 | SGLT2 inhibitors cause you to pee out more glucose.

01:16:54.020 | Acarbose prevents you from absorbing in your gut.

01:16:56.500 | So two different ways to regulate glucose.

01:16:58.620 | Neither of those experiments resulted

01:17:00.740 | in a lower body weight for the mice,

01:17:02.700 | and yet they both lived longer.

01:17:04.020 | Again, there's something very important

01:17:06.060 | about regulating blood glucose.

01:17:08.080 | The other thing that worked is 17-alpha estradiol,

01:17:13.080 | and it only worked in male mice.

01:17:16.220 | So again, suggesting that, well, we can come back to that.

01:17:20.820 | It's more than we wanna get into at the moment.

01:17:22.660 | But the point here is, there are very few molecules

01:17:25.740 | that have withstood the scrutiny of the ITP.

01:17:28.660 | It's a high-bart metformin failed, by the way.

01:17:31.380 | - And the ITP is specifically for offsetting aging.

01:17:36.220 | Is that right? - It is lifespan,

01:17:37.380 | but it also looks at some measures of healthspan.

01:17:39.140 | But it's primarily,

01:17:40.180 | it is the gold standard for lifespan, yeah.

01:17:42.820 | - Because my understanding is that there are some studies

01:17:46.300 | that have explored the role of supplemented NR,

01:17:50.100 | maybe NMN as well, but certainly supplemented NR,

01:17:53.100 | for sake of lowering inflammation

01:17:55.660 | to offset some of the negative effects

01:17:57.740 | of time zone shift, alcohol.

01:18:01.140 | I have a few others listed here, overnutrition.

01:18:05.940 | - Yeah, so let's talk about that.

01:18:07.220 | So in 20, I don't remember what year it was.

01:18:11.100 | It was somewhat recent.

01:18:13.020 | A study was published looking at NR

01:18:15.740 | with something called terastilbene.

01:18:18.820 | So terastilbene is believed to be a sirtuin activator,

01:18:22.740 | like resveratrol.

01:18:24.460 | So commercially available product called Basis,

01:18:27.180 | and it was tested, it was a three-arm study in humans.

01:18:32.140 | Roughly 30 people per arm, so decent-sized study, right?

01:18:35.100 | This is a big study.

01:18:35.940 | So you take 100 people, more or less,

01:18:38.660 | with fatty liver disease.

01:18:40.260 | Now, this was documented with an MRI of the liver.

01:18:45.260 | So they're looking at hepatic fat in the liver by MR,

01:18:50.460 | and using this type of MRI,

01:18:55.340 | if your hepatic fat index is over 5%,

01:18:58.820 | that's a high enough degree of what's called steatitosis

01:19:01.820 | that you have fatty liver disease.

01:19:03.980 | Now, of course, this is not a digital thing.

01:19:08.820 | It's an analog, right?

01:19:09.700 | There's a spectrum to this.

01:19:11.140 | So you start with just fat accumulating in the liver,

01:19:14.380 | but as more and more fat accumulates,

01:19:16.260 | you start to get inflammation

01:19:17.780 | that results in scarring and fibrosis,

01:19:20.580 | and ultimately, you would get to cirrhosis.

01:19:22.220 | So just keeping in back your mind,

01:19:23.580 | the threshold at which we would say

01:19:25.500 | you're in the danger zone is once you hit 5%.

01:19:30.740 | So this study randomized people to either a placebo

01:19:35.660 | or a regular dose of this product

01:19:38.420 | or a double dose of the product,

01:19:40.060 | and I can't remember exactly how much is in the product.

01:19:41.860 | I think it's either 250 or 500,

01:19:44.200 | so then that would be what the regular group got of NR,

01:19:46.740 | and then the other group was getting 2x that.

01:19:48.700 | So it's either 250 and 500 or 500 and 1,000.

01:19:51.760 | I don't recall.

01:19:52.600 | They also looked at something called the...

01:19:57.380 | They looked at many things, right?

01:19:59.840 | So they looked at all sorts of biomarkers,

01:20:02.700 | and the primary outcome for the study was,

01:20:05.340 | did you see a reduction of this hepatic fat via the MRI?

01:20:09.960 | So what happened?

01:20:12.100 | So they did the study,

01:20:13.760 | and lo and behold, there was no difference.

01:20:16.340 | There was no difference in anything, okay?

01:20:17.780 | So at high dose, at low dose,

01:20:20.020 | there was no difference in how much hepatic fat

01:20:23.740 | you had at the end of the study.

01:20:24.980 | There was no difference in body weight.

01:20:27.000 | There was no difference in inflammatory markers.

01:20:29.180 | There was no difference in glycemic markers,

01:20:31.860 | glucose levels, liver function tests, any of those things.

01:20:35.000 | So in that sense, it was a null study,

01:20:38.740 | but they did one sub-analysis,

01:20:42.140 | which, again, you have to be very careful of,

01:20:44.180 | 'cause a sub-analysis is not a primary outcome,

01:20:48.160 | but it's kind of a way to go and parse the data,

01:20:51.340 | and they did find one statistically significant finding,

01:20:55.660 | which was if you limited the analysis

01:20:59.440 | to people who had a hepatic fat score below 27%,

01:21:04.300 | remember I said, once you're above 5%,

01:21:06.860 | you have fatty liver disease,

01:21:09.060 | well, they had people anywhere from 10% to 40%.

01:21:14.060 | But if they looked at people who were below 27%,

01:21:18.620 | in the low-dose group,

01:21:20.620 | there was a statistically significant reduction in liver fat.

01:21:25.640 | If it sounds like I'm machinating, I am.

01:21:28.280 | Let me say it again.

01:21:29.820 | If you limited the analysis to people

01:21:32.080 | who had below 27% on this hepatic fat index,

01:21:36.020 | the people who got the full dose had no difference.

01:21:40.200 | They averaged 20% at the beginning of the trial

01:21:43.540 | and 19% at the end,

01:21:45.200 | no statistically significant difference.

01:21:46.760 | The placebo group averaged 20% at the beginning,

01:21:49.800 | 20% at the end, but the single dose of the drug

01:21:53.840 | went from 20% to 15%, which was statistically significant.

01:21:58.440 | It's not clear that that's clinically significant,

01:22:00.660 | which is a pretty consistent theme in this type of research.

01:22:04.120 | Never confuse statistical significance

01:22:06.880 | with clinical significance.

01:22:08.520 | If I gave you, if your blood pressure is 160 over 100,

01:22:13.520 | and I give you a drug that lowers it to 157 over 97,

01:22:22.000 | that could be statistically significant

01:22:24.320 | if the variance is small enough

01:22:27.320 | between people in this study.

01:22:28.760 | It has no clinical significance.

01:22:30.560 | I haven't changed the course of your life.

01:22:32.560 | So again, that to me is one of the two big findings

01:22:37.560 | that people point to to say,

01:22:39.680 | aha, there was some benefit

01:22:41.440 | in fatty liver disease with this.

01:22:43.960 | But again, when you read the fine print,

01:22:45.640 | which I just vomited out to you,

01:22:47.960 | I don't think anybody's looking at that going,

01:22:49.680 | oh, we just found the solution to NAFLD.

01:22:52.880 | The second study that people point to a lot

01:22:55.080 | was 2021 or 2022.

01:22:58.280 | This came out of a group at Wash U, I believe,

01:23:01.080 | and they looked at NMN, and they looked at glucose disposal.

01:23:06.080 | So in this study, they asked the question,

01:23:08.900 | we're gonna take two groups of people,

01:23:11.320 | you're gonna get a placebo for a period of time,

01:23:13.800 | or you're going to get NMN for a period of time,

01:23:17.040 | and we're gonna then do what's called

01:23:21.080 | a type of glucose challenge,

01:23:23.000 | where we look at how well you dispose of glucose

01:23:26.120 | with and without insulin infusion.

01:23:29.040 | And in the placebo group,

01:23:32.640 | you would look at pre and post,

01:23:34.960 | so pre and post placebo treatment,

01:23:38.120 | was there a difference in glucose disposal

01:23:40.920 | with no insulin?

01:23:42.000 | No.

01:23:42.880 | What about with insulin,

01:23:44.040 | where you would expect to see much more glucose disposal?

01:23:46.280 | No difference.

01:23:47.520 | But when you did that with the NMN group,

01:23:49.720 | there was a statistically significant increase

01:23:52.480 | in glucose disposal with insulin infusion,

01:23:55.840 | but it was quite small.

01:23:57.200 | In other words, it was clinically very insignificant.

01:24:00.680 | And just to make,

01:24:02.080 | just to sort of figure out how insignificant it was,

01:24:04.520 | I went back and actually looked

01:24:05.640 | at some of the red light data,

01:24:07.400 | 'cause there's an interesting study

01:24:08.840 | that shines red light on a person's back,

01:24:11.320 | and then does an oral glucose tolerance test.

01:24:13.560 | Yeah, and you can actually reduce

01:24:15.020 | like postprandial glucose by 8%.

01:24:17.480 | Is that meaningful?

01:24:19.120 | Not really.

01:24:20.220 | I mean, not in this patient population,

01:24:22.560 | because these people were all pre-diabetic

01:24:24.360 | and they had very high glucose.

01:24:25.600 | So it was against,

01:24:26.720 | another example of something

01:24:27.560 | that was statistically significant,

01:24:28.640 | but not clinically significant.

01:24:29.840 | And the same thing was true in this study, right?

01:24:32.220 | But again, people would probably point to these two studies

01:24:36.260 | because they're in humans,

01:24:37.840 | and you had this one,

01:24:39.180 | if you squint and look really hard

01:24:41.240 | and take a sub, sub, subset of the analysis

01:24:43.520 | on this one measurement,

01:24:45.420 | we saw a response of hepatic fat going from 20 to 15%,

01:24:50.420 | which is still three X above the threshold

01:24:52.980 | to have fatty liver disease.

01:24:54.300 | And in this other study,

01:24:55.420 | you had this very, very modest reduction,

01:24:58.400 | pardon me, increase in glucose disposal.

01:25:00.920 | But I mean, like we're,

01:25:02.660 | you know, there's a saying in my sort of mind, Andrew,

01:25:06.900 | which is like, if you have to resort

01:25:08.460 | to really interesting statistical machinations

01:25:10.800 | to see something,

01:25:11.740 | there probably isn't something very interesting there.

01:25:13.880 | - Right, right.

01:25:16.080 | I totally agree.

01:25:17.040 | And I think, you know, at this point,

01:25:19.300 | I'm questioning whether or not I'm wasting my money

01:25:21.360 | taking NMN or NR.

01:25:24.060 | The reason I take NR is really for these anti-inflammation

01:25:27.360 | reported purported effects.

01:25:31.200 | I just want to pay a little bit of attention

01:25:34.640 | to the whole commercial battle around this,

01:25:36.940 | because I think it's relevant.

01:25:38.480 | I mean, I think right now,

01:25:40.280 | as far as I know, the FDA has essentially said

01:25:44.920 | that NMN should not be sold as a supplement,

01:25:47.640 | but it is still being sold as a supplement.

01:25:50.140 | So there's a little bit of ignoring of the FDA's request.

01:25:55.140 | NR, as far as I know,

01:25:58.520 | is authorized for sale as a supplement.

01:26:00.840 | - Yeah, so it's generally regarded as safe.

01:26:03.120 | It has an FDA designation of GRAS,

01:26:05.800 | which means it is not regulated.

01:26:08.200 | It's generally recognized as safe.

01:26:10.280 | - Right.

01:26:11.120 | And so that means anybody can sell it.

01:26:13.920 | The FDA will have no oversight.

01:26:16.480 | They're not telling you whether,

01:26:18.280 | they're not gonna put a stamp on it

01:26:19.920 | that says what they're selling is what it is.

01:26:23.640 | And you can't make a claim about it

01:26:25.840 | that isn't validated by some sort of study.

