Can Aging Be Cured? A Conversation With Biologists David Sinclair and Ali Brivanlou

it's such a pleasure to have these incredible guests tonight Ali I I kind of want to start with you here we're going to do hardcore Sciences you know if you come to Scientific controversies we really love the science but I want to take a minute to discuss um how you both got into this field and Ali I'm going to start with you one of the things I love so much about science uh makes my heart sore is that it's Transcendent it's Transcendent of boundaries of artificial limits and uh I want to ask both of you

how you got into this subject because it's quite an international stage tonight yes well first of all thank you so much for having me in this forum it's the first time I've been in this space and I really admire everything the architecture the ambience the vibe the whole thing so I'm very grateful for opportunity uh how did I get into science I I I think it was a collection of chance and stochastic event ultimately that got me to where I am I was born in tan in Iran long time ago and my father was uh

mdphd working at NC pastor and I remember that from a very young age he took me with him to his clinic and I remember the first pipetting thing that I did he was showing me how to at the time we didn't have the machine so you had to suck with your mouth from the pipet the pipet yeah and there was something extremely attractive about just mixing stuff together you know and that ultimately got me to where I am it was clinical at the beginning it was very practical utilitarian and but then I started asking why

why is it that we're measuring things the way we're measur them what the quantification of units means how do we diagnose something or how do we discover something and gradually I got into this almost addictive um space that I couldn't attach from so after that it was gradual planning to go to medical school started medical school it was not exactly what I was looking for at the same time there was this revolution in molecular biology oh my God DNA the genetic code and the influence of the code in all these different shapes and forms all

animals share the same code in the same DNA or plants we all start as a seed or as a fertilized egg and then we create these entities that are totally complex and mindblowing so I was fascinated and gradually got obsessed and I would say addicted to science and that's what I find myself now well when we talk about your work we can also talk about the contexts in which you could or could not do this kind of work and David what brought you here I actually have a picture of your lab this is one of

your Labs it says do you have multiple Labs what's the story David uh I have one lab uh I used to have one in Australia but uh now I I just uh have a lab of about 25 people at Harvard this is a photo from the lab uh what you're looking at are human brains grown from stem cells yeah uh similar to the work that Ali does we use these to to study whether we can drive aging forwards and backwards in human brain tissue and potentially cure diseases like dementia and Alzheimer's um and then what

we discover in these little brains here we then test it out on on Old mice to see if we can reverse aging of the mouse brain and make them regain their memories and learning you said things like these little brains think can you tell tell me what you mean by that well they have thoughts they have they have electrical fire many many uh cell types they have the same structure as the human brain and we can measure their electrical activity in the dish and they are I'm not sure I could call it thinking but they

or dreaming but they they definitely have waves of electrical activity the same way our brains have waves of thought delta waves Alpha Waves uh I hope they're not conscious I I doubt it uh it would be a terrible existence uh but they can they can grow little eyes they sometimes get two little dots on them it's a little freaky uh but yeah that's a little bit of an understatement it's it's easier than experimenting on on human uh brains in sichu now when you were a little kid dreaming of growing brains and eyes in a FY

dish um were you always drawn to longevity research in particular was that one of the motivators for you to get into this subject uh yeah it sounds crazy that that I've been wanting to do what I do since I was 4 years old but it is it is true uh I can remember the moment that my grandmother told me that everything I knew and loved uh would die and go away and at 4 that was pretty sad uh I'd been watching movies like Snow White thinking everything's great and then to hear this was quite tragic

and I think most of us we learn this at a young age and it's so terrible we push it out of our minds I saw my children go through the same process of realizing that one day their parents would be gone their pet would be gone and they would be gone um but then it take I saw my kids it took them about a week and then they forgot about it and which is what I think most of us do we forget about the tragedy of being mortal and having friends and family that are mortal

it's just too tragic if we thought about it all the time we'd go insane um but I couldn't get it out of my mind to me it is the most tragic uh topic that you can talk about I mean I I agree that climate change is bad but 200 something thousand people die every day from this what I may call a medical condition if not a disease um and I was just flabbergasted as a kid that nobody was talking about it you remember people don't talk about dying typically um especially not in the 1970s when

