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-welcome to the huberman Lab podcast
-where we discuss science and
-science-based tools for everyday
-[Music]
-life I'm Andrew huberman and I'm a
-professor of neurobiology and
-Opthalmology at Stanford School of
-Medicine my guest today is Dr Peter AA
-Dr Peter AA is a medical doctor who did
-his training at Stanford University
-School of Medicine and John's Hopkins
-school of medicine Dr a is one of the
-world's most trusted voices on the
-topics of healthspan and lifespan and
-with good reason he is known to
-systematically review the research
-literature the clinical trials and he
-maintains an avid clinical practice so
-when it comes to the topic of whether or
-not a particular molecule or supplement
-or prescription drug is indeed something
-that we should be thinking about and
-perhaps even taking in order to improve
-our health span and lifespan Dr AA is
-the person that I choose to sit down
-with and discuss it so today we are
-going to discuss the so-called NAD
-pathway this is a pathway that's
-received a lot of attention and recent
-years as a potential Target for
-improving lifespan that is for living
-longer today we discuss the various
-molecules in this pathway and the
-various approaches to increasing NAD
-which is the end Target goal of anyone
-that's trying to augment the NAD pathway
-so to speak so for instance we talk
-about taking NR versus nmn versus direct
-infusions or even orally taking NAD and
-we compare them in terms of both what's
-known known and what is not known about
-their ability to get into cells and any
-efficacy they may have for either
-longevity or health span Dr at and I
-compare and contrast the literature on
-this again both research and clinical
-literature and we discuss whether or not
-he or I take NAD nmn or NR and if so or
-if not the reasons for that we also each
-go through our own supplement regimen
-which of course reflects what we do
-believe can potentially have an effect
-on health span and or lifespan so by the
-end of today's episode you'll learn a
-lot about NAD you'll learn a lot about
-the biological pathway you'll learn a
-lot about the delivery routs the various
-supplements and why people think they
-may be useful why others perhaps even Dr
-AA and myself think they may not be
-useful for longevity you have to listen
-to find out what the answer is there I
-should also mention that we give
-somewhat of an overview or a framework
-for thinking about approaches to
-longevity so if you're interested in
-things like rap amise and Metformin and
-whether or not fasting can improve
-longevity we get into that as well
-before we begin I'd like to emphasize
-that this podcast is separate from my
-teaching and research roles at Stanford
-it is however part of my desire and
-effort to bring zero cost to Consumer
-information about science and science
-related tools to the general public in
-keeping with that theme I'd like to
-thank the sponsors of today's podcast
-our first sponsor is element element is
-an electrolyte drink that has everything
-you need and nothing you don't that
-means the electrolytes sodium magnesium
-and potassium in the correct ratios but
-no sugar now proper hydration is
-critical for the optimal functioning of
-all the cells in your body and that's
-especially true for the neurons the
-nerve cells in fact we know that even a
-slight degree of dehydration can
-diminish both cognitive and physical
-performance so to make sure that I'm
-getting proper hydration in electrolytes
-I personally dissolve one packet of
-element in about 16 to 32 ounces of
-water when I first wake up in the
-morning and I drink that or sip that
-across the first half hour of the day or
-so and then I also make it a point to
-drink another packet of element
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-16 to 32 o at some other point during
-the day and maybe even a third if I'm
-exercising and or sweating a lot I
-should mention the element tastes
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-is watermelon although I also confess I
-like the raspberry flavor the Citrus
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-if you'd like to try element you can go
-to drink element.com huberman to claim a
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-that's drink element.com huberman to
-claim a free sample pack today's episode
-is also brought To Us by levels levels
-is a program that lets you see how
-different foods impact your health by
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-diet using a continuous glucose monitor
-one of the most important factors in
-both short and long-term health is your
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-to get adequate amounts of quality sleep
-each night one of the best ways to
-ensure a great night's sleep is to
-control the temperature of your sleeping
-environment and that's because in order
-to fall and stay deeply asleep your body
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-huberman and now for my discussion about
-NAD and Longevity with Dr Peter AA Peter
-AA welcome how are you great to see you
-again great to be here again should we
-parse this NAD
-thing I think we should do you mind if I
-set up a little bit of a
-framework
-great so for people that want to live as
-long as
-possible I think fig there are at least
-four categories of approaches broadly
-speaking the first I'll just call the
-dos and don'ts you've talked a lot about
-these your book outlive beautifully
-covered these and I tend to regurgitate
-some of what you say on this podcast
-namely you want to move appropriately
-and often enough so get enough Zone 2
-cardio do your resistance training keep
-nerve to muscle connection
-strong avoid the sorts of things that
-would lead to falling and being
-immobile eat right there's a whole
-category of things there we're not going
-to talk about today although we might
-touch on a bit
-and know your genetics and make some
-good decisions on the basis of your
-genetics so the dos and
-don'ts the second category I would put
-under the umbrella of calories glucose
-insulin Etc that all kind of funnel in
-at least in my mind to mtor mamalian
-Target of
-rapamycin a molecule that's robustly
-expressed during development and
-essentially all cells of the body and
-then across the lifespan tapers off
-during puberty especially well let's say
-infancy through puberty cells are
-expressing so much mtor and they're
-growing like crazy and we often
-associate that early stage of life as
-youth not aging because we think of it
-as a kind of a time stamp as opposed to
-the verb but I would argue as a
-developmental neurobiologist by training
-that it's one of the most rapid phases
-of Aging of our entire lifespan look at
-a picture of you when you were five look
-at a picture of you when you were eight
-versus
-15 you look very different and your size
-is robustly different by the way I just
-did this exercise because my daughter
-her birth her 16th birthday is around
-the corner and uh we take a picture of
-her every single year at the minute of
-of her birth so we have a picture of her
-every single year holding a clock that
-says 356 at 3:56 p.m. because that's
-when she was born and I just went
-through and pulled each of the last 16
-of them from the day she was born all
-the way up and you're right the biggest
-changes are actually in about the first
-10 years um you know the difference
-between being 13 and 14 14 and 15 15 and
-16 becomes incrementally less and less
-and less whereas going from 2 to three
-and 3 to four and four to five are
-ridiculous changes yeah I mean the brain
-the same brain has to learn an entirely
-new body every year in terms of how to
-move it limb length
-Etc so a lot of the so-called anti-aging
-or longevity approaches that fall under
-this umbrella relate to things like
-caloric
-restriction or taking drugs such as
-rapamycin and of course Maman Target of
-Ramin is the target of
-rapamycin
-duh in an effort to
-essentially remove excess insulin blood
-glucose and
-thereby reduce mtor activity so
-essentially slow cellular growth and all
-that fits nicely into the logic that
-mtor is associated not just with
-development but with aging because
-development is aging and then I would
-say there's a third category and it's
-the one we are going to talk about today
-which is targeting specific cellular
-Pathways that some people have deemed
-potentially interesting for longevity
-and the pathway that we're going to
-spend some time on is the so-call NAD
-pathway NR nmn NAD being the major
-players and we'll talk about some of the
-biochemical and enzymatic steps in
-between and then I suppose there's a
-fourth category which we could say is
-you know the do everything even the most
-esoteric of things category this is a
-rare category there are folks like Brian
-Johnson who spend a lot of time in this
-category specifically you know taking
-very high doses of polyphenols limiting
-their caloric intake to just early part
-of the day I think he eats dinner at
-11:00 a.m. I don't know if it's still
-qualifies as dinner at 11:00 a.m. but
-his final bite of calories is I believe
-at 11:00 a.m. doing everything from red
-light to PRP platelet platelet rich
-plasma excuse me um and essentially the
-kitchen sink approach to longevity and
-aging did I miss any categories
-so I I I would frame it slightly
-differently because I I like categories
-to be more mey mutually exclusive
-collectively exhaustive um so so I I
-don't I don't know that I would
-formulate it that way right I might say
-look category one are sort of the
-essential behavioral things that you
-have no choice but to engage in whether
-you want to or not right so you have to
-eat you have to sleep you have to
-move you just have a choice in do you
-want to do those things correctly or not
-correctly or do you want to do those
-things in a manner that promotes health
-or erodes Health right so again there's
-nobody listening to us who doesn't eat
-but again you can choose how much you
-eat and what you eat and when you eat
-there's nobody who's alive who isn't
-moving because Locomotion is life and
-the absence of life is the absence of
-locomotion but you can certainly choose
-to move very little you can choose to
-move a lot and you can choose to decide
-on how youve move you alluded to it
-already right you can you can move in a
-certain way that puts your Aerobic
-System in a zone that maximizes fat
-oxidation we call that zone two you can
-move at a level where you consume
-incredible amounts of oxygen at your
-maximum aerobic level you can choose to
-move in a manner that uses resistance
-and and gravity against you and all
-those sorts of things similarly we all
-have to sleep right Matt Walker would
-probably tell us the number of days you
-could go with sleep without sleep before
-you would literally perish um but again
-you have a lot of choices in how you do
-it so anyway I agree that's kind of
-category one but that's kind of the way
-I would frame it and then I would put in
-category two um sort of what are the
-molecules that you would exogenously
-take to try to impact any of those
-systems and maybe and again I'm not
-saying my framework is correct and yours
-isn't I'm just saying this is the way I
-think about it I would then say what are
-the molecules that I could take that
-specifically Target disease
-processes so I kind of think of like if
-we want to live
-longer and I described this I think in
-chapter 4 of outlive there's a that's a
-that turns out to be mathematically
-equivalent in the modern society to
-delaying the onset of chronic disease
-now that wasn't true 100 years ago 100
-years ago if you wanted to live longer a
-few things had to be true you couldn't
-die during childbirth and that because
-that was a huge hit on mortality um and
-then you had to not get an infection or
-succumb to trauma um and and then maybe
-150 years ago that was the case but
-today most of those things are taken
-care of by antibiotics sanitation and
-you know the modern Miracle of
-childbirth in the in in in this era so
-now for you and I to live longer we
-basically have to delay the onset of
-cardiovascular disease cerebrovascular
-disease cancer neurodegenerative disease
-dementing diseases and metabolic
-diseases we have to delay the onset of
-those things the longer we delay the
-onset the longer we will live full stop
-so you can use everything that you
-talked about in the first category plays
-into that but you also have this other
-category of where you can take molecules
-that specifically Target those things
-you can take Metformin or an sgt2
-inhibitor or a glp1 Agonist and you will
-directly impact those things you could
-take uh a pcsk9 inhibitor or a Statin or
-bidic acid you will directly impact
-those disease processes you will delay
-the onset of those diseases and you will
-reduce the mortality associated with
-them then I would go to a third category
-that says are there exogenous molecules
-that you can take that don't Target a
-disease per se specifically but we're
-going to put them in a category called
-geroprotective which is they target
-Hallmarks and Pathways of Aging that
-you've described so we talk about all of
-these things that occur in an aging
-phenotype where we see more inflammation
-we see a greater abundance of senescent
-cells we see
-reduced uh nutrient sensing capacity of
-mtor which you described as the probably
-the most important nutrient sensing
-system in our body um so so we have you
-know these somewhere between 9 and 14
-the number just keeps changing
-arbitrarily but it doesn't really matter
-we have these Central things that
-everybody would agree Define what an
-aging phenotype is and can we use
-exogenous molecules to Target those
-specifically you gave one example which
-I I would argue is the single best
-example which is rapy so rapy targets a
-very specific Hallmark of aging and we
-can talk about what the experimental
-evidence is to suggest that that makes
-you live longer so I would sort of say
-those are the big three categories and
-then basically the fourth category you
-could just say is like how do you put
-them all together and how aggressive do
-you want to be in culminating those of
-course none of this touches on another
-area that I want to talk about that we
-won't talk about today which is like how
-does all that factor into kind of
-emotional health and happiness and and
-and well-being where you know none of
-none of this other stuff matters if
-you're kind of unhappy and so so you
-have to and and you've done so many
-podcast on that topic right you've had
-Paul Con on where you kind of go through
-the understanding of ourselves and our
-minds and and why that's also a very
-important part of it because it actually
-does impact how long you live because if
-that piece isn't working it's very
-difficult to regulate the first bucket
-because the first bucket takes so much
-work so if you can't regulate yourself
-it's very difficult to regulate the the
-dos and don'ts but even absent just
-length of Life stuff it impacts quality
-of life which is this idea of Health
-span as well so I guess that's just my
-slightly different way to frame it but
-it's a little bit more mey um in that
-you know we talk about the behaviors um
-the exogenous molecules that Target
-diseases the exogenous molecules that
-Target uh aging aside from food what
-exogenous molecules do you take
-I take a few right so I take some that
-are disease specific right so I take a
-pcsk9 inhibitor I take bidic acid uh I
-take an sglt2 inhibitor um and then I
-take at least one that is purely just uh
-based on the belief of its capacity and
-Juro protection which is rrap ayin and
-um and also the SG the sglt2 inhibitor I
-think is probably just broadly
-geroprotective and we can even talk
-about that a little bit in terms of the
-success of one of those molecules called
-canaga flosin in the interventions
-testing program the ITP which I am sure
-will talk about in the context of NAD as
-well what dosage of rapamycin do you
-take I take eight milligrams once a week
-for as long as I can tolerate it but
-that I usually have to take breaks why
-is that I get these vicious apus ulcers
-uh little mouth sores canker Source
-yes about 10% of people get them hm it's
-paradoxically the only biomarker we
-probably have so I I secretly uh rejoice
-in knowing that at least I'm getting a
-good batch of rap AIS by virtue of the
-side effect by virtue of these miserable
-side effects but so so in reality what
-it works out to is I'm probably on it
-for two months and then off it for a
-month on it for two months off it for a
-month or thereabouts and the idea there
-is that you're limiting mtor you're
-causing your cells to grow less mature
-slower and and in that sense slowing
-down aging is that the idea yeah I mean
-you know and this will be an important
-theme today right it's like we can talk
-all day long about mechanisms and
-theoretical Arguments for why it would
-work and I think my conviction around
-taking Ramy is less
-about um sort of looking at the
-molecular explanation for why Rapa Works
-although I find that to be quite
-convincing and why does the inhibition
-of mtor stimulate a top Agy why would
-that suppress ccent cells but truthfully
-my conviction around mtor is far more
-based on the experimental data um
-something that is actually sorely
-lacking in the NAD story which we'll