01:26:29.400 | So honestly, Andrew,

01:26:32.080 | I think the whole NMN, NR debate is irrelevant.

01:26:35.920 | I think it's just a commercial debate.

01:26:37.920 | I think it's literally just posturing

01:26:40.020 | about how can I carve out a different market?

01:26:42.560 | I don't think there's a scientific reason

01:26:44.720 | to favor one over the other.

01:26:46.280 | - Well, you just answered the question I was going to ask,

01:26:49.840 | but I suppose the question therefore becomes,

01:26:53.540 | is there any benefit to taking either of them

01:26:56.360 | for sake of lifespan and health?

01:26:58.240 | - There's one benefit I could find.

01:27:00.100 | There's one benefit I could find that I think is genuine.

01:27:02.760 | There are a few other really insignificant ones

01:27:05.240 | that fall into the category of goofy studies

01:27:07.700 | that cherry pick by data mining.

01:27:10.120 | Okay, so there's studies that like gave people NMN

01:27:13.160 | and looked at a shotgun approach of many different things.

01:27:15.960 | Like, did it change LDL cholesterol,

01:27:17.360 | HDL cholesterol, triglycerides?

01:27:18.840 | And the answer is, oh, look, there's a small decrease,

01:27:21.520 | but it was totally insignificant clinically,

01:27:23.640 | even if statistically significant.

01:27:25.080 | And oh, it increased your six minute walking test

01:27:29.160 | or whatever, and it's like a six minute walk test

01:27:31.640 | or whatever in people who were in their 20s is irrelevant.

01:27:35.320 | It had no change in VO2 max.

01:27:37.160 | It had no change in any meaningful metric of performance.

01:27:41.200 | One test, one study I could find

01:27:43.800 | that actually had what looked like a signal to me.

01:27:47.060 | And it was a study that looked at skin cancer rates

01:27:51.740 | with, and I can't remember if it was NR or NMN,

01:27:55.540 | but honestly, I don't think it matters

01:27:57.300 | 'cause I think they're basically equivalent.

01:27:59.940 | - One's just got a phosphate group on there.

01:28:01.460 | You might need to take a little bit more

01:28:03.840 | of the NMN versus NR, or maybe a lot more, who knows,

01:28:07.780 | in order to get the same increase in NAD,

01:28:10.980 | is my understanding.

01:28:11.860 | - So this one study found somewhere between a 60

01:28:14.580 | and 80% reduction in basal cell

01:28:17.140 | and squamous cell carcinomas.

01:28:18.940 | Now, it found no difference in melanomas.

01:28:20.840 | So again, you know this

01:28:21.820 | 'cause you just did a podcast on this.

01:28:23.540 | Melanoma is the skin cancer that kills you,

01:28:25.940 | but that's not to say that squamous cell

01:28:28.500 | and basal cell carcinomas aren't problematic.

01:28:30.820 | They can be very deforming.

01:28:33.920 | They can require pretty aggressive surgeries

01:28:36.720 | to address them.

01:28:37.560 | And so if indeed there is something

01:28:39.560 | that can reduce the risk of basal

01:28:41.280 | and squamous cell carcinomas,

01:28:43.120 | that may be a rationale for taking it.

01:28:45.560 | - And I should say that basal

01:28:46.760 | and squamous cell carcinomas are very, very common.

01:28:49.760 | - They're very common and they are very clearly associated

01:28:53.040 | with sun exposure in a way that even melanoma

01:28:55.560 | is more complicated and has a genetic component

01:28:57.760 | and there are other things going on.

01:28:59.000 | But squamous and basal cell carcinoma

01:29:00.640 | are very clearly related to sun exposure.

01:29:02.980 | As you said, they're quite common.

01:29:04.340 | And so, you know, personally,

01:29:06.460 | that's an experiment I would like to see repeated

01:29:09.020 | because if indeed NR and or NMN reduce the risk

01:29:14.020 | that significantly of squamous cell

01:29:17.940 | and basal cell carcinomas,

01:29:19.660 | I think you could make a case

01:29:20.940 | that if you're an individual

01:29:22.520 | who's at risk for those things,

01:29:23.640 | clearly I'm not, right?

01:29:24.680 | Like I've never had a sunburn in my life.

01:29:26.780 | I mean, I don't work outside.

01:29:28.700 | So it's like, it wouldn't matter to me,

01:29:30.260 | but there are a lot of people

01:29:31.380 | for whom either their skin color makes them more susceptible

01:29:34.560 | or their pastimes or frankly their line of work

01:29:39.540 | makes them more susceptible.

01:29:40.940 | You know, maybe there is a case to be made for it there.

01:29:42.820 | If you could literally take 60 to 80% of your risk away

01:29:47.140 | on squamous or basal cell carcinoma, that could matter.

01:29:49.340 | And by the way, I don't know if this is true,

01:29:51.140 | but you may recall at the outset,

01:29:53.460 | the outset I said that

01:29:54.780 | when you look at all the tissues in the body

01:29:56.860 | where we see a reduction in NAD,

01:29:58.740 | do you remember what had the biggest reduction?

01:30:00.940 | It was skin.

01:30:02.300 | So there's a part of me that wonders like,

01:30:04.460 | is the reason that the only place

01:30:06.960 | we see a really good signal potentially

01:30:09.460 | for NR and NMN supplementation is in a skin cancer?

01:30:14.140 | Although it's not melanoma,

01:30:15.420 | which is the one we'd really wanna see.

01:30:17.000 | I mean, if this reduced the risk of melanoma,

01:30:18.400 | I would take it, right?

01:30:19.780 | 'Cause even though I'm dark skinned,

01:30:21.180 | I'm still susceptible to melanoma.

01:30:22.880 | So I just wonder, that could be true, true and unrelated,

01:30:26.020 | but that's the first thought that crossed my mind

01:30:27.940 | when I came across that literature was,

01:30:30.020 | I wonder if the enormous reduction in tissue, NAD,

01:30:34.460 | in this particular tissue,

01:30:35.860 | explains why maybe there is a benefit to it.

01:30:38.460 | - Assuming somebody is averse to feeling like

01:30:41.660 | they have an elephant stepping on their chest

01:30:44.580 | and they're going to pay $750 for it,

01:30:48.160 | AKA an NAD infusion once a week.

01:30:52.100 | And look, people may opt to do that,

01:30:53.860 | people with a disposable income could do that,

01:30:56.500 | drip it in slower, not feel nauseous,

01:30:58.300 | increase NAD with the hope, hope, hope,

01:31:01.040 | that maybe it's going to extend your life.

01:31:03.700 | Most people considering supplementation

01:31:05.420 | to augment the NAD pathway are going to default

01:31:08.820 | to either taking NR or taking NMN.

01:31:11.300 | - By the way, just going back to the group

01:31:12.740 | that have decided that $1,000 for an NAD infusion

01:31:17.300 | and dripping it in over two hours

01:31:19.280 | is a good use of their time.

01:31:21.240 | What do you think would be the improvement

01:31:23.460 | in their lifespan if they spent

01:31:24.660 | that two hours exercising?

01:31:27.820 | - Significantly greater.

01:31:29.000 | - Interesting, all right, just noting.

01:31:31.780 | And less expensive, but yeah.

01:31:33.620 | - You could also weight train for the first hour

01:31:37.240 | and then enjoy some food afterwards.

01:31:39.900 | Lane Norton taught me that there are data

01:31:42.380 | showing that exercise in particular resistance training

01:31:45.540 | improves the rewarding properties of food,

01:31:48.900 | makes food taste better,

01:31:50.580 | which we've all kind of intuitively experienced.

01:31:52.660 | So you spend the first hour working out,

01:31:55.340 | second hour eating.

01:31:56.300 | - If you had an extra two hours a week

01:31:57.900 | to choose between paying a thousand bucks

01:32:00.220 | or 700 bucks for an NAD infusion,

01:32:01.860 | or lift weights for an hour,

01:32:05.540 | go for a half an hour walk

01:32:06.900 | and listen to your favorite podcast,

01:32:09.360 | like the Huberman Lab,

01:32:10.420 | and then eat a meal for half an hour.

01:32:12.340 | I can just think of so many better ways

01:32:14.620 | to spend time and money.

01:32:16.880 | But anyway, let's not digress.

01:32:19.460 | - Okay, well, I'm going to pull a little bit

01:32:21.740 | from marketing text here,

01:32:25.620 | but I trust these showing--

01:32:28.900 | - Really?

01:32:29.740 | - Yeah, yeah, I do.

01:32:31.620 | Because they have citations to support them

01:32:33.740 | and we can include the citations.

01:32:35.380 | I can say these are not linchpin arguments

01:32:40.060 | for doing one thing or the other,

01:32:41.300 | but we already established that NR and NMN

01:32:45.740 | are quite similar except for the presence

01:32:47.500 | of a phosphate group on NR that gets cleaved off.

01:32:50.100 | So again, you might have a slight dose issue,

01:32:52.380 | but at the end of the day,

01:32:53.940 | you're giving NR, NR is freely taken up into cells,

01:32:57.340 | it turns into NAD.

01:32:58.460 | So this is all a big sort of shell game

01:33:01.780 | of how do you get NAD up.

01:33:03.140 | And again, I think we've established

01:33:04.860 | and we can agree that there is an increase in NAD,

01:33:09.860 | at least in the blood and probably in the liver

01:33:13.580 | when you take exogenous NAD or a precursor.

01:33:17.220 | Let's pause at that. - Or NR.

01:33:18.420 | - Yeah, that's what I mean, a precursor, right?

01:33:19.780 | - Great, well then you took the words right out

01:33:21.220 | of the data I was going to refer to.

01:33:23.780 | Because I asked a few folks that helped develop

01:33:26.060 | some of the NR supplements,

01:33:27.620 | like what are the data that support the use of NR

01:33:31.100 | for increasing NAD?

01:33:31.940 | And they say, NR can cross the cell membrane directly,

01:33:34.900 | NMN cannot.

01:33:35.740 | Okay, but you can just cleave the phosphate group.

01:33:38.260 | Right, right, exactly.

01:33:40.060 | NR, they claim, this is not my claim,

01:33:42.980 | but they claim that NR is quote unquote,

01:33:45.380 | 25% more effective than NMN

01:33:48.140 | in raising whole blood NAD levels.

01:33:49.860 | But I'm guessing that's milligram for milligram, right.

01:33:52.540 | Okay, so then you just adjust the milligram dosage

01:33:54.860 | a little bit and so on.

01:33:56.140 | What's entirely unclear is what raising blood NAD

01:34:01.140 | translates to in terms of getting more NAD into cells.

01:34:05.260 | I don't know that that's really--

01:34:06.100 | - Specifically cells like skeletal muscles, right?

01:34:09.260 | I think based on Josh Rabinowitz's work,

01:34:11.740 | I also had Josh Rabinowitz on the podcast

01:34:13.580 | to talk about this.

01:34:16.100 | And I trust Josh on this much more

01:34:19.100 | than I would trust any marketing material.

01:34:20.820 | - Sure.

01:34:22.300 | - Because he doesn't have a dog in this fight, right?

01:34:23.900 | He just does the work.

01:34:25.660 | And what Josh's research showed,

01:34:28.500 | which is basically NAD flux research,

01:34:30.820 | has demonstrated that look,

01:34:32.140 | the liver is probably the place of greatest uptake

01:34:36.660 | in addition to blood, and that's about all we know.

01:34:40.220 | Like it's not clear how much of this

01:34:42.020 | is getting into other cells.

01:34:44.220 | So, I mean, the rest of it is just,

01:34:49.220 | I think rearranging deck chairs on a Titanic

01:34:52.460 | as far as like, how much does it really matter?

01:34:55.140 | And again, I don't even think it's worth arguing

01:34:57.020 | about whether NMN or NR is more bioavailable

01:34:59.740 | because to your point, you can sort of adjust the dose.

01:35:02.140 | And I trust that whatever you're taking NR or NMN,

01:35:05.140 | you are getting some NR into the cells

01:35:07.620 | and that's being converted to NAD.