I was growing up and I just wanted to scream from the top of buildings wake up everybody there's this thing going on that we need to talk about at least and work on um and I even at a young age realized that working on cancer and heart disease and even uh dementia were really just addressing the symptoms of the main problem which was that we get old and I I thought how tragic that is that God or Evolution uh has produced a species that is conscious and aware of their mortality how cruel is that I

think it's a very cruel thing to do to to an animal like us um and so I've worked through my whole life to get a PhD uh in genetics to train at MIT to get a love at Harvard to build companies to train the next generation of scientists in an effort and wrote a book to educate the planet on what I think is a really important problem now we're going to get into some of the hardcore science here but before we do we're going to do a little bit of a rapid fire because you brought

that right in right into the uh Arena here David the rapid fire is going to be yes or no answer maybe a sentence to three questions okay I'm going to start with you David is aging a disease it should be you mean classified by by the the FDA okay and Ali is aging a disease no fascinating we're going to come back to this so this isn't the only time we're done with the event thank you everybody um Ali will there be your cure to this thing that is not a disease you see uh we might

want to take a second to Define both words well aging yeah and disease so to me this is a rapid fire but go for it no no so no go for it aging is not a disease is at best A syndrome the way we recognize syndrome versus diseases and I think when you talk about disease you think about therapies or cures when you think about syndromes is almost a continuity of life so as an neologist developmental biologist I believe is part of a natural process of progression will there be a cure David uh I wouldn't

say there's going to be a cure there I don't believe in immortality but I do believe that there is no limit to human lifespan there's nothing that says we have to age and that many species live longer than us even mammals now we're going to talk about some those species if there were to be a cure for aging do you take that as synonymous as a cure for death uh no cuz you could get hit by a bus we will still die no matter what uh I think it be very unlikely that we're still around

in thousands of years um but we could easily uh develop ways to live for an additional 100 years that I can see happening with the Advent of AI and how quickly things are changing now and medical progress is doubling in its knowledge every 60 days now is quite incredible so what we need to do is stay alive for longer so we can reap the benefit of all of these changes coming Ali life is a privilege it's not a right I really believe that the fact of being alive and even sitting in this Podium with you

um is not something that was ever guaranteed to anyone I really believe that every single species may you be a plant or an animal begins with a seed or a fertilized egg to me aging begins in the womb the man of the fertilized eggs becomes two egg two cells and you move forward the aging process begins now adolescence is not considered a disease well uh I have an 18-year-old okay well that's our rapid fire so we're going to come back to this sorry I got distracted by thoughts of teenagers I um I want everyone in

the audience to kind of ask themselves those questions as well and and and see if your answers are different at the end of the conversation we do know of species and Oli we've talked about this um that that are Immortal in this kind of proverbial sense or maybe this colloquial sense if not a scientific sense tell us about the Hydra here so you may ask yourself um what do we mean by aging and and dying there are species there are butterflies who live for one day there are other animals that live for hundreds of years

and there are animals that never die this is one of them It Never Dies It Never Dies because it keeps on regenerating itself there are many more examples to that the flat worm the jellyfish and everything else but there is a reason to think about what do we mean by aging if it's not a direct connection with the time moving forward victorial influence so we'll talk about time in the embryonic sense that you study and where it's flexible and where it's rigid but I I have to admit that I was surprised and maybe everybody in

the audience knows this to learn that Coral is an animal I mean I guess I learned this some time ago but I'm still shocked by it I I think of it as a plant but it is not it is an invertebrate animal and it also could potentially if we stopped killing it um live indefinitely it won't die of sence it will not and that's an amazing Point you're making here because if you look from images from other space and you look look at the coral reefs and if you by genetic criteria characterize this as an

animal then that would be the largest animal in on planet Earth the amazing thing about corals is that you they kind of Clone themselves they regenerate themselves and they create chimerism with different species of corals come together to create a new body a new entity I think when we talk about aging we need to consider what is the evolution roots of Aging what do we mean by getting old what do we mean by dying because most species don't have that attribute now before we talk about the human example um we have to talk about the