-discuss so the experimental data are far
-more convincing right which is when you
-look at the administration of Ramy or
-its analoges for example ever alus um
-when you look at the administration of
-these molecules to organisms that are as
-close as possible to the species of
-Interest we the species of interest um
-so looking at mammals such as um mice um
-and small primates um looking at fruit
-flies looking at worms and even looking
-at yeast although that's so far from us
-that you would argue that's the least
-important um you see something that you
-don't see for a single other molecule
-which is uniform life
-extension no other molecule has done
-this it's very important to understand
-there are only two interventions full
-stop that have ever extended life across
-those four categories of UK chariots
-caloric restriction and rap
-ay very important point right how do you
-feel when you're on rap ayon aside from
-the canker Source yeah which fortunately
-aren't that frequent you I I don't feel
-anything and the very few of my patients
-who take it because I I maybe 10% of my
-patients also take it um I've never
-heard actually that's not true I've
-probably heard two people say they feel
-better on it but you know I don't know
-what to make of that maybe they do um
-and maybe that's just a placebo effect
-does it synergize with caloric
-restriction or collide with caloric
-excess meaning if you're taking
-rapamycin but you're slightly over your
-caloric needs maybe you're trying to add
-a little bit of body weight or happen to
-overeat a little bit just because is it
-going to collide with rapamycin's
-potential positive impact on slowing
-aging yeah it's a good question Andrew I
-don't I don't know I don't think we know
-uh we do know that there's one other
-really important readout we're waiting
-for which is um Matt cabin's dog aging
-study um which uh is is is going to be
-an exciting readout in
-2026 um we're also waiting for another
-readout out of the University of San
-Antonio looking at another um another
-trial in mammals and again I think those
-two will be really interesting right um
-because we have a ton of we have just an
-overabundance of mouse data that are so
-reproducible and reproducible in really
-good Mouse models um you know as you
-know I'm sure from your work um the
-model you choose matters right and and
-sort of you you you know in an Ideal
-World you want to use a mouse model that
-is um you know not inbred that is more
-closely related to the what we care
-about which is ourselves and and so when
-you see many Labs getting the same
-result over and over again regardless of
-how they do it you you really start to
-believe there's a signal there so now to
-be able to see this in a higher order
-mammal um and ultimately in companion
-dogs which is where Matt cabin is
-looking I think that's that's going to
-be really exciting and I've often said
-to my patients look in 2026 I'm either
-going to feel a lot more conviction
-about taking rapy and and prescribing it
-to some of my patients though again not
-most or I'm going to you know have a
-second look at this and say you know
-maybe maybe we just shouldn't be taking
-this right because I do think that the
-dogs study is going to be more telling
-um but again we'll have to wait and see
-what that shows without going off track
-too much my understanding is that the
-dog study was halted because of a lack
-of federal funding um is it continuing
-it is going to go on there's there's
-yeah it's so so initially there was kind
-of insufficient funding to do the study
-in an adequate way um and then it turned
-out there was a shortfall of about $2.5
-million um to do the the study that
-really wanted to do and then actually a
-group of us raised that money for Matt
-and did that so great uh me and a so few
-of my patients and a couple of other
-folks came together and put the money in
-to close the gap but yes there has been
-um what's what what did get pulled back
-by the NIH inexplicably and
-um in my view totally incorrectly was
-the ongoing surveillance program the
-funding for the ongoing surveillance
-program that would allow this type of
-work to continue and to allow greater
-followup on this so yes unfortunately um
-until we can get more funding we're
-we're we're not going to be able to
-maybe do as much as we'd like to do and
-understand this which again when you
-look at some of the things that are
-funded it's hard to believe that there's
-not a more interesting question right
-now in biology than this drug that seems
-so promising why we wouldn't want to
-know you know if this is something we
-should all be taking is is kind of a
-mystery to me yeah I was on ni study
-sections for many years reviewing grants
-I rotated off as a regular member a
-little over a year ago and I can tell
-you that the whole process is designed
-to be as um targeted to the best and
-most exciting work possible but there's
-a number of features now that make it
-such that it's largely the work that's
-already mostly completed that gets
-funded you even go like how's that work
-but anyway we could have a whole other
-Journal Club discussion about funding
-but I I had to ask I was curious hope
-hopefully that um uh that study will get
-completed and thanks for raising those
-funds let's talk about NAD yes it's in
-essentially every cell of the body
-except red blood cells correct you know
-I I don't even know if it's in red blood
-cells my intuition is I I I've never
-looked to be honest with you but given
-that red blood cells um have a different
-metabolic pathway right where they're
-purely glycolytic I don't they wouldn't
-have the need for it in the way that
-others would but they might right
-because they still undergo Redux
-potential so it's possible NAD is in
-every single cell yeah and it's
-generally thought to be associated with
-energy production and mitochondrial
-Pathways in every single cell right so
-NAD is again one of the most ubiquitous
-molecules in the body and most of what
-it
-does and I mean most meaning like
-somewhere between five and 600 Pathways
-of it utilize NAD as a
-co-actor meaning that it's not consumed
-in a chemical reaction but rather it
-serves as an electron shutle
-so NAD and nadh basically play catch
-with electrons and that's 99% of what
-NAD is doing in the body and for that
-reason NAD is so tightly regulated in
-the body the levels of NAD in the cell
-are really tightly regulated and that
-shouldn't be surprising just as glucose
-really tightly regulated pH or hydrogen
-ion concentration
-really tightly regulated we as a species
-cannot survive outside of a very narrow
-band of uh pH right if it's below seven
-or above 7.8 on a 0 to 14 scale we die
-full stop um so similarly NAD is managed
-across all ages and across all
-physiologic uh uh uh conditions in a
-super tight band there's another place
-where NAD shows up and that shows up as
-a substrate right so co-actor means used
-co-enzyme used but not consumed recycled
-that's 99% of it a small fraction of it
-is used and it's used by these things
-called cerin that consume NAD as an
-actual substrate in the process of DNA
-repair and maybe we can go into this but
-this is really where the story picks up
-it's also as I recall where the story
-began that's exactly it was some
-experiments where the cerin were mutated
-in One Direction or the other meaning
-gain of function or loss of function
-these days people hear gain of function
-and they immediately think to pandemic
-related themes but gain of function is a
-way of changing genes typically to um
-augment a function increase its
-robustness or in some cases to rescue a
-phena type where you have a knockout
-mouse that lacks a gene so that's loss
-of function or a Trin of yeast that
-lacks a gene and then you do the gain of
-function rescue experiment you re
-reintroduce the the gene of interest um
-it's an important I wouldn't even call
-it a control it's an important
-experiment in any case because loss of
-function will tell you a lot y um but
-gain of function and loss of function
-assuming that the results J uh tells you
-much much more this is one of the major
-areas I think this is very important to
-highlight where human genetics really
-struggles because you can get humans
-with a mutation in a particular pathway
-like I don't know the Sonic Hedgehog
-pathway there somebody is hypomorphic
-for Sonic Hedgehog and you know they
-might actually lack a a major tooth up
-in the middle because the role of Sonic
-hedgehog at the midline and you could
-say okay well loss of function here
-here's the role of Sonic Hedgehog but
-the ideal experiment is to put the gene
-back in and then rescue that phenotype
-because as any logical mind can tell
-there could be many things Downstream of
-Sonic Hedgehog
-that could create the phenotype that you
-observe but if you put Sonic Hedgehog
-back in yes that's still true but you
-get more reassurance that that's the
-gene of Interest so with respect to
-cerin as I recall they deleted the
-cerin let's use another example of what
-the gold standard is here or what a
-great example is so so I recently did a
-podcast with Dina dubal from UCSF on
-clotho which is an amazing scientific
-story and it's a great story because it
-shows how accidents can lead to great
-discoveries right so there was a a
-researcher in Japan who was really
-interested in understanding hypertension
-high blood pressure and they had created
-a mouse model where they were trying to
-knock out certain sodium channels to see
-if they could perturb blood pressure and
-then there was this one strain of mouse
-with this one knockout that died really
-really quickly and it developed like
-devastating neurogen disease and died
-very quickly and you know like a good
-scientist he didn't say well that sucks
-I'm going to discard that one CU it
-didn't give me what I wanted which was
-the blood pressure change and he kind of
-went and figured out what was going on
-and he figured out that there was a
-certain Gene that he had hit that wasn't
-a sodium transporter and instead was
-this other Gene he named it clotho so so
-you had this one piece of evidence right
-now which was if you knock out that Gene
-you kill an animal very quickly now that
-doesn't mean it's a longevity Gene you
-have to do the other experiment to your
-point you have to overexpress that Gene
-and ask the question do you live longer
-and sure enough when they overexpressed
-that same gene that they had just
-knocked out and killed the mouse the
-thing was living 15 to 20% longer so
-it's both necessary and sufficient for
-extended how you can say well that's a
-longevity Gene as many of you know I've
-been taking ag1 for more than 10 years
-now so I'm delighted that they're
-sponsoring this podcast to be clear I
-don't take ag1 because they're a sponsor
-rather they are a sponsor because I take
-ag1 in fact I take ag1 once and often
-twice every single day and I've done
-that since starting way back in
-2012 there is so much conflicting
-information out there nowadays about
-what proper new nutrition is but here's
-what there seems to be a general
-consensus on whether you're an omnivore
-a carnivore a vegetarian or a vegan I
-think it's generally agreed that you
-should get most of your food from
-unprocessed or minimally processed
-sources which allows you to eat enough
-but not overeat get plenty of vitamins
-and minerals probiotics and
-micronutrients that we all need for
-physical and mental health now I
-personally am an omnivore and I strive
-to get most of my food from unprocessed
-or minimally processed sources but the
-reason I still take AG one once and
-often twice every day is that it ensures
-I get all of those vitamins minerals
-probiotics Etc but it also has
-adaptogens to help me cope with stress
-it's basically a nutritional insurance
-policy meant to augment not replace
-quality food so by drinking a serving of
-ag1 in the morning and again in the
-afternoon or evening I cover all of my
-foundational nutritional needs and I
-like so many other people that take ag1
-report feeling much better in a number
-of important ways such as energy levels
-digestion sleep and more
-so while many supplements out there are
-really directed towards obtaining one
-specific outcome ag1 is foundational
-nutrition designed to support all
-aspects of well-being related to mental
-health and physical health if you'd like
-to try ag1 you can go to drink a1.com
-huberman to claim a special offer
-they'll give you five free travel packs
-with your order plus a year supply of
-vitamin D3 K2 again that's drink a1.com
-huberman so let's go to the ceran story
-so it goes back to the late 90s Matt
-cllin again this is amazing right so you
-have this guy who's like the leading
-Authority or one of the leading
-authorities on the on the work going on
-today with Rapa and along with one of
-his colleagues David satini and a few
-others um but when when Matt was a post
-dog he did an experiment in a strain of
-mice uh pardon me a strain of yeast I
-think it was a w303 strain of yeast and
-he overexpressed sir
-two um and lo and behold the yeast lived
-longer now a year later someone else in
-the same lab took a different strain of
-yeast and calorically restricted them
-and they also lived
-longer um I forget the name of that I
-forget what that strain was it was
-something 316 was it but it was a
-different strain of yeast at that moment
-again this is about 25 years ago a
-hypothesis emerged which was we have two
-different strains of
-yeast and in one of them when you
-overexpress sir 2 this gene they live
-longer and in this other strain if you
-calorically restrict them they live
-longer the understandable hypothesis was
-caloric restriction which we had known
-was life extending is working through
-cerin that hypothesis sort of fell apart
-about four years later when Matt cabin
-again this time with Brian Kennedy did
-another experiment in a
-yet a third strain of yeast that allowed
-them to test hypothesis because there
-was a problem with the story I just told
-when you took the 303 strain this is the
-strain that when overexpressing sir two
-lived longer if you took that strain and
-you calorically calorically restricted
-them no change that's odd even more odd
-is when you took the 316 strain and this
-is the strain that lived longer with CR
-if if you overexpress sir to no change
-so right off the bat the story didn't
-make sense but it was further solidified
-that that story didn't make sense when
-Brian and Matt published in 2004 in yet
-a different strain God I'm blanking on
-the name it's like uh B
-by4742 like you know these don't matter
-if you calorically restricted them they
-lived longer if you overexpress sir two
-they lived longer if you did both they
-lived even longer it was additive again
-further suggesting that overexpression
-of sir2 and caloric restriction
-independently and separately extended
-lifespan these are parallel Pathways
-they're parallel
-Pathways for reasons that honestly
-Escape me Andrew there are still people
-who maintain that the benefit of ceran
-overexpression is through the caloric
-restriction pathway and vice versa and
-that's wrong
-my reading of the literature in addition
-to every person I have talked to on this
-who works in the space including Matt
-cin who has done the most research on
-this is that there is no evidence that
-caloric restriction and cerin operate
-through the same pathway and in that
-sense I think there's there's relatively
-uniform agreement that caloric
-restriction extends life across the
-model systems we discussed what about in
-humans what what about it specifically
-that experiment's never been done and
-never will be done the joke I was trying
-to set up for is the one I'll make now
-which is no one wants to be in the
-control experiment um that said nobody
-want want treatment experiment either
-you got me you got me you beat me to the
-punch uh no one wants to be in the
-treatment group either because it
-requires eating so little yeah you know
-it just the the yeah the joke is the
-joke is you probably will live longer
-and it will feel even worse like it's
-just it's yeah caloric restriction which
-by the way there are real debates about
-whether it will extend life in humans
-because it will clearly I shouldn't say
-clearly I think it would be a very safe
-bet that severe caloric restriction will
-absolutely reduce the risk of most
-chronic diseases meaning I I have I
-think there's very good reason to
-believe that if an individual
-constitutively consumed 25% fewer
-calories than they were meant to eat
-their risk of cardiovascular disease
-cancer Alzheimer's disease would go down
-the problem is what things go up what
-does that do to your immune system what
-does that do with respect to sarcopenia
-what does that do to your risk of
-falling fra yeah exactly so you trade
-one set of diseases for another it's not
-at all clear that lifespan goes up and
-by the way when you even look at some of
-the wild um uh like some of the animal
-literature where they're using different
-strains of mice that are not inbred and
-they don't put them in hermetically
-sealed uh situations they don't live
-longer so it's not always the case that
-caloric restriction extends life and
-therefore well um it's safe to say
-caloric restriction probably reduces the
-onset of chronic disease that might not
-translate to an all cause mortality
-benefit based on those downsides but all
