Can We Slow Down Aging? Venki Ramakrishnan on DNA Damage & Protein Synthesis for Extended Healthspan

I'm guessing that this this beer is not conducive to to healthy aging no no beer is but there's more life than worrying about no just kidding folks it's a it's an iced tea oh just having a little bit of fun there venki welcome to the show it's great to be doing this in in person I don't think in fact I'm sure I I haven't had a Nobel Prize winner on the show oh right so this is a a real treat to be able to do it in person while you're here in La is is a

great honor you've just written a new book this is your second book yes okay first book was dedicated to ribosomes and and your the work that you did ear in your it was a scientific Memoir about a race for a very important structure which led to the Nobel Prize which led to the Nobel Prize yes okay so you're a biologist that has had this tremendous interest in in ribosomes and you've been studying them for decades at this point I guess that's right there's been a Splurge of of books on this topic of of longevity and

from from scientists and from journalists you know um people from all walks of life there's also been uh great I guess privatization and commer commercialization of long longevity science over the past uh 10 years there's a lot of public interest in how do we slow aging how do we live longer how do you go from this scientist biologist researching ribosomes to deciding or feeling compelled that you want to enter this conversation about human longevity uh several reasons one is that um firstly my field uh I mean you mentioned ribosomes but ribosomes are really the central

player in the whole process of how uh proteins are made in the body using information in our genes and that process is highly orchestrated and um the whole function of life depends on making proteins at the right time in the right amounts and degrading them when they're not wellmade and that entire process of protein synthesis all those aspects are things that uh are either part of my research or directly related to research but it turns out those are also Central processes in Aging in in other words when protein synthesis goes wrong or when degradation of

proteins goes wrong uh then you have you know accelerate Aging in many different ways and so you can think of my work as my area as having uh a relatively important role in aging even though I don't work on Aging per se um so I when I thought about what to write I did think about how the longevity field has evolved from a somewhat Backwater field that was regarded dubiously by mainstream molecular biologists into uh a a growing and flourishing industry both in basic science and in uh biotech and and pharmaceutical uh industry and it's

driven by many factors although we've known about uh mortality and aging for a long time uh for most of our history there was nothing we could do about it but I think in the last 40 years or so people have started understanding the molecular biology and and the cell biology of Aging and so we're in a for the first time in a position to ask can we do something about it and then of course it leads to a question whether we should do something about it but that's a separate question so I thought I thought

it was a good idea to write a book at this time and as you mentioned there are lots of books but many of these books I should say are written by either scientist who have a a lot of skin in the game they either have a company or they have an agenda they're or they're selling something a product or services or um they're written by journalists who are learning about it secondhand from scientists and uh so I thought somebody like me who's very close to the field but not in it and doesn't have a vested

interest in the field uh could take a hard look at at the evidence you know think about what's promising what's actually solid and what's potentially exciting but not quite there and what's just pure hype and there is a lot of hype in this field yeah I'm hoping that we can unpack some of that you said there are some characters in the longevity kind of science space communication of longevity science that have some conflicts of interest um and that they have you know skin in the game so to speak in the in your book you kind

of jokingly but Ser seriously as well sort of say you do also have some skin in the game so what's what's your personal vested kind of interest and I guess all of our interests well we all have skin in the game and that we're all going to age and so you know we have a vest an interest in trying to see if we can stay healthy as long as possible so that's that's one skin in the game I suppose if you were being very cynical you could see you could say another skin in the game

is of course I'd like my book to do well but that's uh that happened that you know only after I wrote the book at what point in your career did you appreciate the connection relationship between ribosomes and and aging I think you mentioned that earlier in your career you were just studying ribosomes to better understand them oh I think it it it happened organically as the longevity field expanded and uh this phenomenon of proteostasis which is uh preserving the uh correct expression of proteins in the cell and and maintenance of the of the uh Orchestra

of proteins in the cell U being connected with aging that just the evidence built up over years and so you you would just sort of watch uh this happen it's not that there was a particular moment when you suddenly realized you know there's a famous quote from molier where there's a character who suddenly discovers he's been speaking in Pros all his life you know so there's no Magic Moment Like That where I say oh I'm actually working on something related to aging it just happened over time okay I want to come back to ribosomes and

better understand DNA damaging damage and and how all this uh protein synthesis and getting rid of proteins relates to aging before we get there you mentioned that there are some jubia claims or a little bit of overhype in the in the longevity field are there are there any claims or Therapeutics that that stand out that sort of raise your eyebrow eyebrows most that frustrate you uh well there are some claim names in the in the science field that I've gone into um where um a discovery is made then a contrary Discovery is made and um

the consensus then develops against the original Discovery but the original discoverers of course they're not backing down and they still believe in what they believe and rather than tell you now I would say this is uh stuff that I've discussed in detail uh in the book uh but this is this is a case where I think people are applying standards of evidence that they wouldn't apply to other people you know so uh they've got a hypothesis when it's uh dis I wouldn't say disproved but when a lot of evidence bills against it uh they still

stick to it and they still uh you know want to commercialize uh these things so I I think that's um not quite um you know beyond the pale but I you know I think people should be uh somewhat skeptical of claims where the scientist has a lot at stake in it it doesn't mean that scientists developing their ideas and commercializing it is bad that's how medicine develops okay so it's not uh Universal the case that you should dismiss anything just because a person has a company that's you know that's how biotech develops but it does

mean that you need to take a hard look and by hard look me I mean how do how do government agencies how do the international Health Community how do they view it and do they recommend it does anyone beyond the seller or beyond the original proponents support it and if you look at medicines that are universally accepted like statins or high blood pressure medicines it's not just the original proponents who accept it it's accepted by the wide Community uh of of of Med medical practitioners that is different in the Aging field and where only the

it's often just the original proponents who keep pushing these things now the thing that I find really frustrating are the more extreme views and I'm afraid in California they're very popular and there are these things like cryonics where you freeze bodies or even brains and you know assume that science is going to progress at some point and then resurrect these people uh you know I think there's no basis for that uh at all today part of me thinks that we're so scared of death right because what you just EXP there sounds very logical if someone

is presenting a claim and maybe they've they've studied something but they own a company selling you something then there should be a level of healthy skepticism where you as a consumer as someone that is being exposed to that information think has that finding been replicated and are independent bodies also recommending that intervention that makes total sense right but part of me thinks when it comes to longevity AG it's so exciting and I think when you get someone who jumps on a podcast that can speak very well or a brand that has incredible branding I think

people Overlook that and think this is Cutting Edge this is ahead of the government and other recommendations that might come and I don't have time is not on my side so I'm going to I'm going to be drawn in by this compelling story story that there is something I can do right now that will slow my my age of my my rate of Aging or reverse it oh absolutely and you know we saw this earlier with cancer treatments you know there were I think in California again there were people recommending lateral these extracts from apricot

pits or something it turned out to have no real basis but there were people you know it wasn't accepted treatment here so they would go off to other countries I think they went to some of them went to Mexico uh to get these treatments it's because when you're faced with aging and death or in cancer you know you're faced with death directly you know people are desperate because we want we have evolved to want to be alive and you know we don't want to stop existing the you know those of us who are alive don't

don't want to stop existing and so I I think this is a natural worry and and the real worry uh is that as we get older we don't want to be helpless decrepit so anything that promises health and old age and possibly extension of life itself uh people are more predisposed uh to believe that and that's that's just human nature and I would say I wouldn't say these people are necessarily exploiting it some of them actually I think believe in their uh claim names uh but it creates this extremely hyped field right and a field