01:35:09.380 | But we still keep coming back to the jugular question,

01:35:11.740 | does that matter?

01:35:13.100 | Does increasing intracellular NAD matter

01:35:16.780 | when the system is so tightly regulated?

01:35:19.580 | So I think what you see is a lot of marketing material

01:35:22.380 | that tries to make the case that you can do it.

01:35:24.620 | Great, I'll grant you that you can do it.

01:35:26.660 | Does it matter?

01:35:28.380 | Does it matter in lifespan?

01:35:29.500 | The answer appears to be unambiguously no at this point.

01:35:32.900 | Does it matter in healthspan?

01:35:34.220 | I think that's what we're discussing.

01:35:36.300 | - There's something so sticky about the longevity field,

01:35:41.020 | just so sticky about this idea

01:35:42.940 | that one could take something and extend lifespan

01:35:45.100 | and people don't wanna be in the control group.

01:35:47.820 | So they're willing to invest significant amounts

01:35:50.180 | of money to do it.

01:35:51.260 | - Well, I mean, I think the bigger issue is like,

01:35:53.580 | you can't do the longevity experiment in humans.

01:35:56.700 | And I'm sure that these companies that sell this,

01:35:58.620 | and I honestly, I don't follow this space.

01:36:00.860 | I don't know how many of these companies

01:36:01.940 | there are out there.

01:36:02.780 | I can name two because five years ago,

01:36:07.340 | which was the last time I really dug into this,

01:36:09.940 | I knew who the two dominant players were.

01:36:12.300 | For all I know, there could be 20 companies today

01:36:14.060 | that are selling NR and NMN.

01:36:15.500 | I don't know anymore.

01:36:16.340 | - They're probably about 30 to 50 prior to this FDA ruling,

01:36:21.340 | which is kind of an interesting situation in its own right.

01:36:27.220 | What happened there was the supplement NMN,

01:36:31.340 | suddenly the FDA decided that it should not be sold

01:36:36.540 | over the counter anymore,

01:36:39.060 | because there was a clinical trial initiated on NMN,

01:36:43.540 | which essentially makes NMN a drug for clinical testing

01:36:48.540 | and thereby can't be classified as a supplement any longer.

01:36:53.100 | That was the rationale as I understood it.

01:36:55.740 | But as with things like N-acetylcysteine-

01:36:58.380 | - That was more of a lobbying effort though, I think.

01:37:00.900 | I don't think actually that was a scientific decision.

01:37:03.700 | I think that was more of a lobbying decision.

01:37:06.420 | - From a market protections,

01:37:07.980 | from an IP protection standpoint.

01:37:09.700 | - And this had happened prior for N-acetylcysteine, NAC,

01:37:13.260 | which some people take, it's a mucolytic,

01:37:15.340 | it's actually a great decongestant.

01:37:17.140 | If you're congested and it increases glutathione,

01:37:20.780 | that's my understanding.

01:37:22.060 | And I believe somebody checked me on this-

01:37:24.660 | - Does it decrease or increase glutathione?

01:37:27.060 | - Increases glutathione, is my understanding.

01:37:29.380 | If I have that wrong,

01:37:30.220 | someone will tell me quickly in the comments.

01:37:32.140 | My understanding is that in Europe,

01:37:33.740 | NAC might even be available by prescription.

01:37:36.500 | In the US, you can still buy it over the counter.

01:37:38.380 | But a few years back, the FDA said,

01:37:41.060 | "Nope, can't sell NAC any longer."

01:37:43.180 | And there was a pushback lobby to keep it on the market.

01:37:47.020 | And you can still buy it on Amazon.

01:37:50.140 | The same thing has more or less happened with NMN.

01:37:53.680 | And certainly with NR.

01:37:55.740 | Although NR was never in question

01:37:57.620 | in terms of whether or not it should be sold

01:37:58.900 | as a supplement or not.

01:37:59.940 | Because as far as I know,

01:38:00.780 | there's no clinical trial on NR, at least not currently.

01:38:03.680 | So there's a clinical trial on NMN,

01:38:05.720 | which classifies it as an experimental drug.

01:38:08.340 | And therefore the FDA said,

01:38:09.920 | "Nope, you can't sell it as a supplement."

01:38:12.660 | A few companies, major companies,

01:38:14.700 | pulled NMN from the market in the US.

01:38:17.180 | Many smaller companies just kind of watched and waited

01:38:20.620 | and continued to sell it.

01:38:22.140 | And I checked prior to the beginning of this episode,

01:38:24.180 | and you can still buy it online.

01:38:26.020 | But of course, a lot of what we're saying today

01:38:28.020 | is kind of a, "Why would you?"

01:38:30.260 | We're not really coming up with strong arguments

01:38:32.860 | for taking NMN, at least not in today's discussion.

01:38:36.800 | - Yeah, I mean, again,

01:38:37.640 | I think the strongest argument I could make

01:38:39.600 | based on the data would be potentially

01:38:42.280 | on the basal cell and squamous cell carcinoma risk reduction,

01:38:47.280 | if indeed those results are reproducible.

01:38:51.120 | That, again, that would be justification,

01:38:53.880 | again, for the right individual.

01:38:55.280 | Wouldn't be a justification for me,

01:38:56.800 | might be a justification for somebody.

01:38:59.520 | But really, the rest of it is,

01:39:01.360 | why do you need to do experiments on this

01:39:05.760 | if you're selling a supplement

01:39:07.080 | when you don't need to make claims to sell a supplement?

01:39:10.020 | Like, if it's a drug, you have to have an indication.

01:39:12.960 | Can't sell a drug without rigorous trials

01:39:16.200 | that demonstrate both safety and efficacy.

01:39:18.500 | I do think it's pretty safe to say that,

01:39:21.220 | I do think NR and NMN are probably safe.

01:39:24.460 | There has been some voice around the idea

01:39:28.140 | that NR could increase the risk of cancer.

01:39:30.860 | - Right, and the experts in this area,

01:39:32.620 | like Charles Brenner, have pushed back hard on that,

01:39:35.220 | arguing that the studies were not done well,

01:39:39.220 | is that, I recall?

01:39:40.620 | - I think that's probably fair.

01:39:42.100 | I don't think there's been a well-done study

01:39:43.640 | in this entire field, is part of the problem, right?

01:39:47.420 | So, and that's probably too harsh a statement.

01:39:49.620 | But this is not a field that's, like, you know,

01:39:53.120 | that's necessarily lending itself to the rigor

01:39:56.660 | that you would in pharmacotherapy.

01:39:58.700 | And I think there are probably, you know,

01:40:00.260 | you mentioned Charles Brenner.

01:40:01.300 | Like, I think Charles does good work, right?

01:40:03.900 | - And he works on many things, not just this.

01:40:05.620 | - Yeah, and by the way, I don't think,

01:40:08.460 | I don't hear Charles out there saying

01:40:09.860 | that NR increases lifespan.

01:40:11.460 | - No, in fact, I don't wanna quote him at all,

01:40:14.980 | but I think he would argue that sirtuins, NR, NMN,

01:40:19.980 | should not logically or practically be linked

01:40:23.180 | to efforts to extend lifespan,

01:40:25.700 | but that there are some interesting positive effects

01:40:29.180 | of augmenting NR as a means to increase NAD

01:40:33.580 | for sake of anti-inflammation

01:40:36.220 | and some of these other effects that we've been discussing.

01:40:39.060 | - Yeah, that's my understanding of his position as well,

01:40:41.140 | is that I think he firmly agrees with what I laid down

01:40:44.100 | at the outset of this, which is,

01:40:46.340 | there is no meaningful, logical connection

01:40:51.260 | between the relationship of sirtuins,

01:40:54.780 | caloric restriction, and NR.

01:40:56.580 | That's just a, that's a shell game that is empty.

01:40:59.780 | And you're right, I mean, I think part of the reason

01:41:04.580 | why I think there's much better research going on

01:41:07.500 | with rapamycin is that there's really no commercial interest

01:41:11.340 | in rapamycin.

01:41:12.620 | Like, nobody's gonna make money selling rapamycin.

01:41:14.980 | - Because it's so cheap?

01:41:16.260 | - Well, yeah, and it's actually not cheap,

01:41:17.700 | but it's a drug that is off patent, right?

01:41:20.140 | So this is a drug that was approved by the FDA 25 years ago.

01:41:23.460 | - So generic forms are inexpensive enough that no--

01:41:25.860 | - Believe it or not, they're not.

01:41:27.140 | This is the irony of it, is generic,

01:41:29.620 | so rapamune is the brand drug

01:41:32.260 | that was initially approved in 1999.

01:41:37.700 | And today, if you go and buy rapamycin,

01:41:40.660 | you're gonna not buy rapamune,

01:41:42.180 | you're gonna probably buy generic sirolimus or rapamycin.

01:41:47.180 | And yet it's surprisingly quite expensive.

01:41:49.140 | Now, it's not enormously expensive

01:41:50.300 | 'cause you're not taking much of it,

01:41:51.660 | but it's about five bucks a milligram.

01:41:54.780 | That's pretty expensive.

01:41:57.420 | So if you're taking eight milligrams a week,

01:41:59.020 | that's 40 bucks a week is probably what I spend

01:42:01.300 | on rapamycin, that ain't cheap.

01:42:03.220 | - No. - Relative to, you know,

01:42:04.600 | and it's cheaper than some things I take,

01:42:06.060 | but it's not cheap.

01:42:07.380 | But the point is, like, nobody has a commercial interest

01:42:10.540 | in rapamycin, right?

01:42:12.180 | It's sort of an irrelevant drug.

01:42:13.820 | It's, but the interest is scientific, right?

01:42:16.940 | And the commercial interest is in what we call rapalogs,

01:42:20.340 | which are analogs of rapamycin

01:42:22.660 | that are being investigated by a number of companies

01:42:26.020 | to look at new indications.

01:42:28.180 | For example, immunity, immune function, right?

01:42:30.720 | So rapamycin historically is thought of

01:42:33.020 | as an immune suppressant,

01:42:34.580 | because that's the context in which it was approved

01:42:37.300 | for patients undergoing organ transplantation.

01:42:40.560 | But, you know, I think Joan Manik and Lloyd Clickstein,

01:42:46.660 | when they published that paper in 2014, using Everolimus,

01:42:51.240 | where they took a group of 65 year olds

01:42:54.660 | and randomized them to either a placebo

01:42:56.700 | or different doses and dosing schedules of Everolimus,

01:43:01.020 | found an enhanced immunity

01:43:03.860 | in response to an influenza vaccine.

01:43:06.300 | Which again was, for me, that was the turning point, right?

01:43:08.500 | That's when rapamycin went from

01:43:10.820 | something that was interesting,

01:43:11.980 | based on the first ITP in 2009,

01:43:14.900 | to maybe we should be taking this in 2014.

01:43:18.500 | So between 2009 and 2014,

01:43:20.660 | I was kind of looking at the curiosity of rapamycin

01:43:24.140 | and saying, well, cool that it worked in mice,

01:43:27.180 | I don't think humans should ever consider this,

01:43:29.660 | to that study, which was like, wait a minute,

01:43:32.020 | something's different.

01:43:33.460 | If you take rapamycin, as a human at least, every day,

01:43:37.540 | it seems to suppress your immune system,

01:43:39.900 | but if you just pulse it once a week,

01:43:42.700 | as they did in that study,

01:43:43.820 | it seems to improve immune function.

01:43:46.020 | Which again, means it's an immune modulator,

01:43:48.020 | it can go up or down in the immune system.

01:43:49.740 | That was really the hypothesis

01:43:51.420 | that emerged from that experiment.

01:43:53.860 | And so now the question is,

01:43:54.780 | could you design drugs that are more specific

01:43:59.060 | to mTOR complex one, which rapamycin is not,

01:44:02.100 | but you can get around that by dosing it intermittently.

