222 ‒ How nutrition impacts longevity | Matt Kaeberlein, Ph.D.

hey everyone welcome to the drive podcast i'm your host peter etia matt it's great to finally be able to do one of these in person with you we've done a lot of these remotely uh we're taking advantage of the fact that you're in texas for filming a documentary about aging which is pretty awesome so when we knew that this was going to happen we said well let's take advantage of you being here and let's let's come up with something that we both talk about so much over email which is to say i don't think a

week goes by that we aren't exchanging an email about some aspect of the relationship or the interspace between nutrition and longevity uh does that speak to our ignorance does that speak to the ubiquity of such content i don't what does that say about it yeah i mean well i think you know it's an it's an area that a lot of people are really interested in and and um and it certainly intersects with uh popular culture so you know i i having been in the aging field for for a long time i certainly recognize how complicated

that biology is and i think the biology of nutrition is equally complicated and you know when you get at the interface of those two um it's really hard i think sometimes to draw a definitive conclusion so a new paper will come out you know and and you usually read the papers before i do and you're like hey what do you think about this and and then you know we throw it back and forth but i think it's um it's hard sometimes to get to concrete answers so certainly we'll try to do that today but i

also think you know this will be a little bit of a theme that that there are many things we don't understand yet about optimal nutrition and how that intersects with optimal health span yeah and you and i have spent so much time on the podcast speaking about the molecules right the molecules right um of course our favorite being rapamycin but but all sorts of them right we recently talked about nmn and rnad we've talked about metformin and you know basically it's easier almost to ask the questions in the stand from the standpoint of geoprotective molecules

because the intervention is much cleaner yeah absolutely like are you taking this drug yes or no and of course what's interesting about that and i think it speaks to what we're going to talk about today think about the one drug among those that stands out which is rapamycin even within that just i think yesterday or two days ago you and me and david sabatini had a back and forth about timing of the dose you know frequency within the dosing schedule the dose itself i mean even with a drug it's still very complicated to say well

what about during this phase because the study i think we were talking about was looking at mice and it was asking the question of early exposure of rapamycin later in life constant dosing intermittent dosing yep that's for a drug and we're still struggling to piece it together now imagine trying to ask that question of your food yeah and i mean i think you know we'll obviously talk a lot as well about the animal models and what they can tell us about you know what might affect human aging but the big piece that gets lost with

the animal models on top of all that complexity is the environment right so you know we keep these mice in a well-controlled environment usually relatively pathogen-free and they live in that same environment their entire life now you think about the human experience where our environment is extremely complicated we're constantly getting bombarded with all sorts of you know challenges and and uh infectious agents and our environment changes dramatically throughout our lives in fact you know maybe this is something we want to touch on a lot of the epidemiological studies on optimal nutrition are from 20 30

40 years ago right the average human environment is very different today than it was when those studies were done and how does that potentially change the interaction between nutrition and health outcomes i think it's a really interesting but challenging question to to address to anybody's satisfaction honestly yeah that's actually a great point and i made a similar point on a totally different topic which was all of the studies that use uh that talk about cancer screening are are very backwards looking by definition right you have to look at controlled trials that were done in the

past but the technology of radiology is changing so much you know radiology is a very you know physics-based uh field of medicine and so when you read a study that talked about you know mammography for screening well and it you know was a 15-year study right so it's a great study well by definition it was done sort of based on 30 to 20 year old technology that by the time the study has been completed you have the follow-up data you write up the paper it doesn't necessarily represent what's happening today and and that's that's a

huge challenge of evaluating that type of data yeah and and in people because we age so slowly you know there's really not a lot you can do about that if you want to try to do correlative longitudinal studies of aging right because people age so slowly the people who are in their 70s today were in their 30s 40 years ago and so the environment that they were in is probably quite different than the environment that 30 year olds are in today so there's not a great way around that i think the key is to recognize

that limitation and be potentially even more careful about assuming causation from correlation over many decades yeah so as a bit of a mia culpa on the topic of nutrition which is really my least favorite topic despite the fact that it keeps coming up on this podcast and it's unavoidable as i reflect back on my own understanding of this topic the strength with which i held convictions over the past more than decade i would say i've i've gone in reverse right i have looser and looser convictions as time goes on and i view fewer and fewer

things with certainty as time goes on and you know when i think about this problem clinically i have what i would consider to be an incredibly simple framework which is if i'm looking at a patient i'm asking a question are you over nourished or undernourished are you under-muscled or adequately muscled and then on so that's a two by two right and then are you metabolically healthy or not that's sort of my first order question now one of those spaces doesn't really have too many people in it the um adequately muscled undernourished metabolically healthy bucket doesn't

metabolically unhealthy bucket doesn't really exist so it's not these aren't people aren't uniformly distributed in those buckets but it's a pretty good way to sort people and you can't sort someone by looking at them into that bucket but by looking at them doing some functional testing looking at their biomarkers and that might include also doing things like a dexa scan where you can actually get some objective data you can pretty quickly figure that out and the reason we think that's important is it helps us understand do you need an energy deficit do you need an

energy surplus what's your protein intake need to be to achieve that in combination with your calorie needs and you know the hardest of those to treat by far is over uh nutrition under muscled and unfortunately that's a very common phenotype that's a lot of people these days yeah no i mean i think that i think as a general approach first order approach that makes a ton of sense um and i think you know one of the things that that that allows you to recognize right is that that the optimal strategy isn't there's no one-size-fits-all i

guess would be the way i'd say it right different people are going to have different needs nutritionally and what works really well for one person you know may not work at all for another person and so i think i think you know kind of looking at it at that level um allows you to to not have to try to say everybody should be doing x right um so i think i think that that is pretty similar to the way i think about it obviously i don't practice medicine and i i try not to make recommendations

for what people should do but in my own life that's generally the way that i try to approach it as well and i and i hope i'm doing okay you haven't tested me yet so you can't tell me which bucket i'm in but i think i'm doing okay for my age uh with my my nutritional strategies and the other thing that i sort of have have realized similar to what i think you were saying before is that you know it's an ongoing learning process and so i think it's really important that we be willing to

change our beliefs about nutrition and other aspects of health as more data comes in um so i think if you take that strategy then you can you can be open to the possibility that what you believed 10 years ago you know might not have been exactly right and maybe we need to to tweak it a little bit um you know my personal view on nutrition i i'll i'll be honest i have real trust problems with nutritionists and i think it you know in part it stems from i remember very vividly when i was i think

i was probably in my early 20s and i i read you know one of these diet guru books and it was sort of the the sort of the the theme this was i'm going to date myself but this was you know early 90s i guess um the theme back then was you know you could eat anything you wanted as long as you cut out the fat right you could have this really high simple carbohydrate diet just keep it low fat and you know you'll be fine and we now know that's that's exactly wrong right i

mean so i think you know i can't help but look at a lot of what people you know the the the the what i would put sort of on the the fad diet side the diet gurus what they're saying today how do we know 10 years from now we're not going to look back on that and again be like that just makes no sense i think some of us today can look at some of what's out there and say that just makes no sense but you know i think again this gets back to the to

what i was saying before it's not that i it's not that i would say nutrition sciences across the board low quality i think they're actually really good scientists doing really good work in this area it's just a really hard problem and i do think to some extent the biology of aging and the biology of nutrition do share that and that they are these are extremely complicated biological systems that we're trying to understand in the in the context of sort of this this changing environment over time right and so so i don't i don't blame the

scientists i just think we have to be really careful to recognize what the limitations are and not draw really strong conclusions like everybody should eat you know a low protein diet right that's kind of one of the fads that are out there today i think that's that's a mistake to to recommend across the board you know nutritional strategies for everyone um i guess the last thing sorry i'm talking a long time here but i guess the last thing that what you said you know makes makes me think of as well and i think this is

really important because people lose sight of this is you know exactly what you said if you can be you know somewhere close to uh optimal nutritional intake right just say total calories regardless of composition body composition is somewhere close to where it should be that's that's a big chunk of what you need to give yourself the best chance of being healthy going forward right you don't have to optimize every single thing now i know you're all into optimization and i respect that about you i think if you can do that that's great but you don't

have to to get most of the benefits and so i think starting from that big picture perspective allows you to get most people most of the way there and then when they're most of the way there you can focus on how do we get that last 10 20 30 whatever it is actually i i i couldn't agree with you more matt and and i would argue and i do argue now in a very different way from where i used to be a few years ago you know there are most things in my life where i

don't like the 80 20 principle you know uh my good friend tim ferriss like he's the king of this right he's the king of how can i get 80 of the learning with 20 of the time and i've never seen anybody who can do it like tim like the guy can learn a language in a month he could be 80 proficient in a language in a month right um i'm the opposite i'm the guy who loves the tail i love the asymptote i love the perfection of something i would say in nutrition that is exactly

not where my interest lies i agree that you can just get 80 of this right by focusing on you know exactly what we've talked about and the the details the complete optimization are not worth it yeah and it's instead better to put that effort into exercise that's where i think if you're going to really go down the rabbit hole and put more of your mental energy more of your time and more of your focus into something you have far more of an roi on the exercise front than eking out incremental value on the nutrition front

and i've joked about this before other guests on the podcast lane norton and i have had rifts on this back and forth the people who sit there on twitter which i realize is not a representative sampling of the world it's simply a an annoying vocal group of people who will waste endless hours debating the finer points of their dietary pet peeves who can't do 10 pull-ups is amazing i mean there should be a rule that says if you can't dead lift twice your body weight and do 15 pull-ups you shouldn't be allowed to pontificate endlessly

you're not allowed to be out to the finer points of nutrition you know we can we can talk to elon about that maybe that can be a new rule um yeah okay so so let's so look i think we've established nutrition matters here i mean but i think at the same time you know i think david allison said it once to me um it's amazing how little we know about this subject matter kind of rehashing what we've said we know that too much and too little are bad um and for most of our existence we

we were worried about the too little problem that the too much problem has become a relatively recent phenomenon right and they're bad in different ways like acutely chronically they have different limitations um we know that certain things are toxic right acutely or chronically um not a lot we know i mean with definitive clarity there's not a lot we know beyond those things um so one thing that seems to be true [Music] is at least from the animal literature caloric restriction seems to reproducibly improve lifespan and so so let's let's kind of talk about how that

came to be as an understanding sure yeah so i mean this um this area of research is actually quite old so that's 100 years ago yeah the first experiments were published in the early to mid 1930s right which means they were probably started in the 1920s right so almost 100 years ago people were going down this this line of thinking of asking you know what is the effect of um significant restriction of calories on the aging process in mammals so the early studies were all done in rats and actually if if i remember correctly these

studies were originally designed from a developmental perspective so they were really thinking about malnutrition and its effects on development and as a byproduct made the observation that yes when you restrict calories in a in a rat early on in life they have a smaller body size but then if you let them live out their entire lives this is in the laboratory and i think that's really important to keep in mind you know they live 40 50 longer so we're talking really significant increases in lifespan and then the other thing that was appreciated pretty quickly was

not only are they living longer but they seem to be healthier as they're living longer so you know this concept of health span and the period of life that is you know spent in good health free from disease and disability it seemed as if caloric restriction was not only increasing lifespan but but also extending health span so you know that led to obviously a large body of literature since then studying the effect of caloric restriction in not just rodents rats and mice but also all sorts of simpler organisms invertebrates like fruit flies and c elegans

and yeast and the common theme seems to be that again starting from laboratory conditions if you restrict nutrients by a whole variety of different different methods um you can increase lifespan and apparently increase health span proportionally at least proportionally so there's a lot of nuance there a lot that we can dive into and to unpack but i think that's generally the take home right is that over and over and over again across you know the evolutionary distance we're talking about is much much greater than the evolutionary distance between rodents and humans right so so over

a very wide evolutionary distance in pretty much every organism where it's ever been studied you can find evidence that caloric restriction slows aging again there are there are cases where that didn't happen where lifespan wasn't extended where lifespan was shortened maybe we want to talk about this at some point the interaction between genetics and environment and caloric restriction but in general that is the the take-home message is caloric restriction can slow aging in laboratory animals pretty much everywhere where it's been studied um the one i think question question that some people have is whether that's

true in non-human primates and so they were yeah so i was just about to say i was gonna say before we get to nia wisconsin yeah which is perhaps the single greatest experiment that's ever been done to test this hypothesis both in terms of its duration level of control and proximity to our genome let's spend a moment on that before we do any things that come up from the rodent studies that are worth talking about so for example one of the things that i think is always important to point out is there's a very particular

death that tends to fall on laboratory mice they have you know if you look at the death bars for humans there's much more heterogeneity yeah but the leading cause is atherosclerosis now that's true in the united states it's true across the globe so when you mix and develop and undevelop it doesn't matter laboratory mice aren't that way wait they die of pretty much one thing and one thing alone and that is actually it's euthanasia but i know where you're going yeah yeah yeah yeah cancer right they all die right so so certainly every uh old

mouse at time of death will will have cancer and again because of the way animal studies are done usually you have defined endpoints where when a mouse reaches that reaches that end point they have to be euthanized but the the expectation is that it if they hadn't been euthanized they would have died from the cancer so i think you're absolutely right they're not dying from atherosclerosis when you look at their arteries they're not littered with plaques the way ours are at least the commonly used inbred mouse strains that is definitely true for there are you

know this is maybe getting in the weeds a little bit but there are certainly mouse strains that have been designed either transgenically or through selection to develop other pathologies that will shorten their lifespan but if you let a typical mouse strain in the lab live out its natural life it will have a very high tumor burden at the end of life and most likely you know i guess i should know this i don't know exactly i'm guessing 80 percent of yeah i think it's about seventy five eighty percent would it would die from cancer so

it's different from humans in that way and i actually think this is you know this is a legitimate um criticism to some extent of the caloric the interpretation of the caloric restriction literature that is could it be the case that really what caloric restriction is doing is preventing cancer and that's why you see these big increases in lifespan and i think that's really difficult to definitively answer one way or the other what i would say is you know mice do develop functional declines in every tissue and organ as they age very much like people do