where the commercialization is ahead of the science oh absolutely and there's a there's a lot of money in it I'll give you an example again uh from California so scientists at Stanford um found uh something that had been previously suspected but they were the first people to find that if you take blood from a young uh animal young rat and peruse it into an older rat by connecting the two animals the old rat appeared to benefit from The Young Blood and contrary wise the young animal suffered from the blood of the old animal and initially

it wasn't completely clear whether it's because they were connected and you know maybe the young blood was filtering young animal was filtering the old blood it wasn't necessarily just the young blood but they did transfusions of animals which were not connected and showed that actually there were factors in Blood and oddly in that experiment it turned out that old blood is more harmful to Young animals than young blood is beneficial to older animals okay but nevertheless it means there are factors that change as we age in Blood and this is a very an some of

these factors you know promote uh growth of neurons uh other kinds of uh effects and so this is a very legitimate field of inquiry and the original scientists have been extremely careful about what they claim but those scientists uh write that they got you know somewhat creepy phone calls as soon as they uh you know publish their findings and not long afterwards companies would Sprout up which would offer to provide blood transfusions in other words they would collect uh blood from Young donors and presumably give it to Rich uh people who who wanted to benefit

have you come across Brian Johnson oh so Brian Johnson's an interesting case so I I actually don't think he's a bad guy I think he's honestly trying to live as long as possible and age as slowly as possible I would say his way out there he spends about $2 million a year on longevity aspects for his life collecting data take doing this and that and the other treatment and he for a while actually uh had a sort of three-way blood transfusion kept it All in the Family between his son father and father where he would

get blood from his son and then also donate blood to his father and uh I think after a while he also a data freak so he measures all sorts of biomarkers and I think he felt it wasn't having uh much effect and and he stopped and and he I think I believe he said that but he still believes in the principle and there and of course he's right there is there are these experiments which suggest there's something uh in blood that changes as we get older and there are factors that might do something but this

is a case again where uh people have jumped the gun and one of these companies was shut down by the FDA and then was resurrected under a different name and the CEO said well the trouble with clinical trials is that they take too long now think of the absurdity of this what what they're saying is we don't we're not we're not going to bother taking the time to see if this thing actually works finding out what the optimal dose is whether it's efficacious whether it has side effects because our customers don't want to wait and

that's precise what you were saying which is uh people will often jump the gun because they feel time is not on their side right yeah I like Brian too and I I think he's well intentioned and doing some some interesting things and and I've met him and he's a good guy I've heard him say uh what you just explained there that he felt that he didn't derive any benefits from so he had blood from his son but I have heard him state or at least his dad state that his dad seemed to feel some benefits

but how is that Quantified you know the trouble with the bran Johnson experiment it's a data point of one he's not do he's doing a whole range of uh so-called longevity measures uh which essentially muddles up uh the data it it's going to be of almost no benefit to science okay if you want to do proper science you need to do uh you know each treatment has to be done in a controlled manner see how much it contributes before you combine treatments so I think that sort of scientific rigor which is present in almost every

other field is is lacking in in some of these commercialization of comes back to the fear of Aging it seems that the fear of Aging outweighs the possibility of unintended consequences yeah and I'll give you an example during covid so there were lots of tests being done and and Britain is very uh rigorous about randomized trials for one thing it the concept of randomized Trials was invented there and they asked to see if a particular steroid would benefit um people who had come down with covid because part of the problem of D the part of

the reason people died was because inflammation long after the original infection might have been dealt with they they had severe inflammation and uh it turned out steroids did have a benefit but to do that they had to put half the patients not on steroids and the other half on steroids and someone asked them well if you thought steroids would be beneficial why didn't you treat them all with steroids but that's the that would have destroyed the whole experiment you know so the whole point of the experiment was to ask do steroids actually help and I

think that's the kind of rigor you need uh if you want to test longevity um measures fundamentally how would you say your book differs to the other books that people may have been exposed to in the last five years whether whether it's the the material that's in it or your approach to the to the research behind it so I I've tried to take a very fundamental and somewhat historical approach and so what my book does is concentrate on the fundamental biology what are the fundamental reasons uh that we age when we know for example uh

species that live for hundreds of years other species last a day uh so it's not as if uh it's simply some automatic wear and tear uh but there's a a range of biological processes that break down with aging and our body has learned to deal with these problems and but those processes the way of dealing with them also breaks down so it deals with the fundamental biology then it talks about advances and potential Therapeutics and there I talk about the pros and cons and what's not known and what needs to be known and so the

hope is that it gives people the tools for understanding aging they understand roughly where we are now if I talk about the latest thing it's going to be obsolete very soon because the latest thing may be wrong or the field may have moved on or it may have been superseded those are not very useful books this is a book which gives people the tools and then when they read an article or say listen to a podcast they have a mental framework of how to fit that new claim or new information into this broad understanding uh

of the biology of Aging so in that sense it's it's quite different from uh many other books I would say I think the the longest living human the record is is it 12 129 or 127 122 122 okay so 122 years John calmont a French woman okay and and people in this space seem to have different ideas as to whether that is around about the the maximum human lifespan and will'll never be able to improve upon that um and then you know there are certainly some people out there who will point to other species like

the is it the Greenland shark that lives for three or 400 years or something yeah and and and suggest that in the future there'll be ways to kind of uh modify uh our biology in a way that will allow us to hugely exceed that current human lifespan that we've seen what's what's your take on that so if you look at Jean calmont who lived to 122 she died in 1997 because we're living longer on the whole on average the number of centenarians since that time has grown but the number of supercentenarians people over 110 or

115 has not grown uh very much and no one has lived past 120 in the in the 20 five or 30 years uh since she died they many of them seem to live to about 115 or so and then and then they die and that suggests that the our species has a natural limit of about 110 to 120 years and by that I mean you know Evolution has always had to make a choice it makes choices all the time uh to optimize Fitness Evolution cares about uh how successful you are at passing on your genes

it doesn't really care about how long you live so an animal that's like a mouse only lives two years because there's there'd be no point in selecting a mouse that has extremely good uh repair and maintenance mechanisms for it to live very long uh and age very slowly because it's much more it's very likely to be eaten or starved to death because it's so small and so on and so it's very so there's no point and so for the mouse evolutionist chosen a path where it matures very rapidly and and produces lots of Offspring quickly

and the Greenland shark on the other hand has very slow metabolism as you know extensive repair mechanisms and that combination allows it to live over a very long time in both cases what's being optimized is Fitness the ability to uh pass on genes and that's different CH species so for our species our natural biology suggests maybe 110 120 years uh at the most okay and maybe Jean calmont was an outlier maybe there'll be an occasional outlier in the future to tackle that it won't be enough just to remove the causes of disease you know many

of these supercentenarians are l in a sense there's a selection bias they're lucky because they didn't get cancer they didn't get uh accid they didn't die of accidents or infections or things like that so if we just eliminated causes of disease people estimate that we might gain another 10 or 15 years to go beyond that you would have to tackle the causes of Aging itself you would have to slow down the process of Aging or reverse some of the processes of Aging that's a much harder problem which means you have to somehow change the way

that these genes are working or the effect that these genes are having for example we would have to change the rate of damage in our DNA we have to we have to change how whether our telr shorten and and cause syence we would have to change uh the rate at which our genes are methylated uh we'd have to change you know mitochondrial damage so there is a whole set of factors that we would have to change and the reason that those things occur and we're not just living forever is that our our genes have essentially