01:44:04.780 | And then of course, is it a drug that has efficacy

01:44:08.740 | in terms of other things that can be tested in humans

01:44:13.180 | that are not longevity?

01:44:14.220 | 'Cause you can't test lifespan in humans, obviously.

01:44:16.260 | - Right, you're 50, right?

01:44:18.820 | 50 years old? - 51.

01:44:19.660 | - 51, you seem to be vigorous.

01:44:23.260 | You take great care of yourself.

01:44:25.580 | How much do you think taking rapamycin,

01:44:27.660 | for how many years have you been taking it?

01:44:30.180 | - Six.

01:44:31.300 | - Has contributed to your current state or vigor?

01:44:35.620 | - Zero idea.

01:44:36.460 | - This is my opportunity to ask about your belief

01:44:40.740 | or lack of belief in biological aging tests.

01:44:44.660 | Because if somebody is going to experiment

01:44:46.300 | with any or all of these things,

01:44:48.200 | they may want to evaluate

01:44:51.500 | whether or not their biological age is changing.

01:44:54.140 | And there are a number of these tests available.

01:44:57.360 | And people love this stuff.

01:44:59.060 | - Love 'em. - They love 'em.

01:45:00.100 | I mean, who wouldn't wanna see that they are 51 years old,

01:45:02.720 | but their biological age is 37?

01:45:04.540 | - I just did a movement test the other day.

01:45:06.940 | So it's a very fancy camera system

01:45:10.300 | where it's got a million cameras on you,

01:45:12.540 | and you go through this whole exercise.

01:45:14.660 | How high can you jump?

01:45:16.180 | How far can you throw?

01:45:17.500 | Like, it was awesome.

01:45:18.380 | And then it gives you a movement age.

01:45:20.680 | Andrew, I was 22.

01:45:23.620 | - I believe it.

01:45:24.820 | - I mean, I should feel amazing.

01:45:27.380 | Do you actually think I move like a 22-year-old?

01:45:30.580 | I mean, are you freaking kidding me?

01:45:32.740 | I bet you if I went and did that again tomorrow,

01:45:34.820 | I'd come back at 31 or something.

01:45:37.740 | There is so much nonsense in this type of testing.

01:45:41.900 | It is just, you know, look,

01:45:45.100 | there's probably something to be said

01:45:47.900 | if I do that and I come out at 22 as I did versus 92.

01:45:52.040 | - Sure.

01:45:52.880 | - I would grant you that if you took 150-year-olds

01:45:57.160 | and you put them through a movement test,

01:45:59.500 | the ones that really, really are struggling

01:46:01.620 | will come out older,

01:46:02.580 | and the ones that really, really are doing great

01:46:04.540 | are gonna come out younger.

01:46:05.420 | So great, I guess it's nice.

01:46:06.620 | I guess I move reasonably well for a 51-year-old.

01:46:09.500 | But it's simply impossible to believe that I can do today

01:46:13.380 | what I could do when I was 22

01:46:14.760 | with respect to movement and strength and power,

01:46:16.620 | which is what that was assessing.

01:46:18.060 | You're doing a lot of jumping, single leg jump here,

01:46:20.060 | do all this kind of stuff.

01:46:21.380 | Balance testing, all sorts of things.

01:46:23.220 | And I guess I would say the gold standard

01:46:26.660 | for any of these biologic aging tests

01:46:29.100 | has to be the following.

01:46:32.540 | What is a better predictor of remaining years of life,

01:46:37.500 | chronologic age or biologic age?

01:46:40.520 | That's, to me, the most important standard.

01:46:43.100 | So how old are you chronologically?

01:46:45.500 | - I turned 49 in six weeks.

01:46:48.580 | - Okay.

01:46:49.780 | So I'm sure your listeners will not like to hear this

01:46:53.220 | because they would probably hope and believe

01:46:55.800 | that you are immortal, but--

01:46:57.720 | - Some might want to hear

01:46:59.300 | that I'm gonna be taken out soon.

01:47:00.860 | (laughing)

01:47:02.340 | - But let's just grant your mortality as a given.

01:47:05.880 | Based just on your chronologic age,

01:47:10.640 | an actuary would come up with a pretty decent prediction

01:47:13.940 | of how long you're going to live.

01:47:14.980 | Now, I would argue that that's a crude assumption

01:47:17.540 | because it doesn't take into account the fact

01:47:19.660 | that you're metabolically healthy,

01:47:22.000 | that you do all of the things that you do.

01:47:23.740 | But just based on the fact that you are a man

01:47:27.500 | who is 49 years old and who doesn't smoke,

01:47:30.980 | those three things would give me, if I were an actuary,

01:47:35.980 | a very good prediction of your life expectancy.

01:47:39.600 | And because I'm not an actuary,

01:47:40.900 | I don't know the exact number,

01:47:42.180 | but my guess is it would be predicted at this point

01:47:46.420 | at another 37 years.

01:47:49.040 | - Okay.

01:47:49.880 | Well, I bought that chart, my life in weeks.

01:47:52.580 | - Yes.

01:47:53.420 | - In fact, I bought two of them

01:47:54.780 | for reasons that are uninteresting.

01:47:57.260 | But I've watched that chart, Phil.

01:48:01.000 | Not quite what you predicted,

01:48:05.420 | but I put my estimated lifespan to be 95.

01:48:09.820 | - Great, that's fine.

01:48:10.660 | - And then I have little lines on the side

01:48:13.260 | of how much vigor I felt from,

01:48:16.740 | and just overall wellness, completely subjective,

01:48:19.380 | of zero being like completely cratered near death

01:48:23.660 | to 10, like it's best I've ever felt.

01:48:25.540 | - But you make that note every how often?

01:48:28.100 | - Okay, so what I did is from 10 to 15, I felt blank.

01:48:32.660 | And then in my 20s, I actually didn't feel so great

01:48:36.180 | because I was working 80 hour weeks, commonly.

01:48:40.340 | You can ask my former lab technicians.

01:48:42.420 | I was just talking to Feng Wen recently.

01:48:44.060 | And I mean, I used to work to collapse, not healthy.

01:48:46.820 | You know, 80 hour a week, maybe 100 hours occasionally,

01:48:49.380 | maybe 70, maybe back to 40, but just too much work,

01:48:52.300 | not enough sleep, nutrition, not great,

01:48:54.420 | just not doing the right things,

01:48:55.620 | but just gave my 20s to being in lab, basically,

01:49:00.620 | and a lot of my 30s as well.

01:49:02.500 | So I would say from 40 to 45,

01:49:08.100 | my vigor was higher than in my 30s.

01:49:12.140 | And then now I track, I would say about every two months,

01:49:17.140 | I'll start filling in that line.

01:49:18.500 | And it's adjusted for by stressors

01:49:20.340 | and adjusted for by positive things in life.

01:49:23.340 | And the goal for me is to figure out

01:49:25.500 | what are the behavioral tools

01:49:27.140 | and other things I can do or take

01:49:29.140 | that are going to keep the vigor as high as possible,

01:49:32.220 | vigor, wellbeing, internal peace, et cetera,

01:49:35.380 | all of that combined,

01:49:36.220 | kind of what I'm calling wellness

01:49:37.260 | in this very subjective measure,

01:49:40.180 | as high as possible as I transition to my 50s,

01:49:43.980 | my 60s, 70s, and 80s.

01:49:45.980 | And I'm guessing that I'm going to have to do

01:49:47.780 | many more things in my 80s and 90s

01:49:50.060 | in order to maintain a similar,

01:49:53.300 | hopefully, level of vigor and wellbeing than I do now.

01:49:57.660 | And the question is, will I be able to?

01:49:59.740 | - Yeah, maybe, maybe.

01:50:00.660 | I might take a slightly different angle on that,

01:50:05.660 | but let me go back and make one point,

01:50:08.060 | and then we'll come back to this point,

01:50:09.500 | which is actually really interesting.

01:50:10.620 | - Yeah, 'cause I think the chart is great.

01:50:12.300 | I think the chart, more than any supplement for longevity,

01:50:17.680 | gives you a, or gives one a visual perspective

01:50:21.560 | of where they sit in this long arc.

01:50:23.840 | And I don't think the brain is very good

01:50:26.880 | at anchoring us to the notion that we are mortal,

01:50:30.400 | because if we think about that

01:50:32.240 | for even a few moments too long, it makes us anxious.

01:50:35.400 | And I think we are very good at avoiding that reality.

01:50:40.280 | - Yeah, well, it's, as you said,

01:50:42.680 | it's very difficult to contemplate finitude.

01:50:46.640 | So I actually wanna talk about that,

01:50:48.480 | 'cause I think it's so interesting,

01:50:49.520 | but I just wanna make this point

01:50:50.600 | about the actuarial point, right?

01:50:51.960 | So let's just say, actuarially,

01:50:54.600 | your expectation is 40 years more at this point,

01:50:57.600 | because you're 49, you're a male, and you don't smoke.

01:51:00.760 | So we believe you have somewhere between 35

01:51:03.400 | and 40 more years of life predicted

01:51:06.000 | on the basis of your biologic age.

01:51:08.440 | - That's it?

01:51:09.620 | That's all I got?

01:51:10.460 | - You're gonna live to whatever, 88 to 91 or something.

01:51:12.860 | I'm making that up, but that's like, okay.

01:51:14.480 | - I better get cracking on some stuff.

01:51:16.800 | - So now, let's pretend you went

01:51:18.600 | and did a biologic age test.

01:51:22.240 | Okay, so let's say you did that.

01:51:24.320 | And let's say it came back and said you're 25.

01:51:27.340 | So if I had a 25-year-old male, non-smoker in front of me,

01:51:34.960 | what's his life expectancy?

01:51:36.740 | Well, it's about 60 to 65 years.

01:51:43.760 | Does that mean that you, Andrew,

01:51:45.840 | have 60 to 65 more years of life

01:51:48.160 | based on a fact that your biologic clock says you're 25?

01:51:52.640 | Do you believe that?

01:51:53.560 | - No, no way.

01:51:54.740 | - No, of course not.

01:51:56.480 | Now, this would be an easy thing to test, not in humans,

01:51:59.800 | but you could do it in mice, right?

01:52:02.760 | Interesting that, to my knowledge,

01:52:03.880 | that experiment hasn't been done.

01:52:05.840 | So right out of the gate, when I look at people

01:52:11.600 | talking about their biologic age,

01:52:14.000 | well, I'm actually 60 years old, chronologically,

01:52:16.960 | but my biologic age is 35.

01:52:18.960 | My response is, who cares, truthfully?

01:52:23.920 | Is that a good thing?

01:52:24.840 | Yes, probably.

01:52:26.160 | But is it tangibly, measurably meaningful

01:52:31.160 | to have a biologic age of 35 versus 40 versus 30

01:52:37.400 | if you're 60?

01:52:38.760 | I think we're applying a very false level of precision

01:52:43.280 | to something that might only need to be directionally true.

01:52:46.680 | Secondly, we don't really yet understand

01:52:49.720 | the biologic noise in that measurement, right?

01:52:52.520 | So there are lots of things that we measure

01:52:54.320 | that are really noisy.

01:52:56.520 | So if I measured your, I don't know,

01:53:01.520 | let's think of something that's very biologically noisy,

01:53:06.400 | your triglyceride level.

01:53:07.920 | Like, your triglycerides are pretty noisy

01:53:11.320 | unless I do something very important,

01:53:13.680 | which is standardize it by how long

01:53:15.520 | it's been since your last meal.

01:53:17.560 | Like, if you ask me right now what my trigs are,

01:53:20.360 | I have no earthly idea because I probably ate

01:53:24.560 | three hours ago, and I don't even remember what I ate,

01:53:27.440 | how much fat was in it, how much carbohydrate was in it,

01:53:29.360 | I have no idea.

01:53:30.480 | So the only way you could really get

01:53:32.000 | a triglyceride measurement and put any weight to it

01:53:36.080 | is if you've been fasting for eight to 12 hours.