-of that said I think the holster in
-story got off to an incorrect start
-where it basically lopped on to the CR
-story which was hey we've got this thing
-CR that we've known since restrict right
-clor restri we've got this thing which
-you know for 50 years we've known has a
-signal that really says it's life
-extending and we've got this yeast where
-it works and this other yeast where
-ceran activation works oh it's got to be
-St but again if you if you go through
-the story in detail as I just did
-there's no evidence whatsoever that
-cerin have anything to do with chloric
-restriction and vice
-versa it's incredibly interesting
-because I think when you look at cell
-biology and you see these parallel
-pathways when you see these effects of
-experiments where changing cerin or
-changing caloric restriction
-independently increased lifespan combine
-the two you get this what appears to be
-a synergistic effect but it's as you
-pointed out an additive effect seems
-like a pretty straightforward experiment
-to do you could just do an occlusion
-right you could then put back in the
-cerin OR adjust calories and see whether
-or not you get the effectively whether
-the math is corrected yeah you know so
-um now none of this gets to the question
-you raised yet that's just all that's
-all prologue right that's like where did
-this story come up but then the question
-becomes well if you believe that cerin
-are truly um a factor that drives
-longevity how can you activate them
-right how do you activate a ceran so we
-have to now simultaneously start to hold
-things true in parallel that may or may
-not be true so we we we want to then ask
-the question do we believe that what we
-saw in yeast which I think is the only
-reproducible finding I can draw meaning
-this is a reproducible finding in many
-but not all strains of yeast if you
-overexpress sirtuins the yeast will live
-longer so let's park that in the parking
-lot as a very likely
-statement you would then say well if it
-does it in yeast does it do it in flies
-does it do it in worms does it do it in
-mammals you you want to be able to check
-those three boxes because again that's a
-billion years of evolution so if
-something works across a billion years
-we' be much more confident it works in
-US yeah making a fly mutant dropa mutant
-that overexpresses cin a worm cigance
-mutant that overexpresses cins that's a
-pretty quick experiment to do because of
-this short generation time of those
-species right now Mouse it's a longer
-experiment but I'm guessing all of those
-experiments have been done yeah and the
-only one that I can find that has
-demonstrated a survival Advantage is one
-particular transgenic Mouse experiment
-that
-overexpressed uh CT
-6 and it did indeed for the male mice
-increase lifespan by 10 to 15% so this
-is one transgenic Mouse model that
-overexpressed CER six and those mice the
-male mice lived 10 to 15% longer the
-female mice did not we should probably
-clarify what a transgenic Mouse is I
-talked about knockout mice that's when a
-gene or genes in some cases is deleted
-from The genome so it's null it does not
-express that Gene the gain of function
-would be to put back that Gene in that
-would be a Knockin Mouse so in that case
-you still get some normal expression of
-the gene from the endogenous genome but
-now you have a trans Gene that's
-inserted there and there are all sorts
-of important intricacies that relate to
-for instance where the trans Gene is
-inserted if it's you know Downstream of
-of an enhancer that's muscle specific
-then you can get a mouse that it
-overexpresses C to in just in muscle you
-can get it ubiquitously expressed there
-are a number of different ways that this
-can happen I'm assuming this was
-ubiquitous expression of you said CER
-six CT six yeah so every cell in the
-body that normally would Express C six
-would Express more I don't remember
-Andrew to be honest with you I'd have to
-go back and look at the paper I don't
-know if it was muscle specific or whole
-body specific
-I'm guessing unless they made it clear
-that it was tissue specific that it's
-whole body so we're talking about it
-when Peter says transgenic Mouse he's
-talking about a mouse that has this
-trans Gene that causes it to express
-more cer2 in6 than it ordinarily would
-and let's assume although we don't know
-this for sure that the other genes in
-this mouse are functioning as they would
-normally right so again just a summarize
-that that's 2012 we have this one
-transgenic Mouse you put CT six you over
-Express search six and all of a sudden
-the males were living 10% longer again
-to be clear the females didn't
-experience a difference um and that's
-not uncommon or unheard of in longevity
-research there generally are sex
-specific differences and you always have
-to read the fine print the first thing I
-always look at in a study when I see a
-difference in Sexes or frankly any
-difference in longevity but it's always
-great when they parse them out by Sexes
-is how long did the controls live but I
-went back and actually looked at the
-Kaplan Meyer curves on that exact study
-and yes indeed I think that's a real
-effect um so let's take stock of now two
-pieces of information that I think we
-could say is probably true it is
-probably true that in a handful of
-strains of yeast if you overexpress CT
-you are going to live longer that tends
-to be completely independent of caloric
-restriction that's the single thing I
-can say with the greatest confidence and
-there is at least one trans genic strain
-of mice that if you get it to
-overexpress a different C CT six but
-again they're these are homologues
-throughout the species so we don't have
-to get I don't think we need to get
-wrapped up in CT 2 versus C six um you
-will at least make the male mice live
-longer but not the females what sorts of
-things are Downstream of cerin and that
-question translated to normal English is
-what is changing as a consequence of
-increasing the cerin could it be for
-instance well unlikely based on what we
-already know about caloric restriction
-and the fact that they are independent
-parallel Pathways but is it something
-related to glucose metabolism is it
-something related to um clearance of
-senent cells I I'm just throwing out
-possibilities actually you've hit two of
-the big three right off the top right so
-we believe that when cerin are activated
-they're improving mitochondrial
-biogenesis um they are um uh in
-increasing DNA repair so that's probably
-the biggest one by the way that's sort
-of what brings us to um um the um the
-NAD story um and also reducing uh sasps
-right so the soluble products of
-senescent cells so so Tamp so in other
-words those are all three good things
-right so you Tamp down on siness and
-cells uh you increase mitochondrial
-biogenesis and you increase DNA repair
-those would be all great things to do
-and we think that Sans are probably
-doing all of
-them this business of DNA repair and
-reducing
-um you know fragmentation or mutations
-to DNA that are naturally occurring has
-been a hot idea in the field of Aging
-for a long time is that because when
-x-rays became popular or um post nuclear
-fallout that people showed accelerated
-signs of aging I mean how did we get
-from DNA mutation to accelerated aging
-like well I mean I think we we know that
-as we age it's just a stochastic process
-right like given the ubiquity of DNA
-replication and the Fidelity of the
-system which is high very high but not
-perfect there's going to be mistakes um
-actually this is an interesting question
-so in 2016 I went to Easter Island with
-David sabatini and nav chandelle and Tim
-Ferris so the four of us just took a
-trip to Easter Island to see the
-birthplace of Rapa so it's kind of like
-vacation SL science Journey a nerdy
-vacation it was awesome and um you know
-so just picture hiking around this
-incredible Island just talking about
-science all day but this was an
-interesting question that I posed to nav
-and to David which was why do we see
-such a clear and present association
-with cancer uh as we age and why is it
-so nonlinear so it's not just that
-cancer goes up with age it goes up like
-that um and I said I'll offer two
-hypotheses which is more compelling is
-it simply that as we're aging uh DNA
-replication again taking a step back for
-the listener uh cancer is a genetic
-disease meaning uh by
-definition it is uh sort of the
-canonical problem with cancer is a
-genetic mutation that leads to two
-properties of a cell the inability the
-cell to uh rep uh to control replication
-so it interrupts cell signaling so cell
-replicate but then don't know when to
-stop and then the introduction of the
-capacity to spread this property called
-metastasis those are the two Hallmarks
-of cancer so so we know that that only
-happens in the context of genetic
-mutations but why does this happen later
-in life and not at the beginning of Life
-with very few exceptions and and so the
-question is is it because over time
-mutations compound is it because there
-are more mutations as we age or is there
-a third issue which is um all of those
-things are happening normally and
-they're no more abundant when you're 80
-than when you're 20 but your immune
-system can't detect them as well and the
-truth of it is we didn't come up with an
-answer but it's probably all of the
-above so it's probably that as we are
-aging we are undergoing more DNA damage
-and um or at a minimum the DNA damage
-we're undergoing is less amenable to
-repair and that's part of the thesis
-here part of the thesis here is as we're
-aging we are less and less able to to
-repair
-DNA and one of the arguments that put
-forth although we have we're not quite
-ready for this part of the story yet but
-I'll just say it now and we'll come back
-to it is we don't have enough of the
-substrate that the ceran needs to repair
-DNA and that substrate is NAD so again
-remember the outside I said like there's
-two big categories to think about NAD
-most of what NAD is doing is operating
-as a co-actor for electron shuttling
-that's the NAD nadh electron transport
-electron accept blah blah blah blah blah
-okay not consuming NAD just using it to
-pass electrons back and forth but then
-over here we have this other category
-where we use NAD as a substrate it gets
-broken down and that's what the cerin
-are doing to repair DNA okay so if
-that's true and if NAD levels are
-declining with age it's a logical
-conclusion that should we give more NAD
-right if you're running out a substrate
-to repair DNA and DNA repair is an
-important way to thwart a
-it all makes sense so we'll keep that
-over there but before we do I want to
-come back to one other story which is
-the story of ceru and activators so
-what's the most famous ceran activator
-of all time what is the heavyweight
-champion of ceran activators that has
-taken up 99% of the bandwidth in this
-space it's a lovely little chemical
-called RIS veratrol okay so
-Resveratrol which gained a lot of Fame
-and notoriety because it happens to be
-found in Trace element elements in the
-uh skin of grapes and therefore shows up
-in wine uh gained a lot of notoriety
-about 20 years ago when one lab doing
-one experiment somehow was able to
-convince some people including uh a very
-large Pharma company that RIS veratrol
-increased
-lifespan so the thesis was RIS veratrol
-activates
-cerin cerin activation is important
-because of all the things we just said
-right it improves mitochondrial
-biogenesis it suppresses ccent cells and
-it and enhances DNA repair so if you
-have something that is such a potent
-activator of cerin and you give it to a
-mouse that Mouse should live longer now
-lots of experiments were done that
-couldn't find that but one experiment
-was done but it was a it was an
-interesting experiment I've discussed
-this at least on two podcasts including
-one with Rich Miller who runs the ITP
-the interventions testing program which
-later tested ratol and found that it did
-uh categorically nothing in this one
-experiment that worked the investigators
-took a bizarre Mouse model where they
-force fed it uh an enormously high-fat
-diet and in doing so they created such
-an abundance of fatty liver that the
-livers of these mice um uh encroached
-the chest the thoracic cavity of the
-mice so the mouse died
-prematurely because they couldn't
-breathe and in that particular Mouse
-model RIS veratrol rescued the
-mice so again let's just assume that all
-of that is correct and it's possible
-that there were even errors there but
-let's just assume that's correct let's
-assume so this is resveratol delivered
-orally yes in the food yes very high
-doses Mega doses the equivalent of
-barrels of grape exactly like doses so
-high you could there you know if you
-recall we're both of an age that's old
-enough to remember this there was this
-period of time when people thought this
-was the explanation to the French
-paradox right why on average do the
-French live longer when they consume so
-much wine and the answer was it's got to
-be the ratol turns out that's not true
-at all because yeah you would need to be
-drinking your body weight and wine a day
-to get the doses of RIS veratrol that
-were needed to produce this effect but
-for whatever reason there was an effect
-which is if the thing that was going to
-kill you was your liver being so full of
-fat that
-it shot up into your chest so you
-couldn't breathe um which I've never
-seen a human no matter how bad their
-fatty liver has been where that's been
-the case but if that's if that's the
-problem you're going to face it's
-possible at least based on this one
-Mouse experiment that you were going to
-live longer but again it turned out that
-there was no other replication of this
-in Mouse models that matter and that
-always comes back to the ITP the
-intervention testing program which is
-the most robust tool we have
-scientifically to measure these
-exogenous molecules so the ITP is an ni
-funded program that runs out of three
-independent labs and by independent I
-mean they're each doing the experiments
-independently but they're they're in
-sync with doing the experiment but
-they're doing it in triplicate so you
-have three Labs three great Labs doing
-the experiments in
-triplicate and um when they did the RIS
-veratrol experiment and they did it in
-combination with the people who found
-the result of that study so they
-consulted these people and said what
-dose should we give and they said do
-this do this do this and they did it and
-nothing there was no effective RIS
-veratrol and that result has been
-consistent across the board so that's
-also a very important part of the story
-which
-was if RIS veratrol was a ceru an
-activator and I don't know if it really
-is it clearly has no effect on lifespan
-with the one little asterisk that says
-unless your body weight is 50% fatty
-liver then maybe it does I'd like to
-take a quick break to let you know that
-the huberman lab team has launched a new
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-such as how to build muscle and strength
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-it out and give it a subscribe wherever
-you're watching or listening to podcasts
-now again the podcast is called perform
-with Dr Andy Galpin so let's see let's
-just take stock of where we are in the
-story we got the whole yeast ceran
-situation which is at least in some East
-ceru an overexpression lives longer no
-evidence that that works through caloric
-restriction truly no evidence that's
-been known for 20 years now that paper
-was published in 2004 and that was a
-follow-up to papers that had been
-published in 2002 20 1999 Etc um you
-later on you'd have the 2012 transgenic
-Mouse
-study
-um so now the question is okay how do
-you activate certu how do you activate
-well well yeah so so so or or more to
-the point why don't we just give people
-NAD okay so the again the NAD story is
-NAD levels are declining with age in
-most tissues um it appears most
-prevalent in the skin of all places and
-I think we should come back to this
-because there's one interesting finding
-associated with augmenting NAD levels in
-the skin and my thought is I wonder if
-it has to do with the fact that skin
-experiences the greatest decline in NAD
-it's also interesting because catino
-sites in skin turn over every 28 days or
-so so you could imagine because it's a
-novel population of cells that they
-would have steady expression of cerin
-and NAD then they simply die for
-whatever reason or that it starts off
-very high on day one of generation then
-tapers off quickly but that's not the
-case it sounds like
-yeah you know on average skin over the
-course of your lifetime will see about a
-60% reduction in NAD whereas other
-tissues and this is now based on you
-know animal studies the brain might see
-a reduction by 15 to 20% and the same
-would be found even in humans looking at
-the blood so if you just sample you know
-uh whole blood in people at the age of
-20 30 40 50 60 70 80 you're going to see
-about a 20% reduction in NAD what about
-neurons I mean you've got the same set
-of central nervous system neurons your
-entire life and of course some
-peripheral neurons as well but there's
-some regeneration in the periphery so we
-need to let's just talk about brain so
-unless you're talking about the old
-factory bulb where you have constant