immortal jellyfish David I know that you've talked about written about in your book um the immortal jellyfish tell us a little bit of the story of this jellyfish because it doesn't come to maturity and stay that way forever it does some pretty weird pretty weird let's talk about it so this uh this is to opsis it was discovered in Japan uh we tried growing it uh culturing it in my lab it it wasn't successful uh partly because we were sent home during the pandemic uh but it's an extremely interesting organism because it can clone itself

the actual jelly doesn't last forever but it can disintegrate and little pieces of itself will regrow new jellies so in that way it's Immortal I think it's a very good branding exercise cuz it's not really Immortal it just can reproduce itself asexually uh but it's still very interesting that you can have the same clones of animals uh naturally exist potentially forever in the same way that we artificially now can potentially for forever clone sheep and and monkeys uh we do cloning as humans um and so we mammals are not that different you could clone humans

we're not allowed to but you could and we could in that way be immortal but it doesn't mean the individual is around forever just your descendants are I I noted in your book you said uh look the Clones can come from an old cell but the Clone isn't old exactly and this is why I believe that there is a backup copy of Youth in every one of our cells and we can reset the body and be young again and this is what we do to those little brains that you saw and now we're doing it

in mice and now we're doing it in monkeys um and so I I do believe that aging can be reset just the way cloning does but we can do it in our own body so we don't have to go through a one cell stage to live longer we can actually invoke the same processes that embryos used to stay young we can do those in our bodies as well let's talk about the human genome Richard Dawkins titled his famous book The Selfish Gene but he often said he should have called it the immortal Gene that you

know he he kind of like it it created a a bunch of controversy that wasn't necessary in some sense the human genome has some Sheen of immortality it's just our Blobby Vector carriers that don't last forever Ali what do you think of that attitude I think I think um we're passengers in the in the taxi I think the DNA and the genome is the passenger and the taxi is our body I think the idea of moving forward toward the destination has different components to it we like to think of time as a vectorial linear progression

like just when we walk on the streets um for me to come here from Manhattan to Brooklyn I feel like I'm still going on a horizontal space but in reality as you know better than me we're actually working on a sphere so the idea of linearity of time confuses me a little bit I don't think there is such a thing as a beginning or an end I don't think there is something as aging or being young I think it's Cycles within Cycles within cycles and the cloning concept or or reprogramming concept tells you that in

biological sciences you can actually modify time you can move time forward you can accelerate time nobody wants to do that of course but there are diseases like progenia and other things and or or chimeras where you implant a human cell into a mouse umbo and it moves at the rhythm of the mouse you can stop time you know IVF technology with freezing blast toist or eggs or human omonic stem cells with last last forever my cultures are 25 years old from a ball of sales and we know that we can reverse time so somatic cell

nuclear transfer cloning as it was done in 1963 For the First Time by John Gorden in the Frog shows you that you can take a genetic information from a cell that's way ahead in time and bring it back it's like playing a video backwards so starting from the last scene to the first scene and in that sense I think biological time needs to be revised compar compared to what you consider as the physical time or thetical physics time that there is a reversal and a loop in that so to me being young or being old

is being at what point do you find yourself in a circle not at what point you find yourself from a beginning to a destination so just to emphasize you said that you have embryonic cells for 25 years and they don't age that's quite significant David I felt like maybe you had a response or a thought yeah I agree we we have cultures in my lab that that are half a century old uh and you when you freeze them they they don't age they just sit there uh and you can you can have children that that

should really have been born 30 years ago but were frozen that is proof that you can stop time and stop aging um but how do we do it in our own bodies we don't want to have to freeze ourselves and what ear is talking about in terms of Rejuvenation with uh cloning and what we do in my lab for Rejuvenation of tissues and and even uh whole animals now is we don't change the DNA the DNA in our bodies is rather intact we used to think that our DNA was the problem you've probably heard of

the mutation or free radical Theory of Aging that's not so true because you can take an old cell and make a new new animal what really is going on I believe is that there's another type of information that causes aging that's lost over time and that's not genetic but epigenetic information these are the systems of how this DNA is bundled in the cell and controls which genes are turned on and off and that reader system of the DNA is I believe largely what goes wrong during aging and what needs to be reset in the Rejuvenation