so you know a person may die from cardiovascular disease but at the same time if they're in their 80s their kidney isn't functioning as well their heart isn't functioning as well their brain probably isn't functioning as well so mice show all of those same declines in function with age and caloric restriction seems to delay delay prevent those declines as well so yeah maybe the lifespan effect is primarily due to cancer but caloric restriction is having an effect apparently on the underlying biological aging process um in all sorts of of different ways and i really like

the functional measures a lot of people in the field these days are really enamored with you know the aging clocks epigenetic clocks biochemical markers i think those are all useful and important but from my perspective what really gets my attention is if somebody shows that the heart is still functioning like a young heart or the immune system yeah let's uh i wasn't planning to go down that rabbit hole but since you brought it up um can you convince me of the utility of the clocks absent the type of data that would actually demonstrate longitudinally their

benefit which to my knowledge we really don't have yet yeah so i would say a couple things on that i think we need to be precise and what we mean when we talk about the clocks because there's lots of flavors of clocks right most people these days if you just say aging clock that what they really mean are the epigenetic clocks that are showing you know the the characteristic changes in the epigenome the epigenetic marks that are seen with age again in every in every organism where it's really been studied um you do see these

characteristic changes in the epigenome with age and so i would say one place where their utility is clear at least to me is as a chronological measure right now you might ask okay why would i ever want to you know use an epigenetic clock to to tell my chronological age i know how old i am right but forensics for example might be a place where that's useful their crime has been committed they want to know with some level of precision how old the the perpetrator is you could use an epigenetic clock for that reason um

you know in in in my world as part of the dog aging project there are many dogs you know that are rescued an owner might want to know their age so i think that is a that is a real use and clearly the clocks will work for that i think really what you're asking though is can i convince you that the epigenetic clocks and potentially other types of clocks are actually measuring biological aging correct and that's a harder in my mind that's a harder thing to prove and personally i have no interest in convincing you

of that because i'm not convinced right so i think this is an area where the field is in flux a little bit and there are certainly scientists who i respect a lot in the field who believe you know at their core that these epigenetic clocks tell us about biological aging or can be used to tell us about biological aging then there are people like me who want to see the proof and i think that the proof is really being able to show at an individual level that could be in a mouse could be in a

person it could be in a dog at an individual level you can predict someone's biological age at some point in their life and with some level of precision predict what's going to happen in the future what are their future health outcomes how are they how long are they going to live nobody has done that yet what they've done comes close i guess so what has been done is to look at longitudinal studies in people where we have samples from people 10 20 30 years ago measured the epigenetic profiles of those people 10 20 30 years

ago and ask how well does that correlate with mortality outcomes for example in the future and they they do work to some extent i think people will debate how well they work are they any better than other markers you could look at um in predicting mortality i think that's unclear but there is some correlation there so you know again i think it really depends to some extent maybe on how skeptical you are i'm a skeptic by nature and and i want to actually see the proof um i guess the last thing i would say about

this i'm i'm talking mostly about the epigenetic clocks maybe it's worth talking about other types of clocks that people can make the other thing i want to caution people the on though is assuming that the epigenetic clocks are the only important thing about aging there is again you know a small number of very vocal and and uh popular people in the field who talk as if changing the epigenome is going to change everything about aging we have no data to support that there's like i just have to say it that is not true at this

point we have no data to support it um if what we know about the biology of aging is that epigenetic changes are one of depending on how you categorize things you know eight or nine or ten molecular processes that seem to contribute with that the field has reached consensus on it's only one of those things is it possible that it it is sort of in a hierarchy the most important and drives a lot of those other changes yes that's possible we don't have any data to support it so this idea that reversing the epigenome is

reversing aging is at best an exaggeration at worst an outright lie i mean it's just not true how could that be what what a set of experiments technology-wise would you need to be able to do to even test that hypothesis stay in a mouse right we're close well maybe close i guess i should qualify that a little bit um conceptually we're close so there have been these factors called the yamanaka factors that can reprogram the epigenome so this has been done in cells so if you take cells in culture in a laboratory and you passage

them many many times you can see changes in the epigenome just like you might see changes in the epigenome in an animal in tissues and you can put these reprogramming factors into the cells and turn them on now there are four yamanaka there are four yamanaka factors and people but people are trying different different cocktails adding some other stuff in taking some stuff out but yes there are the four classic yamanaka factors and what those factors do is they basically wipe clean the epigenetic changes that have happened over time and also what's amazing is that

they restore those cells back to uh if you take it far enough back to a pluripotent state so essentially you get you know virgin new cells that could differentiate into any cell type in the body right so it's been known for many years what is relatively more recent over the last you know eight or nine years are people are trying to express these reprogramming factors in an animal so so instead of doing it in cells in the laboratory do it in an animal and i think the most compelling work um uh is work in a

premature aging model of mice so it's called a progeroid model um where they're very short-lived they're very sick but these these reprogramming factors can you know extend lifespan by i don't remember what the exact numbers are but a significant amount maybe 40 50 50 well which seems like a lot except you have to recognize these mice live you know maybe 25 of the length of a normal mouse right so they're very sick so but but there are impressive changes that happen that that are consistent with the idea that you fixed or made something better okay

so the experiment to do would be to express these reprogramming factors in an old mouse and make that mouse young again okay and this is where i think the exaggeration i'll use the nice word has gotten ahead of the actual data so what has been done is showing that in one or two maybe three tissues you can see an improvement in function the most impressive i think is work from david sinclair's lab where they they use this optic degeneration model absolutely so uh degeneration of the eye showed that they could reverse that with these reprogramming

factors and then and then tried to do the same thing in an old mouse and there was at least you know the data was was mixed but i think pretty compelling that you could to some extent regenerate the optic nerve in an old mouse okay so that's certainly impressive i think um exciting but nobody has ever taken an old mouse and and turned it into a young mouse and when so when people start talking about reversing aging right that implies that you have taken an old animal or person and to some extent biologically made them

young again that hasn't happened so what i would say needs to happen to really convince me there are two things so i would be convinced that that that it's that this is um uh useful potentially therapeutically and important i'm actually already convinced it could be useful therapeutically um but i would become really excited if somebody could do as good as rapamycin in a mouse so i'm not asking for much in my view right we know rapamycin can extend lifespan 25 percent at least we again dose hasn't been optimized but 25 let's stick with that and

you can reverse functional declines in many tissues right so show me you can do that with reprogramming and i'll be excited nobody's done even that yet yeah show me you can take a two and a half year old mouse make it look like a one-year-old mouse and then it lives to be five years old i'll be really excited look i'll be all on board i might even come on your show and apologize for saying that people were exaggerating although they are exaggerating now but but i think the um the enthusiasm has just gotten so far

ahead of where the science is how is so let's go back to kind of the maybe help folks understand what the yamanaka factors are doing and how one can be sure that even if you fix the aging problem you don't create a new problem so if the objective is i want to take the dna as i had it when i was young right so when i was 20 this is what my dna looked like now that i'm 50 it looks different it has literally these methyl groups that are sitting directly on the cysteine you know

residues like they're it's literally on my dna okay we want to take those off maybe well so first of all it's important to understand why that's even a problem right why people think so why is my 50 year old crappy dna not as good as my 20 year old dna so again this is you know taking a step back to sort of basic basic biology right so so the dna right is where all the information is but then that dna has to get turned into rna that's called transcription or gene expression we'll just call it

gene expression and then that rna has to get turned into protein and in general it's the protein that does the work right so what these epigenetic changes the methyl groups that you were talking about do primarily we think is affect uh expression of the genes so basically what you're seeing with aging we think is a shift in the epigenome that leads to certain genes being expressed that shouldn't be and certain genes not being expressed that should be and i think there's a little bit of a debate about which is more important right now but it

probably doesn't really matter right so the idea is you're getting things turned on and turned off inappropriately as we get older there's a loss of regulation which probably contributes to a loss of homeostasis and homeostasis is i think a really useful way to think about aging right if you're healthy you your body is generally in homeostasis right and what happens as we get older is it becomes harder and harder for our body to maintain homeostasis when you get out of homeostasis if your your defense mechanisms are working right you can get back in right so

you get covid for example your immune system works you're out of homeostasis but you come back in and then you're okay again i think as we get older it gets harder to come back into homeostasis and that's why we start to see pathology and mortality so so let me differentiate two states of pathology um my five-year-old son was on his scooter two weeks ago going down the steepest hill in the world which i had no idea how i didn't see that he was about to do that like face planted and when he came up all

i could think is how quickly can we get to the hospital i mean it was a bloodbath yeah i'm not making this up matt six days later there was one little tiny scar eight or nine days later you you you would have had no idea this kid ripped his face off on the pavement he's five i get a cut it's like nine months until the scar is gone so there's a very clear distinction between a five-year-old's dna and a 50-year-old's dna in terms of how he can literally make new proteins that are better than my

proteins yeah let me let me stop you there just for a second because i think this is actually the crux of the question right you said it's a different in your difference in your well i'm asking i think what i'm trying to get at is yeah how much of because that's a clear case of the protein that he makes is better than my protein right he's making much better proteins certainly functions better absolutely yeah so so um i guess what i was getting at though is the question one question i think that's really important here

is there can be changes to the dna to the sequence right so the sequence of the dna is the information yep right those are called mutations and those accumulate as we age and that's that's honestly what drives a lot of cancer right yeah so we've known this for a long time the epigenetic changes are sort of on top of that right yeah and while it more regulates expression right i'm wondering how much that factors into the example i just gave it's a good question i'm sure it does to some extent absolutely what else explains why

his collagen is so much better than mine what are the other factors that go into that i mean i think there's there are probably many reasons why um uh healing declines with our ability to heal your claims with age i actually again i mean i know we've talked about this before i think inflammation is a huge driver of uh our loss of ability to recover as we get older so you know all sorts of things go wrong if you have a high level of sterile inflammation in your body including the ability of stem cells to

function and a lot of a lot of injuries require stem cells to function to build back you know what what's been broken so it's complicated i guess i would say but but that could be that i have more senescent cells and more senescent cell factors that are impairing the ability of cells to heal just to throw a wrench in that though there's actually a body of thought that senescent cells actually promote wound healing so it's again this is where the biology is so complicated um but i think the the the crux of the question we

started from is if you only fix the epigenome do you feel whatever you fix all these things do you fix everything and and and you know nobody knows i think is the fair answer i think i would be um shocked if that was the case that epigenetic changes drive all of aging i think the but it's possible i think we have to be open to that idea that epigenetic changes sit on top of or upstream of you know the other hallmarks of aging first of all let me say one thing it won't fix everything you

will not fix mutations by fixing the epigenome okay the question is do do mutations do they happen uh with enough frequency to be a major contributor to functional declines that go along with aging certainly cancer you can you can point out cancer for sure but let's now talk about something else which is near and dear to your heart no pun intended but ejection fraction again because you study dogs uh not only is cancer a big problem but so is heart failure so now we're dealing with a muscle a set of cells that really aren't being

turned over the way skin is so when we think about the example of my son when you think about your gut epithelium being sluffed off when you get sick when you think about your fingernails and your hair it's really easy to think about those things as rapidly being turned over but neurons cardiac myocytes these things don't get turned over a whole heck of a lot so what is it about reprogramming that we think is going to fix an aging neuron or an aging cardiac myocyte yeah so i mean again i think again this is an

area where the biology of what's really happening at least to my knowledge is so poorly understood that i think the real answer is we don't completely know i'm going to give a very simplistic answer um uh which is that what people are trying to do is not reprogram all the way back to the pluripotent state so it's called partial reprogramming right so so which would be pretty dangerous well that's what i was gonna say if you're a single-celled organism no problem going back to the the pluripotent state right you can then you can then you

know start over in a complicated animal if we reprogram you back to the pluripotent state that's not gonna end well for you no right so so i think the idea is to go back far enough that you uh restore the epigenome to its uh pristine state young state and then hope that when you do that you restore gene expression to where it's supposed to be maybe one way to think about it is you restore the homeostatic mechanisms to a more youthful state where then the homeostatic mechanisms that all of our cells have can basically clean

up the rest of the mess right because we know as we get older for example we all accumulate damaged mitochondria right changing the epigenome which is the nuclear genome isn't going to fix anything that's wrong with your mitochondria directly but maybe by fixing the epigenome you restore the homeostatic mechanisms that then maintain mitochondria in a healthy state and you can fix the damage to the mitochondria right so that's the that's the concept and again you know i would say the evidence is suggestive that if you do it just right you can improve function in at

least some aged tissues and or organs by partial reprogramming i've yet to see anything that convinces me that anybody has made you know an old heart into a young heart in an old animal with partial reprogramming in in the heart but you can't improve function i would also say the same thing's true with rapamycin right we don't i would not argue we see that short-term treatment with rapamycin in mice makes an old heart function functionally to some extent more like a young heart i would never argue that we have you know taken that heart and

now it's young it's just in an old body we don't know that and that's hard to prove but i think you can you can see some evidence that it should be possible with partial reprogramming to do that and you know the question is will it work everywhere will it work in some tissues and organs and not in others we don't really know the brain is the one so let's just say 10 20 years from now people have figured out a lot of the complexity we're starting to move these things into the clinic you know maybe

maybe we will see really um uh large effects on lifespan and healthspan in mice what i've yet to hear anybody give a convincing explanation of is how you do that in the brain because so much of who we are and what we are comes from our experiences and our memories and and so how do you ensure that you can reprogram somebody's brain in a way that isn't going to change that and i i just think that's going to be a really hard problem to overcome but you know maybe somebody will figure it out there are

there are tons of really smart people working in this area lots of resources going into this area so i think it's exciting again my my big um concern is that we don't mislead people into thinking that you know that we're close to reversing aging um and i think it's a problem from the perspective of the general public i think it's a problem from the perspective of the scientific community science other scientists look at that and they're like this is snake oil right this is just not true yeah and my my concern with it is actually

in terms of the impact it has on people yeah which are hey this is awesome this thing's going to get worked out i can do whatever i want i can do whatever i mean literally yeah it's like i can sort of do what i want because in 10 years they're going to reprogram me and my view on that is even if that is true yeah or even if you have a high degree of confidence that that is true how would you not hedge right like you know again hedging is such an important part of how

companies manage risk so the difference between good companies and bad companies when it comes to risk management is everything that's why some companies do really well in economic downturns and others don't yeah it's basically about risk management and a very important part of risk management is indeed hedging so if we think of ourselves each as little companies so you know you're the ceo of matco i'm the ceo of petco um i can't think of a more important asset within my company to manage than my own life yeah right like you know sure you know do

i have enough money yet you know do i you know have enough fun yeah those are all important assets but like existing would be the number one asset and to not take a risk management approach of hedging to that is insane and yet what i see is so many grand promises of this stuff and nobody's sort of paying attention to what they eat or how much exercise they do because i don't need to this is going to be worked out so so the thing that i always find amazing is some of the most vocal advocates

for this stuff like don't have an ounce of muscle on them don't have you know they're overweight or whatever like they don't look healthy yeah and i'm like guys you can do both right you can you can you can believe that in 10 years we're going to fix this problem but you could still you know actually care about your health yeah no i think that's a really important point and um you know having again been in this field for a long time now i i think you can just look back you know over the last