-turnover throughout the lifespan you
-have the same hippocampal neurons except
-a small population same hipocampal
-neurons cortical neurons retinal neurons
-that you were born with are we observing
-NAD levels tapering off as we in animals
-yes obviously in humans we're not doing
-that experiment but
-yeah now here's an interesting point in
-2015 a study was published in pnas that
-looked at NAD levels in whole blood over
-time and it found indeed NAD levels were
-going down about 10 to 20% over four
-decades or so but that same study said
-nadh levels were going up by the same
-amount explain the role of nadh for
-people nadh is the um electron acceptor
-so when you when you the so let's maybe
-take a step back like
-what how do we why are you and I sitting
-here talking and not dead like because
-we have enough NAD right right what's
-going on right so right you and I ate
-something at some point in the
-foreseeable past that contained chemical
-energy so we ate something that was
-organic so it had um so primarily fats
-and carbohydrates contain carbon carbon
-bonds and carbon hydrogen bonds and
-those bonds contain a ton of energy but
-how do we liberate energy so we break it
-all down into these constitutive
-molecules namely glucose on the
-carbohydrate front and free fatty acids
-on the fat front and then our bodies
-break those things down further into
-smaller molecules that get shuttled into
-the mitochondria where the Lion's Share
-of our energy Liberation comes from and
-what we do is we take that chemical
-energy that is stored in a carbon to
-carbon Bond or a carbon to hydrogen bond
-and we turn it into elect electrical
-energy and people have heard this term
-it's called the electron transport chain
-so there are these four complexes in the
-mitochondria and there's an inner
-membrane in an outer membrane across
-which these mitochondrial uh uh these
-large mitochondrial complexes reside and
-what they're doing is they're building
-up a huge electron gradient by by
-breaking them apart and taking the
-electrons and transferring them between
-NAD and nadh so that at the end they can
-do another trick which is transfer those
-electrons to M ADP and ultimately make
-ATP the finished product is water and
-carbon dioxide so we eat and we take
-that chemical energy and food we utilize
-oxygen in the mitochondria to make
-ATP carbon dioxide which we breathe out
-and water which we breathe and pee out
-so what NAD and nadh are doing is
-playing an absolutely essential to life
-role in facilitating the transfer of
-chemical energy to electrical energy
-back to chemical energy ATP is just
-taking it from one chemical form in food
-to the electrical form as the
-intermediary in the mitochondria back to
-an electrical form of ATP so you and I
-are walking around flush with ATP which
-as we sit here right now we're
-constantly firing off phosphates again
-now turning the chemical energy back
-into electrical energy and away we go so
-yeah this this whole NAD nadh thing is
-like you know it's as Central to our
-existence as any form of respiration so
-my point let's go back to the story the
-story was NAD levels are going down as
-we age but nadh levels are going up
-suggesting that the total amount of NAD
-and nadh is the same and what's
-declining as we age should less be
-thought of as a reduction in NAD and
-should more be thought of as a reduction
-in what's called Redux potential the
-ability to do what I just said so when
-people say NAD levels decline with aging
-the answer is yeah but what's really
-declining as we age and this kind of
-comes back to what you said at the very
-very outset like what's happening at the
-cellular level I think what's happening
-is our mitochondria are not as good as
-we age and we have less Redux potential
-and I would say a fair number of
-so-called anti-aging approaches are
-targeting the so-called reactive oxygen
-species Ross's which impede
-mitochondrial function essentially
-uh this is an opportunity for me to call
-out the work that I think is at least
-intriguing which is uh the work of a
-colleague by the name of Glenn Jeffrey
-at the University of College London he's
-been in the field of visual Neuroscience
-for a very long time and a few years
-back he started doing some experiments
-on animals and now also two studies
-published on humans showing that
-exposing the Aged eye so 40 and older to
-red light and near infrared light for a
-couple minutes a few times a week
-can spare
-certain processes involved in Vision
-photo receptors how does this work well
-the idea this isn't proven yet the idea
-is that it's reducing reactive oxygen
-species and thereby improving
-mitochondrial function in what is
-perhaps the most metabolically active
-cell type in the entire body not just
-the eye which are the photo receptors so
-it's an intriguing set of studies again
-we don't have all the mechanisms worked
-out but it brings us around again to
-this idea that mitochondria are vitally
-important for the functioning of cells
-things that impede the function of
-mitochondria can either reduce the
-output of Andor kill cells and so
-anything that can improve
-Redux can potentially keep a cell around
-longer functioning better so when I hear
-about the role of NAD in this pathway I
-think like most people I think okay well
-then I should just take more anad and
-maybe I will age more slowly or I will
-replace some NAD that's missing as I age
-in whatever cell type turns out that
-might not be so straightforward right I
-mean I don't want to jump to
-supplementation just yet but if we are
-to back up from NAD a little bit and
-look at the pathway leading to NAD it's
-NR nmn and NAD we'll spell these out in
-a moment and the sort of competition
-that's out there in the market is around
-either infusing or in some cases
-ingesting NAD
-directly taking nmn which is the
-precursor to NAD orally I haven't heard
-of anybody infusing it or taking oral
-form NR which is the precursor to nmn my
-understanding is that nmn is simply NR
-minus a phosphate group yeah and and
-I'll take a step back from this first to
-say the following again let because this
-topic is so confusing I think it's just
-worth reminding everybody of what we now
-everything we've said and where it
-brings us right so I'm not going to
-repeat the whole ceran thing let's just
-leave that alone because everything
-we're on right now is Upstream of cin
-yeah it's basically like once you
-establish that we think cerin matter
-even though they don't work through
-caloric restriction and that's about the
-single most obvious thing I can say they
-might still matter even though we don't
-have things that we figured out can
-activate cerin like RIS veratrol we
-don't seem to have things that we can
-give you that activate cerin we're now
-on to the next part of the story which
-is okay cerin matter they don't seem to
-matter we think cin matter because of a
-few of these overexpression experiments
-um and we're making a big leap that
-because they mattered in yeast they're
-going to matter in us that's a huge leap
-for which there's zero evidence right
-and I'm only leaping further to this
-discussion about how to increase NAD
-because I know that's in the back of
-people's minds we're not we're not going
-to double click here just yet I just
-want to frame that up because ultimately
-ultimately that's where we are headed in
-terms of people making decisions as to
-whether or not they should take NR or
-take nmn NAD or none of the above and
-the reason I'm being such a hard ass
-about this Andrew is I spend so much
-time Fielding questions on this that I
-realize we just have to talk about this
-and excor it just in the most detailed
-fashion possible so that people
-understand why because it is just too
-easy right there's this great quote by
-JFK that I'm going to paraphrase that is
-basically people Ure you know enjoy the
-comfort of opinion without the
-discomfort of thought right so we need
-to sort of this is this is a podcast to
-get people to think and understand the
-entire history of this field so that
-they can actually make an informed
-decision about a supplement that I'm
-going to argue has very little
-scientific basis for its justification I
-I would say scientific justification for
-longevity I'll I'll go on record now
-saying that I take nmn and in some cases
-I will take NR and nmn and I observe
-this is just n of one self-
-observational data I observe a very
-clear positive effect but I don't think
-it has anything to do with extending
-lifespan and and we should talk about
-both Health span and lifespan benefits
-when we get to that part but we're so to
-bring us up to where we are now where
-you are with should people be
-supplementing NAD we're we're basically
-at the point where we're taking a lot of
-leaps of faith and saying because NAD
-levels are going down and Redux
-potential is going down we believe
-supplementing NAD in one form or another
-makes sense but before we do that we
-should acknowledge something yes NAD
-levels are going down but we have no
-reason to believe that raising NAD
-levels will correct a problem in other
-words if the body operates between this
-level and this level of NAD and if you
-go below this level you die and you go
-above this level you die and levels as
-you age go like this do we believe that
-raising them to this does anything we
-have there's no evidence that says it
-does so that's a leap of faith it's okay
-to take leaps of Faith you just have to
-know you're taking a leap of faith okay
-so leap of faith number one is
-the ceran thing leap of faith number two
-is the ceric Restriction thing leap of
-faith number three is this matters in
-our species the species of Interest leap
-of faith four is you know the whole uh
-ceran activator thing and now this leap
-of faith is if we just increase NAD
-levels in us it will produce a positive
-benefit okay so now how do how do we how
-do we do that now you get into the
-tactic okay there were three ways to do
-it as you said um one is you can
-intravenously take NAD by the way you
-could probably also orally take NAD it
-would just break down in the gut into
-its constitutive products um and then
-probably reform but for the purpose of
-how people actually do this they
-intravenously get NAD because it's not
-orally bioavailable or as you said they
-orally take two precursors NR and
-nmn my personal view on this is there's
-not really much of a difference in what
-you do in other words at the end of the
-day all of these things are generally
-going to increase NAD levels in the
-blood so a couple of um kind of
-practical notes I've taken NR in capsule
-form I've taken nmn typically in
-powdered form where I put it
-sublingually under the tongue my
-understanding is that have you done
-intravenous NAD I sure have and um and
-did you experience nasin flush no I I
-took NAD in a um as an infusion I
-probably done it five or six times and
-for the first 10 minutes of the infusion
-you feel like somebody stepping on your
-chest with a boot your legs cramp up you
-feel nauseous I did not take the
-anti-nausea Med that was offered I don't
-like taking things if I can avoid it I
-just figured I'll just experience this
-it was very uncomfortable MH to the
-point where you couldn't read a paper or
-a book you just you just want to be left
-alone you actually get a little bit
-irritable you're like this is awful you
-know every noise in the room is a bit
-too loud during that first 10 minutes
-and then by the way do you know how many
-people have said to me that because of
-that experience they know it must be
-doing something good oh my goodness to
-to which I'm like why don't you spread
-your legs let me kick you right in the
-nuts that's going to feel even worse is
-that doing something good like the fact
-that something feels so awful shouldn't
-be used as an explanation for why it's
-doing good physiologically right I don't
-know what it was doing physiologically
-except making me feel miserable during
-the infusion there are ways to adjust
-this even without the anti nausea meds
-for instance you can slow the
-infusion um that's the typical way
-people will put it in over the course of
-several hours anywhere from 3 hours to
-as brief as 30 minutes is kind of the
-record that I've heard about for 500
-milligrams of NAD if you put 1,000
-milligrams in there obviously it's more
-painful and you have to anyway there are
-a bunch of practical
-considerations you feel now maybe it's
-Placebo but one feels quite good
-afterward so as soon as the drip is done
-you feel better than you did prior to
-the drip how do you feel if you just
-receive an IV infusion of the same
-volume I've done that because I've
-received saline drips um you also feel
-pretty good yeah um it's hard to
-disentangle these things um and
-typically they'll put other things in
-the bag glutathione some vitamin C you
-know they tend to sell these as kits I
-just decided to try it it it seemed fine
-I did it when traveling I don't know
-maybe I'm due for another one soon but
-for me the more typical way to try and
-increase NAD or whatever because I don't
-know what it's doing exactly but I like
-the effects of taking sublingual nmn the
-single most let's say Salient to me uh
-anecdotal data on taking sublingual nmn
-is that it makes my hair grow really
-fast it makes my nails grow really fast
-and I do feel an increase in energy and
-I take it first thing in the morning
-morning um and what dose one and a half
-gram 1500 milligrams so by by the way if
-you translate you know the the doses
-that they give mice in the studies where
-they're testing the
-efficacy um are typically on the order
-of
-500 to 1,000 milligrams per
-kilogram whoa yeah I'm 100 kilograms
-yep whoa okay so picture that the next
-time you're giving yourself some NAD or
-NR I'm not even approaching that yeah um
-at all well it's clear to me um based on
-my read of the data that NR can cross
-the cell membrane directly directly very
-easily there's no obstacle to NR getting
-into cells okay and nmn cannot because
-of that extra phosphate group so that if
-you take it sublingually or you ingest
-it orally it goes into the gut the
-phosphate group is clean
-and because of that the argument is that
-if one were to compare the benefits of
-taking NR versus nmn they're more data
-to support NR as a precursor to NAD a
-more effective precursor to NAD than
-orally ingested nmn but some people will
-say well I'll just take more nmn than I
-would NR and then this gets into the
-realm of Cost
-effectiven commercial starts becoming a
-battle between commercial sources and
-and I don't dispute that NR
-makes more sense as a precursor
-especially at dosages of you know 300 to
-600 milligrams versus 1500 milligrams
-but I've opted to take sublingual nmn
-mostly based on cost and are at the
-dosages people recommend is quite
-expensive imagine you had to take it at
-the mouse doses right you'd be spending
-about 300 bucks a day right it's just
-it's not feasible it's just not feasible
-so you know I don't have a deep desire
-for my to grow faster or my nails to
-grow faster it's more the increase in
-energy effect now I will say that
-sublingual nmn is also a bit of a
-laxative so there all these and I say
-that you know somewhat chuckling but you
-know some people say it makes them feel
-better well is that because you're you
-know evacuating your bowels a few
-minutes or hours later and then you feel
-less bloated and you have more energy
-you know it's very unclear I think what
-has not been done as far as I know is to
-compare early and ingested NR at say 600
-milligram a relatively high dose versus
-a gram of sublingual nmn and then
-actually measure blood levels of NAD if
-that experiment has been done and I'm
-not aware of it I'm not aware of it then
-forgive me maybe someone we'll put in
-the show note captions but I guess this
-gets down to the question of how many
-people are taking oral NR or n and Men
-or are taking NAD infusions which by the
-way are quite expensive mhm anywhere
-from
-$300 to $1,000 a drip that's pretty
-expensive what benefits are they getting
-what are they getting out of this like
-what are they getting is it an acute
-increase in NAD that that what that that
-causes them to live what a week longer I
-mean we have no idea well so so let's
-let's try to use data to answer the
-question right so this is exactly the
-thing that the ITP the interventions
-testing program was designed to test and
-again um I I would I would if people are
-interested in this they should go back
-and listen to my two discussions with
-Rich Miller where we go through gory
-detail of every molecule that has gone
-through the ITP the ITP is hands down
-the most rigorous tool we have for
-testing molecules in anything other than
-the species of interest because we can't
-do these experiments in human we cannot
-test lifespan interventions in humans
-for the obvious reasons so what is the
-next best thing well it turns out it's
-doing it in a noninbred mouse in
-triplicate in three institutions like
-you can't get more rigorous than this
-the ITP has tested probably north of 50
-molecules meaning it has done the same
-experiment for 50 different molecules
-and very few have extended lifespan and
-the notable failure is NR NR was tested
-and I believe it was tested at a very
-robust dose either 500 or 1,000
-milligrams per kilogram and there was no
-extension of life
-there was no improvement in health span