01:53:38.440 | Then we can at least say, hey, a triglyceride level

01:53:41.720 | of 50 milligrams per deciliter is excellent,

01:53:44.280 | whereas a triglyceride level of 120 milligrams

01:53:46.400 | per deciliter is lousy.

01:53:48.440 | But if you measured my trigs today,

01:53:50.480 | meaning at this moment, and they were 150,

01:53:52.240 | that could be totally reasonable,

01:53:54.040 | even though at fasting levels, I'm at 50.

01:53:57.120 | So we know that because we know exactly

01:54:00.040 | what goes into the triglyceride measurement.

01:54:02.360 | But when you look at a biologic clock

01:54:04.440 | that takes into account your glucose level,

01:54:06.400 | your vitamin D level, your epigenetic marker here or there,

01:54:10.360 | those are very noisy things.

01:54:12.400 | So how do I know when I measure it in you now

01:54:15.000 | versus when I measure it in you a year from now,

01:54:17.720 | I captured you in the exact same space?

01:54:20.600 | I mean, I don't.

01:54:21.960 | So it's for that reason that I just have a very hard time

01:54:25.360 | putting any stock in this.

01:54:26.760 | Now, does that mean that in the future,

01:54:30.180 | we won't find some benefit in this?

01:54:31.680 | I think we probably will.

01:54:34.320 | I do think of all the things that go into it,

01:54:36.760 | probably the epigenetic part of it

01:54:39.040 | would be the most interesting.

01:54:40.960 | But again, what most people don't understand

01:54:43.560 | is sort of a dirty little secret

01:54:44.880 | is how difficult it is to measure the,

01:54:48.720 | and to sequence the epigenome, right?

01:54:50.660 | So to my knowledge, none of the companies

01:54:54.000 | that are doing this, I may be incorrect on this, by the way,

01:54:56.120 | but the last time I looked, which was about a year ago,

01:54:58.680 | not a single company was correctly sequencing

01:55:01.740 | the epigenome on these things.

01:55:03.380 | So they were not able to accurately say what,

01:55:06.400 | they were giving you an average representation

01:55:09.000 | of your methylation,

01:55:10.000 | but they weren't going base pair by base pair

01:55:12.280 | and actually sequencing this

01:55:14.080 | the way we would sequence the genome.

01:55:16.000 | So again, you just, it's so much noise in this system.

01:55:19.600 | And I just think it creates a little bit of a distraction

01:55:23.320 | for people, truthfully.

01:55:24.680 | - Do you avoid going through the non,

01:55:29.040 | let's just say the non-traditional scanner at the airport,

01:55:33.040 | the one that might use higher levels of radiation?

01:55:35.340 | - No, no.

01:55:36.180 | - Do you think about how many flights you take

01:55:37.340 | as a source of radiation?

01:55:38.720 | - No, let's just keep this all in context.

01:55:40.700 | So the NRC recommends that a human being,

01:55:44.980 | or at least an American, should expose themselves

01:55:47.540 | to less than 50 millisieverts of radiation a year.

01:55:52.540 | Okay, so that number doesn't mean anything to somebody.

01:55:54.920 | So let me give people a sense of what that means.

01:55:56.820 | So how many millisieverts of radiation do you and I receive?

01:56:00.780 | 'Cause we both live at sea level.

01:56:02.500 | So just ambient radiation, living at sea level,

01:56:06.020 | is one millisievert a year.

01:56:08.700 | Okay, so we just chewed up 2% of our annual allocation.

01:56:12.680 | What if you moved to Colorado?

01:56:14.980 | Now you're a mile up.

01:56:17.380 | That increases you from one to two millisieverts a year.

01:56:21.340 | Okay, what if you had a CT scan of your chest,

01:56:26.340 | a CT angiogram?

01:56:28.800 | Well, it depends on where you got it done.

01:56:30.100 | If you got it done at a really good place

01:56:31.640 | with a fast scanner and great software,

01:56:33.620 | probably three millisieverts a year.

01:56:35.620 | If you got it done at a place that's sort of average,

01:56:38.300 | might be 10 to 15 millisieverts, pardon me, per scan.

01:56:41.340 | Now here's what's really interesting.

01:56:44.500 | By the way, I'm totally fascinated by this question,

01:56:46.860 | which is how much radiation is too much.

01:56:49.740 | A DEXA scan, by the way, you can't even measure

01:56:52.320 | how many millisieverts you're getting.

01:56:53.700 | So a DEXA scan is like less radiation

01:56:56.480 | than a cross-country flight.

01:56:58.060 | So it's super, super, super low,

01:56:59.660 | less than an X-ray or anything like that.

01:57:01.760 | People who work in nuclear plants, I'm told,

01:57:09.080 | I haven't looked at the primary data on this,

01:57:10.600 | but I've talked to people who incessantly do this.

01:57:13.080 | So it's possible I'm a little bit off on this,

01:57:15.040 | but I'm told that these people are at 10 times

01:57:20.040 | that level of radiation exposure and sometimes higher.

01:57:23.640 | So they're not getting 50.

01:57:24.800 | They might be getting like 500 millisieverts a year.

01:57:28.480 | And yet, interestingly, they're not

01:57:29.720 | at an increased risk for cancer.

01:57:31.740 | I'm not sure what to make of that.

01:57:33.440 | But it suggests to me that we probably don't need to worry

01:57:38.720 | about things like airport scanners and flights.

01:57:43.200 | In fact, even if you look at pilots

01:57:45.040 | who do constant flights across the poles,

01:57:48.000 | 'cause you're gonna get the most radiation

01:57:49.480 | going over the pole, to my knowledge,

01:57:51.580 | there's no convincing data that suggests

01:57:53.320 | those people are at an increased risk of cancer either.

01:57:55.520 | And they're obviously at the upper end

01:57:58.040 | of what a civilian would experience in terms of radiation.

01:58:01.120 | So I'm not convinced that that's something

01:58:05.840 | we should be stressed about.

01:58:07.180 | - I think you just relieved a lot of people

01:58:09.600 | of some unnecessary concern.

01:58:11.680 | - I wanna go back to what you were saying earlier

01:58:12.880 | about what you need to do in your 90s

01:58:14.340 | versus what you're doing now.

01:58:16.240 | So you said you think that in your 80s and 90s,

01:58:18.720 | you're gonna have to work harder

01:58:20.660 | to preserve the vitality that you have now.

01:58:23.280 | - Yeah, grip strength, jumping, cognitive function.

01:58:27.360 | I mean, I've got very good genes in terms of longevity

01:58:29.960 | on one side of my family, pretty good on the other,

01:58:32.560 | although not as robust.

01:58:34.220 | I mean, if I just look historically.

01:58:36.280 | Yeah, who knows, right?

01:58:39.680 | I mean, but my sense is that I'll live to be 95

01:58:44.160 | if, you know, barring, you know, bullet buster cancer.

01:58:47.900 | - So I would say that, yes, you're gonna have to work hard

01:58:51.640 | in that last decade of life to preserve those things,

01:58:53.880 | but I think it's the work we do now

01:58:57.060 | that sets the stage for that.

01:58:58.480 | It's the foundational work that we do

01:59:00.200 | in this period of our lives.

01:59:01.480 | You know, you and I are only a couple of years apart,

01:59:03.620 | but I think this is the critical decade.

01:59:06.560 | It's in your 50s to your 60s and in your 60s to your 70s

01:59:10.040 | that I think is the deciding time.

01:59:12.720 | - 50s to 70s. - 50s to 60s.

01:59:14.680 | Yeah, 50s to 70s.

01:59:15.680 | So what is it about this window

01:59:18.520 | that you and I are just entering now?

01:59:20.680 | And why is it so important?

01:59:23.100 | I think it's important because we're getting to that point

01:59:27.360 | where aging does start to show up.

01:59:30.360 | Like, I think if you and I are being brutally honest,

01:59:32.920 | like we're kind of half the men we used to be.

01:59:35.320 | And again, that just means like, look,

01:59:39.440 | like a night of poor sleep shows up more, right?

01:59:43.080 | When you were working in the lab

01:59:44.360 | as hard as you were describing it,

01:59:46.240 | you could probably walk through walls

01:59:47.520 | when you were exhausted.

01:59:48.560 | - Yeah, a short nap would reset me near completely.

01:59:51.520 | - Yeah.

01:59:52.360 | - I got more colds and flus in that time

01:59:54.400 | because I wasn't taking such good care.

01:59:55.720 | But then again, I was indoors more.

01:59:56.960 | So it's an imperfect experiment, but you're right.

01:59:59.320 | I think that as I've approached 50, I need to do more.

02:00:04.320 | - You need to do more self-care.

02:00:06.960 | You need to be more mindful of what you're eating,

02:00:08.960 | how you're sleeping, how you're recovering

02:00:10.840 | from those workouts 'cause we still do hard workouts,

02:00:13.440 | but recovery plays a greater role.

02:00:14.920 | In other words, we're just not quite as resilient

02:00:16.880 | as we used to be.

02:00:18.160 | You know, I was telling somebody the other day,

02:00:19.360 | they asked me about my residency.

02:00:21.520 | I don't think I'm being hyperbolic when I say this.

02:00:23.760 | I couldn't do one month of what I did for five years.

02:00:27.960 | I really couldn't do it.

02:00:29.120 | I don't think there's any,

02:00:30.640 | there's no way I could go back to that level

02:00:33.200 | of sleep deprivation for a month, let alone five years.

02:00:36.440 | So, you know, that's just a fact of aging, I think.

02:00:41.440 | So, but what we have to do during this period of time

02:00:45.360 | is build up as much physiologic reserve as possible.

02:00:49.640 | And so the important thing is, you know,

02:00:52.280 | we have to stay in the game

02:00:53.680 | because compounding makes such a difference, right?

02:00:57.640 | So, you know, we're still young enough

02:01:00.480 | that we can actually put on muscle mass.

02:01:03.120 | Now, that's not always gonna be the case.

02:01:05.080 | It's gonna be very difficult to add muscle mass

02:01:08.600 | when you're in your mid to late 70s.

02:01:10.240 | It's doable, but it's very, very difficult.

02:01:14.280 | So instead, we wanna be putting on

02:01:16.680 | as much muscle mass as we can

02:01:18.520 | and increasing or at least maintaining strength

02:01:21.360 | as much as we can.

02:01:23.000 | Again, probably increasing it is unlikely.

02:01:25.100 | Clearly we're not increasing power as we age, right?

02:01:28.120 | Andy Galpin has talked a lot about this.

02:01:30.120 | The atrophy of the type two muscle fibers,

02:01:32.600 | the two way muscle fibers,

02:01:33.960 | really start to atrophy in your 20s and 30s.

02:01:36.840 | So I know I don't have a fraction of the power

02:01:39.240 | that I used to have.

02:01:40.060 | And I know that because my vertical jump

02:01:42.020 | is literally half what it was when I was a teenager.

02:01:45.120 | - Mine was never very good, so I--

02:01:48.040 | - It doesn't matter how good it was.

02:01:49.320 | My point is like,

02:01:50.160 | if you know what your vertical jump was at 18, 19, 20,

02:01:53.000 | and then you do it today, I mean, it's literally 50%.

02:01:55.560 | And that's one of the purest tests of power.

02:01:58.520 | So power's going down, strength is going down,

02:02:00.960 | but not as much.

02:02:01.800 | Muscle mass is actually not,

02:02:03.280 | 'cause remember, that's the order

02:02:04.700 | in which you lose things, right?

02:02:05.800 | You're gonna lose power, strength, and size of muscle.

02:02:09.000 | But again, size still matters.

02:02:10.480 | It's still a glucose sink, all these other things.

02:02:13.600 | But what we don't wanna do is, you know,

02:02:17.120 | be out of the game, right?

02:02:18.260 | What we don't wanna do is injure ourselves

02:02:21.820 | and get a setback that becomes very difficult

02:02:24.140 | to recover from.