process yeah I think this is really significant I didn't mention what this was I'm not a biologist it's my understanding this is a human cheek cell but the significant thing is there's a nucleus and there's DNA in the nucleus and we all if we understand it or not know that there's a human genome there's DNA in the nucleus but you're saying and I think this is really a pivotal sort of moment of understanding that there is no Gene for aging that aging is epigenetic it comes from what happens around the genome would that be yeah

exactly and and we used to think that DNA was our destiny well that's not true when it comes to aging and your chance of dying from certain diseases it's only 10% is from your parents genetic the rest is epigenetic and epigenome the epigenome in each cell can be changed depends on what you eat whether you exercise whether you smoke uh and whether you've taken a medicine or a supplement the epigenome is modifiable which is why I say we can treat Aging in fact we can probably reverse aging in the next 5 to 10 years and

that's why aging should be considered a medical condition that's treatable because we can treat it and when we do that then diseases like heart disease diabetes and even cancer will be pushed much further into the future but consider this if there's a universal cause of Aging such as the loss of epigenetic information like the reader of the DNA then the same pill or injection that prevents heart disease will also prevent Alzheimer's and diabetes and all the other diseases of Aging which is why I think that's a better place to put your money than to try

and treat diseases that are the end result of the process because then it's first of all often too late but also that medicine is not going to help you with other diseases which are all going up exponentially with time and that's why even if you cure a disease in Old an old person they're going to die in a few years because something else will kill you cuz you're not addressing the root cause of the problem MH now I've heard you say that the first person to live to be 150 you believe has already been born

um I think it's possible um I'm happy I said that I'm happy to put some money on it right but as a scientist nothing is certain in the future right there's no proof that that's going to happen but I think there's a good chance that it's going to happen even if there's no breakthroughs 50% of children born today will make it to 100 that's just mathematics that's the trend that it's we've been on as a species but there are breakthroughs that are coming that are going to radically change in the same way that AI and

computer chip and compute power now is going off you know off the charts it's the same with longevity science I was a ban of a few scientists in the 1990s working on aging and now there's thousands of scientists and billions of dollars being invested it's it it's really going to change quickly and with the Advent of AI we can do experiments in a day better hurry up better hurry up it's on I I could have done my PhD in about 3 milliseconds today's technology I kid you not it's like that so the f so you

know trying to project into the future is always dangerous right uh it you can be wrong all right I'm happy to be proven wrong but I think that given the pace of change that children born today will live well into the 22nd century who knows what we'll have then even 10 years from now it's hard to know what we'll have but I know it's going to be a lot more interesting than what we have now as medicines now Ali you said tonight that aging begins at the moment of fertilization this is actually a human Blas

assist from your lab is that right 5 days 5 days fertilized what do you mean by that that aging begins at the moment of fertilization yeah so this picture is actually a picture of all of us in this room this is what will look like 5 6 days after fertilization is absolutely mind-blowing to me I have colleagues and uh scientists and clinicians in the audience that would recognize this in details you would not believe but to me if aging is a vectorial progression in time then again it begins in the womb so we begin aging

the moment fertilization happens there are a lot of up and downs and drama going on 50% of the fertilized eggs or plastoy don't even attach um those who attach undergo different Journeys and I think it's very important from the onset to realize that when we talk about a single individual may it be a jellyfish or a human that we're not really talking about one genome or one epigenetic change what a collection of many millions of microorganism living inside of us in our skin you know the whole idea of microbiome we're a collectiveness we're not an

individual the number of bacteria viruses and worms and everything else that lives inside of you as a symbiotic relationship forces you to Define what do we really mean by aging is this an individual trade or is a collective trade I do not imagine life in this kind of collective environment to be a single attribute of time I think is integration of time and many different DNA information and epigenetic outcome I think it's almost crazy to think that we are one indiv visual measuring time I think where integration of many times measured by many different information