20 30 years and look at predictions people made on how fast these things were going to come along and get into you know the clinic and none of that has happened right so i totally agree with you i i guess also being you know in the center of it i i take a view of again pretty strong skepticism when people say this is going to happen in 10 15 years i honestly have not appreciated that there are maybe a lot of people out there looking at what they read you know in the new york times

or on cnn and thinking to themselves oh i don't have to worry about this this is going to get get worked out so so my advice would be don't expect major changes in treatments to improve lifespan and health span in the next 20 years and that doesn't mean i'm not optimistic i think there are opportunities there it would not surprise me if we do see some of these things get into the clinic but i certainly wouldn't expect it because there are so many barriers that we don't yet appreciate there are lots of barriers just in

moving something through the clinical trial process i think the the reprogramming stuff is a perfect example so you actually alluded to this earlier right are there are there potential side effects right absolutely you push it too far right you reprogram too far you're gone we know that can't certain types of cancers are a side effect of this partial reprogramming in mice again it doesn't mean it can't be worked out but there there are really reasons i think to be concerned that this is going to be hard to implement therapeutically the other thing i would say

even if those things can be worked out the fda is going to be extremely skeptical of this kind of approach so you know as people move these through the clinical trial process they are going to have to show with really rock solid compelling data that these these reprogramming strategies are not going to cause significant side effects so i think it's a long road before we have you know reprogramming strategies to get into the clinic maybe somebody will identify a small molecule that can do some of this and i know people are working on that maybe

that'll be an easier path but um but for now i think it's gonna i think it's gonna take a while and that's that's the best case scenario that's if we really can you know partially i'm going to say partially reverse aging reverse aspects of aging um it's still going to be a long road and i wonder if the first wins are going to be things like what david sinclair has done where you've got one very niche application i think another one that would be amazing would be osteoarthritis like if you could reach if you could

figure out a way to regenerate human cartilage yeah um without joint replacements you know again those are huge wins that seem at least a little more feasible but again i i agree with you i think this stuff takes four times as long and costs four times as much yeah as we think well and i mean you know building a house yeah and you and i are i mean honestly we're pretty lucky right because we know about a lot of this stuff we actually can start practicing some of this stuff like rapamycin before it gets out

there right again i'm not i'm not recommending anybody take rapamycin necessarily without talking to your physician first but you know we know this this stuff and we i think have at least you know a pretty good idea of the relative risk reward but in before it gets out to where you know it it hits the the of the mainstream right from a clinical perspective yeah it's a really long path i totally agree with what you said though about um uh specific indications where you can target it very precisely hopefully um and where there's no other

solution currently right i think those are opportunities um that's exactly the strategy that people have tried to take with analytics right these molecules that will clear senescent cells and even that's been hard right i mean unity is the the the sort of largest uh company in in this space and their first clinical trial for osteoarthritis failed right so now they're looking at the eye because again it's it's a it's a nice indication where for some of these eye diseases there isn't any solution and you you can in principle target it quite precisely to the eye

so yeah i think that is exactly the strategy that people will be taking um and hopefully it'll be successful um i mean look i i i i want this stuff to work i just uh i try to be a realist at the same time yeah i guess the the way i would kind of describe this to people is if you want to bring it back to a financial analogy it's a lottery ticket and so if your entire financial planning system is based on winning the lottery the odds that you're trying to win are pretty low

instead if you're going to play the lottery play it in the context of an otherwise great saving and investing strategy yeah and i guess the other thing i would add to that is that again this is what we talked about before you don't have to do everything right right get 80 of the way there right which nutritionally i don't think is i mean for some people it's very challenging but i think most people could do that uh exercise you don't have to you don't have to optimize your physical activity do something right and that'll get

you most of the way there so yeah i totally yeah the exercise curve which we've covered a lot in previous podcasts um you get most of the benefit going from you get i would say literally 50 of the benefit based on at least the the the so-so epidemiologic data about 50 of the full benefit of exercise is captured going from nothing [Music] to about 15 met hours per week so uh you know that would be depending on you know 15 mats times one hour would be one way to get there but in reality that's no

one who's that unfit is gonna do 15 minutes but that would be like three hours a week of five yeah to put that in perspective and five mets is like a very very brisk walk or a slow jog right you know something to that effect so you get a sense of like 15 met hours per week is but by extension i do about a hundred met hours per week of exercise yeah i think of everything in terms of med hours but the point is that you can get depending on the study 30 to 50 of

the benefit going from being completely sedentary to 15 met hours per week is pretty amazing which is a big benefit right and again it's sort of remarkable that that information isn't out there and for the gen most people in the general public don't know that right yep so i you know i don't know what the solution is i think you're obviously doing a great public service by trying to get that information out there but um it's unfortunate because i think again you know if most people understood how much benefit they could get you know from

from just getting out and moving a little bit maybe a lot maybe three hours a week is a lot for some people but the magnitude of the benefit compared to the effort that that you put in um i think most people just don't know that and and it's unfortunate so let's go back to the cr stuff so what do we know about the effect of cr in the laboratory animals on the immune system right so it's a little bit complicated um uh so first of all laboratory uh animals in the laboratory are kept in in

what's called a specific pathogen-free environment so that doesn't mean there's no pathogens but it's a relatively low pathogen in environment where they are not obligated to really use their immune systems against all the challenges that you know we would face in the real world so one question has come up uh are animals that are on calorie restriction immune compromise and again i think the data's a little bit mixed but certainly people have there have been studies where people have done pathogen challenges on cr animals and they respond better at least the old animals respond better

than than age-matched ad libitum fed control so ad libitum just means eat as much as you want um but then for certain types of challenges they the caloric restriction clearly causes a deficit so yeah the sepsis experiments are pretty clear with the cr animals compared to controls when you induce sepsis in them the cr animals die much more quickly right and so of course the obvious uh implication of that is that maybe cr would impair immune function in people and lead to higher risk of all sorts of infectious diseases and this this gets additionally complicated

though by the the question of you know optimal cr with optimal nutrition so you might sometimes you'll see this cron c-r-o-n right caloric restriction with optimal nutrition or cran caloric restriction with adequate nutrition right so that that can be done in a mouse right we can control all of that so we make sure that they get all the micronutrients and vitamins that they need when they're on this cr diet when you move into the real world and people start practicing caloric restriction that all goes out the window right like i would if i wanted to

do caloric restriction off the top of my head i wouldn't even know what to do to make sure that i'm getting optimal nutrition right and so in that state where you are cr without optimal nutrition i think that's where i really become worried about the side effects particularly as as you raised immune deficits because you may not you may not be be getting the nutrient value or the specific micronutrients and vitamins that you need to maintain a functioning immune system sure you may affect some aspects of the biology of aging in a way that you're

aging biologically more slowly that doesn't matter if you get influenza and die right so again i think that's an additional complication that comes into play when we start talking about we haven't talked about all the other you know anti-aging nutritional strategies when we start talking about recommending those nutritional strategies to the general public based on solely on mouse studies i get really concerned because of this environmental complexity that humans live in um not and we haven't even talked about the genetic complexity right so there's all sorts of things that are just different about laboratory animals

compared to people living in the real world and then what can we say about frailty sarcopenia as it changes in an animal in a cr environment and and can that be extrapolated also yeah so i think it's it's pretty clear i think that um uh most much like rapamycin most functional measures of aging seem to be preserved in calorically restricted animals including measures of frailty and measures of sarcopenia and you know this the same thing again is true with rapamycin this actually surprised a lot of people when the first studies were done because you know

the expectation was because mtor plays such a big role in muscle synthesis that if you inhibit mtor with rapamycin or caloric restriction which is a potent inhibitor of mtor that you would actually uh see accelerated sarcopenia and that just isn't the observation in laboratory animals again we have to be careful not to extrapolate to people but but it doesn't seem to be the case that you lose muscle muscle mass and function in the way that people would define sarcopenia i think the important complication here is that all of the caloric restriction studies that i'm aware

of when they look at muscle function normalized yeah and the calorically restricted mice weigh substantially less than the ad libitum fed mice usually i think it's on the order of 30 35 yes so yeah so it's usually grip strength normalized to weight right so what you're actually seeing is that the calorically restricted mice have maintained muscle function proportionate to their body weight and and i don't know the answer to this but it's something that i thought of when we were talking about this show um you know is let's just say you did that in a

person right so you've got you would you would be able to answer this i'm sure you've got a 60 year old person you know who needs to lose 30 of their body weight but of course you want to maintain their muscle mass right their muscle function would it would you view it as a good thing or a bad thing if they lost 30 percent of their body weight and 30 of their 30 of their strength no we i don't think we would and i don't think we would view it as a good thing if that

if that because again if you're telling me that someone needs to lose 30 of their body weight presumably their body composition isn't great to begin with so no i think you would you would view that as maybe a better thing than where they started but not optimal either yeah right optimal might be you would lose 30 percent of your body weight but it would disproportionately be adipose tissue and you might only lose 10 percent of your strength or none at all right right so again this this depending on the change in lean body mass yeah

this is just a complication of the cr studies and again you know even it's hard for me sometimes it takes me you know 20 30 minutes of trying to dig through the paper to really figure out you know how how did they how what normalization did they do to look at metabolic rate or muscle mass or lean mass or or or fat mass or muscle function right but usually these studies will be normalized to body weight this actually comes up also in some of the um the intermittent fasting studies where you know the question sometimes

in these studies is are they isocaloric or are they calorically restricted when they're put on intermittent fasting and people will claim they're isocaloric but the mice lose weight and what they really are is isocaloric when normalized body weight right so you know they're really calorically restricted but you have to kind of dig to to to to get how the normalizations were done to really understand now in when we think about what we know in humans you know there was a study that looked at the difference in bone mineral density in people who underwent equal amounts

of weight loss one driven by a caloric restriction strategy one driven by an exercise driven strategy and the exercise driven weight loss group did not experience a reduction in bmd but the cr group did yeah so you know that's interesting that's yet another thing that makes you think there's a little more nuance to this which is not to say cr from a weight loss perspective isn't valuable but it begs the question you know is cr the right tool for longevity once you've achieved optimal weight is additional cr beneficial that makes the assumption we know what

optimal weight is i mean i think that's kind of the crux of the question right we're asking does cr impact longevity positively we know if you go on cr you're going to lose weight so if the answer to that is yes then by definition optimal weight is lower than what we think right so right yeah i know but we don't i would say we still don't really know what optimal weight is uh so so again this i think just reflects the the challenges and coming to definitive answers and i mean i think maybe the way

i think about it more so is um you know what are the concept so so what are the what are the uh downsides potentially to caloric restriction and if we don't know that caloric restriction has big benefits in terms of health span and perhaps lifespan um what are the downsides and do those downsides outweigh the uncertainty we have about whether caloric restriction is beneficial and unfortunately i think this is something that not very many people in this field pay attention to right people are you know we all expect if you do a clinical trial of

a drug you're going to report adverse events and and you're going to look at side effects very rarely do people think about that before they write a book recommending that people should do diet x right even in the clinical trials some of the nutritional clinical trials they don't really carefully monitor adverse events and i think it's just again it's a bias in the way we think about interventions we feel like nutritional interventions are by their very nature safe and i think you know certainly for extreme nutritional interventions that's clearly not true so i think we

should be thinking about what are the risks associated with significant caloric restriction in people as a therapeutic strategy let's go back to the the sort of the study that will never be done again right the the the the nia monkeys so boy if i can get my facts straight on this one uh i want to say that this starts this study started in the late 80s ah it sounds about right it might even been might have would have been probably the early 80s okay so we're talking rhesus monkeys you know these are my these are

animals that are going to live what 30 years potentially yeah uh 40 yeah i think the average was close maybe closer to 40. yeah so let's talk about the experiment end-all experiments with respect to caloric restriction which is the very famous one we alluded to earlier at the university of wisconsin and the nia so and i like i've read this study a thousand times if i can get the details right once i'll be happy but between the two of us i hope we can do this you had two groups of animals one at the university

of wisconsin and one directly in bethesda maryland this was obviously a huge nih-funded effort it ran for a couple of decades given the lifespan of rhesus monkeys the wisconsin animals were fed the controls and the treatment uh cr animals were fed a very processed diet right uh at least after the fact the examiner the investigators there suggested they wanted to more mimic a standard american diet uh of note i recall the amount of sugar pure sucrose in their diet was 28 and a half percent of total calories so this is this is this is a

high quality diet facetiously the cr animals the calorically restricted animals were fed 25 of what the control animals were fed and in that experiment we found a benefit to caloric restriction that's right cr animals outlived the control animals and they had fewer age-related diseases so i think if you if you go back to that original 2009 paper you know the lifespan effect is compelling and it looks real but but what again you know is i think really indicative of that it might be having an effect on biological aging is that they saw reduced rates of

cancer again not surprisingly as we talked about in mice but also heart disease um and metabolic disease so you know it's consistent with the idea that in that cohort of monkeys again given what you mentioned about the dietary composition caloric restriction was in fact having a beneficial impact on the aging process and those animals all came in at about the same age right so that was sort of an apples to apples comparison now we go down the road to bethesda we have a totally different experiment in a way and i don't know how much of