through evolution been developed to help us get to an age where we can procreate pass our genes on to our Offspring and then to some degree it doesn't matter how much further we live I mean you you might you might think there'd be a selection for us to live long enough to bring up our Offspring so that they can carry on H beyond that it's it's all it's all gravy you know it's it's bonus and and and so and and that's happened uh well there were there's apparently a change due to various things that happened

maybe 40,000 years ago when we increased our lifespan but then more recently uh say 150 years ago we increased average life expectancy but that average life expectancies mainly because we eliminated early mortality uh infant mortality due to infectious disease due to uh other factors Nutrition a and uh in the last few decades we've also made some progress at the other end we've improved treatment of heart disease of diabetes of cancer uh not so much of dementia so another problem that we're facing as we get older is the fraction of people with dementias gr up in

the older population because that's something we uh don't know how to deal with and so we'd have to deal with um you know the process of Aging itself to go beyond uh that those current advances right I just did an episode on on dementia with a preventative neurologist and I there was some new guidelines written in the Lancet and it surprised me they they identified 14 risk factors again none of this was really sexy stuff but they suggested that if you if we could eliminate these 14 risk factors which were things like elevated cholesterol and

blood pressure and hearing loss and vision loss you could eliminate perhaps up to 50% of cases of dementia but not all of it right and I I I I'm not even sure about the eliminate I think what they might do is slow it down yeah compress it the number of years you're affected by it possibly or or delay the onset of dementia you know I think eventually um you know dementia is due to essentially this loss of proteostasis and our cells uh proteins misbehaving uh at least that's the uh accepted Theory uh but in any

case you know I I think neurod degeneration uh can be delayed and and you know one of the uh things I I'm sure was part of it was exercise and and uh avoiding obesity city was certainly in there you guys know this already at the center of good health lies a healthy microbiome when you feed your microbes they reward you with drug-like compounds that improve blood sugar control lower inflammation act as precursors to important neurotransmitters in the brain and plenty more step one in achieving this is a Prebiotic reach plant-based dietary pattern if you want

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code the proof that's 38t r a.com and use the coupon code the proof for 10% off uh you know something that blows my mind is and you wrote about this in in your book and I've thought about this for for a long time so you mentioned there ourselves kind of misbehave or they become dysfunctional as we as we AG they're not they're not as good at doing various functions as they were earlier in life and nor are we nor are we and that's the biology of Aging which we're going to unpack but something that I

find fascinating is we can be 40 or 50 and have a child and somehow we produce a human with brand new cells that are completely youthful So within us resides that information for cells to act in a way that is youthful yet we can Target that towards Offspring but not towards our own cells yeah no this is a a very it's a it's a fascinating thing this idea that we can reset the clock every generation and one thing I say is that uh a child born to a 40-year-old woman isn't born 20 years older than

a child born to a 20-year-old woman so they're both born and they're the same age their age zero when they're conceived and uh so uh how does that work well it works due to a number of things firstly our germline cells the eggs and sperm or or sperm the you know precursors of sperm sperm cells they they're seem to be more protected against DNA damage and other kinds of damage and even their methylation patterns uh are different and but that's not all what happens is that eggs undergo a tremendous selection uh in the process of

maturation and ovulation and of course sperm are also highly selected because you know they're tens of thousands or hundreds of thousands of sperm and they all have to compete and it's only the sperm that's actually fit energetically uh that is successful in fer fertilizing and so there's a huge amount of selection going on uh for Fitness which weeds out all of the eggs and sperm that are have defects of various types possibly due to aging and then once the embryo is formed the fertilized egg is formed and grows into an embryo there's selection of that

process too there are lots of uh even after fertilization there are lots of fertilized eggs that don't actually make it and you know people are even unaware of it uh and and even during embryo development even within the embryo defective cells are are uh selected against so because of this tremendous selection U what you've essentially done is eliminated some of the baggage that older cells adult cells have accumulated okay so so it's a two-way thing germ cells are better protected and have better repair mechanisms and then and best of the best get through and then

the best of the best get through so so that's the way that this resetting uh works now if you look at so the country example or not coun example but an interesting situation is cloned animals so when Dolly the sheep she was Dolly was not the first cloned animal but it was first cloned mammal and when Dolly the sheep was cloned she turned out to be very sickly and died at about half the age of a normal sheep and had shorter telr so everybody said oh well this is because uh you know this is a

a sheep cloned from an old cell and therefore had all of the Aging de defects and so of course you wouldn't expect the Sheep to to survive uh but it turned out that there were other animals that were cloned around the same time they all apparently they were whimsically given uh girl names beginning with A D like Dorothy or Debbie or Daisy or something and anyway many of these sheep actually led a norm had a normal lifespan and and were re and were reasonably healthy and that suggests that at least in principle you could take

an adult cell reprogram it back all the way to uh you know for f the situation of fertilized egg and grow a new animal and the animal would then have a complete whole extra life uh ahead of it and that is the one of the main things that's done is the marks on our DNA which are these so-called methylation marks are wiped out during that process and reset and so that would be an animal with a different Consciousness though it would be an animal of course right yeah yeah completely it's not the same animal what

about the idea of taking those cells and and somehow using that to create youthful liver cells or heart cells to regenerate those tissues oh I think that's a that's a that's a whole program a lot of it is not related to aging at all it's it's an entire field of regenerative medicine which is using stem cells and reprogramming them to form different kinds of tissues so for example uh let's say you have uh a defective liver defective pancreas let's say and and you have diabetes is it possible that you could produce stem cells that would

you know regenerate the insulin producing cells in the pancreas and and or uh for example regenerating cartilage you know which main cause of joint uh problems as we age or regenerating muscle you know heart cardiac muscle for example if you were able to replace cardiac muscle after a heart attack so I think those those things are very that's a broad field of regenerative medicine and aging is a small part of it they kind of intersector rightt if you are able to to restore the function of important key organs presumably you're either improving Health span and

or lifespan possibly and there are some there are some promise when you say totally intersect I I would point out one difference if you're treating a specific problem like cartilage replacement or um you know pancreatic replacement you know eyelet replacement or a heart tissue replacement you're you're uh running a very focused program where you have very good measures of success you have a disease that you're you know and you're treating it you can you can measure whether you've got something I think with one problem with aging is you know how do you measure uh success

and how do you also do this reversal in a way that's holistic that you know you can do it to the entire body uh because our organs don't age at the same rates and you know you would have to try to make sure that you're doing it in a concerted way what do you think about but there are promising and kind of rate of Aging calculations whether it's looking at DNA methylation or or other fact is are we able right now to truly measure aging quantify Aging in some way so that if you were to

intervene you can actually check if you're I think this is another problem uh with the Aging research field and that is um people want to do trials that you know even the scient the scientists who want to do rigorous trials normally in in a disease you would say okay we'll measure the rate of cure and cancer it's typically 5 years survival or something like that and uh and other diseases that's a a definite end point where you can say this person no longer has a disease with aging if you did that you'd have to wait

for a long time if you just measured mortality for example and so people want to measure these markers so as we age uh the these methylation marks on our DNA CH change the pattern changes and that turns out uh seems to be more correlated with mortality and and and therefore biological age than simply counting the number of years since our birthday and so uh that's one marker and in in fact you know the person who U discovered uh the most popular of those was uh right here Horvath in in Cal actually in LA and um