genetics that are encoded in that and this is called the H holot uh hypothesis it challenges darwinian Evolution because D we can all agree adaptation of the Fest to unexpected environmental changes it's what's the key of survival but then we need to revise that because that hypothesis was based on the individual for each species I think is much more like a a team selection so when we talk about Evolution adaptation or we talk about aging we're not talking about humans we're talking about the collection of everything that makes us human there are more DNA in

our body that are not ours there are more microorganism fungus and viruses in our body that are not us so what is aging really if it's not integration of all of this information David I feel like you have a response well there's a simple answer to that this is what what was there's a simple answer to that you just replace your microbiomes as well that that's not difficult I can do that tomorrow in my lab just take a Young Person's FAL matter and eat it uh but so what what we know about your poor grad

students my God yeah I'm not suggesting you do that by the way uh you'd have to put it in a pill anyway uh you wouldn't just eat it uh but the the the the the embryo is very interesting because the same processes that make an embryo possible from a single cell this is the epig genome at work because these what makes us the uh 20 trillion cells of many of which are functioning differently what makes a liver cell different than a nerve cell is the epigenome because almost all of our cells have the same DNA

it's the epigenome that that tells the cell turn on the genes to be a liver cell or turn on the genes to be a nerve cell and according to my theory the information Theory of Aging it's that distinction between cell types that goes wrong over time so that breaks to DNA and other insults to the cell or crushing nerves causes such a catastrophe in the C cell that the cells you know molecularly forget which genes to read and now the nerve cell starts to look a bit more like a skin cell and the liver cell

starts to look like a kidney cell we see that that's a fact and I think that is the reason that we don't heal well and it's why our guts become leaky and why we forget things because our cells are not turning on the youthful pattern of genes that they did when we were young and the good news is that we found that there's a backup C of that information we can reset the system so that they read those genes again like they were young and when we do that cells behave like they're young again because

they literally are young again and people are doing this now in whole mice and the mice are living longer dramatically but what when you say they're doing this they're they're uh injecting feeding somehow getting the mice to have certain proteins enzymes that affect the epigenome or around the DNA and they convince the DNA to start operating in a youthful way again right would that be fair yeah yeah think of the epigenome as as the software of the system you can reboot it but what we do in practice what my students are doing almost every day

in my lab is we take a set of three genes that are on in those embryos keeping those embryos Young and the the egg young there are three genes called o4 Socks 2 kf4 you can use these plus a few others to make stem cells we don't do that we don't want to make a stem cell in the body we want to make youthfulness those three genes when you turn them on in the adult tissue the eye the muscle the brain the whole animal you get Rejuvenation you get the cell to turn on a program

that resets the epigenome so now the cell is essentially permanently reset and it takes a few weeks for the cell to go back in time and behave like a young cell again but the fact that this system exists and we could turn on just three genes again the fact that that works is is as close to a miracle as I know of right a biological miracle that we can use your systems that you study in your lab put them into an adult animal like a monkey's eye and we get Rejuvenation it's fantastic now eari what

do you think of of these very different techniques these epigenetic approaches and I know that you very much get in there with the stem cells right in there tell me explain to me how I'm to understand the differences in these approaches oh David is right yeah Rejuvenation is part of at least to me natural program of of evolution not only in darwinian Scales but evolution in our own development from the way we look like5 yeah so you that look look how gorgeous you are you have a tail you have gills where's the tail is that

ta no you can tell the tail is the gills you don't have lungs you're like a fish you're swimming in the uterus that's part of the processing of information that information is already contained with your DNA your DNA sequence has the information that's necessary and sufficient to make a tail to make gills that information is processing time it's like a keyboard of a piano the DNA sequence is limited we have 25,000 genes plus or minus whatever but you can create infinite number of Harmony from the same keyboard in such a way that you can generate