this was delivered and how much of it was not the diets were different so that's that's maybe a good contrast these animals were actually fed the closest diet that could mimic their real diet um so it didn't have any you know sugar in it really i think it was like about three percent sucrose um you know it was almost kind of like a you know a vegetarian pescetarian sort of diet uh fish was the dominant source of protein but it it was a high quality diet relative to the wisconsin air quality for sure the complicating

factor here was the animals didn't come in at all the same age so you had some animals that came in young some animals that came in old the net results of the study was there was no difference the cr animals did not outlive and so while the wisconsin study was first published in 2009 and it said cr works the 2012 publication for nia said cr doesn't work right at least that's the lay press interpretation of it so how do you kind of reconcile these findings yeah so one i think one thing to add to that

is the the nia study at bethesda in their paper at least they did show some evidence for improvements in at least some health span metrics so if you read that paper closely you know what they're i think what they're really saying is cr didn't extend lifespan but it did have what appear to be some beneficial effects on healthspan metrics so it wasn't a complete failure in the in that sense so i mean i think it's interesting because since then the you know when that i remember when the the the 2011 paper came out the wisconsin

people were pretty upset um understandably so i think um since then they've had sort of a reconciliation paper and where they try to you know figure out what does it mean that we got these different results and i and i think you know their conclusion which certainly is plausible is that a lot of it comes down to the difference in diets and if you look at the actual body weights of the animals and how much food they ate not just the composition but actually how much they ate you know you could make an argument that

the bethesda monkeys were somewhat slightly calorically restricted um again the controls the controls yes the controls at bethesda ate less than the controls in wisconsin right and that would have narrowed the gap between them and the treatment right yes so then i think as you as you also alluded to the fact that the bethesda study was a little bit less controlled for age of onset and i should i don't remember the details exactly there were also some genetic differences in there so there's a combination of factors that make it a little bit difficult to conclude

that it all is about the diet right so the the monkeys in the bethesda study came in at different ages there was at least a hint i think that the the monkeys that came in at older ages started cr at older ages maybe got a somewhat of a benefit whereas the ones that started early didn't get any benefit so it's complicated to interpret and you know it's interesting because we see this a lot of times in the basic biology of aging basic science studies where different labs will get different results in in what seems to

be the same exact experiment and then you start to dig into it and yeah there's all these differences in the way it was done it's really hard to know which of those differences contributed to the different outcomes in this particular case because it was a you know 30 40 year experiment we're never going to find out right this is it can't be done again yeah it just won't be repeated both because of how long it takes and also because again the um the view on primate research these are rhesus mccox right the view on primate

research publicly has changed right so i just don't think we'll ever see that that experiment done again my gut feeling is that um [Music] that the wisconsin study to some extent probably does mirror what is closer to a typical american situation at least these days i i do not believe that they started with that intention but but but where we're at today it probably is relatively um you know as close as you can get for a controlled laboratory study uh the question though in my mind is between these two studies do they suggest that caloric

restriction you know slows aging and let's just start relative to the typical american diet right somebody is moderately obese and they're eating terrible is it caloric restriction or is it just returning to i think maybe what you would call like an optimal body weight right optimal uh uh body mass and i don't think we know the answer right i think from these studies you can't draw many conclusions i think the one thing you can do and then and uh roz anderson who's still at wisconsin has really i think been a leader in this is you

can study the molecular signatures of caloric restriction in the monkeys and ask does it look similar to the molecular signatures of caloric restriction in rodents and you might ask well why would you do that it seems obvious but again a lot of the questions that people have around caloric restriction studies in mice is will that will will it work the same way in people and obviously rhesus mccox are much closer evolutionarily to people than mice are so if you see the same molecular changes it's suggestive that caloric restriction is having the same molecular changes in

people certainly in primates and in fact that seems to be the case a lot of what we see in terms of you know changes in mtor signaling and mitochondrial function and and other metabolic pathways is in fact shared between mice and monkeys so i think that's a that is one important outcome from these studies that we can we can definitely say is rock solid um i tend to believe that the pretty dramatic declines in age-related disease seen in the wisconsin studies are telling us something but again is it just telling us that not being obese

reduces your risk for a lot of these diseases and and you know we kind of already know that from the from the human literature as well exactly the other thing that isn't entirely clear um given that the nia study uh didn't find a difference is we don't know how much of this was the cr versus the dr the dietary restriction in other words what the wisconsin experiment suggests is if you have an awful diet reducing the amount of awful food you eat is a good thing right what the nia experiment doesn't tell us is the

contrapositive it doesn't suggest that if you have a good diet eating less of that will help you live longer it might yeah but it isn't definitely well and so we don't know right if the wisconsin animals lived longer simply because they lost weight or because they lost weight and they were eating less processed food right right and i think the other thing to add to that is the nia monkeys which were eating you know what we'll call a superior diet to the wisconsin monkeys also ate less than the wisconsin monkeys in total yeah so in

other words if you ate more of a good diet would that be detrimental we also don't know that it's an interesting question actually and um it's too bad we don't know the answer to that but i think if they had been body weight matched or caloric consumption matched that would have been an interesting comparison to be able to see are there differences there and the other thing that just kind of gets off into weeds that we don't need to necessarily go into is i don't really have a great understanding of even how we differ from

the the rhesus monkeys so you know i recently read herman ponzer's book where he i don't have you read it by the way no so he kind of goes into the ecology and evolution of of humans as a species and how different we are even from our closest evolutionary cousins and one of the fundamental differences our incredible capacity to store excess energy yeah so our metabolic rate so this is you know he documents this through lots of assessments of doubly labeled water on not just ourselves but also kind of you know hunter gatherers that are

still around today and then of course all the primates is you know we're really kind of unique in our energy expenditure our our energy needs are far greater than anything else and you know people like that would argue hey that was kind of an advantage that we took to allow our development including our brain development so there's kind of a reason we're at the top of the food chain which is we have a much greater grain and the price we pay for that is higher energy expenditure and the price we pay for that is we

better be able to store energy because we will have a much harder time tolerating a low energy environment yeah and so he he talks about how even when you put these animals in captivity and you over feed them they're not getting that much fatter right they're they're actually putting on lean mass now they you know i think what you could argue and he doesn't talk about this but knowing what we know about human biology you might argue that they're still getting metabolically sick right just as humans when you're over fed the real metabolic sickness comes

not with the inflation of your subcutaneous fat it's when that spills out into the viscera into the liver into the peripancreatic space into the perinephric space into the pericardial space it's that fat that escapes the normal depot of sub-q fat that is truly inflammatory and truly metabolically disturbing so i throw all that in there just to say like it's just one more confounding variable that makes it difficult to compare us even to an organism as complex as a rhesus monkey yeah yeah and i mean people certainly have made that criticism of the caloric restriction literature

you know writ large not even taking into account the monkey studies but but the mouse studies right that there are you know all sorts of differences between people and and mice and the the metabolic state that people have evolved to fill is just completely different having said that you're absolutely right that even mice in the laboratory as they get older will show metabolic syndrome right you will see many of the same changes insulin resistance for example that you see in in people and i don't and do you see it absent the adiposity can you see

it well my skin adiposity with hd they do in fact uh uh become obese with age right on a again on a pretty crappy diet right outstanding well i don't know if it's crappy or not the standard mouse diets right so and and i don't remember what the number is you may you may but in the wisconsin study right a significant fraction of the control fed monkeys develop diabetes right so yes uh i i want to say like a quarter of the controls were pre-diabetic by the end of the study again which probably speaks to

even though they weren't overweight when they got a when you get 28 and a half percent of your calories from sugar right it's probably going to impair your metabolism yep so i i think though the other you know the other point that's maybe worth at least just mentioning here because i hear people you know talk about how certain diets are better for humans because it more mimics you know what we evolved to eat right i don't know whether that that's true or not you could argue both sides of that i don't see any particularly compelling

reason to think that that was the optimal longevity diet that that you know i think that argument is um is illogical on several fronts the first is uh and i don't know who coined this phrase but it's so ubiquitous that it's and it's obvious like by necessity we had to be opportunistic omnivores right like there's simply no way about it like to even suggest that our hunter gatherer uh forefathers were sitting around pontificating about what they were and we're not going to what they should be yeah i mean it's just the dumbest thing i've ever

heard right like of course and i don't think people are actually arguing that yeah but my point is the argument becomes so nonsensical when you realize our evolution necessitated the most flexibility from a nutritional standpoint yes and therefore we ate anything and everything and uh i think because we never probably existed in an environment where food abundance was so great right that we could reach the level of over nutrition it gave us even more flexibility with what we could eat right and and kind of where i was going with this and i mean it's interesting

to think about is does is that um maybe part of the reason why humans seem to be fairly robust towards eating really really crappy diets i mean certainly obviously we have an obesity epidemic and all of that stuff um happening but people seem to be able to tolerate a wide variety of different diets some of which are pretty darn bad for them from for many many years before you start to really see the the significant consequences i was going to make a totally different point that's almost orthogonal to that which is i you can you

can make a case that people can survive in really remarkable health with diets that look nothing like one another in other words you can look at somebody eating a really well formulated strict vegan diet where they're not getting any animal protein which clearly our ancestors all had animal protein whenever they could um they're often protein a little protein malnourished but they're very healthy yeah and similarly look at the opposite end of that spectrum you can look at somebody on a ketogenic diet who you know the only thing they would have in common between that other

person is probably a lot of leafy vegetables but other than that it's a much higher fat higher protein diet they can be very healthy yeah that to me speaks to the resilience of our genome in terms of its interaction with nutrition yeah and that's sort of where i started which is that there's no reason to think that that the ancestral diet is best right there's there's no reason to to think that um but but the other thing that i you know was thinking about when i started down this path is that like many other things

our as a species our um dietary options and the typical diet is evolving rapidly now right the the quality of the food the stuff that's in it the preservatives you know is dramatically different than it was 50 years ago right both in caloric content and nutritional content and so in many ways humans you know and taste it tastes great absolutely which contributes to why a lot of people want to eat more right so high calorie really good tasting food that's that's often cheap um but but so so the environment that we evolved into obviously is

completely different than it is today but our environment is is changing at an accelerating pace i think and that makes it really again complicated to try to get into the minutia of what is optimal maybe we should be thinking about what's good enough first right because i think it's going to be really hard and again it's this is where i struggle with the data that comes from epidemiological studies of people 20 years ago the the the the the environment the food quality is just very different from most people today though the grandmother test comes in

right and this is where when i watch like the extremists on both sides argue i i say two things the first is look there are really good and really bad ways to do your respective diet right so i don't want to hear somebody tell me that everybody on a vegan diet is doing well because i watched a lot of those kids in college and they literally were going to kill themselves eating ramen noodles and crackers and cookies all day so you can be vegan and eat pure garbage you could be keto and eat pure garbage

the second thing i would say is if you're eating those diets well i'm being a little subjective when i say well you're all shopping on the outer part of the perimeter of the grocery store yup like it doesn't matter if you're carnivore vegan keto low-carb paleo whatever if you're if you're doing those diets in the way that they were at least thought to exist you aren't going down any aisles of the grocery store and that's kind of this grandmother test like if your great grandmother didn't recognize what you're eating you just it doesn't mean it's

not good right i don't want to say that a protein bar is not a good thing to eat you just have to acknowledge there's a little more risk there right there's you know eating a carrot is inherently less risky than eating a protein bar with 14 ingredients in it yeah that's just a fact um and we so we just have to have a little i think this is what you're getting at just a little bit of a humility around what is known what is not known and as we push the envelope of convenience of nutrient

density of economics price you know shareability portability right the ability to preserve things we're going to take some risks yeah yeah i think that's exactly right so let's let's talk about kind of more broadly a paper you wrote how long has it been two years well we probably wrote it longer than two years ago i think it came out at the end of 2021 oh okay okay yeah so it's fairly recent you're trying to figure out the science page yeah and i'd read it before so maybe november 2020 right so talk about the impetus for

that paper which was that was a great paper and we should discuss it yeah um so i i was asked by one of the editors at science to write a review i think on mtor actually and and i was like well lots of people have written reviews on mtor i've been thinking a lot about you know caloric restriction um and particularly other nutritional strategies that people have been studying in the field like ketogenic diet protein restriction time restricted feeding intermittent fasting and you know what do we actually know about those diets and and their effects

on aging right because i was of the before i started to really dive into it and this isn't something that my lab researches directly so we've previously done work on caloric restriction in in invertebrates and c elegans but we never really have done a lot of dietary interventions in in mice and so you know before i kind of dove into the literature i had this impression you know that all of these diets were similar in some ways and had maybe comparable effects on lifespan at least that's the way it gets portrayed if you read some

of these reviews and i don't even like to call them reviews because i don't think honestly much of what gets into the literature as review articles are actually reviews it's more one person's opinion piece on their specific thing that they study which is unfortunate but if you read most of the reviews on caloric restriction and other dietary interventions they're very one-sided and they they usually have phrases like you know fasting is known to have all of these fantastic benefits and you know slows aging in all every place where it's been looked at and you can

see that for all these different dietary strategies so so i i proposed to the editor that you know maybe we should do a critical review of this space and think about what do we know what do we don't know are they equivalent and to the extent possible can we gain any insights into whether or not these nutritional strategies that whether there's evidence that they have an impact on the aging process in people so that's kind of where we started and i knew it was an ambitious thing to tackle when i said it and i'm not

sure i really appreciated exactly how challenging that was going to be because it's a huge area of literature um and it turns out maybe not shockingly that there are many more questions than there are answers when you really dive into it um so we really just started so what was your process yeah so we really just start the first step was and i should say i had a fantastic set of um co-authors all you know really great early career scientists who who really helped me with this and did a lot of the leg work um

i just want to mention them by name please so so alessandro beto who was a postdoc with me um uh mitchell lee who is a former graduate student with me and crystal hill who's at the pennington biomedical research institute and she works on fgf21 and protein restriction so those three were co-authors on this paper with me all just just really fantastic early career scientists so so we started by um asking ourselves okay what are the different popular dietary interventions that people have claimed have an effect on aging and we we came up with i don't