-there was no change megad do NR
-Placebo same result conversely let's
-consider some of the successes of the
-ITP rap a when you give rap a the first
-time they did it because they had a hard
-time formulating the Rapa they weren't
-able to started until the mice were like
-21 months old which is very old for a
-mouse that's like a 60-year-old Mouse
-and at that point they almost aborted
-the experiment because they were like
-well what's the point nothing is going
-to work when you start this late
-including caloric restriction by the way
-although it has worked in one experiment
-but nevertheless it worked and when you
-gave Raa that late in life it still
-worked then they redid the experiment
-and they gave it earlier it worked
-kagaoan as I mentioned which is an sglt2
-inhibitor it worked acarbose a drug that
-inhibits glucose absorption worked and
-interestingly didn't require weight loss
-so the th pis behind giving a carbos to
-the mice was it's a caloric restriction
-mimetic a CR mimetic and it worked but
-then but the but the treatment mice
-weren't any lighter than the
-non-treatment mice which actually goes
-back to something you said at the very
-outset which suggested that tight
-glycemic control independent of weight
-is a longevity benefit the same was true
-with the sglt2 inhibitor canaga floen
-sglt2 Inhibitors cause you to pee out
-more glucose a carbos vents you from
-absorbing in your gut so two different
-ways to regulate glucose neither of
-those experiments resulted in a lower
-body weight for the mice and yet they
-both lived longer again there's
-something very important about
-regulating blood glucose the other thing
-that worked is 17 beta sorry 17 Alpha
-estradiol and it only worked in male
-mice so again suggesting that um well we
-can come back to that it's more than we
-want to get into at the moment but Point
-here is there are very molecules that
-have withstood the scrutiny of the ITP
-it it is it's a high bar met foran
-failed by the way for and the ITP is
-specifically for offsetting aging is
-that right it is it is lifespan but it
-also looks at some measures of Health
-span but it's it's primarily it is the
-gold standard for lifespan yeah because
-my understanding is that there are some
-studies that have explored the role of
-supplemented NR maybe nmn as well but
-certainly supplemented NR for sake of
-lowering inflam
-to offset some of the negative effects
-of time zone shift
-alcohol um I have a few others listed
-here um overnutrition yeah so let's talk
-about that so so in
-20 I don't remember what year it was it
-was somewhat recent um a study was
-published looking at NR with uh uh
-something called teras Bean so tertill
-Bean is believed to be a ceran activator
-like RIS veratrol so commercially
-available product called basis and it
-was tested there was a it was a three
-arm study in humans um roughly 30 people
-per arm so decent size study right this
-is a big study so you take 100 people
-more or less with fatty liver disease
-now this was documented with um uh an
-MRI of the liver so um they're looking
-at um hepatic fat in the liver um by Mr
-and um using this type of MRI
-if your hepatic fat index is over 5%
-that's a high enough degree of what's
-called steatosis that you have fatty
-liver disease now of course this is not
-um this is not an a digital thing it's
-an analog right there's a there's a
-spectrum to this so so you know you
-start with just fat accumulating in the
-liver but as more and more fat
-accumulates you start to get
-inflammation that results in scarring
-and fibrosis and ultimately you would
-get to therosis so just keep in back of
-your mind the Threshold at which we
-would say you're you're in the you're
-get you're in the danger zone is once
-you hit 5% so this study randomize
-people to either uh a placebo or a
-regular dose of this product or a double
-dose of the product and I can't remember
-exactly how much is in the product I
-think it's either 250 or 500 so then
-that would be what the regular group got
-of NR and then the other group was
-getting 2x that so it's either 250 and
-500 or 500 and a th000 I don't recall um
-they also looked at something called the
-um they looked at many things right so
-they looked at all sorts of biomarkers
-um and the primary outcome for the study
-was did you see a reduction of this
-hepatic fat via the
-MRI um so what happened so they they did
-the study and uh lo and behold there was
-no difference there was no difference in
-anything okay so so at high dose at lowd
-dose there was no difference in how much
-hepatic fat you had at the end of the
-there was no difference in body weight
-there was no difference in inflammatory
-markers there was no difference in
-glycemic markers glucose levels liver
-function tests any of those
-things so in that sense it was a null
-study H but they did one
-subanalysis which again you have to be
-very careful of because a
-subanalysis is not a primary outcome but
-it's kind of a way to go and parse the
-data and they did find one statistically
-one statistically significant finding
-which was if you limited the analysis to
-people who had a hepatic fat score below
-27% remember I said once you're above 5%
-you're you're sort of you have fatty
-liver disease well they had people
-anywhere from you know 10% to 40% wow
-but if they looked at people who were
-below
-27% in the lowd do group there was a
-statistically significant reduction in
-liver fat
-if it sounds like I'm masting I am let
-me say it again if you limited the
-analysis to people who had below 27% on
-this hepatic fat
-index the people who got the full dose
-had no difference they averaged 20% at
-the beginning of the trial and 19% at
-the end no statistically significant
-difference the placebo group averaged
-20% at the beginning 20% at the end but
-the single dose of the drug went from 20
-% to 15% which was statistically
-significant it's not clear that that's
-clinically significant which is a pretty
-consistent theme in this type of
-research never confuse statistical
-significance with clinical significance
-if I gave you if your blood pressure is
-160 over
-100 and I give you a drug that lowers it
-to 157 over
-97 that could be statistically
-significant if the variance is small
-enough between people in the study it
-has no clinical significance I haven't
-changed the course of your life so again
-that to me is one of the one of the two
-big findings that people point to to say
-aha there was some benefit in fatty
-liver disease with this but again when
-you read the fine print which I just
-vomited out to you I I don't think
-anybody's looking at that going oh we we
-just found the solution to to Naf D the
-second study that people point to a lot
-was 2021 or 2022 um this came out of a
-group at washu I believe and they looked
-at
-nmn and they looked at glucose disposal
-so in this study they asked the question
-um we're going to take two groups of
-people you're going to get a placebo for
-a period of time or you're going to get
-nmn for a period of time and um we're
-going to then do what's called a a a
-type of glucose challenge where we look
-at how well you dispose of glucose with
-and without insulin
-infusion and in the uh placebo group you
-would look at pre and post glucose so so
-pre- and post Placebo treatment was
-there a difference in glucose disposal
-with no insulin no what about with
-insulin where you would expect to see
-much more glucose disposal no difference
-but when you did that with the nmn group
-there was a statistically significant
-increase in glucose disposal with
-insulin infusion but it was quite small
-in other words it was clinically very
-insignificant and just to make just to
-sort of figure out how insignificant it
-was I went back and actually looked at
-some of the red light data because
-there's an interesting study that shines
-red light on a person's back and then
-does an oral glucose tolerance test yeah
-and you can actually reduce like
-postprandial glucose by 8% is that
-meaningful not really I mean not in this
-not in this patient population because
-these people were all pre-diabetic they
-had very high glucose so it was again
-another example of something that was
-statistically significant but not
-clinically significant and the same
-thing was true in this study right but
-again people would would probably point
-to these St two studies because they're
-Inhumans and you had this one if you
-squint and look really hard and take a
-Sub sub subset of the analysis on this
-one measurement we saw you know a result
-a response of hepatic fat going from 20
-to 15% which is still 3x above the
-threshold to hepati liver disease and in
-this other study you had this you know
-very very modest reduction pardon me
-increase in glucose disposal but I mean
-like we're you know there's a saying in
-my in my sort of Mind Andrew which is
-like if you have to resort to really
-interesting statistical machinations to
-see something there probably isn't
-something very interesting there right
-right I totally agree and I think you
-know at this point I'm questioning
-whether or not I'm wasting my money
-taking NN or
-I take NR is really for these
-anti-inflammation um reported purported
-effects um I just want to pay a little
-bit of attention to the whole commercial
-battle around this because I think it's
-relevant I mean I think right now as far
-as I know the FDA has essentially said
-that nmn should not be sold as a
-supplement but it is still being sold as
-a supplement so there's a little bit of
-a ignoring of the and of the fda's
-request NR as far as I know is
-authorized for sale as a supplement yeah
-so it's generally regarded as safe it
-has an FDA designation of grass which
-means it is not regulated generally
-recognized as safe right and so that
-means um anybody can sell it the FDA
-will have no oversight they're not
-telling you whether they're not going to
-put a stamp on it that says what they're
-selling is what it is um and they you
-can't make a claim about it that isn't
-validated by some sort of study so um I
-honestly Andrew I think the whole nnnr
-debate is irrelevant I I think it's just
-a commercial debate I think it's
-literally just posturing about how can I
-carve out a different Market I don't
-think there's a scientific reason to
-favor one over the
-other well you just answered the
-question I was going to ask but I
-suppose the question therefore becomes
-is there any benefit to taking either of
-them for sake of lifespan there's one
-benefit I could find there's one benefit
-I could find that I think is genuine
-there are a few other really
-insignificant ones that fall into the
-category of goofy studies that cherry
-pick by data mining okay so so there's
-studies that like gave people nmn and
-looked at a shotgun approach of many
-different things like did it change LDL
-cholesterol HDL cholesterol
-triglycerides and the answer is oh look
-there's a small decrease but it was
-totally insignificant clinically even if
-stati Ally significant and oh it
-increased your you know six-minute
-walking test or whatever and it's like a
-six-minute walk test or whatever in
-people who were in their 20s is
-irrelevant it had no change in V2 Max it
-had no change in any meaningful metric
-of
-performance one test one study I could
-find that actually had what looked like
-a signal to me and it was a study that
-looked at skin cancer rates um with and
-I can't remember if it was NR or nmn but
-honestly I don't think it matters
-because I think they're basically
-equivalent um once just got a phosphate
-group on there you might need to take a
-little bit more of the nmn versus NR or
-maybe a lot more who knows in order to
-get the same increase in NAD is my
-understanding so this one study found
-somewhere between a 60 and 80% reduction
-in basil cell and squa cell carcinomas I
-found no difference in melanomas so
-again you know this because you just did
-a podcast on this melanomas the skin
-cancer that kills you but that's not to
-say that you know squa cell and basil
-cell carcinomas aren't problematic they
-can be very uh you know deforming uh
-they can require pretty aggressive
-surgeries to address them and so if
-indeed there is something that can
-reduce the risk of basil and squel
-carcinomas that may be a rationale for
-taking it and I should say that basil
-and Squam Cel carcinomas are very very
-common they are very common and they are
-very clearly associated with sun
-exposure a way that even melanoma is
-more complicated and has a genetic
-component and there are other things
-going on but squamous and basil cell
-carcinoma are very clearly related to
-sun exposure uh as you said they're
-quite common and so you know personally
-that's an experiment I would like to see
-repeated because if
-indeed um NR and/or nmn reduce the risk
-that significantly of sell and basal so
-carcinomas I think you could make a case
-that if you're an individual who's at
-risk for those things clearly I'm not
-right like I've never had a sunburn in
-my life I mean I I don't work outside so
-it's like it wouldn't matter to me but
-there are a lot of people for whom
-either either their skin color makes
-them more susceptible or their their um
-you know their pastimes or or frankly
-their their their line of work makes
-them more susceptible you know maybe
-there is a case to be made for it there
-if if you could if you could literally
-take 60 to 80% of your risk away on S Mr
-basell carcoma that could matter and by
-the way I don't know if this is true but
-you you may recall at the outset the
-outset I said that when you look at all
-the tissues in the body where we see a
-reduction in NAD do you remember what
-had the biggest reduction it was skin so
-there's a part of me that wonders like
-is the reason that the only place we see
-a really good signal potentially for NR
-and nmn supplementation is is in a skin
-cancer although it's not melanoma which
-is the one we'd really want to see I
-mean if this reduce the risk of melanoma
-I would take it right because even
-though I'm dark skinned I'm still
-susceptible to melanoma um so I just
-wonder that could be true true and
-unrelated but that's that's the first
-thought that crossed my mind when I came
-across that literature was hm I wonder
-if the enormous reduction in uh tissue
-NAD in this particular tissue explains
-why maybe there is a benefit to it
-assuming somebody is averse to feeling
-like they have an elephant stepping on
-their
-chest and they're going to pay $750 for
-it AKA and NAD infusion once a week and
-look people may opt to do that with the
-disposable income could do that drip it
-in slower not feel nauseous increase NAD
-with the hope hope hope that maybe it's
-going to extend your life most people
-considering supplementation to augment
-the NAD pathway are going to default to
-either taking INR or taking nmn by the
-way just going back to the group that
-have decided that $1,000 for an NAD
-infusion and dripping it in over two
-hours is a good use of their time what
-do you think would be the Improvement in
-their lifp if they spent that 2 hours
-exercising significantly greater
-interesting all right just just not and
-and less expensive but yeah right you
-could also weight train for the first
-hour and then enjoy some food afterwards
-Lane Norton taught me that there are
-data showing that exercise in particular
-resistance training improves the
-rewarding properties of food makes food
-taste better which we've all kind of
-intuitively experienced so you spend the
-first hour
-working out hour eating if you had an
-extra two hours a week to choose between
-paying a th000 bucks or 700 bucks for an
-Adu infusion or you know uh lift weights
-for an hour go for a half an hour walk
-and listen to your favorite podcast uh
-like the huberman lab and then eat a
-meal for half an hour like I can just
-think of so many better ways to spend
-time uh and money but anyway let's let's
-not digress okay well I'm going to pull
-a little bit from marketing
-text here but I trust
-these showing really yeah yeah I do
-because they have citations to support
-them and we can include the citations
-these are not um I'm not going to say
-these are these are not Lynch pin
-Arguments for doing one thing or the
-other but we already established that
-NR and nmn are quite similar except for
-the presence of a phosphate group on NR
-that gets cleaved off so again you might
-have a slight dose issue but at the end
-of the day you're giving NR NR is freely
-taken up into cells it turns into NAD so
-this is all a big sort of shell game of
-how do you get NAD up and and again I
-think we've established and we can we
-can agree that that there is an increase
-in NAD at least in the blood and
-probably in the liver when you take
-exogenous NAD or precursor let's yeah
-that's right so great well then you took
-the words right out of the the data I
-was going to refer to that's right
-because I asked a few folks that help
-develop some of the NR supplements like
-what are the data yep that support the
-use of NR for increasing n and they say
-NR can cross the cell membrane directly
-NN cannot okay but you can just CLE the
-phosphate group right exactly um NR they
-claim I'm not this is not my claim but
-they claim that NR is quote unquote 25%
-more effective than NN in raising whole
-blood NAD levels but I'm guessing that's
-milligram for milligram right okay so
-then you just adjust the milligram