Anatomy that we don't even recognize after we're born there are many transgend organs in our anatomy as we develop they come and they disappear what is exactly getting old what is aging to me transition states of different organs is part of aging there are structures in my brain like the subplates that come and create the scaffold for the entire brain just like when you make a building you make the scaffold and then you tear down the scaffold but the building keeps on evolving I think the idea of a linear progression in either our anatomy or

our genetic or epigenetic as David has shown beautifully might be limited not to include the information processing that we inherently have in our DNA sequence this information is in you I can if I'm successful one day you know people are they interested in making pancreas and heart and liver I'm interested in making a human gal or a human tail you know I mean this to me is Rejuvenation how's your funding going not not very well well I do have to say that what you're describing speaks exactly to that idea of the immortal Gene that Gene

has propagated for millions of years the gene has survived and and that sense of immortality is really quite I think um quite intriguing there's a concept in omology that says um onogen follows philogen there was a hypothesis to say that as we grow in the uterus and we go through riogenesis we actually recapitulate Evolution we start as a fish and the non and amniotic traits and and finally human um this was the bun some time ago but it's coming back to be Revisited again if you consider that you can make a chimeric animal where you

take human cells and you put it inside of a mouse UMO or inside of a bird egg and you watch the human cells grow together with their host that already tells you that time is very plastic because the host always dictates the temple a m station is what is it 21 days I think so human obviously the gestation of the mouse is 21 days but if you put a human cell inside of a mouse blist it will follow the rhythm of the host you can accelerate time of differentiation time is not the limiting factor and

if you make a human inside of a bird egg it will also follow the rhythm of the bird so is the outside the nonautonomous influence that dictates time if we accept like we do that you can stop time in IVF with freezing blasto sees in oning stem cells in cancer cells if you believe that we can accelerate time in the chimeras with human and mouse and human and birds and we know that we can reverse time what every time you do a nuclear transfer 1963 Nobel Prize for John giren was to take a nucleus from

a tall that was ahead in time to put it back into an egg and watch that nucleus take life from the first cell cycle onward that tells you already that nothing was lost all the inform all the keys are there on the keyboard is the way you played it that changed you told me uh one time when we were talking that you could take a blastic like this cleave it in half like an apple have an old blastic and an young am I saying this right put them together and by the way if you visit

our store artist Andrea Lowa has made Patches by coincidence that uh she just patches for all the scientific controversy series which you can wear all over your clothes it's quite adorable and by by coincidence she she represented exactly this like an old pomegranate and a young pomegranate on two different sides and what happens to it then was sort of what you're describing so this is an experiment I did when I was at Berkeley as a graduate student following on JN G payment because it was about directionality of time we didn't even call it aging the

way it should be perhaps but if you take a ball of cells in the Frog and that are ahead of the another ball of cells from the same female and you cut them in half like an apple and then you glue them back together frogs are very plastic they can deal with everything if you glue them back together young to young old to old they will continue they will make a t pull but if you cut a young part and you glue it to an old part something amazing happens the old part stops until the

young part gets to the same point and then they go in synchrony so that tells you that time is controllable there are there are checkpoints in times that this is not the physical attributes the way we look at our watch that is very plastic you can tune it and retune it that was an Awakening experience for me as a graduate student to say oh this is where the information resides it's physical forces that guide biochemical and molecular Pro you called that heterochronic heterochronic grafts David just a thought that I had uh so we're talking about

how similar we are all to other species and we can even mix embryos and we can grow together we are remarkably similar to our animal Brethren uh whether it be a chicken uh or a frog um but consider how close we are to a bowhead whale bowhead whale is a mammal it has live births it it breastfeeds has milk and they live over 200 years and we are biologically speaking almost identical to them we're certainly s more similar than to them than a chicken um and so I make the the the concl come to the

conclusion that there shouldn't be that many changes we need to make to a human to be able to survive as long as a boohead whale cuz we're so similar now let's talk about that because again you're talking about influencing um this very interesting sense of a biological clock which is not exactly the theoretical physicist clock right really quite different you talk about influencing it at genetically with um external influences can you tell me about one of these experiments with the slime mold here that that you did because I think it really illustrates the point of

how this information Theory of Aging Works uh yeah so uh it's a bit of a story I I started off studying the epigenome in yeast cells in at MIT and I landed at the right place at the right time speaking of serendipity and under the chud of lonard garti we started trying to understand why don't yeast cells get old oh why do yeast cells get old why are they they not Immortal and these are the same organisms that you use to make beer and bread so you just grow them on plates um and we figured