that's uh one marker there are other markers for example as we get older the so-called sugar or carbo hydrate groups that we add to our proteins what are called uh glycosilation or actually glycation uh those uh patterns also change and we start producing aberant proteins uh especially in the immune system this causes uh loss of function so that's another marker so some people will measure uh glycation rates other people will measure the battery of enzymes in our blood and that changes with age U we talked about the blood transfusion earlier or or um you know

just all of the markers in our blood so there are whole set of markers and the the trouble is these people don't sort of bring all their uh you know cards to the table and arrive at a a set of a panel of markers uh that they can agree on what it means because they may have slightly different meanings you know age you could it's a multifactorial process you know you things age at different rates and what do you mean by aging and when you give somebody a single number as a biological age uh that's

a misnomer because part different parts of you uh don't have the same age but I think the whole marker thing is is going to be crucial to actually measuring uh how effective various measures are yeah maybe there's a way of having some type of global composite score that that looks at the the age of various tissues biological age of various tissues then somehow seates that yes absolutely I think and and perhaps not even uh not even cement it but say look this is the panel of markers and if you get these then these are the

range of things uh that are happening so it it it it should be a more complex picture than just just say this is your biological age it's I think that's a somewhat meaningless concept going back to that idea of passing on genetic information to our Offspring so as I understand it through that process you just explained essentially The Offspring sort of starts life with a clean slate in terms of how it cells are are functioning but I and maybe this where genetics and epigenetics comes up I had thought that to some capacity your lifestyle and

maybe it's epigenetics could be passed through to offspring is there any truth to that yes for for a limited number of generations some of these uh patterns can survive uh you know for about two or three generations and these are the marks in our not so much in our DNA but marks in our histones the proteins that are associated with DNA uh and so people have found for example uh you know in the Dutch Famine of uh you know 1945 I think um that The Offspring uh of women who had trauma starvation and other trauma

during pregnancy uh had epigenetic marks and then their children also showed uh some effect but it's not as it's not a good evolutionary selection mechanism because it it doesn't persist for for several Generations in your book you talk about this idea of antagonistic plot tropy yes I thought this was super fascinating this idea that we can inherit genes that are great for fitness and they're on our side early in life they help us have Offspring but then they can kind of come back to haunt us later in life yeah so I can give you a

couple of examples for example uh our response to DNA damage and uh you know losing telome uh and having cells go into sence what's a telr if someone's hearing that for the first time so our chromosomes are linear so they're not circular so they have ends and the ends of our our chromosomes have a special DNA SE quence which is repeated and it also has a special structure now what happens as cells divide is that in the normal process of cell division the mechanism that replicates our DNA can't copy the ends and so the ends

start getting shorter and shorter with each cell division and um when it gets short short Beyond a certain point there are special structure unravels and when that unravels the cell thinks that that end of the DNA is a broken piece of DNA so it thinks of it as a as a DNA strand break and it triggers a DNA damage response which would also happen when we have normal DNA damage occurring in a variety of other ways and what the DNA damage response does is send the cell into either apoptosis which is cell death or into

a state called cence and when it goes into State called cence cell can't divide anymore what determines if it goes down cell death apoptosis very well understood okay okay and but when it goes into syence then um what happens is that not only does it not divide it's not functional but it also secretes inflammatory molecules now these molecules are signals to the immune system system to come and clean up the area because there may be the sight of an infection or a wound and it also gets rid of the senescent cells okay and why would

you want to do that well if you were to allow a cell with DNA damage to persist that cell could become cancerous and kill the entire organism if you get rid of one cell or even a million cells it doesn't matter because we're we're killing you know millions of cells in us are dying all the time we don't even notice it in fact it's usually a good thing and so early on it's beneficial it's a cancer preventing mechanism but as we age what happens is the cells become damaged more damaged and more ccent cells produced

and at the same time the mechanism to clear them is also not working as well because it's aged as well and so you get this buildup of senescent cells you have buildup of inflammation the inflammation itself induces more inessence so you get this vicious cycle and so you get aging so cancer prevention early on uh the same things that prevent cancer early on are causes of Aging uh later on that makes treatment tricky because then if you were to intervene on that part of biology to try and slow aging I guess depending on the time

that you intervene you could inre risk of cancer absolutely all of these things for example people talk about uh telr lengthening you know that one idea is that you lengthen your telr maybe the cells will live longer I I I think you know I have to say I'm somewhat skeptical uh about that notion because there is this potential uh for cancer uh you know reprogramming of stem cells this is this idea that you know maybe you can take cells backward in development and be able to regenerate tissues again there's there's a potential risk of cancer

and so this interplay between aging and cancer is a complex one and any um Therapeutics for uh aging has to take into account that that problem because remember unlike a disease if you have cancer you you're willing to take nasty treatment radiation therapy or or or horrible chemotherapy because the alternative is you're going to die and so or if you're a diabetic you're willing to take uh drugs that are prevent you because getting diabetes is a serious problem uh but if you're a healthy individual then the bar is much higher for you to take something

that potentially might give you 10 years extra healthy life at the end so I I think that's one of the problems of of Aging Therapeutics there's another example that I've read about of antagonistic cleat tropy you've probably heard of LP little a it's this like very atherogenic lipid and at least from what I've read um I mean we know now that people who have genetically High LP little a are much higher risk of thrombosis and developing atherosclerosis later in life but there's this Theory or idea out there that high LP little a at least historically

when we were more at risk of infection and bleeding and whatnot was actually really important for wound healing absolutely absolutely and that is uh there's also a flip side and that is the one the the variance of this Gene that uh has been found over represented in some centenarians for example uh that variant also makes you uh have a higher risk of cancer and infection but a low risk of Alzheimer's okay so depending on your environment in our primitive environment it was much more important to make it through adulthood not get infections early and then

later on if we uh you know developed Alzheimer's or or aged or developed atherosclerosis doesn't matter it didn't matter as much for evolution and whereas now we're less at risk for infection because we've got public health and antibiotics and so on and so this other variant is is that's interesting to to think of in in and of itself because I think uh certainly the environment has changed a lot and lifestyle has changed no doubt that explains a lot of disease we see today but what I'm hearing from you here is that some the genetic predispositions

that we have to developing disease later in life our ancestors would have also had these and and so you would have seen higher rates of you know dementia for example had they been able to live long enough exactly so most of them didn't live long enough in fact average life expectancy at Birth was only about 40 years 150 years ago so the number of people who would get uh heart disease cancer uh dementia and things like that was much smaller uh than it is today and one thing that is happening as we are having more

success at treating heart disease cancer and diabetes is that we're seeing an increase in the uh number of people with dementia as we get older in the in the older population and that comes back to the point you made earlier that even if you get rid of these chronic diseases it may not I mean 10 to 15 years this is significant amount but it it because ultimately there are these genes that are kind of limiting Lipan to a degree unless that changed yeah then right you know we can't really Escape our biology so I think

you know the more sensible there's a very famous bet uh in the longevity field between Steph aad and Jay olansky and uh the bet is whether somebody who's going to to live to be 150 uh has already been born now 150 you might think is not that much more than say 122 but remember 122 is still a very much of an outlier and most people don't live to be 100 so so the idea that somebody could be live to be 150 is already born uh seems a little far-fetched but I think those scientists are not

arguing about what it would take they would agree that it's not enough to eliminate some of these major uh diseases but that you would require fundamental advances in in aging itself breakthroughs breakthroughs and and and actually slowing down aging and I think the bad the difference of opinion is How likely is that while we're on Evolution I'd love to get your perspective on this there's this idea online uh kind of way of living called ancestral living which you know I think some ele elements of it are are good in terms of the practical sense of