-dosage a little bit and so on what's
-entirely unclear is what raising blood
-NAD translates to in terms of getting
-more NAD into cells I don't know that
-that's specifically cells like skeletal
-muscles right I think based on Josh
-Rabinowitz his work I also had Josh
-Rabinowitz on the podcast to talk about
-this um and I trust Josh on this um much
-more than I would trust any marketing
-material um because he doesn't have a
-dog in this fight right right he just
-you know he just does the work and um
-what Josh's research soed which is
-basically NAD flux research has
-demonstrated that look the liver is
-probably the place of greatest uptake uh
-in addition to blood and that's about
-all we know like it's not clear how much
-of this is getting into other
-cells
-um so I mean that's the rest of it is
-just you know I think rearranging deck
-chairs on a Titanic as far as like how
-much does it really matter and and again
-I don't even think it's worth arguing
-about whether nmn or NR is more
-bioavailable because to your point you
-can sort of adjust the dose and I trust
-that whatever you're taking NR or nmn
-you are getting some NR into the cells
-and that's being converted to NAD but we
-still keep coming back to the jugular
-question does that matter does
-increasing intracellular NAD matter when
-the system is so tightly regulated so I
-think what you see is a lot of marketing
-material that tries to make the case
-that you can do it great I'll grant you
-that you can do it does it matter does
-it matter in lifespan the answer appears
-to be unambiguously no at this point
-does it matter in health span I think
-that's what we're discussing right
-there's something um so sticky about the
-longevity field just so sticky about
-this idea that one could take something
-and extend lifespan and people don't
-want to be in the control group so
-they're willing to invest significant
-amounts of money to do it well I mean I
-think the bigger issue is like you can't
-do the longevity experiment in humans
-and I'm sure that these companies that
-sell this and I honestly I don't follow
-the space I don't know how many of these
-companies there are out there I can name
-two because the you know five years ago
-which was the last time I really dug
-into this I knew who the two dominant
-players were for all I know there could
-be 20 companies today that are selling
-NR and NN I don't know they're probably
-about 30 to 50 prior to this FDA ruling
-okay which is kind of an interesting
-situation in its own right yeah you know
-what happened there was the supplement
-nmn
-suddenly the FDA decided that it should
-not be sold over the counter um anymore
-because there was a clinical trial
-initiated on nmn which essentially makes
-nmn a drug for clinical testing and
-thereby can't be classified as a
-supplement any longer that was the
-rationale As I understood it but as with
-things like anical cysteine that was
-more of a lobbying effort though I think
-I I don't think actually that was a
-scientific decision I think that was
-more of a lobbying decision um from a
-from a market protection from an IP
-protection standpoint and this had
-happened prior for netal cysteine Knack
-which some people take it's a mucolytic
-it's actually a great decongestant yep
-if uh you're congested and it increases
-glutathione that's my understanding and
-I believe somebody checked me on does it
-decrease or increase glutathione
-increases glutathione is my
-understanding if I have that wrong
-someone will tell me quickly in the
-comments my understanding is that in
-Europe Knack might even be available by
-prescription in the US you can still buy
-it over the counter but a few years back
-the FDA said nope can't sell Knack any
-longer and there was a push back lobby
-to keep it on the market and you can
-still buy it on Amazon the same thing
-has more or less happened with nmn
-and certainly with NR although NR was
-never in question in terms of whether or
-not it should be sold as a supplement or
-not because as far as I know there's no
-clinical trial on nnr at least not
-currently so there's a clinical trial on
-nmn which classifies it as an
-experimental drug and therefore the FDA
-said nope you can't sell it as a
-supplement a few companies major
-companies pulled NN from the market in
-the US many smaller companies just kind
-of watched and waited and continued to
-sell it and I checked prior to the
-beginning this episode and you can still
-buy it online but of course a lot of
-what we're saying today is kind of a why
-would you um we're not really coming up
-with strong arguments um for taking nmn
-um at least not in today's discussion
-yeah I mean again I think the strongest
-argument I could make based on the data
-would be potentially on the um on the on
-the basil cell and squa cell carcinoma
-uh risk reduction if indeed those
-results are reproducible um that again
-that's that would be justification again
-for the right individual wouldn't be a
-justification for me might be a
-justification for somebody um but really
-the rest of it is
-um why why do you need to do experiments
-on this if you're selling a supplement
-when you don't need to make claims to
-sell a supplement like if it's a drug
-you have to have an indication you can't
-sell a drug without rigorous trials that
-demonstrate both safety and efficacy um
-I do think it's pretty safe to say that
-I I I do think NR and nmn are probably
-um there has been some voice around the
-idea that NR could increase the risk of
-cancer right and the experts in this
-area like Charles brener have pushed
-back hard on that arguing that the
-studies were not done well is as I
-recall I I think that's probably fair I
-don't think there's been a well done
-study in this entire field is is part of
-the problem right um so so and then
-that's probably too harsh a statement
-but but this is not a field that's like
-you know
-that's necessarily lending itself to the
-rigor that you would in in in
-pharmacotherapy and I I I think there
-are probably you know you mentioned
-Charles brener like I think Charles does
-good work right um and he works on many
-things not just this yeah and and and
-and by the way I don't I don't think I
-don't hear Charles out there saying that
-NR increases lifespan No in fact I don't
-want to quote him um at all but I think
-he would argue that sirtuin NR and a men
-should not logically or practically be
-linked to to efforts to extend lifespan
-but that there are some
-interesting positive effects of
-augmenting NR as a means to increase NAD
-for sake of anti-inflammation and some
-of these other effects that we've been
-discussing yeah that's my understanding
-of his position as well is that I I
-think he firmly agrees with what I laid
-down at the outset of this which is
-there's
-no
-meaningful logical connection between
-the relationship of uh ceran caloric
-restriction and NR that's that's just a
-that's a shell game that is empty um and
-and you're right I mean I think part of
-the reason why I think there's much
-better research going on with rap ay is
-that there's really no commercial
-interest in Rapa like nobody's going to
-make money selling Rapa because it's so
-cheap well yeah and it's actually not
-cheap but it's a drug that is off-
-patent right so this is a drug that was
-approved by the FDA 25 years ago so
-generic forms are inexpensive enough
-that no believe it or not they're not
-this is the irony of it is is generic so
-rap immune is the brand drug um that was
-initially uh uh approved in 1999 and
-today if you go and buy rapamycin you're
-going to not buy rapamune you're going
-to probably buy generic uh ceramus or
-rapamycin and yet it's surprisingly
-quite expensive now it's not enormously
-expensive because you're not taking much
-of it but it's about five bucks a
-milligram that's pretty expensive so if
-you're taking 8 milligrams a week that's
-40 bucks a week is probably what I spend
-on Rapa and that ain't cheap no relative
-to you know and it's cheaper than some
-things I take but it's not cheap um but
-the point is like nobody has a
-commercial interest in rapy right it's
-sort of an irrelevant drug it's but the
-interest is scientific right and and and
-the commercial interest is in what we
-call rapalogs which are analoges of Rapa
-and that are being
-um investigated by a number of companies
-to to look at new indications for
-example immunity immune function right
-so rapy historically is thought of as an
-immune suppressant because that's the
-context in which it was approved for
-patients uh undergoing organ
-transplantation um but you know I think
-Joan manik um and Lloyd klickstein when
-they published that paper in 2014 using
-everolimus where they took a group of
-65y olds and randomize them to either a
-placebo or different Doses and dosing
-schedules of everolimus found an
-enhanced immunity in response to an
-influenza vaccine which again was for me
-that was the turning point right that's
-when Rapa went from something that was
-interesting based on the first ITP in
-2009 to maybe we should be taking this
-in 2014 so between 2009 and 2014 I was
-kind of looking at the curios of rapy
-and saying well cool that it worked in
-mice I don't think humans should ever
-consider this to that study which was
-like wait a minute something's different
-if you take rapamycin as a human at
-least every day it seems to suppress
-your immune system but if you just pulse
-it once a week as they did in that study
-it seems to improve immune function
-which again means it's an immune
-modulator it can go up or down on the
-immune system that was really the the
-hypothesis that emerged from that
-experiment um and so now the question is
-could you
-design drugs that are more specific to
-empor complex one which ramyon is not
-but you can get around that by dosing it
-intermittently um and then of course you
-know is it a drug that has efficacy in
-in terms of other um other things that
-can be tested in humans that are not
-longevity because you can't test
-lifespan in humans obviously right
-you're 50 right 50 years old
-51 you seem to be vigorous you take
-great care of
-yourself how much do you think taking
-rap ayin for how many years have you
-been taking it six has contributed to
-your current state or Vigor zero idea
-this is my opportunity to ask about your
-belief or lack of belief in biological
-aging tests because if somebody's going
-to experiment with any or all of these
-things um they may want to evaluate
-whether or not they're biological ages
-is changing and there are a number of
-these tests available mhm um and people
-love this stuff love them they love them
-I mean who wouldn't want to see that
-they are 51 years old but their
-biological age is 37 I just did a
-movement test the other day so it's a
-it's a it's a very fancy camera system
-where you it's got a million cameras on
-you and you go through this whole
-exercise how high can you jump how far
-can you throw like it was awesome and
-then it gives you a movement
-age Andrew I was 20
-I believe it I mean I'm on I should be I
-should feel
-amazing do you actually think I move
-like a 22y old I mean are you freaking
-kidding me I bet you if I went and did
-that again tomorrow I'd come back at 31
-or something there is so much nonsense
-in this type of testing it it is just
-you know look there's probably something
-to be said if I do that and I come out
-at 22 as I did versus 92 sure I would I
-would grant you that if you took 150
-year olds and you put them through a
-movement test the ones that really
-really are struggling will come out
-older and the ones that really really
-are doing great are going to come out
-younger so great I guess it's not I
-guess I move reasonably well for a 51y
-old but it's simply impossible to
-believe that I can do today what I could
-do when I was 22 with respect to
-movement and strength and power which is
-what that was assessing you're doing a
-lot of jumping single leg jump here do
-all this kind of stuff balance testing
-all sorts of things
-um and and and I guess I would say the
-gold standard for any of these biologic
-aging tests has to be the
-following what is a better predictor of
-remaining years of life chronologic age
-or biologic age that's to me the most
-important standard so how old are you
-chronologically I turned 49 in six weeks
-okay so um I'm sure your listeners will
-not like to hear this because they would
-probably hope and believe that you are
-Immortal but some might want to hear
-that I'm going to be taken out
-soon but uh let's let's just grant your
-mortality as a given um based just on
-your chronologic age an actuary would
-come up with a pretty decent prediction
-of how long you're going to live now I
-would argue that that's a crude
-assumption because it doesn't take into
-account the fact that you're
-metabolically healthy that you do all of
-the things that you do but just based on
-the fact that you are a man who is 49
-years old and who doesn't smoke those
-three
-things would give me if I were an
-actuary a very good prediction of your
-life expectancy and because I'm not an
-actuary I don't know the exact number
-but my guess is it would be predicted at
-this point at another 37 years okay well
-I bought that chart my life in weeks yes
-in fact I bought two of them um for
-reasons that are uninteresting
-but I've watched that chart Phil um not
-quite what you predicted but I put my
-estimated lifespan to be 95 great that's
-fine and then I have little lines on the
-side MH of how much Vigor I felt from uh
-and just overall Wellness completely
-subjective of zero being like completely
-cratered near death to 10 like it's best
-I've ever felt but you do that you make
-that note every how often uh okay so
-what I did is you know from 10 to 15 I
-felt you know blank and then um in my
-20s I actually didn't feel so great
-because I was I was working 80 hour
-weeks commonly you can ask my former lab
-technicians um I was just talking to
-Fong win recently and I mean I used to
-work to collapse not healthy you know 80
-hour a week maybe 100 hours occasionally
-maybe 70 maybe back to 40 but just too
-much work not enough sleep s nutrition
-not great not just not doing the right
-things but just gave gave my 20s to
-being in in lab basically and a lot of
-my 30s as
-well so I would say from 40 to
-45 my Vigor was higher than in my 30s MH
-and then now I track I would say about
-every two months I'll start filling in
-that line and it's adjusted for by
-stressors and adjusted for by positive
-things in life life and the goal for me
-is to figure out what are the behavioral
-tools and other things I can do or take
-that are going to keep the Vigor as high
-as possible Vigor
-well-being internal peace Etc all of
-that combined kind of what I'm calling
-Wellness in this very subjective uh
-measure as high as possible as I
-transition to my 50s my 60s 70s and 80s
-and I'm guessing that I'm going to have
-to do many more things in my 80s and 90s
-in order to
-maintain a simil
-hopefully level of vigor and well-being
-than I do now and the question is will I
-be able to yeah maybe maybe I I might
-take a slightly different different um
-um different angle on that but let me go
-back and make one point and then we'll
-come back to this point which is
-actually really interesting yeah because
-I think the chart is great I think the
-chart um more than any supplement for
-longevity gives you a or gives one a
-visual perspective of where they sit in
-this long Arc and I don't think the
-brain is very good at anchoring us to
-the notion that we are mortal um because
-if we think about that for even a few
-moments too long it makes us anxious and
-I think we are very good at avoiding
-that reality yeah well it's it's it's um
-as you said it's very difficult to
-contemplate finitude um so I I actually
-want to talk about that because I think
-it's so interesting but I just want to
-make this point about the Actuarial
-point right so um let's just say
-actuarially your expectation is 40 years
-more at this point because you're 49
-you're a male and you don't smoke so we
-believe you have somewhere between 35
-and 40 more years of life predicted on
-the basis of your biologic age that's it
-that's all I got you're going to live to
-whatever 88 to 91 or something I'm
-making that up but that's like okay I
-better get cracking on some stuff so now
-let's pretend you went and did a
-biologic age test okay so let's say you
-did that and let's say it came back and
-said you're
-25 so if I had a
-25-year-old male non-smoker in front of
-me what's his life
-expectancy well it's about
-60 to 65
-years does that mean that you Andrew
-have 60 to 65 more years of life based
-on a fact that your biologic clock says
-you're 25 do you believe that no no way
-no of course not now this would be an
-easy thing to test not in humans but you
-could do it in
-mice right interesting that to my
-knowledge that experiment hasn't been
-done so right out of the gate when I
-look at people talking about their
-biologic age you know well I'm I'm
-actually 60 years old you know
-chronologically but my biologic age is
-35 um my response is who cares truth F
-like is that a good thing yes probably
-but does it is it is it is it tangibly
-measurably meaningful like to have a
-biologic age of 35 versus 40 versus 30
-if you're 60 I don't think I I think
-we're we're applying a very false level
-of precision to something that might