02:02:25.400 | Because, you know, when you're our age,

02:02:28.180 | if you're inactive for months at a time,

02:02:32.300 | it's gonna be two to one or three to one ratio

02:02:35.300 | of inactivity to activity to get it back.

02:02:38.540 | - What about energy, sorry to interrupt,

02:02:40.480 | but since we've been talking about molecules

02:02:43.120 | and energetic pathways, what about energy?

02:02:47.040 | Just that get up and go.

02:02:49.600 | Let's just say after a decent night's sleep,

02:02:51.440 | seven and a half hours, waking up same time, more or less,

02:02:56.000 | you know, 6.30, 7 a.m. probably for you or me.

02:02:59.200 | And why is it that as we get older, we have less energy?

02:03:03.580 | Our mutual good friend, the late Ben Barris,

02:03:05.920 | used to ask about this.

02:03:06.980 | He used to say, he called me Andy.

02:03:08.520 | He was like, "Andy, why do I have so much less energy?"

02:03:10.920 | I was like, "I don't know, I don't know."

02:03:11.760 | It's a great question.

02:03:13.120 | Now, unfortunately, he died of pancreatic cancer,

02:03:14.880 | so there may have been other things going on,

02:03:16.380 | but that was prior to the cancer,

02:03:19.160 | at least as far as I know.

02:03:20.960 | You know, it's a very interesting question.

02:03:22.520 | Why do we have less energy?

02:03:24.980 | And I don't think anyone's ever been able

02:03:26.800 | to answer that question.

02:03:28.340 | - No, and when you have kids,

02:03:30.880 | you're gonna be even more starkly confronted with that.

02:03:35.240 | 'Cause actually, it's one of the things I am most amazed by

02:03:38.740 | when I look at my kids, especially the youngest ones,

02:03:41.940 | the boys who are seven and 10,

02:03:44.820 | is what I just described as spontaneous outbursts of energy.

02:03:48.240 | Like their inability to sit still,

02:03:52.480 | their kinetic desire to just, like they will,

02:03:57.140 | like I remember once we were kind of walking through a mall

02:04:00.500 | and we're walking through the mall,

02:04:02.540 | they are sprinting ahead of us, sprinting back,

02:04:05.420 | sprinting ahead of us, sprinting back.

02:04:06.940 | Like imagine if you and I were walking through the mall

02:04:10.500 | and I just started running ahead and running back.

02:04:13.340 | - You'd be so sore the next day.

02:04:15.220 | - Yeah, but it's like, it just wouldn't occur to me

02:04:17.260 | to ever run unless being chased, right?

02:04:19.940 | Like it's just, I mean, like we now live a life

02:04:23.380 | like I think our ancestors did, which was, you know,

02:04:26.580 | if we're not deliberately in the business of moving

02:04:30.060 | for a reason, like you're exercising,

02:04:32.280 | you're going for a walk for the sake of going for a walk,

02:04:34.740 | like you just wouldn't, it wouldn't occur to you

02:04:36.860 | go and expend energy for no reason.

02:04:39.700 | And yet kids do this, it's amazing.

02:04:42.040 | And look, it's gonna go down by the time you're a teenager,

02:04:45.320 | like just going from being, you know, sort of 10 to 18,

02:04:49.700 | there's probably a significant reduction

02:04:51.620 | in spontaneous outbursts of energy,

02:04:53.780 | let alone where we are now.

02:04:55.640 | And it's a great question.

02:04:58.340 | Maybe it's NAD.

02:05:00.300 | I mean, I don't know.

02:05:02.020 | - Maybe, although up until now,

02:05:05.060 | we've been talking about all these ways

02:05:06.420 | to try and increase NAD in the bloodstream

02:05:08.420 | and hopefully in cells.

02:05:09.420 | And I don't know, I take my NMN and my NR

02:05:12.500 | and I feel a little bit of a boost in energy,

02:05:14.500 | but I can't say that it's so significant

02:05:16.780 | that I feel like I can sprint back and forth

02:05:20.300 | just spontaneously.

02:05:21.660 | - Again, it's just so hard for me to imagine

02:05:24.100 | that any supplement or any drug, including rapamycin,

02:05:28.220 | which I think is the most promising

02:05:30.820 | geroprotective drug we have,

02:05:33.040 | I just can't imagine that those things even compare

02:05:37.940 | to what good sleep, good exercise and good nutrition do

02:05:42.780 | for your energy levels and vitality.

02:05:45.500 | And the reality of it is all three of those things

02:05:48.860 | are hard to do, you know?

02:05:52.180 | - Yeah, they do.

02:05:53.020 | - Especially if you're an adult,

02:05:53.840 | like especially if you have a real life,

02:05:55.660 | you know, you got kids, you got a job,

02:05:58.220 | which is presumably many people listening to us right now.

02:06:01.020 | Like there's very few people listening to us right now

02:06:03.460 | whose only purpose in life is to take care of their health.

02:06:06.320 | Everybody's got something else they have to do,

02:06:08.320 | which means you have competing interests

02:06:10.660 | for how do you take care of yourself.

02:06:13.100 | So to sleep is not easy, right?

02:06:15.980 | Like we all are busy as hell.

02:06:17.640 | We don't want to have to stop what we're doing

02:06:20.220 | to undergo a nighttime routine,

02:06:22.740 | to put ourselves in the right head space,

02:06:24.620 | to be able to sleep, do all the things necessary,

02:06:27.060 | give ourselves that eight hours in bed

02:06:29.020 | to hopefully get seven, seven and a half hours of sleep.

02:06:32.300 | Even people like me who like exercise,

02:06:34.420 | I know you like exercise,

02:06:36.340 | it still is a sacrifice in terms of time.

02:06:38.620 | And for many people, certainly for me,

02:06:42.820 | food is the hardest of these all, right?

02:06:44.420 | If left to my own devices,

02:06:46.260 | I'd eat fricking Froot Loops all day.

02:06:47.700 | Like I love Froot Loops, right?

02:06:49.140 | - Interesting, by way of contrast,

02:06:50.960 | the food part is easy for me.

02:06:52.260 | I like healthy food and--

02:06:53.900 | - Oh, I like healthy food.

02:06:54.740 | I just like all food.

02:06:55.580 | - Okay, yeah, I don't like unhealthy food.

02:06:57.740 | I've weaned myself off.

02:06:59.300 | I never really liked it that much.

02:07:00.620 | I mean, I like a great tasting slice of pizza

02:07:02.420 | or ice cream every once in a while,

02:07:03.460 | but I much prefer meat, fish, chicken, eggs,

02:07:06.980 | fruits, vegetables, rice, oatmeal.

02:07:08.740 | I just like that stuff.

02:07:10.380 | I'm a weirdo that way, I suppose.

02:07:12.060 | But on the topic of exercise,

02:07:14.060 | as it relates to vigor and longevity,

02:07:16.580 | I'm intrigued by how some forms of exercise

02:07:20.860 | give us more energy, especially the same day,

02:07:25.020 | and how some forms of exercise

02:07:26.700 | or even timing of exercise tends to deplete us.

02:07:30.060 | Because I think one of your major sort of calls

02:07:32.900 | to the public has been to move more

02:07:35.740 | for sake of their healthspan and lifespan.

02:07:39.240 | But because of the time investment that it takes

02:07:41.140 | to work out in a gym or to go for a run or a rock,

02:07:44.460 | I think some people think, well, that's a lot of time,

02:07:48.180 | but if it gives you more energy

02:07:49.740 | and more focus to do other things, well, then it's great.

02:07:52.220 | So it's not just about living longer,

02:07:53.760 | it's about being able to do more.

02:07:55.180 | And I've noticed, I don't have any science to back this up,

02:07:58.060 | but I'd love someone to run a test on this,

02:08:00.780 | that if I complete my workout before 9 a.m.,

02:08:04.020 | even if I have to start it while I'm a little bit fatigued,

02:08:06.620 | I have more energy all day long.

02:08:09.100 | But that if I initiate that workout,

02:08:11.340 | say mid to late morning,

02:08:12.960 | I'm pretty tired in the afternoon.

02:08:15.860 | It's like I give everything I have to that workout.

02:08:19.060 | And so it becomes a little bit defeating

02:08:20.700 | since I'm not a professional athlete

02:08:22.180 | or even an amateur athlete.

02:08:23.700 | I'm working out for healthspan, lifespan,

02:08:25.900 | but I wanna do exercise that gives me more life

02:08:30.340 | during my waking hours.

02:08:31.920 | I think somebody should study this.

02:08:33.540 | And I'm convinced that it has something to do

02:08:35.900 | with the change in body temperature

02:08:37.740 | that occurs across the day

02:08:39.020 | and the additional change in body temperature

02:08:40.660 | that occurs as a consequence of exercise.

02:08:43.180 | That's my hypothesis.

02:08:44.260 | - Do you notice a seasonal change in that?

02:08:46.460 | Do you experience it more or less

02:08:48.100 | in one season or the other?

02:08:49.260 | - I haven't thought about it that much, but not so much.

02:08:51.700 | Not so much.

02:08:52.540 | And I wonder whether folks like our friend Jocko Willink

02:08:56.060 | are able to do so much.

02:08:58.340 | He has so much vigor, that guy,

02:09:00.480 | in part because he basically exercises

02:09:03.780 | just after the lowest temperature phase

02:09:06.580 | of the circadian rhythm.

02:09:07.880 | And he uses exercise, presumably,

02:09:09.380 | to drive himself out of that

02:09:11.020 | and get that temperature increase

02:09:13.060 | that's the consequence of waking.

02:09:14.980 | But in his case, he's waking up so early.

02:09:16.700 | 4.30 is when he starts those workouts.

02:09:19.160 | So it's something for people to play with.

02:09:21.200 | It's something that I don't think gets discussed enough,

02:09:23.980 | which is, yes, you should exercise,

02:09:25.820 | do resistance training, do cardiovascular training,

02:09:28.620 | but play with the timing of those

02:09:30.760 | and see how at a given intensity,

02:09:33.760 | it impacts your energy levels for the remainder of the day.

02:09:36.960 | I think it's an important metric that,

02:09:39.220 | again, I just don't see a lot of attention to.

02:09:42.620 | Because I think if people could experience

02:09:44.560 | the increase in energy

02:09:46.700 | that is the consequence of working out

02:09:48.460 | at the right intensity in the right way

02:09:49.980 | at the right times for them,

02:09:52.220 | they'd be much more apt to do it.

02:09:53.860 | It wouldn't feel like this,

02:09:55.300 | like spending money on something

02:09:57.340 | that sure will make you live longer,

02:09:58.580 | but then you're depleted and you can't do cognitive work.

02:10:00.940 | There's something pretty impressive about the fact that,

02:10:03.340 | as far as I know, the last three,

02:10:06.820 | let's just call them, I don't want to call anyone out,

02:10:08.460 | specifically major pillars of the high-level administration

02:10:11.740 | at Stanford School of Medicine,

02:10:12.900 | to my knowledge, were all 5 a.m. runners.

02:10:16.280 | There's something about early morning exercise.

02:10:18.600 | And my good friend, Eddie Chang,

02:10:19.720 | who's the chair of neurosurgery at UCSF,

02:10:21.560 | he's been on this podcast,

02:10:23.000 | known him since we were seven years old.

02:10:25.760 | He's an early morning exerciser,

02:10:27.440 | and then he's got tons of energy all day.

02:10:29.880 | - What about the reverse causality there?

02:10:32.040 | Do you think it's possible that they have a whole,

02:10:35.400 | they have a system of high energy

02:10:36.800 | that makes Jocko who he is,

02:10:38.540 | or makes these people who they are?

02:10:41.000 | And as a result of that,

02:10:42.500 | they're able to work out five o'clock in the morning.

02:10:44.740 | - Yeah, I don't doubt it.

02:10:45.620 | I just have noticed that in the few times in my life

02:10:47.980 | where I've kicked my own butt to get out

02:10:50.980 | and start working out really early,

02:10:53.260 | I have more energy all day long.