things that are being advocated for but the idea sort of underpinning ancestral living is that if our ancestors did it they must have adapted to it and therefore it must be good for longevity I I don't I I'm I'm a little skeptical because our ancestors did whatever they could to to to survive it doesn't mean it was optimal and we live healthily much longer than our an sisters ever did I mean even in my own family you know I'm 72 years old I go hiking in the Grand Canyon and ride ride my bicycle and uh

do all sorts of things even though I I do have problems with my knees or shoulder but if you if you looked at my grandparents there is no way that they were in the kind of shape uh to do that so we have actually improved Health uh you know and health span and so I I think I think this idea this it's somewhat romantic okay uh there is one thing though that we uh are living in a time of plentiful food and we've not evolved to curb our appetites and so not surprisingly there's this sort

of uh you know rise in obesity and all the attendant problems and our ancestors would not have had that and that that of course would have been uh better for the for for health uh so but that's something we need to work on in in various ways requires some some pretty big environment shifts environment shifts and marketing shifts just social shifts along with you know possibly medical advances yeah so why is it that let's say for example hypothetical uh Discovery here that we find out a thousand years ago humans were drinking sap from some tree

and all of a sudden that becomes the Elixir for for longevity why and we've kind of gone through this but I think it would be good to kind of make it clear to people just because our our ancestors were drinking sap from some tree why is it that we we can't assume that that is necessarily a good thing for longevity because the they didn't have any trials they it was all anecdotal and they may have liked the sap for all sorts of reasons um I think there's no reason to think it's not true for example

many medicines have come out of traditional practices you know many important medicines have come from looking at uh sort of indigenous tribes and plants that they use um and uh even for treating cancer uh or other diseases so it's not just because something is traditional uh doesn't mean it's not true but it also means that you have to test it and I would just say you can be open-minded and and and put it to the test and many of them it'll turn out are just superstitions or Traditions but often there'll be things that actually do

have uh some benefit I mean a very very recent example is aramin as a treatment for malaria came out of Chinese traditional medicine uh nobody really knew uh whether how it work but then they did uh proper trials and now it's used to was used to treat chloroquin resistant uh malaria and the woman who uh developed it won the Nobel Prize for medicine for her Discovery so I'm not saying that you know just because people did it a long time ago it's obsolete or right or or you should it doesn't mean it's necessarily good or

bad no if it was a fact based on what I'm hearing from you it would suggest that you know maybe it helped them get to an age to procrea but it doesn't necessarily speak to longevity that's right and it may have had it may have been an accident it had no effect or or it may have had some effect that needs to be Val validated you said at the outset that one of the things that makes your book different is really the focus on the biology of aging and and certain principles that you would like

people to walk away with as opposed to you know just citing single new studies breaking science where do you start if you're if you're at dinner with someone that's not an academic so you're not at a a a biology conference and they say to you you know what what's happening from a biology point of view as I'm getting older where do you start so I think it's you know this came about because I uh visited the Santa Fe Institute where they think of uh complex systems and you can think of Aging as a breakdown of

a complex system and one thing they did is they put biological Aging in a in the same C categories all kinds of Aging for example aging of cities or companies or societies you know cities age and die companies agent die at a faster rate in fact the larger The Entity apparently probably the longer lived it is and in our own case our cells die all the time but we survive much longer than most of our uh cells and so um that's one way to look at it that aging uh is really this gradual breakdown of

a complex system that has to work but when you look at then you have to ask what are the causes of this breakdown and and they're getting the damage itself is a cause of Aging but even just as interestingly the response to the damage which occurred as I mentioned as potentially a cancer prevention mechanism also as a cause of Aging so there you have DNA damage then you have the shortening of our chromosomes which is again is related to our genome the chromosomes is is where the genetic information is held that's right the all our

DNA is in sort of 23 pairs of molecules Each of which is called a chromosome and and then there's the DNA apart from damage uh under goes changes it it has marks added to it called methylation marks among other marks and these marks themselves change which genes are expressed and which are shut down so it changes the pattern of which genes we're using and that changes as we age and again that might have had an important role early on that you wanted to shut down V various genes because they might be uh predispose you to

cancer or proliferation but then as we age it it has a consequence that it's shutting down genes in in ways that are detrimental to us and prevent optimal function so so that's another thing then we have in our cell so now these genes are basically coding uh for all of the proteins that make life work which do all carry out all the functions chemical functions of Life which build all the structures in our body and so on and that Orchestra of proteins also if your Gene genetic program isn't right that Orchestra isn't made correctly it's

not working properly and as those proteins you know malfunction or unfold they have to be uh removed from the cell there's elaborate disposal mechanisms uh in the cell for that those things also break down with aging so that so that's a next level then you can go beyond that to organel in our cell like our mitochondria which are the place where you know energy compounds are made and where a lot of chemical damage also occurs and these mitochondria age they they even have their own little piece of DNA uh because they're descendants of bacteria that

we ended up one of our SE ancestral cells swallowed up and we've lived for two billion years as a happy couple ever since well not so happy because the mitochondria age and they cause problems to the entire cell and and therefore to the organism and then going beyond that you have cells themselves the stem cells that are responsible for regenerating tissues you know we get depleted of them many of them become ccent and then how to restore that is a problem and then cells talk to each other the immune system is a collection of cells

that uh you know interacts with the rest of the body and and that can go into problems causing uh more Pro being more prone to infection but also causing inflammation and arthritis and things like that so so there just a whole range of of complexity going all the way from molecules to tissues and the idea is to understand what is happening and which of the sort of aging anti-aging measures uh where do they act at which Step do these anti-aging measures act and and and what can we do about each of these processes can we

is there are there ways to reverse any of these processes is what you have just kind of walked through there at a high level is that distinct to the kind of H marks of Aging or nine Hallmarks of Aging people it's very much built on the non nine Hallmarks of Aging I should say one of the authors of that book uh was a colleague of mine uh at the Royal Society Linda Partridge and uh really throughout writing this book I would constantly you know exchange emails with her and uh I think the nine Hallmarks are

are a useful way of looking at aging by thinking about what are the things that are present in aging individuals that if you eliminate the Hallmark or reduce the the Hallmark you you improve the symptoms of aging and if you increase the Hallmark you accelerate aging so that's the sort of definition of the Hallmark so in 1997 that's when you won the Nobel Prize with two colleagues 2009 2009 not sure where I got 1997 from oh that's when John calmont died okay okay so apologies for getting the dates mix up so 2009 yeah okay so

much more Rec uh that that is when you were awarded the Nobel Prize for your work on ribosomes right where do ribosomes intersect with the the biology of Aging that you've kind of just walked us through so for example um everybody knows that caloric restriction um is has been shown to benefit uh you know in a let me back up if you take animal and you let one group of animals eat all they can they can eat and you restrict the other set of animals to the bare minimum number of calories uh that they need

to survive not starve but just but survive it turns out those animals resemble much younger animals in in sets of markers in terms of their sort of physical properties their movement their fur uh things like that and and so there is this idea that the number of calories you consume is related to aging and it turns out that some of the pathways that are involved in how the cell senses nutrients like calories uh is one of the major Pathways is called the Tor pathway so if you look at the Tor pathway one of its main