-only need to be directionally true
-secondly we don't really yet understand
-the biologic noise in that measurement
-right so there are lots of things that
-we measure that are really noisy so um
-if I measured
-your I don't know let's think of
-something that's very biologically noisy
-your triglyceride level like your
-triglycerides are pretty noisy unless I
-do something very important which is
-standardize it by how long it's been
-since your last meal like if you ask me
-right now what my trigs are I have no
-earthly idea
-because you know I probably ate 3 hours
-ago like and I don't even remember what
-I ate how much fat was in it how much
-carbohydrate was in I have no idea so
-the only way you could really get a
-triglyceride measurement and put any
-weight to it is if you've been fasting
-for 8 to 12 hours then we can at least
-say hey a triglyceride level of 50
-milligrams per deciliter is excellent
-whereas a triglyceride level of 120
-milligrams per deciliter is lousy but if
-you measured my trigs today and they
-meaning at this moment and they were 150
-that could be totally reasonable even
-though at fasting levels I'm at 50 so we
-know that because we know exactly what
-goes into the triglyceride measurement
-but when you look at a biologic clock
-that takes into account your glucose
-level your vitamin D level your
-epigenetic marker here or there those
-are very noisy things so how do I know
-when I measure it in you now versus when
-I measure it in you a year from now I
-captured you in the exact same space I
-mean I don't so
-it's for that reason that I just have a
-very hard time putting any stock in this
-um now does that mean that in the future
-we won't find some benefit in this I I I
-think we probably will um I do think of
-all the things that go into it probably
-the epigenetic part of it would be the
-most interesting but again what most
-people don't understand is sort of a
-dirty little secret is how difficult it
-is to measure the and to sequence The
-epig genome right so to my knowledge
-none of the companies that are doing
-this I may be incorrect on this by the
-way but the last time I looked which was
-about a year ago not a single company
-was correctly sequencing The epig genome
-on these things so they were not able to
-accurately say what they were giving you
-an average representation of your
-methylation but they weren't going base
-pair by base pair and actually
-sequencing this the way we would
-sequence The genome so so again it just
-it's so much noise in this system and um
-I I just think it creates a a little bit
-of a distraction for people truthfully
-do you avoid going through the um non uh
-let's just say the non-traditional
-scanner at the airport the one that
-might use higher levels of radiation no
-do you think about how many flights you
-take as a source of radiation no let's
-just keep this all in context so the NRC
-recommends that a human being or at
-least an American should expose
-themselves to less than 50 MTS of
-radiation a year
-okay so what that number doesn't mean
-anything to somebody so let me give
-people a sense of what that means so how
-many mills of radiation do you and I
-receive because we both live at sea
-level so just ambient radiation living
-at sea level is one Miller a year okay
-so we just chewed up 2% of our annual
-allocation what if you moved to
-Colorado now you're a mile up that
-increases you from one to two Ms a year
-okay what if you had a CT scan of your
-chest uh uh a CT angiogram well it
-depends on where you got it done if you
-got it done at a really good place with
-a fast scanner and great software
-probably three Mill certs a year if you
-got it done at a place that's sort of
-average might be 10 to 15 Mill cevers
-pardon me per scan um now here's what's
-really interesting uh by the way I'm I'm
-totally fascinated by this question
-which is how much radiation is too much
-um a dexa scan by the way you can't even
-measure how many Ms you're getting so a
-dexa scan is like less radiation than a
-cross-country flight so it's super super
-super low less than an xray or anything
-like that
-um people who work in uh in nuclear
-plants I'm told I haven't looked at the
-primary data on this but I've talked to
-people who incessantly do this so so
-it's possible I'm a little bit off on
-this but I'm told that these people
-are at 10 times that level of radiation
-exposure and sometimes higher so not
-they're not getting 50 they might be
-getting like 500 m seits a year and yet
-interestingly they're not in an
-increased risk for cancer I'm not sure
-what to make of that um but it suggests
-to me that we probably don't need to
-worry about things like airport scanners
-and flights in fact even if you look at
-pilots who do constant flights across
-the poles because you're going to get
-the most radiation going over the pole
-to my knowledge there's no convincing
-data that suggest those people are't an
-increased risk of cancer either and
-they're you know they're obviously at
-the upper end of what a civilian would
-experience in terms of radiation so um I
-just I'm not convinced that that's like
-that's something we should be stressed
-about I think you just relieved a lot of
-people of some unnecessary concern I
-want to go back to what you were saying
-earlier about what you need to do in
-your 90s versus what you're doing now so
-you said you think that in the in your
-80s and 90s you're going to have to work
-harder to preserve the vitality that you
-have now yeah grip strength
-jumping cognitive function I mean I've
-got very good genes in terms of
-longevity on one side of my family
-pretty good on the other although not as
-robust I mean if I just look
-historically um yeah who who knows right
-I mean but my sense is that I'll live to
-be 95 if you know barring you know
-bullet Buster cancer so I would say that
-yes you're going to have to work hard in
-that last decade of life to preserve
-those things but I think it's the work
-we do now that sets the stage for that
-it's the foundational work that we do in
-this period of Our Lives you know you
-and I are only a couple years apart but
-I think this is the critical decade it's
-in your 50s to your 60s and in your 60s
-to your 70s that I think is is the
-deciding time 50s to 750s to yeah 50s to
-70s so so what is it about this this
-window that you and I are just entering
-now and why is it so important
-um I think it's important because we're
-we're getting to that point where aging
-does start to show up like I think if if
-you and I are being brutally honest like
-we're we're kind of half the men we used
-to be um and and and and again that just
-means like look like a night of poor
-sleep shows up more right when you were
-working in the lab as hard as you were
-describing it you could probably walk
-through walls when you were exhausted
-yeah a short nap would reset me near
-completely yeah I I got more colds and
-flu in that time because I wasn't taking
-such good care but then again I was
-indoors more so it's an imperfect
-experiment but you're right I think that
-um as I've approached
-50 I need to do more you need to do more
-self-care you need to be more mindful of
-what you're eating how you're sleeping
-how you're recovering from those
-workouts because we still do hard
-workouts but recovery plays a greater
-role in other words we're just not quite
-as resilient as we used to be you know I
-was telling somebody the other day they
-asked me about my residency I don't
-think being hyperbolic when I say this I
-couldn't do one month of what I did for
-five years I really couldn't do it I
-don't think I I don't think there's any
-there's no way I could go back to that
-level of sleep deprivation for a month
-let alone five years so um you know
-that's just a fact of Aging I think so
-um but what we have to do during this
-period of time is build up as much
-physiologic Reserve as possible and so
-the the important thing is we you know
-we have to stay in the game because
-compounding makes such a difference
-right so you know we're still young
-enough that we can actually put on
-muscle mass now that's not always going
-to be the case it's going to be very
-difficult to add muscle mass when you're
-in your mid to late 70s it's doable but
-it's very very difficult so instead we
-want to be putting on as much muscle
-mass as we can and increasing or at
-least maintaining strength as much as we
-can uh again probably increasing it is
-unlikely clearly we're not increasing
-power as we age right Andy Galpin has
-talked a lot about this the atrophy of
-the type two muscle fibers the 2A muscle
-fibers really start to atrophy in your
-20s and 30s so I know I don't have a
-fraction of the power that I used to
-have and I know that because my vertical
-jump is L literally half what it was
-when I was a teenager I was never mine
-was never very good so I it doesn't
-matter how good it was my point is like
-if you know what your vertical jump was
-at8 192 and then you do it today I mean
-it's literally 50% and that's one of the
-purest tests of power um so power's
-going down strength is going down but
-not as much muscle mass is actually not
-because remember that's the order in
-which you lose things right you're going
-to lose power strength and size of
-muscle um but again size still matters
-it's still a glucose sync all these
-other things um but what we don't want
-to do is you know be out of the game
-right what we don't want to do is injure
-ourselves and get a setback that becomes
-very difficult to recover from because
-you know when you're our age if you're
-inactive for months at a time it's it's
-going to be 2: one or 3:1 ratio of
-inactivity to activity to get it back um
-what about energy sorry to interrupt but
-since we've been talking about molecules
-and energetic
-Pathways what about energy just that get
-up and go let's just say after a decent
-night's sleep 7 and half hours um waking
-up same time more or less you know 6:30
-7: a.m. probably for you or me and why
-is it that as we get older we have less
-energy our mutual good friend the late
-Ben Baris used to ask about this he used
-to say he called me Andy he was like
-Andy why do I have so much less energy I
-was like I don't know I don't know it's
-a great question now unfortunately he
-died of pancreatic cancer so there may
-have been other things going on but that
-was prior to the cancer at least as far
-as I know you know it's a very
-interesting question why do we have less
-energy and I don't think anyone's ever
-been able to answer that question no and
-when you have kids you're going to be
-even more starkly confronted with that
-because I actually it's one of the
-things I am most Amazed by when I look
-at my kids especially the youngest ones
-the boys who are seven and 10 is what I
-just describe as spontaneous outbursts
-of energy um like their inability to sit
-still
-their kinetic desire to just like they
-will like if we I remember once we were
-kind of walking through a mall and we're
-walking through the mall they are
-sprinting ahead of us sprinting back
-sprinting ahead of us sprinting back
-like imagine if you and I were walking
-through the mall and I just started
-running ahead and running back you'd be
-so sore the next day but it's like it
-just wouldn't occur to me to ever run
-unless being chased right like it's just
-I mean like like we now live a life like
-I think our ancestors did which was you
-know if we're not deliberately in the
-business of moving for a reason like
-you're exercising you're going for a
-walk for the sake of going for a walk
-like you just wouldn't it wouldn't occur
-to you go and expend energy for no
-reason and yet kids do this it's amazing
-and um look it's going to go down by the
-time you're a teenager like just going
-from being you know sort of 10 to 18
-there's probably a significant reduction
-in spontaneous outbursts of energy let
-alone where we are now um and it's a
-great question who maybe it's
-NAD I mean I don't know maybe although
-up until now we've been talking about
-all these ways to try and increase NAD
-in the bloodstream and hopefully in
-cells and I don't know I take my nmn and
-my NR and I feel a little bit of a boost
-in energy but I can't say that it's so
-significant that I feel like I can
-Sprint back and forth Just spontaneously
-these again it's just so hard for me to
-imagine that any supplement or any drug
-including rapy which I think is the most
-promising geroprotective drug we
-have I just can't imagine that those
-things even compare to what good sleep
-good exercise and good nutrition do for
-your energy levels and
-vitality and the reality of it is all
-three of those things are hard to do you
-know
-yeah they especially if you're an adult
-like especially if you have a real life
-you know you got kids you got a job
-which is presumably many people
-listening to us right now like there's
-very few people listening to us right
-now whose only purpose in life is to
-take care of their health everybody's
-got something else they have to do which
-means you have competing interests for
-how do you take care of yourself so to
-sleep is not easy right like we all are
-busy as hell we don't want to have to
-stop what we're doing to undergo
-nighttime routine to put ourselves in
-the right head space to be able to sleep
-do all the things necessary give
-ourselves that eight hours in bed to
-hopefully get seven seven and a half
-hours of sleep um even people like me
-who like exercise I know you like
-exercise um it still is a sacrifice in
-terms of time um and and and for many
-people certainly for me food is the
-hardest of these all right if left my
-own devices I'd eat freaking Froot Loops
-all day like I love fro Loops right
-interesting by way of contrast the food
-party is easy for me I like healthy food
-and oh I like healthy food I just like
-all food I like I don't like unhealthy
-food I've weaned myself off it I never
-really liked it that much I mean I like
-a great tasting slice of pizza or ice
-cream every once in a while but I much
-prefer meat fish chicken eggs fruits
-vegetables rice OB I just like that
-stuff I'm a weirdo that way I suppose
-but on the topic of exercise as it
-relates to Vigor and
-Longevity I'm intrigued by how some
-forms of exercise give us more
-energy especially the same day and how
-some forms of exercise or even timing of
-exercise tends to deplete us because I
-think one of your major um sort of calls
-to the public has been to move more yeah
-for sake of their health span and
-lifespan but because of the time
-investment that it takes to work out in
-a gym or to go for a run or a Ruck I
-think some people think well that's a
-lot of time but if it gives you more
-energy and more Focus to do other things
-well then it's great so it's not just
-about living longer it's about being
-able to do more and I've noticed I don't
-have any science to back this up but I'd
-love someone to run a test on this that
-if I complete my workout before 9:00
-a.m. even if I have to start it while
-I'm a little bit fatigued I have more
-energy all day long but that if I
-initiate that workout say mid to late
-morning I'm pretty tired in the
-afternoon it's like I give everything I
-have to that workout and so it becomes a
-little bit defeating since I'm not a
-professional athlete or even an amateur
-athlete I'm working out for health span
-lifespan but I I want to do exercise
-that gives me more life during my waking
-hours I think somebody should study this
-and I'm convinced that it has something
-to do with the change in body
-temperature that occurs across the day
-and the additional change in body
-temperature that occurs as a consequence
-of exercise that's my hypothesis do you
-notice a seasonal change in that do you
-experience it more or less in one season
-or the other I haven't thought about it
-that much but not so much not so much
-and I wonder whether folks like our
-friend Joo willink are able to do so
-much he has so much Vigor that guy in
-part because he basically exercises at
-the just after the lowest temperature
-phase of the Circadian rhythm and use
-his exercise presumably to drive himself
-out of that and get that you know
-temperature increase that's the
-consequence of waking but in his case
-he's waking up so early 4:30 is when he
-starts those workouts so it's something
-for people to play with it's something
-that I don't think gets discussed enough
-which is yes you should exercise do
-resistance training do cardiovascular
-training but play with the timing of
-those and see how at a given intensity
-it impacts your energy levels for the
-remainder of the day I think that's I
-think it's an important metric that
-again I I just don't see a lot of
-attention to because I think if people
-could experience the increase in energy
-that is the consequence of working out
-at the right intensity in the right way
-at the right times for them
-they'd be much more apt to do it it
-wouldn't feel like this like spending
-money on something that sure will make
-you live longer but then you're depleted
-and you can't do cognitive work there's
-something pretty impressive about the
-fact that as far as I know the last
-three let's just call them I don't want
-to call anyone out specifically major
-pillars of the high level administration
-at Stanford school of medicine to my
-knowledge were all 5 am. Runners there's
-something about early morning exercise