know six or seven um and they were the ones i've already mentioned so there's true caloric restriction which is pretty straightforward that you know really just means limiting the overall caloric intake that an animal gets you know by somewhere between 20 towards the low end and up the the the most i've ever seen is 65 percent of cash you were doing this in animals and humans or you were trying we started we were mostly focusing on mice we narrowed it pretty quickly when we realized the scope of what what we had undertaken so we could

have tried to do it in you know fruit flies and worms and all that stuff we said let's start with mice see what's known and then try to look into humans and ask are there parallels right okay so caloric restriction pretty straightforward we actually don't go very deep into caloric restriction because that that literature is huge and other people i think have done a pretty good job of of reviewing true caloric restriction um but there are some points there that we probably want to touch on that are important and then there are variants of caloric

restriction which include um intermittent fasting uh time-restricted feeding um how did you differentiate those two right i have a definition but i want to make sure yours is right so in mice um i think well so first of all the first differential differentiator we need to put across all of these things is is it isocaloric or is it a flavor of caloric restriction because it turns out i would say the vast majority of studies in mice of all of the things that we're going to talk about are flavors of caloric restriction and what i mean

by that is the the experimental group ate less calories than the right so it's time restricted feeding but it's really caloric restriction in a narrower window intermittent caloric restriction maybe the way you want to think of it and there's actually some nuance there that that we can get to but um right so so how am i differentiating between time restricted feeding and intermittent fasting so i in a i would say to my view the easiest differentiator is time restricted feeding is limiting the number of hours in any 24-hour period that the animal or person eats

right and there are obviously you're aware of this there are flavors of time restricted feeding and people where the window you know can be anywhere from 12 to 6 sometimes even more extreme than that right but you limit the hours per day that the animal or the person eats intermittent fasting i would put in a 24 hour or more fast right i think that's a that's a reason that that's actually the definition i use basically any yeah an intermittent fast is a fast that occurs at a frequency of greater than once a day right exactly

yeah the other thing i would say though is as the time restricted feeding gets even more complicated than that because there's evidence that it's not only about how big the window is but where in the day the window is and that's actually one of the things that that you know came out of our our review of the literature is there is this there is this clear connection between how much we eat and when we eat that ties into circadian rhythms and that circadian biology even since this review came out there have been papers that have

come out that that re-emphasize the importance of when we eat and what we eat i don't think it's either i think it's both um uh that suggests that that's probably going to be um significant in terms of the the consequences of the long-term health effects i'm hoping i'm going to remember to come back to that but let's keep going okay so then there's uh what people call fasting mimicking diets which are diets that have been um engineered to some extent to induce the same metabolic changes as caloric restriction usually very low sugar relatively low protein

high fat but also very low calorie so that clearly goes in the bucket of flavor of caloric restriction there's ketogenic diets as is another one um uh and then there's protein restriction i think that's the iso-caloric protein restriction both so again you really have to look you have to take each paper one by one and figure out is it iso-caloric or isn't it and that's in some cases just not simply not possible because the data is just not there but but you have to look closely so there are examples of both i guess one way

to think about it is is it ad-lib or not is one way to sort of think about it in other words an ad-lib ketogenic diet might end up restricting energy yeah non-deliberately that's one way to think about it but i don't i don't know that that answers the question of whether the benefit no it does caloric restriction so that's the complication but i agree with you that is it it's it's different and you know we don't think about this much in in mice but certainly in people it's true if you are not ad lib there

are psychological consequences to not eating when you want to being hungry all the time good bad indifferent but there are those are those those those have biological consequences as well right so they are different absolutely yep let's go back to the the circadian one i want to kind of get the the insights there um how do so first of all let's talk about what you know in mice yeah and then let's figure out if there's any extrapolation so so when we wrote the paper there wasn't much on this i mean people were thinking about it

particularly in the context of um uh time restricted feeding right that that there might be differences in the window of time restricted feeding for in humans right early in the day late in the day um there's been a couple of papers that have come out uh since we wrote the review in mice that i think make a pretty compelling case that the life span benefit from say a 30 caloric restriction diet is a combination of when the animals are eating and how much they're eating most of the benefit seems to come from the calories so

you know let's just say this may not be exactly right but i think it's close let's just say that you get a 30 lifespan extension from 30 caloric restriction that the two-thirds of that benefit comes from the calories but one-third of the benefit actually comes from the fact that those mice eat all their food in a short window and are fasted essentially the rest of that 24-hour period and if you force them to i mean i say force because if you give a calorically restricted mouse it's food it's going to eat it right away so

if you force them to eat little bits throughout the day you lose a portion of that lifespan benefit which is really interesting now a mouse eating in an hour and then going 23 hours without food what would we even compare that yeah i mean this is i i really don't don't feel comfortable even speculating so i mean i think that the you know the the first simplistic uh approach would be to say well a mouse lives about three years a human lives about you know i was thinking more of like how long does a mouse

take before it dies from starvation yeah so that's where i was going to go next i think that that sort of length of lifespan is not the approach you take when it comes to metabolism so so i would say that uh and this is total back of the envelope calculation but a one day maybe it's like a one to one to four ratio so one day mouse fast might be a four or five day fast in in people um but that's not even perfectly true because a mouse you know a mouse will go into ketosis

relatively quickly within 24 hours right and a human can go into ketosis that quickly depending on depending on their incoming diet yeah exactly right so so it's not it's not a perfect equivalency but but maybe one to four or five i hope i'm not saying something totally stupid here but i think that's probably pretty close um so yeah so again it's very different uh potentially these kinds of studies in mice the other thing that i think most people don't appreciate unless they've actually done these caloric restriction experiments is that if you go back to the

you know the classic experiments of rick weinrich and roy walford um those were those mice are fed a calorically restricted diet they're also fed three times a week so so they are in fact that's insane it's like they're they're basically doing a two-week fast between their meals yeah and so what you see even in 24 hours in a fasted mouse is you see pretty dramatic reductions in organ size right and so you know if the mice are being fed three times a week they're going through this you know uh uh reduction in organ size and

then this huge rapid hypertrophy right right so and you can see that that sort of uh decrease in organ size and then rapid rapid increase even on some of the fasting mimicking diet work that walter longo has done so again you know i think this just has anybody done their reverse experiment where you try to actually mimic the way humans eat and you take two groups of mice and the controls are fed whatever 100 of the nutrient but they're fed every two hours over the course of the day and the cr group are given you

know 70 of that but they're fed at the same time intervals constantly throughout the day in other words you make it purely a calorie thing and you really take out the fasting except when they're sleeping yep yeah in fact i think at least one of these two studies that that that i was referring to did that right oh so that said they were able to identify that two-thirds of the benefit came from the reduction in calories and a third of it came from the additional fast right right exactly so and in my mind i think

this is really important because this is one of the this is one of the points that we made in our review is if you look at the vast majority of the literature around intermittent fasting and time restricted feeding and fasting mimicking diets they're calorically restricted so there there's a fasting period and a caloric restriction component and none of the prior studies really really teased that out in a way that allowed us to have an understanding of how much is calories and how much is fasting and maybe how much is when you're fasted that's still i

think is an open question okay so what else can we say about early feeding versus late feeding what do we know early in life like no early in day versus late day yeah i mean this is an area i'll admit i'm not i'm not an expert in so i don't honestly have a an opinion about which is better and again this is where i think mice are are not going to be a good model for humans right so so i think that we really those studies need to be done in people and you know again

that gets now some some have suggested that an early feeding window versus a late feeding window produces better pairing of our insulin sensitivity to our nutrient arrival right i think that makes sense right i mean i think i think most most people would agree that particularly if you're eating uh eating something that causes your blood sugar to spike that doing that right before you go to bed probably sub-optimal right so i think that maybe that can explain you know most of that uh the observation that has been made that it might be better to do

if you're going to do a time restricted feeding might be better earlier some somewhere at least right not right before bedtime i guess i would say um but again i think these these kinds of questions are really complicated in in humans because you know you could ask what benefit are we looking at right so if you're looking at you know uh overnight blood glucose levels sure making no difference yeah of course if you look at sleep quality maybe it's going to be different or maybe it's going to be different in different people right if you're

looking at other biomarkers you know again it could be different so so i think it's again in my mind at least maybe you have a different opinion on this in my mind at least it's not even really clear how we evaluate you know what is better and what is sub-optimal it may depend on what your what your endpoint is what you're actually interested in optimizing right yeah i mean clinically we see in people who wear cgm that early feeding produces an overall lower average glucose for sure because even if you get the same spike let's

say with an earth like if you're doing the same meal early in the day versus late in the day there's something about how long it takes to come down at night versus in the morning now that could be you're more insulin sensitive in the morning and therefore it comes down quicker um it could be something to do with pairing sleep with the nutrition that is tweaking this and that there's a feedback loop where the excess glucose creates a little more cortisol you get a little more hepatic glucose but again that i don't really know if

that makes sense i mean i've heard people argue that at the same time you theoretically should have the lowest cortisol at night anyway so that really shouldn't be an issue i don't really know what it is other than just to say i've observed it empirically um and you know it generally doesn't produce a great quality of sleep but um again to me this starts to get into which i want to hear more about but this gets into the minutia of like you know at some point you just got to focus more on other things but

i want to go down this rabbit hole just for the sake of completeness yeah sure so i mean again i think that to some extent that's almost where we ended up right was that it's you know i think i guess let me give the big picture answer for why i think um this is important so i think these nutritional intervention studies in mice are very powerful for dissecting the biological mechanisms that underlie the effects that they have and some of these diets clearly have effects on aging right i i'm very very hesitant to suggest that

people should adopt any of these diets based on the rodent literature where it's at today um and i think there's a whole variety of reasons for that but but that's kind of where i ended up right i think they're super useful for understanding the biology i'm really not sure that they're going to work the same way what did you learn about the protein restriction in the ketogenic diet mechanistically in the mice yeah so so again the couple things to say about that the ketogenic diet studies there's really only been two that i'm aware of that

looked at lifespan and health span in in mice um they were they were slightly different uh but in mice you have to go to really really low sugar to actually get the mice to go into ketosis essentially one percent or less carbohydrate diets so again that's a difference from from people um the the stud one of the studies that fed a ketogenic diet lifelong saw no effect on lifespan but they did an intermittent ketogenic diet i don't remember the exact protocol but it was something like every other day or maybe once every three days or

something um and there there was about a i think a 15 percent increase in lifespan and i'm sorry what did they do on the other days the animals a regular diet sorry regularly yeah so it was just back and forth between the control diet and the ketogenic diet yeah yeah and that didn't result in caloric restriction the that's the thing the mice were calorically restricted so it's in some ways it's a intermittent caloric restriction right and this is what i would say it's also interesting because the fasting mimicking diet papers are intermittent ketogenic diets so

so i think that you know maybe that's one thing to agree on is that intermittent ketogenic diets in mice can increase lifespan and seem to have benefits for health span um but uh but the ketogenic the effects aren't huge right again that's the other take-home i would say from from our study there are two nutritional interventions that relatively consistently give big effects on lifespan one is caloric restriction and one is protein restriction and they you know again caloric restriction the the most extreme study that i've seen is 65 restriction and that gave about a 65

increase in lifespan so these are big big sizes um i i wasn't aware of that uh uh walford and weinrich and walford paper okay okay and and when did they start that and how long did that restriction last that's a good question i don't remember it was probably six or nine months i think most of their studies were you know early onset caloric restriction um and they did this study was really interesting because they did you know a graded response from you know 90 80 60 percent 50 40 of ad-lib and you get essentially a

graded response in lifespan and it's roughly linear so so i think you know that's why i said about six so ninety percent animals ninety percent but they didn't go that far they didn't go they didn't go beyond and i also think this is an interesting study because i don't think you could do that study today because the animal care uh uh wouldn't allow you to yeah this gets back to you there's an element that we don't think about enough which is what were those what did those mice feel like like think about how angry those

mice would have been on a third of their normal caloric yeah i mean you know again i haven't done these kind of mouse caloric restriction studies myself i've obviously talked to a lot of people who did i think to really appreciate that you've got to probably be in the animal room you know feeding them seeing them right certainly um uh activity goes up quite dramatically that's one of the remarkable things about caloric restriction in mice is that they are more active throughout life um than ad-lib fed mice are and maybe it's a sort of you

know foraging response evolutionarily selected foraging response but but they are definitely you give them a running wheel and they'll just run and run and run and run um so yeah there are behavioral changes for sure in mice that are calorically restricted and this is actually one of my real concerns about caloric restriction in people i mean i think first of all you know we should we should be realistic and recognize you're never going to get a significant fraction of the population to calorically restrict right it's hard enough to get people to calorically restrict down to

a healthy weight to get them to go 30 beyond that it's just not going to happen um but of the people i know who and i mean being in this field i i know people who have done every possible you know anti-aging intervention you could imagine and of the people i know and i know a lot of people who've dabbled in various forms of caloric restriction um [Music] certainly true caloric restriction has real psychological consequences and i and and and i really would be concerned um i have been concerned for some of the people i

know who've done this uh if a lot of you know if we if we started trying to do this in in the general public right i mean there's there's social isolation that you get when you're calorically restricting but then there's you know the the biological changes in the brain and you're hungry all the time so again i i just think we you know we often don't appreciate those aspects of some of these nutritional interventions but in the mice i think it's hard to know what they're psychological and what do we know about caloric restriction later

in life in the mice versus earlier i mean the sort of traditional thinking is you you have a window in which you can do it early and beyond that it's not as effective yeah uh i think we're going to talk about some data that counter that and then of course you have the nia experiment we talked about earlier in the monkeys where the early fast didn't improve longevity the late fast appears to have although right that was sort of a subgroup analysis hard did it hard to draw causation there yeah um so so what i

would say about the mice is that for a long time the sort of dogma was that caloric restriction didn't work if you started it you know past i don't know 15 months of age which is maybe the mouse equivalent of a 40 50 year old person um so most of the early caloric restriction studies were done like i said starting sometimes pre-development uh the early rat studies were pre-development and then sometimes you know six nine months of age um so that was sort of when i first started in the field that's kind of what i