02:10:54.740 | Sometimes I still require a brief nap,

02:10:56.400 | but it's a pretty striking effect

02:10:58.440 | as compared to the 10 a.m. workout effect.

02:11:01.700 | So I've started setting a standard

02:11:03.620 | of trying to get my workout done before 9 a.m.

02:11:06.900 | So anyway, it's something for people to play with,

02:11:08.500 | because the more energy to live in your waking hours,

02:11:13.500 | perhaps not longer,

02:11:15.100 | but certainly have more energy in terms of output,

02:11:18.340 | I think is a significant and undervalued parameter.

02:11:22.460 | So let's quickly return to supplements.

02:11:26.340 | We, I think, are converging on an answer

02:11:29.700 | about NR, NMN, and NAD, which is you don't take them.

02:11:35.920 | - Correct.

02:11:36.840 | - I take NR and NMN with not a lot of religious adherence,

02:11:41.840 | I should say.

02:11:43.700 | If I ran out, I might not buy it for a while.

02:11:45.860 | And the only observed effect for me

02:11:48.060 | is this accelerated hair growth,

02:11:49.620 | which is a pain in the butt, frankly,

02:11:51.020 | 'cause it just means I have to get my hair cut more often.

02:11:52.940 | I'm not trying to grow my hair faster.

02:11:54.420 | But okay, what are some other supplements,

02:11:58.540 | if any, that you take that are peripheral to this pathway

02:12:02.220 | or separate from this pathway?

02:12:04.180 | Rapamycin is a prescription drug only, right?

02:12:06.880 | So are there any over-the-counter things that you take

02:12:10.160 | that you would place into the lifespan category?

02:12:13.200 | Maybe they touch into healthspan as well.

02:12:15.800 | I'm happy to list off what I do,

02:12:17.040 | but what are your, let's just say top five, at least.

02:12:21.440 | - Well, I don't take that many,

02:12:24.100 | so a top five would be a pretty exhaustive list.

02:12:27.440 | I think the other supplements that I take,

02:12:29.760 | I do take EPA and DHA.

02:12:31.720 | - In the form of liquid or capsule fish oil?

02:12:33.920 | - Capsules, not because I have an affection

02:12:37.620 | for capsule over liquid.

02:12:38.740 | It's just gonna increase my compliance.

02:12:40.460 | If I take, I've done both,

02:12:42.100 | and I noticed when I was taking liquid,

02:12:44.180 | 'cause you're storing it in the fridge,

02:12:45.540 | it's just one more step removed,

02:12:47.500 | and I was just less likely to remember

02:12:49.100 | to take it twice a day.

02:12:50.600 | I take theracumin,

02:12:57.220 | and there's some reasonable evidence in MCI patients

02:13:03.200 | that theracumin improves cognitive function,

02:13:06.520 | so I think there's a relatively low downside

02:13:11.460 | to the hypothesis that theracumin

02:13:14.420 | may preserve cognitive function.

02:13:17.780 | Again, I wouldn't put that in the category

02:13:20.820 | of beat the table for it.

02:13:22.300 | I think it's just reasonable evidence.

02:13:25.400 | I take, I do take vitamin D because interestingly,

02:13:31.080 | despite the fact that I'm outside every day,

02:13:34.320 | without supplemental vitamin D,

02:13:36.320 | my levels are surprisingly low.

02:13:38.420 | - How much do you take?

02:13:39.540 | - I take 5,000 IU,

02:13:41.080 | and that takes me from kind of a level of 30-ish

02:13:47.220 | to a level of 50-ish,

02:13:49.040 | and there's a lot of debate

02:13:52.220 | about how high vitamin D levels should be.

02:13:54.040 | That's a whole separate podcast.

02:13:55.360 | We could waste time on that in 10 years, yeah.

02:14:00.000 | My appetite to talk about that one.

02:14:02.160 | Let me think, what else do I take?

02:14:04.000 | 'Cause I sure, oh, I do take methylfolate and methyl B12,

02:14:07.620 | and again, the rationale there is

02:14:11.560 | I do think there's some evidence

02:14:16.840 | that elevated levels of homocysteine

02:14:19.520 | are bad in and of themselves,

02:14:23.040 | so there's no denying the fact

02:14:24.800 | that elevated levels of homocysteine

02:14:26.440 | are associated with bad things.

02:14:28.120 | That's unambiguously clear,

02:14:30.320 | meaning there's an association

02:14:31.900 | between badness and homocysteine.

02:14:33.960 | What's not clear is, is it causal?

02:14:36.860 | Now, there's definitely one mechanism you can point to,

02:14:40.360 | although, again, mechanisms are what they are.

02:14:42.800 | We just spent how many hours talking about mechanisms

02:14:45.660 | that theoretically make sense that never pan out,

02:14:48.400 | but mechanistically, homocysteine will inhibit the clearance

02:14:53.400 | of something called symmetric

02:14:56.360 | and asymmetric dimethyl arginine.

02:14:58.120 | Have you heard of these things, SDMA and ADMA?

02:15:00.760 | So, ADMA and SDMA regulate nitric oxide synthase,

02:15:05.760 | and homocysteine impairs their clearance,

02:15:10.080 | and therefore, when you have high levels of homocysteine,

02:15:13.640 | it results ultimately in impaired nitric oxide synthase,

02:15:17.940 | and therefore, lower nitric oxide.

02:15:20.320 | So, this has been proposed as at least one mechanism

02:15:23.740 | by which homocysteine might negatively impact

02:15:26.460 | vascular disease.

02:15:28.660 | So, and we also know, by the way,

02:15:31.320 | that ADMA and SDMA are cleared by the kidneys,

02:15:35.080 | and therefore, this is also proposed

02:15:37.140 | as one of the mechanisms by which impaired kidney function

02:15:40.620 | impacts vascular health, 'cause that's a known, right?

02:15:44.500 | If your kidneys don't work well,

02:15:46.180 | your risk of heart disease goes way up.

02:15:48.340 | So, this is now proposed as a link

02:15:50.100 | between what we observe with homocysteine

02:15:52.460 | and impaired renal function.

02:15:54.220 | So, we know that if you take methylfolate

02:15:59.020 | and methyl B12, you're gonna lower homocysteine.

02:16:02.980 | That's abundantly clear.

02:16:04.520 | So, the thinking is that that might actually lower ADMA,

02:16:09.300 | SDMA, and raise nitric oxide synthase.

02:16:11.480 | Again, relatively low cost,

02:16:13.940 | low risk thing to take at modest doses.

02:16:17.700 | I also, there's probably some evidence

02:16:18.980 | that over-supplementing vitamin B is problematic,

02:16:22.220 | especially B6.

02:16:23.860 | So, I don't-- - Because of peripheral

02:16:25.380 | nerve damage. - Exactly.

02:16:27.020 | So, I don't supplement B6.

02:16:28.540 | I'm just taking a bit of folate and methyl B12.

02:16:32.560 | Let me think, what else do I take?

02:16:33.900 | 'Cause I do take a couple other things.

02:16:35.860 | Oh, I take magnesium L3 and eight

02:16:40.420 | and ashwagandha for sleep.

02:16:42.200 | I take SlowMag, which is just a magnesium chloride

02:16:48.980 | slow-releasing version of magnesium,

02:16:51.580 | and I take methyl, pardon me, I take magnesium oxide.

02:16:55.540 | So, I take magnesium in three forms.

02:16:57.020 | So, I'm long magnesium.

02:16:58.980 | - You're carpet bombing. - Yeah, I'm big on magnesium.

02:17:02.560 | Great for bowel function, great for, I mean,

02:17:05.580 | I don't know the last time I had a cramp in my life.

02:17:07.900 | It's been years since I've had a cramp,

02:17:09.980 | despite exercising in a really hot place

02:17:12.700 | like Austin, Texas, where I'm sweating

02:17:14.380 | like there was no tomorrow.

02:17:15.740 | Whether you call it a supplement or not,

02:17:18.780 | I take electrolytes, I take Element,

02:17:23.780 | which I should disclose I'm an investor in that company.

02:17:27.940 | So, I drink an Element a day.

02:17:29.620 | I take creatine monohydrate, five grams a day.

02:17:32.740 | I take AG most mornings.

02:17:34.060 | Oh, and I take Pendulum, the probiotic.

02:17:37.300 | - Got it. - Yep.

02:17:38.300 | As far as I know, there's no other probiotic

02:17:40.280 | that has any meaningful effect on the body

02:17:42.780 | outside of Pendulum, right?

02:17:44.220 | Pendulum's the, 'cause if you buy the argument

02:17:46.980 | that a probiotic for your gut

02:17:49.020 | needs to have anaerobic bacteria in it,

02:17:51.180 | there's no value in giving you aerobic bacteria.

02:17:53.860 | So, you have to have something anaerobic.

02:17:55.220 | So, Akkermansia, which works through

02:17:57.920 | the GLP-1 butyrate pathway, is anaerobic,

02:18:02.260 | and Pendulum's the only company that can make it.

02:18:04.060 | I have no affiliation with this company.

02:18:05.820 | I think you should have the CEO,

02:18:07.760 | Colleen Cutcliffe, on your show.

02:18:09.900 | She's an actual scientist, and she's fantastic,

02:18:12.880 | and it's a really interesting story

02:18:16.140 | how they kind of developed this and how difficult it is

02:18:18.540 | to actually make an anaerobic bacteria.

02:18:22.300 | And so, this is kind of an odd company

02:18:24.220 | 'cause it's a supplement company,

02:18:25.860 | but they have to basically adhere to pharma GMP conditions

02:18:29.180 | to make it because of the anaerobic vats

02:18:32.540 | that you have to use infused with nitrogen

02:18:35.220 | to be able to make an anaerobic bacteria.

02:18:37.220 | So, anyway, so I take three of their products.

02:18:39.220 | I take something called Glucose Control,

02:18:41.180 | I take Polyphenol, and I take Akkermansia.

02:18:44.020 | - Okay. - And I think that's the list.

02:18:45.940 | - Okay. - Yeah.

02:18:47.020 | - I'll try and move through my list pretty quickly.

02:18:49.620 | I may miss one or two things,

02:18:51.060 | and I don't know, maybe we'll put the list someplace online

02:18:53.500 | and fill in any gaps.

02:18:55.460 | I definitely take AG1.

02:18:59.180 | You know, that's my typical ad read.

02:19:01.340 | I've been doing it since 2012.

02:19:02.540 | That's true.

02:19:03.380 | Take one or two servings a day, three if I'm traveling,

02:19:07.620 | and I'll generally do that first thing in the morning

02:19:11.180 | or in the evening.

02:19:15.360 | For me, it's really about capping off the vitamin minerals

02:19:19.300 | that I might be lacking in my diet,

02:19:22.400 | and also the whole adaptogen business, I think,

02:19:26.940 | and polyphenols.

02:19:28.420 | And I'm very interested in Pendulum

02:19:31.620 | because part of the reason I take AG1

02:19:34.300 | is for the gut health aspect.

02:19:36.640 | I think just bowel movements are more where I'd want them.

02:19:41.420 | I mean, it sounds kind of weird to talk about,

02:19:43.820 | but you just feel better when your gut motility is right.

02:19:47.140 | I feel like it adjusts my gut motility

02:19:48.940 | so it's neither too fast nor too slow.

02:19:50.860 | So that's first and foremost.

02:19:53.680 | I take a quality fish oil,

02:19:57.560 | either the one that AG makes or Carlson's in liquid form

02:20:03.460 | that has that lemon flavoring,

02:20:05.260 | and I make sure I get above one gram per day of EPA.

02:20:08.760 | So that's usually a tablespoon, sometimes two tablespoons.

02:20:13.340 | I make sure that I get enough D3,

02:20:17.140 | typically from the dropper,

02:20:18.900 | 5,000 IU per day, approximately.

02:20:20.980 | Sometimes 3,000, sometimes 7,000.

02:20:22.980 | I kind of play around that.