-and my good friend Eddie Chang who's the
-chair of neurosurgery at ucss he's been
-on this podcast known him since we were
-7 years old he's an early morning
-exerciser and then he's got tons of
-energy all day what about the reverse
-causality there do you think it's
-possible that they're they have a whole
-they have a system of high energy that
-makes Joo who he is or makes you know
-these people who they are and as a
-result of that they they they're able to
-work out 5 o' in the morning yeah I
-don't doubt it I just have noticed that
-in the few times in my life where I've
-kicked my own butt to get out and start
-working out really early I have more
-energy all day long sometimes I still
-require a brief nap but it's a pretty
-striking effect as compared to you know
-the 10: a.m. workout effect yeah so I've
-started setting a standard of trying to
-get my workout done before 9:00 a.m. so
-anyway something for people to play with
-because the more energy to live in your
-waking hours um perhaps not longer but
-um certainly have more energy in terms
-of output I think is a significant and
-undervalued parameter so let's let's
-quickly return to supplements we I think
-are converging on an
-answer about NR nmn and NAD which is you
-don't take them correct I take NR and
-nmn with not a lot of religious
-adherence I should say if I ran out I
-might not buy it for a while and the
-only observed effect for me is this
-accelerated hair growth which is a pain
-in the butt frankly cuz it just just
-means I have to get my hair cut more
-often I'm not trying to grow my hair
-faster but
-okay what are some other supplements if
-any that you take that are peripheral to
-this pathway or separate from this
-pathway Romy is a prescription drug only
-right so are there any over-the-counter
-things that you take that you would
-Place into the lifespan category maybe
-they touch into Health span as well I'm
-happy to list off what I do but um what
-are your let's just say top five at
-least well I don't I don't take that
-many so top five would be a pretty
-exhaustive list um I think the other
-supplements that I take I do take EPA
-and DHA in the form of liquid or capsule
-fish oil capsules not because I have a
-an effection for capsule over liquid
-it's just going to increase my
-compliance if I take I've done both and
-I noticed when I was taking liquid
-because you're storing it in the fridge
-it's just it's just one more step
-removed and I was just less likely to
-remember to take it twice a day um I
-take uh
-thumin um and there's some reasonable
-evidence in MCI patients that thumin
-improves cognitive function um so I
-think there's a relatively low downside
-to the hypothesis that theum uh May uh
-preserve cognitive function um again I I
-don't I don't I don't I I wouldn't put
-that in the category of like beat the
-table for it right I think it's just you
-know reasonable evidence um I take I do
-take vitamin D because interestingly
-despite the fact that I'm outside every
-day without supplemental vitamin D my
-levels are surprisingly low how much do
-you take I take 5,000 IU um and that
-takes me from kind of a level of 30ish
-to a level of 50ish mhm um and there's
-you know there's a lot of debate about
-how high vitamin D levels should be
-that's a whole separate podcast we could
-you know waste time on that in in 10
-years yeah my appetite to talk about
-that one uh let me think what else do I
-take because I sure oh I do take methyl
-folate and methyl
-B12 um and again the the the rationale
-there is
-um I do think there's some evidence that
-elevated levels of homosysteine
-are uh bad
-in and of themselves so there's no
-denying the fact that elevated levels of
-homosysteine are associated with bad
-things that's unambiguously clear
-meaning there's an association between
-Badness and homocysteine what's not
-clear is is it causal now there's
-definitely one mechanism you can point
-to although again mechanisms are what
-they are we just spent how many hours
-talking about mechanisms that
-theoretically make sense that never pan
-out but mechanistically homocysteine
-will um inhibit the clearance of
-something called symmetric uh and
-asymmetric dimethyl Arginine have you
-heard of these things sdma and adma so
-adma and sdma uh regulate nitric oxide
-synthes and
-homocystine impairs their clearance and
-therefore when you have high levels of
-homocystine it per it results ultimately
-an impaired nitric oxide synthes and
-therefore low lower nitric oxide so this
-has been proposed as at least one
-mechanism by which homosysteine might
-negatively impact um vascular disease uh
-so and we also know by the way that um
-adma and sdma are cleared by the kidneys
-and therefore this might this is also
-proposed as one of the mechanisms by
-which impaired kidney function is is um
-uh impacts vascular health because
-that's a known right if you if your
-kidneys don't work well your risk of
-heart disease goes way up so this is now
-proposed as a link between what we OB
-erve with homocysteine and impaired
-renal function so um we know that if you
-take methyl folate and uh uh methyl B12
-you're going to lower homocysteine
-that's abundantly clear so the the
-thinking is that that might actually
-lower um adma sdma and raise nitri oxide
-synthes again relatively low cost
-lowrisk you know thing to take at modest
-doses I also there's probably some
-evidence that overs supplementing
-vitamin B is problematic especially B6
-so I don't because of peripheral nerve
-damage exactly so I don't supplement B6
-I'm just taking a bit of folate and and
-and methyl B12 let me think what else do
-I take because I do take a couple other
-things oh I take um magnesium L3 and8
-and ashwagandha for
-Sleep
-um i' take slow mag which is just a a
-magnesium chloride slow relasing version
-of magnesium
-and I take methyl pardon me I take uh
-magnesium oxide so I take magnesium in
-three forms so I'm I'm I'm I'm long
-magnesium you're carpet bombing Mages
-I'm big on magnesium right great for bow
-function great for I mean I don't know
-the last time I had a cramp in my life
-you know it's been years since I've had
-a cramp despite exercising in a really
-hot place like Austin Texas where I'm
-sweating like there's no tomorrow um
-whether you call it a supplement or not
-I take uh I I take um
-uh like electrolytes I take a element um
-which I should disclose I'm an investor
-in that company um so I I drink an
-element a day I take creatine
-monohydrate five grams a day I take AG
-most mornings oh and I take pendulum the
-probiotic got it y as far as I know
-there's no other probiotic that has any
-meaningful effect on the body outside of
-pendulum right pendulum is the because
-CU if you buy the argument that a
-probiotic for your gut needs to have
-Anor robic bacteria in it there's no
-value in giving you aerobic bacteria so
-you have to have something anerobic so
-acrania which works through the um glp1
-butyrate pathway is anerobic and
-pendulum is the only company that can
-make it I have no affiliation with this
-company I think you should have the CEO
-Colleen cutcliffe on your show um she's
-an actual scientist and she's fantastic
-and um um it's a really interesting
-story how they kind of developed this
-and how difficult it is to actually make
-an aerobic bacteria and so this is kind
-of an odd company because it's a
-supplement company but they have to
-basically adhere to Pharma GMP
-conditions to make it because of the
-anerobic Vats that you have to use
-infused with nitrogen to be able to make
-an Anor robic bacteria so anyway so I
-take three of their products I take
-something called glucose control I take
-polyphenol and I take acromania okay I
-think that's the list okay yeah I'll try
-and move through my list pretty quickly
-I may miss one or two things and I don't
-know maybe we'll put the list someplace
-online and fill in any
-gaps I definitely take AG ag1 you know
-I've my typical ad read I've been doing
-it since 2012 that's true uh take one or
-two servings a day three of I'm
-traveling and I'll generally do that
-first thing in the morning
-or in the
-evening um for me it's really about
-capping off the vitamin minerals that I
-might be lack lacking in my diet and
-also the whole adaptogen business I
-think and polyphenols and I'm a very
-interested in pendulum because part of
-the reason I take ag1 is for the gut
-health aspect I think just bowel
-movements are more where I'd want them I
-mean it sounds kind of uh weird to talk
-about but you just feel better when your
-gut motility is right I feel like it
-adjusts my gut motility so it's neither
-too fast nor too slow
-so that's first and
-foremost I take a quality fish oil
-either the one that AG makes or
-Carlson's in liquid form mhm that has
-that lemon flavoring and I make sure I
-get above one gram per day of EPA yep so
-that's usually a tablespoon sometimes
-two
-tablespoons I make sure that I get
-enough D3 typically from The Dropper
-5,000 IU per day approxim sometimes
-3,000 sometimes 7,000 I kind of play
-around that and I test my blood levels I
-also take methyl
-B12 and I also take Tonga Ali so I take
-one capsule of that in the early part of
-the day that has lowered my sex hormone
-binding globulin freeing up a bit more
-testosterone it's why I like it um and I
-take a couple of green tea capsules in
-the morning I drink yamate that's more
-of a stimulatory effect and I take the
-NM in powder form sometimes NR as well
-and again if I run out of that I tend to
-go long periods of time without I use
-element MH as an electrolyte so people
-are probably noticing this is all pretty
-basic I take in my case 10 grams of
-creatine monohydrate per day I sometimes
-forget to take it that's why I take 10
-grams I'll sometimes miss a day okay um
-and I certainly feel the effects of that
-in the gym because of the greater water
-volume in the muscles but there are a
-lot of data on creatine monohydrate for
-sake of either maintain paining or
-offsetting some of the cognitive
-dysfunction associated with sleep
-deprivation maybe aging altitude and
-some other things as
-well and then for a few months I was
-playing around with let's say um
-nicotine gums I stopped doing that um
-first of all I was dipping it and I
-ended up lifing for uh an entire episode
-of The Lex Freedman podcast and I only
-realized later so I stopped taking it
-also because it gave me a kind of a tick
-and off when I wasn't chewing it and
-then I felt like I needed to chew it and
-it's a little too stimulatory for me um
-before sleep I take magnesium 3 and8 I'm
-really bullish on magnesium as well
-appenine 50 milligrams which is
-essentially chamomile extract and
-theanine and occasionally I'll take 900
-milligrams in netl also um or instead I
-kind of mix those up and around and then
-I use a quality way protein as a protein
-replacement that kind of thing and I've
-played around with various things like
-Sheila G and you know sometimes get the
-sense that it's having an effect but
-then I'll stop taking it for long
-periods of time um you know there are
-very few things that I've stayed with
-for long periods of time and I basically
-just described what those are you know
-if ever someone were to design a
-supplement that would provide more
-energy all day long that wasn't caffeine
-I'd probably look to that but I ingest
-caffeine in the form of yerbamate and
-coffee I've played around with caffeine
-tablets you know taking you know 50
-milligrams of caffeine in tablet form I
-mentioned that only because it has a
-distinctly different feel than ingesting
-caffeine through liquid form it feels
-stronger and I don't know why that is in
-fact I there's a very well-known
-podcaster who drinks peppermint tea and
-takes caffeine tablets as a way to uh I
-don't know drink peppermint tea which
-sounds very nice and mellow but also get
-the stimulant effect so anyway that's
-pretty much and then I do a lot of
-things as I know you do mainly based on
-suggestions you've made about getting
-zone two cardio rucking weight vest
-walks and Hikes three times a week
-resistance training three times a week
-cardiovascular training one long one
-medium one short and I try to hit the
-sauna and the cold once a week and um
-yeah that's pretty much it um I think
-there are a bunch of other supplements
-that are really interesting and kind of
-fun to play with if one wants to like
-600 million Mig of alpha GPC or 900
-milligrams of alpha GPC in a Double
-Espresso prior to a workout you feel
-different it's a stimulant but I don't
-like to do that too often because of the
-increase in tmao that occurs and then
-you have to take 600 milligrams of
-garlic to offset that increase and you
-start getting if we believe tmao matters
-right if you believe tmao matters and um
-okay great even better I'll maybe skip
-the garlic so things like that I prefer
-to just eat garlic anyway um so there
-are a bunch of things like that that are
-kind of fun to play with as pre-workouts
-but yeah that's the core um supplement
-regimen and it's the one I've stuck with
-for
-gosh at least 10 years or in the case of
-AG near more than you know more than
-that
-so I should say because any discussion
-around supplements I think it's going to
-you know have people pricking up their
-ears to okay this is like a sales pitch
-or something I absolutely want to go on
-record the things you choose to do and
-not do are going to have much greater
-effect on your healthspan and lifespan
-that is the behavioral things in
-particular sleep exercise nutrition
-sunlight Etc than any One supplement
-that you're going to take so I do view
-supplements I think through the
-appropriate lens which is that they are
-indeed a supplement they are not
-necessary many of them are simply
-sufficient to serve as an insurance
-policy or to augment mental and physical
-health maybe longevity uh in ways that
-make it worthwhile given my disposable
-income that I want to devote to
-supplements but I don't think you need
-them yeah I'll go even more extreme on
-that statement everything we have talked
-about on this podcast today whether it
-be NR NAD nmn thumin magnesium this
-supplement that supplement all of that
-stuff while potentially mattering I
-would put in the category of was the
-Titanic serving LOB Lobster or
-steak
-look I I like steak more than Lobster
-that's a relative discuss exercise sleep
-nutrition emotional health is the
-question of what was the heading of the
-Titanic okay so I just want people to
-understand the magnitude of what we're
-talking about how you eat how you sleep
-how you train and how you take care of
-your mental health is the equivalent of
-what Direction was the Titanic going
-with respect to the iceberg all this
-supplement that we just talked
-about is equivalent to were they serving
-Lobster or were they serving steak and
-was the band playing this song or that
-song I'm not saying those things don't
-matter but just put them in the context
-of the direction the Titanic is going
-okay so I completely agree with you
-exercise sleep nutrition and emotional
-health not listed in any particular
-order Peter and I both completely agree
-those are the critical four
-before we
-close nrnm
-NAD and NAD in particular how do we view
-this is it a pathway that we should be
-focusing on in terms of supplementation
-or infusions for sake of extending our
-life my answer on that is no yeah I
-would say the same you know I I don't
-remember who said this but someone maybe
-it was Nim TB said don't tell me what
-you think show me what's in your
-portfolio like meaning people who
-pontificate about this stock versus that
-stock he's kind of like assuming it was
-him that said this he's like okay I I
-don't care what you're telling me tell
-me what you own that's going to show me
-your conviction so through that lens
-look I'll show you my conviction on
-exercise I'll show you what I do I'll
-show you my conviction on sleep this is
-what I do I'll show you my conviction on
-all these other things I mean I don't
-take these supplements full stop I don't
-take them because I can't afford it's
-not that I can't afford them it's not
-that there're any inconvenience to me to
-take them I passionately do not believe
-they do anything for me and why would I
-waste time money anything on something
-that I really don't believe makes a
-difference now again I am always happy
-to be proven wrong and I am very happy
-to say that two years from now five
-years from now we could be doing this
-exercise again and in the presence of
-new information maybe I'm not taking rap
-ay and maybe I am fist fulling you know
-NR and nmn possible I will I will
-reserve the right to change my my mind
-for the rest of my life in the presence
-of new data but as it stands today I do
-not take these supplements and I have no
-foreseeable plan to do so until
-information changes great thank you for
-that clear stance and the willingness to
-change it in light of new data Peter so
-good to sit down with you again and talk
-science talk health and in this case
-talk about the supplements that we're
-not going to take in addition to the
-ones that we do take we will do this
-again sometime very soon hopefully in
-Austin would love that
-thanks Peter thanks man thank you for
-joining me today for my discussion with
-Dr Peter Atia if you're learning from
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-[Music]
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