was told like this is a settled question um more recent studies that have been done in in some ways more carefully different diets uh certainly if you do a graded onset of caloric restriction in other words don't go right from ad-lib to 40 restriction the next day if you do sort of a graded onset you can get lifespan benefits from caloric restriction you know 20 22 months of age so whether it's as good as starting early i think the consensus is still that the answer is no you're never going to get the same magnitude of

benefit from caloric restriction starting late as you do starting early but that could be wrong so i would say that's the consensus but i don't think we know we know for sure whether it's possible if you did it just right that you could get you know most or all of the benefits from starting late in life so matt on this topic of cr and mice you know um again the dogma has generally been and i've been victim of this just sort of blindly assuming it to be the case that you know cr and mice only

works early in life uh again is that how how applicable is that to humans i don't know um but you know a listener of the podcast actually pointed out that you know in fact there are some data that try to get at this question elsewhere so there's this han study 2019 which we'll link to that looked at um 800 female uh mice now this is a pretty elegant experiment right so for the first three months they ran these mice out on a ad libitum diet and then at three months they were split randomized to i

believe a 40 yeah calorie restriction versus ad lib they ran that out until 24 months and then each of those groups was further spread split ad-lib versus continued on so you had one group that was everybody's the same until three months one group that spent the rest of their life on dietary restriction one group that spent the rest of their life ad lib and then you had the middle groups 21 months calorie restricted then to ad-lib 21 months ad-lib to then calorie restricted okay so the ends of this were not interesting right meaning the ad-lib

group lived the shortest uh we were looking at the figure earlier today 1200 days roughly going back to a maximum life space yeah maximum lifespan that's right median lifespan would have been looking at the graph about 900 days yeah which is pretty good again yeah so i was going to say how does that stack up with what we talked about in the last podcast about length of like a reasonable uh lifespan for control i think if i remember correctly this was also done not in c57 black six but in a little bit longer-lived hybrid stream

that's right f1 hybrid absolutely it's reasonable life span yep okay looking at the all cr all day mice looks like they had a maximum life span of just below call it 1400 and change with a median that i'm going to say was about 11.50 yeah so it's good good lifespan extension okay so so now what's interesting is the middle groups which is really true so i'm going to just give you my little ipad so you can look at that table which will link to this okay i've got it right here you got it right here

all right i just i remember i remember the take home you do okay yeah yeah yeah so what happened to the two middle groups right so i mean the interesting thing well the one thing i would say is i think this is a pretty early onset of crs it really is it's three months yeah this gets back to what i was talking about before that you know it it seems likely from the early studies that were done in rats where they got some of these really really large effects that that some of the benefits of

cr come from actually being restricted during development itself right so i think that's useful to to put into context so then the big question here is what happens if you start caloric restriction late in life or what this study did that i'm not really aware of anybody you know doing doing previously is kind of the flip it's almost like a crossover that's right right it totally is yeah so so in this case um when they uh when they started cr late in life there is a significant but not huge effect like the the magnitude of

the lifespan extension is much less than in the mice that were on cr from three months of age that makes sense that fits with what else is in the literature um there have been there were earlier studies i think steve spindler did one you know not too many years maybe four or five years before this one that did sort of a similar sort of approach starting around 15 months of age and they saw a significant but not as large benefit from starting late in life so that seems to be the consensus the thing that's really

interesting here is you know what happens if you're you know cr'd for uh an earlier period in life and then back on al do you lose the benefit and it seems like the answer is no right those animals actually were longer lived than the mice that went on cr late in life so so you could ask i mean you could do so you could ask some questions about is it about the total amount of your life that you're restricted is it about when you go on and when you come off and i think in mice

this is still an open question we don't really know what the mechanisms are although the earlier life mice had a longer median the median life expectancy was the ones that were on cr and then switched to ad lib yes yes that's right yeah so they lived a little bit longer but the bigger difference was the median life expectancy was higher than the slip than the flipped yes although i think i think we're we have a little bit different difference in definitions right i i would i tend to think first about median you seem to think

first about maximum but yeah i mean i think what you're saying is right the median lifespan is uh quite different between those two groups that is the difference the maximum is very trivial yep that's right so so i mean i think um again you know the real question here is well aside from what does this mean for humans which i would say we can't draw too many conclusions from humans from this but what is what is the underlying mechanism and and is it really just about how the total amount of time that you've been on

cr or is it is there an interaction with how old you are the developmental process and then you know what happens at the end of life which is mostly the degenerative process and when you go on cr yeah i think maybe one thing that's that's worth adding to this too is it's an interesting comparison to what we know about mtor and rapamycin right so with rapamycin you know the data are pretty clear that you can start rapamycin certainly well into middle age and maybe even a very old age and get most of the benefit so

if you compare the curve here where they started the mice on cr at 22 or 24 months whatever it is the effect is pretty small compared to cr with rapamycin you get almost exactly the same benefit starting at 20 22 24 months as you do starting early in life so that might tell us that there's a difference right there clearly there's a different mechanism potentially as well it could be that rapture is doing something different or it's a different dose effect exactly so so that that's an open question exactly why it's different but it seems

to be it seems to be different i'm really glad you brought that up because you know we talked about that with rich miller on his podcast which was a fortuitous accident right basically because they couldn't get the formulation of rapamycin my favorite studies one of my favorite stories inside yeah yeah tell people that story yes right so um so take a step back the the nia started this program called the interventions testing program um must have been early 90s and the idea here was was maybe early 2000s sorry i'm dating myself again losing my decade

so early 2000s and the idea here was i think really smart the idea was that we could create a tool where the scientific community could nominate interventions for lifespan testing in mice and it was set up so that it would be done in triplicate right so there are three three sites there still are three sites for the itp um so anybody in the community can nominate any intervention uh there's a selection committee that selects them ever every year and if an intervention is selected then the the intervention testing program sites start the cohorts of mice

on that intervention you know in whatever year it was selected for so sometime back in the early 2000s dave sharp nominated rapamycin and you know some ways he was ahead of his time because this was i think when he nominated rapamycin it was even before the first invertebrate studies on mtor and rapamycin right around the same time they were being published so you know he i think was thinking about it from a cancer perspective primarily in any case he nominated rapamycin it got selected it went into the cohort and they typically test five or six

interventions or drugs each year so they have a huge number of animals at each of these three sites that are destined for these interventions to be tested in and rapamycin was one of them and um randy strong who's one of the the pis on the itp um who's also got a strong biochemistry background i think recognized pretty quickly that the rapamycin wasn't stable in the food we could actually come back to this if you want to because this is relevant for for people as well so and it gets broken down in the ph of the

the gut right so so basically if they just put the powder in the food there's no bioavailability it doesn't get taken up by the mice and so they recognized that right when they were supposed to start the experiment and you know of course they were like crap what do we do you know we could just not test rapamycin um and i and i don't know if it was randy or who somebody said well i think i can figure out a way to to stabilize the rapamycin put it in the food so that we can give

it to the mice and we can do the lifespan experiment i think what they didn't recognize was that it was going to take 18 months or so to figure this out so once they finally developed this in what they call e-wrap encapsulated rapamycin it it's basically designed so that it won't break down in the gastric ph once they developed that they were now 18 months into this lifespan experiment before this everybody i think everybody myself included in the field thought you had to start early in life or you weren't going to get much of a

benefit there was really almost no chance a drug was going to increase lifespan starting that late in life but fortunately they went ahead with the experiment starting at 20 months of age and what they found was that they got this robust lifespan extension from starting with rapamycin treatment at 20 months of age and just to give some context that's about the mouse equivalent of a 60 or 65 year old person and i love the experiment i love the outcome obviously because you know first of all nobody thought it was going to work except maybe rich

miller maybe i'll give rich credit maybe he thought it was going to work um uh and it was really the first time anybody had convincingly shown that you could start an intervention intervention not even and get robust lifespan extension and for me honestly i reviewed that paper and when i when i first time i saw that result i'm like this changes everything we actually have a chance for translational geroscience because because you might be able to intervene late in the aging process and have significant impacts so it honestly in in that was 2009 paper came

out so in the 13 years since then the whole paradigm in the shields field has changed right most people who are studying interventions today are studying things that they test for efficacy late in life because that's what we need to do in people so it was a super important result for the field for that reason and it all came about by an accident nobody would have designed that study that way beforehand right yep so yeah it's fortuitous for sure now you were going to make a point about the bioavailability around as well this is something

that's only recently come across my radar but i've heard several um results now that convince me that that it's true so you know i mentioned the reason why they had to make this e-wrapa is because rapamycin isn't stable at the gastric ph of mice same thing seems to be true in people so you know there are people who are getting their rapamycin from uh from like the rap immune which is the brand name generic or the brand name sarah limus that likes comments comes in these triangle-shaped pills they're also people who are getting it from

compounding pharmacies and i've heard of several cases now where the bioavailability is much lower in the the compounded rapamycin in a capsule than in the actual rapid triangle the blue the white and yellow triangle yeah so it's just something for people to be aware of and i don't think most physicians are aware of it i don't think most compounding pharmacies we've never had it compounded so we've only prescribed uh syrollamus or uh or rap immune and um you know it's not a cheap drug so i can understand why there's a desire to compound it because

it's got to be like five six bucks a milligram yeah i think that's about right yeah so matt obviously one of the other things that came out of that review article in the animal stuff was as you said the protein restriction and i think of all the topics in nutrition this is the one i'm most interested in uh i really don't care that much about fat and carbs don't tell anybody but i care an awful lot about protein you know in fact when you came over today you probably saw me chasing down what was left

of a protein shake and i think i was mentioning to you or my wife like that's the only part of nutrition that is kind of um i don't want to say a chore but it's a very deliberate part of how i go about the day which is i really have to think about it and the reason is i'm trying to eat a gram of protein per pound of body weight spread out into four buckets right right because if you you know i think there's reason reasonable evidence to suggest that if you consume too much protein

in one sitting uh and it's typically more than about 0.25 grams per pound is the general thinking you're going to end up oxidizing some of that protein so it's not that it's harmful it's just that you're not getting the amino acids you need for muscle protein synthesis which is of course our objective so that means i'm kind of walking around trying to get 40 grams here 40 grams there 40 grams here 40 grams there and truthfully that's um not trivial if you're not willing to consume a whole bunch of crap with it i mean if

you're really just trying to focus on the protein quality so look the rda says i'm crazy right the recommended daily allowance of protein is 0.8 grams per kilogram right which is less than half of what i would consume where do you see the and by the way it's not just that i'm making up the amount that i'm consuming i i'm doing it on the basis of other data that suggests that this is the amount of protein consumption you need for optimal muscle protein synthesis right so where's this disconnect yeah so i mean i think first

of all um we can talk about the rodent studies right which is in the biology of aging i think the rda question you know they're that that's a different question it's my understanding that that actually was developed to be protein balanced for 95 of the population when sedentary right so i think what that means first of all that's a minimum amount not necessarily the optimal amount and it probably very much depends on lifestyle right and lean body mass to begin with even though it's sort of normalized so i think i think and the reason why

i bring this up is i think there's a lot again a lot of confusion among the general public about what the rda means and it's not it's not necessarily a bad thing to be above the rda in some areas right maybe a lot of areas so i think that's just worth worth you know expanding on just just a little bit yeah i think i agree completely i i sort of jokingly think of the rda for protein as what you need to not waste away and wither up and die right exactly yeah so right so you're

not losing muscle mass yeah so so then the question of what is the relationship between protein and aging i think is a really important one and it's gotten a lot of attention in the field um and like i think a lot of other things there's a lack of clarity about what we actually know and what we should be recommending to people so let's take a step back and start with the animal studies that the mouse studies i think there it's pretty clear that you can extend lifespan through protein restriction and there are actually again a

couple of flavors of protein restriction you can restrict all protein down to you know some some percentage some low percentage um or you can restrict specific amino acids particularly branched chains tryptophan methionine or branched chain amino acids are the ones that have been studied and and again i make that distinction because it's not really clear that the mechanisms are the same across these different flavors of protein restriction the common mechanism that that does seem to uh potentially underlie all of these forms of protein restriction is inhibition of mtor and again that's partly why this becomes

complicated when we especially when we start talking about extrapolation to human you and i both recognize that inhibition of mtor can have beneficial effects in the context of aging and health span certainly in mice almost certainly in people i would say and protein is an activator of mtor and we know a fair amount about the biochemistry of that that particularly branched chain amino acids can directly activate mtor through cestrons and that's sort of all worked out um and so it seems counter it seems intuitive that protein restriction would be beneficial by turning down mtor seems

counterintuitive that that what you were just talking about would be beneficial because you might be hyper-activating enter so we can dive into that but i think that that's kind of the that's the that's the simplest possible mechanism i can think of for why protein restriction especially branch chain amino acid restriction would be having an impact on lifespan and health span in mice um the other player that seems to be important particularly in um total protein restriction is a protein called fgf21 fiber fibroblast growth factor 21 that is uh secreted in response to a low protein

diet and then has effects on liver metabolism and and also inhibition of mtor reduction of igf-1 so that seems to be required for the lifespan extension that is seen from protein restriction in mice potentially partially upstream of of mtor and liver metabolism the interesting thing there is fgf21 overexpression by itself has also been reported to be sufficient to extend lifespan and mice so um so it kind of fits that that that could be part of the the story um so the question then one question is is protein restriction always beneficial in mice and can we

separate it from caloric restriction and so this is where you really have to look closely at the studies and determine you know did the mice on protein restriction eat less eat the same amount and eat more and it's interesting because you can actually find examples of all of those and honestly i don't really understand why that's the case except it's something about the different compositions of the diet what does seem to be the case is that when you restrict for certain amino acids you're if you're deficient for a methionine for example or tryptophan the mice

absolutely will eat more and they don't gain weight and they do seem to live a little bit longer so that could be a somewhat distinct mechanism there um that we don't really understand so tell me what was the most compelling evidence you saw when you tried to tease apart the relationship between protein and total intake um so again i think the branched chain amino acid and methionine restriction studies are are pretty clear that those animals are consuming more calories more calories than certainly if you matched a weight then they add little mice and they're living