effects is to when it's inhibited it shuts down protein synthesis its role is during growth this is another example of this antagonistic plot tropy early on we want to grow and and grow rapidly and so on and and so the Toral pathway is switched on and it allows you to make proteins and you can that process helps you mature so you can have Offspring exactly but then later in life if that pathway is not properly controlled you're making too much protein and uh the you know proteins are misfolding and you're it's out outstripping your ability

to clear uh your body of defective proteins and so on and so when you sense uh you know deprivation of nutrients then you you switch off uh protein synthesis well that happens uh by a process that we've actually been studying in the last 20 years which is how to ribosomes know where to start on the MRNA to start making proteins and it turns out that one of the effects of the Tor Pro pathway inhibition is to stop ribosomes from getting started this process of initiation so that that's for example a direct link between uh initiation

of translation and aging bya the Tor pathway and there are there are other examples there's another program uh there's another process called the integrated stress response which in which cells respond to stress including infection or sensing unfolded proteins and also shut down uh initiation of protein synthesis so there is really a a you know a strong link between some processes of aging and so just a double click on some biology 101 and it's taking me back to University which is a while back now but so the the genetic information that's in our DNA gets copied

to mRNA to mRNA that's a a duplicate of it and the ribosomes are what help read that yes and then that says produce this protein yeah so the ribosome is this giant well Giant in molecular terms it has about half a million atoms in in humans and so you can think of it as a large molecular machine and what it does is latches on to the MRNA and it has to and that process is called initiation and and that's what's inhibited by any of these uh you know Pathways anyway when it initiates it then starts

reading the MRNA and based on the code the genetic code in the MRNA it puts together a particular protein it's synthesizes a particular protein so many of us have taken mRNA Jabs uh for covid vaccines and what that mRNA has is the instruction to make the covid spike protein and so the idea is to trick the body into making the spike protein and then our immune system recognizes it as foreign and starts mount a response then when you get Corona virus infection it's already prepared you have the memory there it has the memory it sees

the spike protein says aha this is something I know how to attack are there any potentially um deleterious or unintended consequences of blocking that initiation blocking the the Rome with things like calorie restriction oh I think you know initiation of translation is is essential for for life so if you were to block initiation you know in all our cells we we would just die so calorie restriction just dampens it turn it dampens it it's a transient uh response it dampens it and it also turns on other genes which are involved in stress response genes which

help clear uh you know the sort of unfolded proteins or misfolded proteins and and so um so it is really a sophisticated uh each of these responses is quite sophisticated and it's tuned so that you know what you're what you're talking about is a tuning where you're trying to get the optimal level and it if you damp if it's if if you're making too much protein and you dampen it uh then you're impr improving the situation but if you have a normal amount and you're dampening it even further then it's it could be delerious so

I think in all of these cases it's going to be a it's going to be tricky to find just the right balance between uh you know making too much of something and depening it too much and so if we take calorie restriction as a real world kind of example there are a number of people that probably practice it yeah and so my question to you is how do you take the research that's largely from animals but not not entirely and translate that to hum so we know what is the optimal kind of dose of calorie

restriction and when would start I think you know there are many people who practice caloric restriction and apart from I think that you know many of one of the effects of caloric restriction by the way is that you're hungry all the time uh many another other side effects are your cold you have uh slower uh you know healing of wounds which is itself a problem as you get a older and uh and loss of libido is another uh thing that hungry you might be hangry exactly so so there all sorts of issues uh but nevertheless

there are some enthusiasts who who who practice it and they seem okay you know they're not dying or anything and they swear that they feel better so so I think it it probably varies uh from Individual to individual but and and I think you you know the body has all these feedback mechanisms if you feel start feeling really miserable you won't do it you know so I think that's just how we've we've evolved I but I think the bigger danger is when you start using drugs that mimic Cal caloric restriction and you you know not

each drug will affect one particular pathway but caloric restriction might have multiple affect multiple Pathways not just one pathway is rapy and rapy you know it's a darling of the anti-aging Community why is it a darling because it affects this tor pathway that I mentioned which is this nutrient sensing pathway that turns off protein synthesis but it also does other things it does many other things not just turn off protein synthesis or or dampen uh protein synthesis so Romy inhibits that now Romy was discovered as an immunosuppressive drug in fact it's approved precisely for that

and used by organ transplant recipients but it also is known to make you more prone to infection it's known to have other side effects many of the side effects of caloric restriction and in animals it had it showed benefits like in older animals uh you know seem to have benefited from rap aice in in ways similar uh to caloric restriction so people felt that this is a way that you can have the benefits of caloric restriction without you know actually starving yourself right well not starving but you know limiting your tius much and I think

it comes with uh risks that have to be have to be measured uh The Advocates would say well maybe we can adjust the dose so that we can have the benefits without the uh deleterious side effects uh that's yet to be proved and uh the other possibility is they say well we might not use Romy we might use analoges of Romy they call them rapalogs which have the benefits but not not the side effects which are somewhat more specific for the benefits again a lot of this stuff has to be uh tested properly before it's

ready for prime time but it hasn't stopped people from taking Romy on the side even scientists you know have been taking it but which goes back to the problem early on people feel time is not on their side and they they want to do it h you know they don't want to wait 20 years for uh rigorous trials to to yeah I had char brener on on the show a while back oh yeah I know you guys know each other in fact he introduced us um maybe you might not have trusted me to come on

the show if he hadn't so thank you thank you Charles and one of the things that he's brought up is that some of these experiments looking at like calorie restriction or inhibiting this m to pathway are not necessarily representative of the way we live our life so looking at animals in a confined environment is different to humans out in the wild who have to have a certain degree of strength and mobility and vitality I think he's absolutely right and I'll tell you even with caloric restriction uh people found that the caloric restricted animals were no

better than animals in the wild in some cases and there was also a very interesting study where two two groups did studies on calorically restricted monkeys and one of them fed their control animals a very rich diet the other one fed their control animals uh a reasonable diet you know much healthier diet and of course that group found much less difference between theorically restricted and control monkeys and so some people have argued that you know all these studies show us that eating all you can eat a rich diet is not good for you you know

it's not so much that the and so calorie restriction might be more effective in the context if if you're eating a standard Western diet but if you're eating a high quality diet like exact mediterran and nobody has done proper trials I think even in animals uh you know how what if you gave animals a really healthy and moderate diet so they didn't overeat they're a healthy diet and then give them a similar diet but with the bare minimum calories how much extra would you gain uh from that you might not say much you might not

see a huge difference might not make the headlines coming back to DNA damage uh thinking about the causes and then the response if we start with the causes my understanding is DNA damage is to some extent inevitable it happens happen right now it's happening right now what is uh let's say normal DNA damage and then what would some of the causes be of you know unnecessary or extra DNA damage that people may encounter so DNA damage occurs even in just water DNA can get damaged and this was a finding of a famous DNA damaged scientist

named Thomas lindal who went on to win the Nobel Prize to show how that damage is corrected and it that work really led to the realization the DNA damage has been there ever since life evolved and we have evolved very sophisticated mechanisms to constantly Monitor and correct damage and so what the cell does is all these repair mechanisms to repair damage but it also has mechanisms so that when it cannot repair the damage it then deals with the cell by as I said sending it to apoptosis or death or to sending it into cence and

so so it it takes DNA damage uh very seriously now the things that can increase DNA damage are exposures to uh various chemicals that may be uh carcinogenic exposed to radiation like a c scan something yeah I mean I I would say that CD scan is very unlikely to do very much to you because we have all these repair mechanisms uh but let's say if you had a profession where you constantly exposed to very very high radiation uh you know before we knew about their effects for example people who worked with uh radiation often Marie