out why they get old it turns out that they have genetic instability they get broken DNA same way we do every cell gets broken DNA every day a few few chromosomes break every day um but that then distracts the epigenetic Control Systems because the epigenetic control systems also help repair DNA and I believe that that that's important because you want to control your epome in response to DNA damage so why not have the same proteins control both things um and these proteins we gave them a name we called them cerin there were seven in our

body five in yeast and they actually they don't just repair DNA they protect against aging so when you put more cin copy Gene copies of the cerine genes in yeast they live longer turns out that's also true for fruit flies and worms and mice yeah but then the question was well is are these epigenetic changes really causing aging or is it just some that happens you know and some we call an epip phenomenon an association and in Sciences you know you you want to break something and see what happens right and so what we thought

we would we do is we'll go in and break some chromosomes and if we're right then the yeast cells should get older and they did they aged rapidly and then in 200 uh 7 uh I said to a postto in the lab Philip Obed offer um how about we do this in a mouse and he said you're crazy it'll kill the mouse or that it'll get cancer and I said okay but just do it and uh he was pretty um and what I said to him was all you have to do is prove me wrong

and then you can do something else just prove that this does this won't work and actually two years later he came into my office and said I I I think it might be right but he was really skeptical so what we did and why it's relevant to this organism you can see here is this uh slime mold poly cilum pharum makes a very special enzyme that's part of its immune system and when you purify that enzyme or take the gene for that enzyme and put it into a human or a mouse cell it will cut

the chromosomes very rarely which is good you don't want to cut the chromosome to Pieces it'll kill the cell so it cuts the human genome in roughly 20 or so places and the other good thing about it is it makes uh staggered Cuts in the DNA so it cuts the DNA ladder over here and then over here so you end up with what are called sticky ends the the bases of the DNA come apart like a zipper and the cell can just find those ends and put it back together so you don't get a mutation

the way we did it so now we could test the hypothesis if you distract those seruan protective enzymes with cutting of chromosomes what happens and the mouse could have died nothing could have happened could have gotten cancer could have gotten aging and uh I remember I was in Australia and I got uh I was had one of the first iPhones and uh I got a text saying the mice are sick and I said okay send me a picture of the mice I want to see and uh I saw the picture of a mouse and I

said that's not a sick Mouse that's an old mouse how old is it she said it's 2 months old mean let me guess that's the one that had this enzyme in it so you accelerated the aging process we we we caused Aging in an animal and we published this last year in the journal cell and it was 43 signs scientists it took us 13 years of work um it was a lot of work to convince the scientific community that we caused aging and not just made a mouse get old or or look old um but

by every aspect it was old it had an older epigenetic clock we can measure uh DNA methylation changes they're called we can track that it was older but it had all the signs of aging and we can dial up aging as fast as slow as we want in those mice we can make them age in 2 months or in 16 months but we definitely caused aging and this was the first evidence that the information Theory of Aging was true for a living organism as complex as a mouse well see I'm a little confused because I

thought you were curing aging and you're causing aging well we did that to test the theory but once you can cause something we believe you can take it away and that was our next project so are you seeing that the seruan are somehow you're honing in on as a fundamental vehicle for both the accelerating aging process as well as the reversal of the aging process yes 100% we have a lot of evidence that that's true that these cins protect you but if you distract them with other problems if you smoke if you eat a lot

of processed Meats uh or other things go in the sun you will uh distract them and they won't be protecting your body they'll be doing other things so what you want to do is encourage them encourage them you can simulate damage without causing damage you can fast you can go for a run you can jump in a sauna these are things that turn on the cin it's it's called hormesis what doesn't kill you makes you stronger but it cannot be damaged that's so overwhelming that it's a net negative you want to be a net positive

and the cin get less active as you get older for a variety of reasons and we can either chemically or lifestyle-wise uh raise their activity back up again so they can simultaneously or there's enough of their activity that you can repair the broken chromosomes and maintain the epigenome in a youthful State and we also we have some evidence now that in this Rejuvenation State um the Frog experiment um and also our Rejuvenation of the animal that the cin are involved and what's happening is that they're going back to where they should be rather than being