02:20:24.140 | And I test my blood levels.

02:20:25.580 | I also take methyl B12.

02:20:28.380 | And I also take Tonga Ali.

02:20:32.220 | So I take one capsule of that in the early part of the day.

02:20:34.940 | That has lowered my sex hormone binding globulin,

02:20:38.340 | freeing up a bit more testosterone.

02:20:40.220 | That's why I like it.

02:20:42.420 | And I take a couple of green tea capsules in the morning.

02:20:47.180 | I drink yerba mate.

02:20:48.180 | That's more of a stimulatory effect.

02:20:49.740 | And I take the NMN in powder form, sometimes NR as well.

02:20:52.860 | And again, if I run out of that,

02:20:54.280 | I tend to go long periods of time without.

02:20:56.060 | I use Element as an electrolyte.

02:20:58.940 | So people are probably noticing this is all pretty basic.

02:21:01.820 | I take, in my case, 10 grams of creatine monohydrate per day.

02:21:06.080 | I sometimes forget to take it.

02:21:07.160 | That's why I take 10 grams.

02:21:08.180 | I'll sometimes miss a day.

02:21:10.660 | And I certainly feel the effects of that in the gym

02:21:13.700 | because of the greater water volume in the muscles.

02:21:16.380 | But there are a lot of data on creatine monohydrate

02:21:18.900 | for sake of either maintaining or offsetting

02:21:21.640 | some of the cognitive dysfunction

02:21:23.100 | associated with sleep deprivation,

02:21:25.260 | maybe aging altitude and some other things as well.

02:21:28.440 | And then for a few months,

02:21:30.940 | I was playing around with, let's say, nicotine gums.

02:21:35.940 | I stopped doing that.

02:21:38.280 | First of all, I was dipping it

02:21:39.340 | and I ended up lifting for an entire episode

02:21:42.340 | of the Lex Friedman Podcast that I only realized later.

02:21:46.860 | So I stopped taking it also

02:21:48.900 | because it gave me a kind of a tick and cough

02:21:50.900 | when I wasn't chewing it.

02:21:52.620 | And then I felt like I needed to chew it

02:21:54.780 | and it's a little too stimulatory for me.

02:21:56.820 | Before sleep, I take magnesium threonate,

02:22:01.220 | really bullish on magnesium as well.

02:22:03.500 | Apigenin, 50 milligrams,

02:22:05.780 | which is essentially chamomile extract and theanine.

02:22:09.660 | And occasionally I'll take 900 milligrams inositol also,

02:22:13.660 | or instead, I kind of mix those up and around.

02:22:16.420 | And then I use a quality whey protein

02:22:18.180 | as a protein replacement, that kind of thing.

02:22:20.920 | And I've played around with various things like Sheila G

02:22:24.100 | and sometimes get the sense that it's having an effect,

02:22:27.540 | but then I'll stop taking it for long periods of time.

02:22:30.480 | There are very few things that I've stayed with

02:22:33.980 | for long periods of time.

02:22:35.440 | And I basically just described what those are.

02:22:37.940 | You know, if ever someone were to design a supplement

02:22:40.500 | that would provide more energy all day long

02:22:44.380 | that wasn't caffeine, I'd probably look to that,

02:22:46.440 | but I ingest caffeine in the form of yerba mate and coffee.

02:22:50.140 | I've played around with caffeine tablets,

02:22:54.580 | you know, taking, you know,

02:22:55.540 | 50 milligrams of caffeine in tablet form.

02:22:58.020 | I mentioned that only because it has

02:22:59.540 | a distinctly different feel

02:23:01.380 | than ingesting caffeine through liquid form.

02:23:04.500 | It feels stronger and I don't know why that is.

02:23:07.320 | In fact, there's a very well-known podcaster

02:23:09.560 | who drinks peppermint tea and takes caffeine tablets

02:23:12.120 | as a way to, I don't know, drink peppermint tea,

02:23:15.380 | which sounds very nice and mellow,

02:23:16.800 | but also get the stimulant effect.

02:23:19.000 | So anyway, that's pretty much it.

02:23:20.760 | And then I do a lot of things as I know you do,

02:23:22.800 | mainly based on suggestions you've made

02:23:24.880 | about getting zone two cardio,

02:23:26.080 | rucking, weight vest walks and hikes,

02:23:29.260 | three times a week resistance training,

02:23:31.640 | three times a week cardiovascular training,

02:23:33.800 | one long, one medium, one short.

02:23:36.240 | And I try and hit the sauna and the cold once a week.

02:23:39.360 | And yeah, that's pretty much it.

02:23:42.720 | I think there are a bunch of other supplements

02:23:45.400 | that are really interesting and kind of fun to play with

02:23:47.840 | if one wants to, like 600 milligrams of alpha GPC

02:23:51.680 | or 900 milligrams of alpha GPC in a double espresso

02:23:54.880 | prior to a workout, you feel different, it's a stimulant.

02:23:57.980 | But I don't like to do that too often

02:23:59.360 | because of the increase in TMAO that occurs.

02:24:01.600 | And then you have to take 600 milligrams of garlic

02:24:03.480 | to offset that increase and you start getting-

02:24:05.520 | - If we believe TMAO matters.

02:24:07.160 | - Right, if you believe TMAO matters.

02:24:08.720 | - I don't. - Okay, great.

02:24:10.080 | Even better, I'll maybe skip the garlic.

02:24:11.880 | So things like that, I prefer to just eat garlic anyway.

02:24:15.000 | So there are a bunch of things like that

02:24:17.040 | that are kind of fun to play with as pre-workouts,

02:24:19.520 | but yeah, that's the core supplement regimen.

02:24:23.680 | And it's the one I've stuck with for, gosh,

02:24:26.180 | at least 10 years, or in the case of AG,

02:24:30.240 | more than, you know, more than that.

02:24:32.440 | So I should say, because any discussion around supplements,

02:24:36.560 | I think it's going to, you know,

02:24:37.720 | have people pricking up their ears to,

02:24:39.160 | okay, this is like a sales pitch or something.

02:24:40.880 | I absolutely want to go on record.

02:24:43.600 | The things you choose to do and not do

02:24:46.600 | are going to have much greater effect

02:24:49.640 | on your healthspan and lifespan,

02:24:52.320 | that is the behavioral things, in particular,

02:24:54.140 | sleep, exercise, nutrition, sunlight, et cetera,

02:24:57.520 | than any one supplement that you're going to take.

02:24:59.480 | So I do view supplements, I think,

02:25:01.320 | through the appropriate lens,

02:25:02.480 | which is that they are indeed a supplement.

02:25:05.120 | They are not necessary.

02:25:08.440 | Many of them are simply sufficient

02:25:10.720 | to serve as an insurance policy

02:25:14.280 | or to augment mental and physical health,

02:25:17.440 | maybe longevity, in ways that make it worthwhile,

02:25:21.080 | given my disposable income

02:25:23.080 | that I want to devote to supplements.

02:25:24.700 | But I don't think you need them.

02:25:27.440 | - Yeah, I'll go even more extreme on that statement.

02:25:31.720 | Everything we have talked about on this podcast today,

02:25:34.520 | whether it be NR, NAD, NMN, theracumin, magnesium,

02:25:39.120 | this supplement, that supplement,

02:25:41.200 | all of that stuff, while potentially mattering,

02:25:45.440 | I would put in the category of,

02:25:48.120 | was the Titanic serving lobster or steak?

02:25:51.800 | Look, I like steak more than lobster.

02:25:56.320 | That's a relative discussion.

02:25:58.320 | Exercise, sleep, nutrition, emotional health

02:26:02.320 | is the question of what was the heading of the Titanic.

02:26:07.400 | Okay, so I just want people to understand

02:26:09.520 | the magnitude of what we're talking about.

02:26:12.400 | How you eat, how you sleep, how you train,

02:26:16.080 | and how you take care of your mental health

02:26:18.280 | is the equivalent of what direction was the Titanic going

02:26:22.240 | with respect to the iceberg.

02:26:24.640 | All this supplement bullshit that we just talked about

02:26:27.600 | is equivalent to, were they serving lobster

02:26:30.320 | or were they serving steak?

02:26:31.920 | And was the band playing this song or that song?

02:26:34.600 | I'm not saying those things don't matter,

02:26:36.760 | but just put them in the context

02:26:38.960 | of the direction the Titanic is going.

02:26:41.000 | - Okay, so I completely agree with you.

02:26:43.360 | Exercise, sleep, nutrition, and emotional health,

02:26:45.400 | not listed in any particular order.

02:26:47.160 | Peter and I both completely agree.

02:26:48.720 | Those are the critical four.

02:26:51.360 | Before we close NR, NMN, NAD, and NAD in particular,

02:26:56.360 | how do we view this?

02:26:59.520 | Is it a pathway that we should be focusing on

02:27:01.440 | in terms of supplementation or infusions

02:27:03.880 | for sake of extending our life?

02:27:05.720 | My answer on that is no.

02:27:08.360 | - Yeah, I would say the same.

02:27:09.840 | I don't remember who said this,

02:27:11.280 | but someone, maybe it was Nassim Taleb said,

02:27:14.640 | don't tell me what you think,

02:27:15.680 | show me what's in your portfolio.

02:27:17.640 | Like, meaning people who pontificate

02:27:19.600 | about this stock versus that stock,

02:27:21.200 | he's kind of like, assuming it was him that said this,

02:27:23.240 | he's like, okay, I don't care what you're telling me.

02:27:26.400 | Tell me what you own.

02:27:27.800 | That's gonna show me your conviction.

02:27:30.040 | So through that lens, look,

02:27:32.080 | I'll show you my conviction on exercise.

02:27:33.920 | I'll show you what I do.

02:27:34.760 | I'll show you my conviction on sleep.

02:27:36.280 | This is what I do.

02:27:37.240 | I'll show you my conviction on all these other things.

02:27:40.060 | I mean, I don't take these supplements, full stop.

02:27:43.840 | I don't take them 'cause I can't afford.

02:27:45.160 | It's not that I can't afford them.

02:27:46.600 | It's not that there are any inconvenience

02:27:48.400 | to me to take them.

02:27:49.360 | I passionately do not believe they do anything for me.

02:27:53.280 | And why would I waste time, money,

02:27:56.020 | anything on something that I really don't believe

02:27:58.680 | makes a difference?

02:27:59.820 | Now, again, I am always happy to be proven wrong.

02:28:03.600 | And I am very happy to say that two years from now,

02:28:07.120 | five years from now, we could be doing this exercise again.

02:28:09.600 | And in the presence of new information,

02:28:11.620 | maybe I'm not taking rapamycin

02:28:13.240 | and maybe I am fist-fulling, you know, NR and NMN.

02:28:17.440 | Possible.

02:28:18.280 | I will reserve the right to change my mind

02:28:20.580 | for the rest of my life in the presence of new data.

02:28:23.100 | But as it stands today, I do not take these supplements

02:28:26.740 | and I have no foreseeable plan to do so

02:28:28.720 | until information changes.

02:28:30.420 | - Great, thank you for that clear stance

02:28:32.440 | and the willingness to change it in light of new data.

02:28:35.260 | Peter, so good to sit down with you again

02:28:36.780 | and talk science, talk health.

02:28:39.500 | And in this case, talk about the supplements

02:28:41.140 | that we're not going to take.

02:28:43.020 | In addition to the ones that we do take.

02:28:45.420 | We will do this again sometime very soon, hopefully.

02:28:48.100 | - In Austin.

02:28:49.440 | - Would love that.

02:28:50.980 | Thanks, Peter.

02:28:51.980 | - Thanks, man.

02:28:52.980 | - Thank you for joining me today

02:28:54.100 | for my discussion with Dr. Peter Atiyah.

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02:30:26.380 | Thank you once again for joining me for today's discussion

02:30:28.800 | all about NAD and longevity with Dr. Peter Attia.

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Dr. Peter Attia: Supplements for Longevity & Their Efficacy

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