C who worked with radium you know came down with a nasty I think a blood disease which was caused by her exposure to radiation uh so I think uh that's another source but even if we eliminated all of those things we would still have natural DNA damage and some of the damage occurs because in our own cells as we metabolize energy we produce uh these reactive species with called reactive oxygen species which has to do with partially partial products uh during oxidation of glucose of our fuel and these reactive oxygen species in our mitochondria which

are those organel I mentioned uh can go go and cause damage and so uh there are those causes now you would think that taking antioxidants would would help uh because then you know you're reducing the amount of these reactive oxygen species but the evidence for that has been quite mixed and partly is because the when we consume these it's not necessarily going uh to the site where they're needed in the form that they're needed to to to affect it it doesn't mean that you know the principle is is not correct but it just means that

uh preventing it is more comp complicated than we might have imagined the other thing that I find interesting about some of those antioxidant studies is using isolated kind of compounds versus how those compounds may be utilized or absorbed when they're eating in a in a food Matrix right right yeah so getting them to the site involves many things and absorption is one of them but then targeting it to particular cells and then to the mitochondria uh is another issue so I think there and you know mitochondria have sophisticated ways of getting things from the rest

of the cell and and out so there are no compounds or like bit supplements or drugs that that we know of now that can reduce DNA damage I don't I don't know if anywhere it's actually been proved that this this thing is going to reduce uh chemical damage or DNA damage um but it's not to say it doesn't exist but I I think that's that's one of these areas where you need rigorous signs what about the response so you said a couple times if there is DNA damage and it can't be repaired yeah then it

can go down well really three Pathways the worst being that it becomes cancerous so hopefully it goes down this pathway of apoptosis where you know the cell sort of commits suicide yeah or inessence where it becomes dormant why why not just have the single pathway there why not just have all cells that have DNA damage go down this pathway of apoptosis and therefore you're not exposed to the ccent cells I think because ccent cells actually play a role for example the reason that the cell may have been stressed or incurred damage may have been due

to infection it may be the sight of a wound or sight of infection or some other problem so the sence cell early in life is a signal to the immune system and and the other blood cells to say come here and fix the problem and so they served a very they serve a very important Pro purpose uh through much of our Lives it's just that the balance goes uh off kilter as we age so this class of compounds I believe are analytics yes is it I guess the the AIM more challenge there is how do

you temper dial down ccent cells without taking it too far and then affecting the immune system in a negative way yeah so that's a promising approach so there have been studies in animals where they have targeted ccent cells and those animals seem to improve by various criteria uh that they measure uh the the problem always is that when you give it to a human you have to make sure that they're very specific for sent cells you have to be also able to get them into the person in a an appropriate way and you have to

make sure they don't kill normal cells and and they don't have other uh weird side effects so again giving it to healthy individuals over a long period uh raises a higher bar uh than if you have a life-threatening disease where you're willing to take side effects of various types you know what about these like essentially basic areas of our lifestyle that we all know are healthy exercising regularly getting sleep you know trying to reduce stress eating a healthy diet do we do we understand the ways in which these types of behaviors are actually influencing the

biology of Aging I think we're getting a much better understanding so these these kinds of advice have been around for a long time you know everybody you can you can read uh the anatomist Galen uh from you know ancient from The Classical period and and you'll see in in Greek in ancient Greek uh the guy has written about benefits of exercise so but I think what we're understanding now is what does exercise do and what exercise does is it uh helps with all of these factors involved in regeneration it can regenerate muscle muscle loss is

a big problem as we age and leading to Frailty and it can uh even be involved in regeneration of mitochondria uh so there are number of Pathways that are affected sleep is when many of our repair and maintenance mechanisms operate there's a weird thing about sleep which I didn't realize until I read a very interesting book called why we sleep by Matthew Walker and that and of course once he mentioned it it was obvious that sleep is not just because we have a brain or eyes and we can close our eyes and go to sleep

very primitive animals even unicellular animals have the equivalent of sleep they have circadian rhythm which is the the program of gene expression changes uh through the day and so it's a highly conserved process you would think sleep shouldn't evolutionarily exist because we're vulnerable to predators right EX in spite of that the fact that we need sleep and it's preserved means it's doing something really really important and some of it is is you know proper development and some of it is is this maintenance and repair during aging and diet of course we've talked about all these

Pathways involved in caloric restriction and and how an important diet is is is beneficial and more than that a bad diet is also detrimental in many ways for example obesity turns on uh various Pathways which are in a which are harmful and I wouldn't have thought obesity would cause cancer but the link between obesity and cancer is very well established now uh and of course obesity and heart disease and diabetes is is very well known so so I think this Trio uh one thing that we we've learned in the last few decades is how this

Trio actually works in various ways we still don't understand all of the details and there's a lot of work going on but we understand some of the thing ways in which they affect our metabolism to keep us healthier uh as we age and the you can think of them as a three-legged stool for example if you exercise you're more likely to sleep better you know if you sleep better you're also going to be less stressed and you're going to uh not overeat and you you maybe more feel more like exercising so they they tend to

act in a synergistic way a bit like a three-legged stool all supporting each other and beyond that they help you with things like stress uh which also uh is still terious for aging and these things I mean they do come with some cost but they're accessible to most to most of us particularly people that are listening to this show right now and have two hours to to spare to to listen to us yeah talk uh versus you know some of the things like Brian Johnson's doing that are extremely expensive yeah although I should say he

probably does exercise and watches diet and these are the foundations and I think to his credit one of the thing that things that he uh really underlines and emphasizes te's Community is that the majority of the things that we know will influence aging and improve your health span are either free or not that expensive relative to all of the speculative very expensive things that he's doing and that's a good it's a good reminder for people because you could kind of land in this place where you think gosh I just don't have the mains you know

even in the UK which has a National Health Service the life expectance the lifespan difference between the the top 10% and the bottom 10% in in terms of wealth is over 10 years and in the US it's over 15 years and even worse than that if you look at the health span the the difference in health span is almost double the difference in lifespan that means the poor are not only living shorter lives but they're living a bigger fraction of their Liv unhealthy okay you know at the end of life and so we talked about

these three measures and how they come at no cost but you know a poor person who's holding down two jobs doesn't have the time to prepare good food and has to eat on the run you know typically some fast food and as a result it's also stressed and doesn't sleep well all these factors act against you if you're poor so it's it's okay to say they're free but they're only free to people who do have the time right that's still a privileged State still a privilege I I I can acknowledge that we need to raise

the bars of society and improve quality of life across the board so they become more accessible yeah absolutely earlier you you mentioned that there are some species that live extraordinary extraordinarily long lives major Mitchell's cocko I think you wrote about yes that's an Australian yes I was I was pleasantly surprised to see that in there and and we spoke about the shark the the Greenland shark if we think about the biology of Aging some of these things we've gone through when you when you look at their cells and how they're behaving are they doing a

better job at repairing DNA and and so if you look at these animals many of the animals that are long lived have very slow metabolism for example the Greenland shark has a very slow metabolism uh another darling of Aging researchers with something called the naked mole rat also has a very slow metabolism and that then slows down a lot of the progression of Aging however uh well major mitell caku doesn't have I mean it's a bird and flies around doesn't have a as slow metabolis one thing they've found with uh some of the whales that