longer and what do we think is the uh route or mechanism through which methionine exerts this effect i don't know that that's still really being being worked out there are lots of mechanisms that have been proposed i suspect mtor plays a role um you know people have thought about so of course uh you know methylation methyl donors are important for a bunch of different epigenetic modifications so there may be a role there going back to the epigenome that we talked about methionine is the first amino acid in every protein so there could be effects on

protein synthesis there's evidence linking methionine restriction to sulfur amino acid uh biology which has been implicated in in aging so it's hard to know and maybe it's not one thing it's hard and those all sound like potentially just a substrate reduction problem right like less sulfur cross bridging less protein synthesis right well yeah and again you know if you look back in the the literature in the invertebrates inhibition and inhibition of protein synthesis in some cases is enough to extend lifespan and of course mtor is a primary regulator of protein synthesis so when you inhibit

mtor you can also inhibit protein synthesis so there's that's part of the challenge here is this network is so interconnected that when you tweak one part of it you have effects throughout the network and it's really hard to know which of those effects are causal so let's talk about time course right yeah so when you consume a protein-rich meal um do we have a sense of how long mtor is being activated in response to that set of amino acids i'm sure somebody does i i don't know the answer to that i i mean i think

again almost certainly it's going to depend on um what you eat in combination with the protein when you eat yeah exactly like how active you are i remember talking to david sabatini about this through the lens of bcaa drinks yeah so if you're going to pound branching amino acids during a workout because you want as much anabolic signal as and possible is a couple of years ago so so maybe things have changed but based on that work i think bobby sutton had done the work in his lab if i'm getting his name right was it

bobby sutton was the guy who did that science paper that looked at the leucine sensor right on mtor right the answer was it didn't stay on long at all yeah free amino acids were so short in their ability to turn on mtor that unless you had an intravenous drip of this stuff it was going to be very difficult so much so that the idea of using bcaa analogs to treat sarcopenia was going to require drugs that could stay on much longer is that kind of within your frame of thinking i think so and i think

it also it also makes sense in a in a biological context right i mean i mean cells and tissues you know again this gets back to the whole homeostasis concept right cells and tissues have evolved to maintain metabolites and amino acids are metabolites right they're involved in many different metabolic reactions within certain levels and there are all sorts of mechanisms to ensure that if if at a metabolic it's outside of that range that we soak it up we do something else with it right so i think it makes sense that you're probably not going to

have you know a a persistent uh increase in branched chain amino acids far outside the normal range what i would say though is that slightly elevated branched-chain amino acids chronically can have big effects on the sort of downstream processes and there are there are some you know inborn diseases of childhood where you have elevated levels of branched-chain amino acids we know that there are consequences to even having you know somewhat modest increases in mtor hyperactivation of amateur signaling chronically so again i think the context really matters but yes it's my intuition that that it's probably

hard to get very large persistent increases in mtor simply from you know taking a branched chain amino acid supplement doesn't mean you might not doesn't mean it couldn't have some effect on you know muscle building right after a workout or um but but i suspect it's hard to have long term um persistent effects i mean the the the anabolic data suggests it's not necessary it's just again muscle protein synthesis window is open long enough that simply delivering a great source of whey protein in the hours after a workout seems sufficient to not restrict uh muscle

potential growth i think the other thing though that is also important to appreciate and this is true with um with rapamycin as well i think a lot of people get confused about this is it's not only about how high m tour gets turned on or how low it gets turned down it's also about where that happens right and this is again you know um people for a long time thought that rapamycin would cause muscle loss right we don't see that i mean we just don't see it in mice and we don't see it in people

and i think it's probably because i'm guessing you're not seeing it in dogs we have not seen anything to suggest that in dogs yeah so i'm i'm guessing that has as much to do with how much for maybe more to do with where mtor is being affected than than how much we're inhibiting mtor when we're inhibiting mtor and so i think the same thing's probably do we know where the selectivity of rapamycin is i mean is it more selective in hepatocytes is it more selective in adipose tissue i mean i i don't know of any

good studies that have really carefully looked at this there have been a few studies in mice that tried to look at at um tissue mtor signaling you know uh in the context of rapamycin again this is a very technically challenging problem well and this is what i'm just going to say it gets even more complicated because even in a mouse where you can essentially control almost everything right um what the mice are eating and when they last ate has if anything as as big maybe bigger effect on mtor signaling than rapamycin right so so i

i don't there have been like i said a couple studies that looked at this and i'm not sure and they got different answers and i'm not sure who to believe because i don't think the only way i could imagine doing this is you have to be able to do subtractive studies where you have to be able to do it in the context of a whole bunch of different diets first get kind of a baseline that you then pull out of potentially what you're seeing but yeah that's it just gets caught it's complicated and again that's

why i you know often will gravitate back towards what are the functional consequences we can actually measure right sure i get it you think that treating a mouse with rapamycin is going to cause sarcopenia let's do the experiment and find out the answer is no it doesn't right so that tells us it's at least not as simple as we thought it was going to be we may we certainly don't understand now what about the flip side of that is uh more protein versus less protein activating rap mtor in a way that is counterproductive i think

it can um i think there i think there are probably certain certainly cases where it can again you know i don't i don't know that anybody has really carefully done that study in mice there there was a study it's a really interesting study by um steve simpson and colleagues with where they did this nutritional geometry work where they basically looked at different compositions of carbohydrates and he's in australia yeah exactly and you know looked at i don't remember how many diets there's a whole range of diets right different compositions of the three macronutrients tried to

control for caloric intake which is hard as you can imagine but i think they did a pretty good job um and then asked you know what what does it look like in terms of metabolism energy expenditure lifespan so the lifespan studies i think are are pretty clear that most of the diets where the mice lived the longest were towards the low end in protein but there were some things that i think called into question exactly what was going on there because it wasn't the case that the the the mice that were energetic the diets that

were energetically lowest gave the longest lifespan as you might expect from caloric restriction and the diet that actually gave the absolute longest lifespan had like i don't know it's like a 40 protein in it right so so the way i interpret that is that there are many ways to get to and how calorie restricted was that they were they were not calorically restricted at all so you're saying a diet that was ad lib with 40 protein had the best outcome the best absolute lifespan yes again how do we even reconcile this body of literature yeah

and this is sort of what i was just going is i think that my view is there are probably multiple paths to longevity and we really don't understand the the inner relationships of these macronutrients in in the diet with enough sophistication to to get beyond sort of broad general predictions and again you know i sort of this is an area where i i really i believe like i can't prove it but i my intuition from from the the data that i've seen and just my observations of people is that in humans it's probably very this

relationship between protein and health during aging is probably very different than it is in mice i think mice are able to tolerate a very low protein diet without you know some of the consequences that we see in people that's my intuition i don't you know i don't know that that's true i mean it's my intuition well as well because clinically what we see in what i call the death bars the death bars is our internal nomenclature for how people die we just constantly look at death bars and we double click and double click and double

click all the way to try to tease out everything that is reducing lifespan and health span and the problems that occur in humans when they are under-muscled are insane and it ranges from the metabolic consequences of being under-muscled our muscles are a sink for glucose they are the single most important sink we have for glucose and our ability to tolerate glucose and maintain glucose homeostasis in the presence of larger more metabolically healthy muscles is the difference between having diabetes and not having diabetes furthermore when you think about sarcopenia and when you think about osteoporosis which

again i just don't think we're talking about how these things impact animals like we don't study any animal including primates in a setting where sarcopenia and osteoporosis are problematic and yet i would ask anyone to consider the entire population that they know over the age of 75 and i would ask you take every person that is alive today that's over 75 and tell me how many of them are not suffering at least some consequence of one or both of those phenomena and if somebody did that analysis i would be shocked if we didn't find at

least 80 percent of people over the age of 75 are experiencing this and if you look at the activity just monitor the activity level of people over the once they hit 75 they fall off a cliff so muscle mass dramatically plummets activity levels dramatically plummet it difficult to say which one's feeding which but there's no question that something is happening to our species at about the age of 75 right that is a structural problem and none of this other stuff matters if that sucks right like i don't care if i live to 100 and don't

have cancer if i'm an invalid for the last 25 years and i can't play with my grandkids and throw a ball like it for me personally i'm not saying that's a that's not a view that everyone should take in the world i'm just telling you that's my view yeah yeah yeah i mean i think that's absolutely correct i guess the question and i think this is still where some of the confusion comes from is um how important is dietary protein in that maintenance of muscle or loss of muscle and people who are going to go

you know the wrong direction and i think the data is that it is quite important i mean when you there are lots of studies that have compared you know the rda versus you know kind of the the double rda standard and it's a significant difference yeah um protein makes a very big difference you know following obviously um the training that that is necessary to stimulate muscle protein synthesis so i think those have to be coupled to some absolutely yeah yeah i believe there are data and i hate when i have to say this because i

just i'm going to say something and it's going to be wrong and 20 people are going to say okay i do it all the time so just in anticipation of the fact that that there are data that i've read and i i don't have the memory i once had um i believe there are data that show just the protein difference alone can make some difference yeah but it's not nearly the difference you get when you pair it with hypertrophy training yeah that that's that's my recollection as well right which which brings you know us to

the interesting question then why is it that there is a camp and in my field it's a pretty vocal camp in the aging field right that would argue that low protein is the best nutritional strategy for aging and health span in people and you know this is this gets back to the point i i kind of started with which is that you can find the answer you want for almost any question in this area that intersects at nutrition and aging there will be a study right that will fit your belief so i think you really

have to be careful i try at least to take a global view and and try to to understand what is what is the totality of the data say right but there are epidemiological studies and and one in in the field that most people will point to when they go to humans and they talk about low protein and it was this um the study that uh walter longo was um i think the senior author on and morgan levine was the first author on where they looked at um protein consumption and uh all-cause mortality uh as a

function of age in people there were some some studies in i think they had some yeast studies in there as well maybe some cell culture studies but they looked at the the take-home message was that low protein is beneficial up to about 65 years of age and then once you get above 65 years of age it kind of flips and people who ate a higher protein diet have lower all-cause mortality i should be clear when i say beneficial we're talking specifically about all-cause mortality which at the end of the day is a very important metric

sure you want to be alive yeah yeah it's not the most important metric necessarily you could argue it's equally important to the health span metrics but it i mean that's that's okay so let's make sure people understand what that means that means below the age of 65 the epidemiologic data in this study suggested people eating less protein had lower mortality and i'll cause mortality and above 65 you saw that reverse that's right yeah now did that paper make any attempt to quantify the net impact on mortality because the very misleading thing about an assessment like

that is when you look at mortality adjusted by population before the age of 65 it's relatively low above the age of 65 it goes up very non-linearly yeah um so when we do our death bar analysis it's like you know this is the more this is the death per hundred thousand people if you're 40 50 60 70 80 90 like you know what i mean it just it becomes insane so you could argue through that analysis that you're much better off with a high protein strategy even if it's throughout life because the absolute reduction in

mortality would unquestionably be lower as a result of the benefit you would have later in life so i would um i i i absolutely agree with with conceptually with what you said right the the impact of a change in mortality late in life is going to usually swamp the impact certainly swamp the impact the same impact on mortality early in life i think the question here is what are the relative effects that's right and so so they did try they did model this a little bit and it is um in their model which i i

i couldn't get the data for like i don't know i can't evaluate exactly what they did but in their model the uh the the relative risk um crossed somewhere you know in the 60s right in other words you know your your total mortality benefit uh was lower eating a high protein diet i think it was starting somewhere in the 60s and that actually surprised me because because for exactly the reason you said the relative impact of the high protein diet um early in life would have to be an order of magnitude greater than the relative

impact of the so i'm sorry say what they're finding was again at the age of i don't remember the exact number it's in the it's in the paper right you can see the curves you can see the curves crossed it was much later than i thought it would be given that 65 was the point that they they kind of picked i see yeah so i would have thought maybe in your 50. so i actually tried to do my own modeling of this off of the data that i that i could find on you know relative

risk for low and high protein again where you what you define low what you define high you know there and you're trying to ask the question when should you switch the diet or maybe more formally at what age do the does the risk equal out yeah right yeah what's the crossover yeah yeah and what did you find so mine was closer to like 50. yeah um that that's that's the point where uh once you get past 50 they're the benefit of a high protein diet on mortality seems to outweigh any detriment that you would get

from so that's odd to me because whether it's 50 or 60 matt it's a benefit on mortality which is really i think where more of the argument is there's can't be any benefit on health span from low protein no from high protein early in life or late why why can't there be a benefit oh late in life i'm saying why not well i'm saying like if you're protein restricted late in life i i mean i think low protein has no benefit on you yes yeah yeah yeah well i mean again unless so i would agree

with you intuitively but i also i'll exclude special cases so i'm not talking about people who have renal insufficiency for whom they have to you know yeah i agree with you conceptually the only thing that makes me hesitate a little bit is i've just seen like i was talking about the mouse rapamycin experiments where everybody who knew anything about muscle said that if you gave a mouse rapamycin throughout life it was going to get sarcopenia and that just didn't happen so you know what i'm saying we have clinical data yeah that suggests that when when

when when people over the age of 65 are protein deficient versus protein significant there's a there's a there's a huge difference in muscle mass which we know is going to be associated with frailty right right pour out yeah i would totally agree with that i mean i think that that it's very likely to be true i think what we don't again we i don't know do we have controlled studies where people were eating low protein and doing resistance training late in life i mean they're nuanced here they could complicate yeah but i think in general

you're probably i think the other area where this gets very complicated is the um i don't want to say by necessity but just by convention we use igf-1 as a biomarker for protein intake yeah and uh it's certainly associated with protein intake but you want to tell people what igf-1 is you know a little bit of background of you know where it comes from and what it's a proxy for sure so igf-1 is insulin-like growth factor one um it's uh a hormone that's in in the growth hormone pathway so when so it's you can think

of as a growth promoting hormones are sort of part of this central pathway that um promotes uh growth in many many different tissues so if you have high growth hormone levels you'll have high igf-1 levels and that in high m tour right so this is a this is a a part of the mtor pathway as well upstream of mtor so um the reason why people have been really interested in in igf-1 in the field of aging biology it comes you know from studies again in the very simple laboratory uh model systems so um the most

famous and and one of the first uh genes that was shown to to clearly from a mechanistic perspective affect aging is it comes from cynthia kenyon and even tom johnson a little bit before her which is the insulin-like receptor in c elegans called daf2 and cynthia published a classic paper showing that if you make a mutation in daft ii could double the lifespan of worms and they seem to be healthier about twice as long and what that mutation does is it turns down signaling through this pathway now it's a little bit more complicated than worms

because it's called the insulin igf-1 like signaling pathway so it's not identical and so there's one pathway in in worms that kind of takes the place of both igf-1 signaling and insulin cycling but you can kind of think of them as equivalent and then there are a whole bunch of studies in mice for mostly mutations in the growth hormone upstream signaling uh upstream of igf-1 that lead to increased lifespans so there so this means gh does not activate the production of more igf-1 that's right so you have you have through a variety of high gh

low igf-1 animals well low gh signaling right yeah yeah yeah but they probably are high enough oftentimes it's the receptor that's mutated that's right yeah so um so those animals tend to be very long-lived they are they rival caloric restriction in terms of the magnitude of lifespan extension um and there are several different mutations in that pathway um the the mutations in igf-1 i guess i should know this the the current state of that literature a little bit better it's complicated and there have been some controversies in the field about the different mutations that directly

affect igf-1 itself and the effects on lifespan so i'm not going to wade into that because i think it still hasn't been resolved but there's no question that mutations that reduce growth hormone signaling in mice extend lifespan now it's important to understand though that with one exception those studies are all cases where the animals are growth hormone signaling deficient through development so they are very very small animals and then they have constitutively low levels of signaling through that pathway for the rest of their life there's one study that that that i think it used a

monoclonal antibody to the igf-1 receptor in mice this is from near bars and hosey cohen yeah where they treated mice with this antibody lately and they got you know a reasonably sized lifespan extension i think it was i don't know 14 15 percent median lifespan so was that also that was an antibody that did not penetrate the cns if i recall i think i remember near talking about this and saying you would get all the benefits of igf in the brain right without the benefits of igf in the without the potential harm of igf in

the periphery right yeah and that's another complication right where the the effects of igf in the brain might be fundamental on for health span and cognitive function much might be fundamentally different than high igf-1 in in the periphery um so that study i think is the best evidence in mice that you can get some benefit specifically from reducing igf-1 signaling in middle age and this is such an important question i get asked all the time i have a lot of patients that are asking to be put on growth hormone yeah and and you know we

just don't do it um and there the reason is i just am not comfortable with i don't see enough data in humans to suggest that it's necessarily safe um conversely i don't really see evidence to suggest it's not yeah this is sort of a weird thing with growth hormone like if you buy hook line and sinker the argument that more growth hormone equals more igf equals more mortality and you look at how much growth hormone is being used i mean it is hands down the most abused drug in sports it's like it's first second third

nobody's even within the zip code yeah and this is going back 35 maybe 40 years probably to the early 80s where are the bodies yeah like there need to be more bodies so so i'm stuck with like i don't see where the bodies are but at the same time it's still a bit of a leap for me and i don't have the luxury of rapamycin data where i can at least point to all of the humans who have taken rapamycin for 23 years and we know what that looks like and then even though it's not

for gero protection and then all of the mechanistic stuff that is consistently pointing the right way so so you know there's going to be some patient of mine listening to this saying peter you almost talked me into taking growth hormone based on your discussion and it's it's like no i i i can't you know it's funny i even took it for a week after my shoulder surgery i had sort of you know looked at some literature using gh and anabolic steroids to help with recovery and it could have been true true and unrelated but like

i felt the worst i've ever felt after a week of growth hormone and nandrolone and i was like yeah i'm done i just abandoned it now again i think it was i was i happened to be sick as well um but my blood pressure went up my blood sugar went up i felt like crap i couldn't sleep again a lot of confounding factors shoulder surgery and a nasty virus so again it could all be irrelevant but i think i think the point you made is actually a really important one so first of all you know

obviously i've never given growth hormone to anyone i've never taken growth hormone my you know i'm not an expert in the human application of growth hormone but i've certainly tried to follow that literature you know because based on the mouse studies you would have predicted right that growth hormone therapy should be the most toxic therapy you could give a human yeah certainly should should cause increased risk for a bunch of different diseases including cancer mostly cancer yeah yeah and and my understanding of the literature here is that um like you said it's not clear that

there are significant benefits particularly for strength i think i think there's some evidence that muscle mass may increase but but strength doesn't but it's also not clear that there's any real detriments right that there's any significant risk which is a little bit surprising yeah it is surprising and i do have a couple of patients who have taken it uh usually other doctors were prescribing it or you know they came in under the care of somebody else and they all seem to claim they feel infinitely better on it um there may be something to that right

it might be that in 20 years we have enough data to say you know what by the time you're 60 you should just be on a slow amount of growth hormone for all of these reasons um i'd love to see somebody do this study because again it's it's a very important question to be asked and i also think we have enough data to suggest that such a study is not unethical right in other words we don't have an abundance of data in fact we have a positive data suggesting it's harm that it would justify ethically

doing a study like this um so anyway that's that's sort of a hope i would have because i i really find this to be one of the most confusing questions in this space yeah i agree and again i think you know this is sort of why i've i personally have settled around the idea for now at least that um that that igf-1 particularly is is probably not that informative in people particularly you know once you get past 50 years 50 years is arbitrary but that's kind of where i would i would put the number um

obviously again igf-1 itself is complicated because you don't really know what that means in terms of igf-1 signaling and downstream activity but yeah important i guess for people to understand that just like testosterone is mostly bound to sexual binding globulin there's only a small amount of testosterone that's free it's the same with igf-1 it has these igfbps or binding proteins that bind most of it and therefore total igf is not really completely informative as to what's happening even in terms of the quantity that's there for signaling because it's not the unbound portion of it so

some people look at things like igf2 igfbp ratio the bigger that number is in theory the more igf signaling you would have but you know this gets to now when you look at sort of the epidemiologic curves which on the x-axis would show in you know deciles or quartiles or whatever buckets igf levels rising and then on the y-axis would show you mortality i've never seen one of those curves that just goes up yeah right they're sometimes they're u-shaped sometimes they're down sloped sometimes they're flat and it depends on the indication yeah but the story

seems much more complicated than igf is bad i agree and again i think you know going back to the the levine paper that we were talking about again i think it's a it's an important paper it's a well-done paper you really have to recognize that um the population you're looking in might make a big difference as well right so we you know if you're talking about a population of people where 30 of them are obese some high percentage have metabolic disease or diabetes you know having high igf-1 in that context might be very different than

somebody who is sensitive exercising eating a high protein diet right and again that those kinds of things don't typically come out in these epidemiological studies the other thing i'll say is you know and kind of thinking about what we might talk about today you know i went and tried to look through the literature and see what other studies have shown you know that that same uh relationship and they're all over the place you can find studies that really don't show any for protein con protein consumption particularly you can find studies epidemiological that really don't show

any downside to eating a high protein diet in people so it's hard to it's hard for me to draw too much confidence that high protein is significantly detrimental when you're younger than 50. and i i feel pretty confident that a higher at least certainly higher than the rda uh level of dietary protein intake when you're above 50 is beneficial particularly if you're exercising i mean that's where i would be a little bit concerned if you've got somebody who's overweight obese diabetic sedentary so high calorie plus high protein totally i totally agree yep yep i think

that's a and by the way i frankly think a lot of the epidemiology is tainted by that yeah it's high protein in the context of high calories exactly yeah the other thing that i think is is also potentially interesting to think about in human are these these people who have mutations in the growth hormone pathway right so this is now maybe more akin to these mouse models where they have low growth hormone signaling you know from development even in utero potentially they go through their entire lives there have been a a couple of studies again

walter longo obviously prolific in this area had a study on these the the little people of ecuador right there have been several studies but but the most ron dwarfs yeah that's right the laurent syndrome yeah the uh the most famous study is one that was published in science where they looked at you know lifespan and age-related health outcomes um in the the people with low growth hormone signaling versus you know uh controls in their same environment environment yeah um it's sort of it's a really fascinating stuff so so i mean i think that again the

interesting things are there's no difference in lifespan but the the uh people with low levels of growth hormone signaling the reduction in cancer risk is is profound i mean i i don't remember the exact numbers but i think it was zero like i think they did not have any maybe there was there was one person in their cohort who developed a cancer i remember what it was and she was treated and then she she lived the rest of her life but none of them died from cancer um and the rate of diabetes was lower in

the uh the the little people but but ecuador at least that part of ecuador at that time had a very low diabetes rate to begin with something like five percent so it's a little bit harder to say but certainly cancer dramatic reduction in risk of cancer so why didn't they yeah why didn't they and it's a little bit ambiguous they don't really say but you know they say that there is a higher much higher rate of alcoholism um uh liver failure and accidents and so you know this gets back to sort of what i was

i've alluded to in passing a couple times which is the social and psychological consequences in humans that are just different than we have in mice right the the growth hormone deficient mice aren't going to be subject well they might be probably not subject to the same social pressures that somebody you know has very low growth hormone signaling in people is subjected to which may contribute to other other things later on like alcoholism so anyways fascinating though um biology which does which is consistent with the idea i think that you can impact at least a subset

of age-related biology by being constitutively low in growth hormone through your entire life you know what would happen if you did that in bursts you know like post-developmentally just after puberty say from your 20s and 30s who knows right we don't have any there are no naturally occurring examples of that i don't or very few that we could look at and actually evaluate by the way do we um do we have examples is there enough data to look at um people with acromegaly during different periods of their life to see if that's had the exact

op have we seen a higher incidence of cancer i don't know i don't know the answer to that um i mean i'm you know those those populations would be relatively small but yeah maybe maybe it's possible yeah yeah it seems like i don't know i i imagine somebody's looked at that the incidence of cancer and people with acromega adult onset acromegaly or something to that effect right um the other thing i would say on the igf thing before we leave that is uh the interplay with insulin yeah and so you know high insulin high igf

low insulin low igf hi low insulin high igf i mean these are very different physiologic states it's very difficult to think that we're teasing those out when we look at broad swaths yeah and again i think this just comes back to the fact that these especially these epidemiological studies are a mixture of you know normal people typically right and so the lifestyles that are that most people are living right are what gets weighted in those types of analyses and that may be very different you know as you as we talked about if you are normal

weight high protein maybe high calorie because you're extremely active right yeah then if you're overweight sedentary and eating a high calorie diet i really think that's underappreciated and you know probably really really important um and you know in thinking about the cancer risk again i this is going to be some pure speculation on my part though right but but there's no question i don't think that high growth hormone signaling and high igf-1 signaling everything else being equal in a person leads to a higher risk of developing cancer you don't i i don't i don't i

think that's true oh you do think that's true okay i i believe that that's true everything else being equal of course everything isn't going to be equal but if we just look at that though that one variable signaling through that pathway higher signaling higher risk of cancer so then if it's the case which i think you could you know we could we could make an argument that that doesn't seem to be the case at least in certain populations of people that that high growth hormone signaling or treating with growth hormone dramatically increases the cancer incidence

so why is that or in people who are and by the way we should also differentiate between high causes it versus low removes it in other words just because we have a genetic example of where not having it uh creates a a deficiency of cancer right it doesn't mean so so going from sort of 100 to 30 decreases cancer doesn't mean going from 100 to 30 increases cancer 100 to 130 increases cancer that's right no that's that's absolutely true yeah i mean we don't know it could but yeah yeah and actually i mean i think

the word you use there is interesting because you said removes it and i know this isn't what you what you meant but this is this is i think something that is also important to appreciate so to go from you know pre-initiation of cancer right to cancer to metastasis to you know somebody dying from it there's there's steps that have to happen there right and there are different defense mechanisms that act at each of those steps my guess is growth hormone and igf-1 is primarily acting at the very early steps right where we know that if

you if you promote cell division that that is a sort of a permissive early environment for mutations to happen and cancers to to get a foothold but in in most cases it seems to be the case that those early cancers are detected and wiped out by our immune system right and and one of the reasons why i think a lot of cancers become more prevalent as we get older is because the immune the function of the immune system to detect and clear those cancers declines there's obviously other stuff going on accumulation of senescent cells which

contributes to this process but if you are say i shouldn't even say this because i i bother people about the biological clocks let's just say though theoretically you know you're a 60 year old person but biologically because you are exercising eating a appropriate diet biologically you're 40 years old at least your immune system is functioning like a 40 year old you might have a little bit higher igf-1 you might have a little bit higher of that early cancer risk but you have a much lower total risk of developing cancer because your immune system has a

much better chance of catching it and getting rid of it and those are things we don't even even think yeah yeah well matt i don't know that we settled anything today did we i i it's pretty safe to say there's we've probably for the listener created more questions than answers uh no i'm sure we've done some good yeah i mean i think again it's it's a complicated question and you know we we actually did not dive into the genetic interaction with caloric restriction so i mean i think the take home there is that even in

mice where we can control everything else if you look across genotypes you get different results from the same diet and the effect of caloric restriction on lifespan so you know i maybe we can't answer the the the big detailed questions i guess the take homes i i would have are again we've learned a ton from these nutritional studies in laboratory animals about the biological mechanisms we've learned a lot about which proteins are and and pathways are important and that has led us to things like rapamycin right which might be a more effective uh intervention in

humans so they have value for that um and i think you know the other take-home that we've talked about is you don't have to worry about every little detail right i think i think again most people can get a big chunk of the way there by eating a relatively healthy diet don't worry so much about how much protein how much carbs how much fat eat good foods right don't overeat and be active right exercise and and i i do worry a little bit that we you know society does this but but scientists do it sometimes

too when we start you know really getting into the weeds and making recommendations to people that we overthink things a little bit right and give people anxiety about worrying worrying about am i eating a low enough protein diet or am i on you know am i am i still in ketosis yeah what should my fasting window be yeah should it be 16 hours versus 18 hours yeah so the the the questions are out there to what extent do any of these things have big benefits i think you can get most of the benefits without worrying

about a lot of that yeah i agree well matt glad we finally got to do one of these in person yeah maybe maybe the next one should be in person as well absolutely [Music]