are very long lived and recently the Greenland shark as well is they tend to have uh very extensive uh DNA repair mechanisms in fact where we may have one copy of a DNA repair Gene uh they might have multiple copies and so that's definitely a possibility that their uh ability to repair the fundamental damage you know at the very beginning DNA damage which then may lead to other kinds of uh problems are better dealt with and and and we don't know whether their ability to clear damage you know these things called autophagy where we clear

out debris and un you know Mis dysfunctional uh components from the cell uh we don't know if that's better in these uh species or not so it's going to be interesting to study them but I'm not sure how much relevance that has for humans okay it's interesting as to study to see what's happening uh but then to how how would you implement that in in humans are we going to do gene therapy and clone in multiple copies of these DNA repair genes we don't know and we don't know uh whether that's safe and what that

what consequence that'll have uh so I I think uh right now it's in the realm of academic research thinking here a little more philosophically I know you like to go there uh if we manage to significantly improve health span and perhaps lifespan a little bit what are the pros and cons of that well currently a lot of the field is is motivated by the fact that we're living a longer Li lives anyway and we're living just the same fraction of our lives with several morbidities and so we're spending many years maybe even a couple of

decades in poor health at the moment and that's why you know all our Advanced societies are filled with nursing homes and Care Homes with people uh needing assistance and uh and care and so the idea is to try to improve health to the point where as we age we stay healthy stay independent and preferably productive and that's motivating a lot of uh what we do now the problem is whether if we do that we'll keep life fixed so that we only have a short rapid decline that's a a process called compression of morbidity it's not

clear that we we can achieve that because in the past everything that we've Advanced has also extended Our Lives you know all these progress that we've made in medicine has also extended our so we're just pushing back the two decades where we're affected by disease that's that's a question whether we can do that or not and there are people who believe yes we can compress it but I don't think there's any evidence that that that that's true uh and you know it may be true uh and that our eventual lifespan is fixed and that we

can make more bigger fraction healthy and then we'll just rapidly decline there's some evidence that supercentenarians people who live over 110 live extraordinarily healthy lives uh and then suddenly decline but there's also uh there's an article saying that these super centenarians may be the subject of selection bias that is these are the people who've been lucky enough to void infections or cancer just by pure chance and they've survived and so it's not so they had genes they do have they may have some genes that help them and if they're lucky enough to get through the

earlier part of their life where they might have had increased risk they enjoy the decrease R his yeah possibly that's one way uh that they might have succeeded and another way maybe just pure chance you know maybe they didn't even have those genes but they didn't develop some of these things so I think that's uh not not clear but if for example you did solve this issue then everybody would start living let's say to 990s or or 100 or so even without cracking the barrier you know by affecting aging and fundamental ways then you would

have a situation where you would have a a a society that's getting older uh fertility rates are dropping if they don't drop and everybody lives longer then then you would have a population uh expansion and then the pressure that puts on the earth the pressure yeah ecological pressures economic pressures all sorts of pressures resource uh that would be a problem but let's say even if that doesn't happen it doesn't have to happen Japan has increased life expectancy and its population is actually declining because fertility fertility is dropping even faster so if that happens then you

have a society where the turnover is very slow and I you know we do undergo cognitive decline as we age and it doesn't necessarily happen later in life and if you look at when people have been the most creative uh it's it's been when they're relatively young especially in Science and Mathematics but even in literature uh authors often write their most uh famous or groundbreaking work when they're uh relatively young it's not as if they live a long life and gain wisdom and then write their big Masterpiece Tolstoy wrote waren peace in his 30s so

so what would happen is we might have a relatively stagnant Society where you know same people are hanging around there's less turnover of ideas new uh sort of generational turnover uh changes in culture uh many many of our social movements civil rights women's rights they were often driven by uh young people who were not s of vested in the in the status quo and it's because they see life fresh and it's not just about biological aging it's it's a fact that you when you see things fresh you're more open-minded and and can think out of

the box and be more creative and that's not going to change and I I'm I'm skeptical that an older Society will be a a better Society but I'll tell you the flip side people said to me they argued that well you know 150 years ago we lived half as long on on average as we do now are you suggesting we should go back to that time you know because turnover was even faster then and and you know there is a point to that you know and most of us wouldn't want to trade our current lifespan

for a shorter one there's probably a sweet spot there though right I I think that's a sweet spot and you know this quest for immortality is endless okay if we started Living to be 200 then we'd be wondering well why do we have to die at 200 why don't we you know we should be aiming for 400 so it's a it's a NeverEnding struggle and eventually there's no such thing as immortality you have to go there'll be other causes there'll be external causes and and so that that that quest which pulls us out of the

the the present moment is you there's a quote in your uh book The the butterfly counts not months but moments and has time enough yes exactly and and that's a f it's it's by an Indian poet rindon tagor and actually I think having a sense of our Mor mortal existence is a great driver it it it it's a driving force to make make the most of what we have and Achieve things while we're around I think if we lived you know 200 years we would just do the same amount of stuff but would take 200

years to do it that's my feeling I mean there's the famous Parkinson's law that work expands to fill available time right so if you have two months to do something you'll take two months and if you have one month you'll get it done in a month so I mean up to a point and I think there is some element of that I'm not sure we're going to do twice as as much if we lived 200 years rather than 80 years how do you approach this personally if you take your science hat off as someone that's

researching a well it's complicated because I think as humans we we've been we've evolved not not want not wanting to die you know we don't want to stop existing and even the most rational of us if you are most philosophical of us if you came and somebody said look here's a pill all of the it's been completely validated that it it'll give you 10 years of extra healthy life with no side effects uh most of us would take it okay and I'm I'm taking statins and blood pressure medicines why am I doing that so that

I can stay healthy presumably for a longer time so I think it's a it's a hard problem where what's good for society and Humanity as a whole uh is in conflict with what the individual wants and we see this all the time we see this in climate change we know what's good for uh humanity and and and Society but we make individual choices that are not necessarily uh consistent with that right so I think that's that's a problem yeah I went to a dinner with Brian Johnson he had had a group of people at's house

not sure I've spoken about this publicly but it was a it was an interesting thought experiment and he started at the night asking a question which is essentially what you just stated there where he says if there was an algorithm and you were told exactly what to e exactly what exercise to do every decision you made through throughout your day was determined by this algorithm and it would bring you the best mental spiritual and physical health would you opt in to the algorithm or not and there was this you know ongoing debate or debate through

the night about most people were uh were grappling with the idea of letting go of your autonomy yeah I I I personally I I'd like to think that I would probably not opt in you know and just make my decisions uh I think this obsession with with you know longevity and and so on it's okay up to a point you know you don't want to be unhealthy in old age and you you you want to do the things that that keep you healthy but but this extreme obsession with life extension and Longevity I think it

prevents you from actually enjoy I mean what is life about you know it's about enjoying it and doing other things it's not about you know prolonging life what what do you want to prolong it for and when you ask that question you realize actually I want to spend most of my life doing other things and and doing and and just enjoying life oh than you Dr ramakrishna thank you very much for doing thisk you as I said at the the beginning it's a real trait to to be able to sit down with you in in

person and um thank you for your contribution to science thank you for writing why we die the new science of aging and the Quest for immortality I encourage all all of the listeners to to go and get a copy um we only just covered many of the concepts at a at a surface level thank you very much thank you for having me there you have it friends I hope you enjoyed this episode if you did and want to stay up to date with future episodes be sure to hit that subscribe button on YouTube and follow

on Apple or Spotify finally thank you for showing up and the effort that you're making to take control of your health I look forward to hanging out with you again in the next episode