lost somewhere because of getting distracted by DNA so you're luring the back to do their job again to keep the DNA yes and so here's the biggest question in my lab and arguably one of the biggest in biology how do they know where to go back to where is that information and we're looking for that now Ali this is again quite different from what you're doing because David's not directly interfering with the DNA you directly interfere with the DNA can you please explain you you've mentioned Chima a couple of times in the conversation what that

is exactly what's a chimera so and this is a real picture from your lab so so terrify us with what this is terrify I think it's beautiful I think it's gorgeous so this is a mouse human camera the red cells are human the green cells are a mouse so so you somehow splice together the DNA of a mouse in a human being no the cells so these are human um bionics them cells transferred into a mouse Blas and you can see the contribution of the human and that was actually the first proof that human umic

stem cells are pury poent you know stem cells have a functional definition they're not based on molecular signatures of OCT for SO2 or nanog or whatever molecular fingerprints it's a functional definition is a cell that can contribute to all cell types right so for that including cells of a different animal yeah so how do you prove that in humans in order you cannot transplant a human stem cells into a human and say oh yeah it contributed the daughters went to all the organs this was a substitute a functional way to prove that human unbr themselves

can contribute to the structures but amazingly they change Rhythm they actually go 10 times faster than what they would because the mouse evolves that tells you the ecosystem is the environment it's not the genetic endowment itself is where do you find yourself at a given time in that ecosystem the cells will adapt to that and they will take the fate of the tissue they're landing on or the lineage they're contributing to it's also very important to realize that time and aging is not an individual attributes again uh in every single one of us sitting in

this room you realize your skin is changing every 120 days you're totally different skin the lining of your gut the lining of your lungs stem cells are made to replace old cells in your body so aging becomes a cell autonomous event almost in addition to the ecosystem in which they find themselves we're not a single entity operating in a single window of time we're a collection of entities that are operating at different times within a given space so um you consider for example a bone marrow transplant you can take a bone marrow from a young

person to an old person old person to young person it would immediately adapt to create what it's supposed to do um this integration of different aging and timing at the molecular level at the cellular level at the tissue scale is all the integration of what we call aging that's why at the beginning I was asking we might need to define those words a little bit more carefully we like to think about it as a single attributes I really think is an integration of many different clocks that contribute to a main clock that we we call

life but you can reverse it you can push it forward you can stop it and you can recreate it like tell me about this yeah so this is this is also from your lab this is a sythetic human umbo so it's a human umbo in vitro in a microchip so it's synthetic yeah so is made from Human omonic stem cells this is the work of a lot of my colleagues sitting in the audience right now and what this shows is that he can generate or clone a human being obviously not invivo but inv vitro in

a microchip by giving it the first signal that allows the differentiation and timing and the amazing thing about this structure is that we learn about where we come from it would be otherwise impossible to think that we can have a glimpse of where we come from without this kind of approach it's beautiful and you know I love the fruit fly I love the Frog my favorite organ I love the mouse I love non-human primates But ultimately we need to answer this question about our own existence and we're different than a mouse and we're different than

a bird and if we're going to be serious about realizing where things come from and the progression of time we have no other choice than recapitulating those events at a stage where women don't even know they're pregnant so this technology allows to have a view a birth ey view certainly not perfect but much better than nothing about the origin of where things happen and to me this is a very qu quantifiable aspect of learning how we age or how do we progress in time do you know how old the person was that gave those s

the donor was an adult yeah originally the donor of the stem cell it was a it was a skin cell originally ium no so this these ones are called is a collection called R Rockefeller University uming stem cells they are derived from a six day old Human umbo by plucking a cell and culturing them in a in a way that they don't progress in time and so you grow them in microculture and then you give the first stimulus and they self organized to create all the gem layers and all the cell types can you do

this with an ipsc yes yes yes well then then that's from an adult yes so then so that's great right so if you can do this with an adult cell then that means I can clone you a thousand times from a piece of your hair yeah let's go right but it would it would never be you I have a lot to do it would never it would be anatomically you genetically you but it would never be the David Sinar sitting here right because that comes with more than just genetic information it comes your experience is

your history your culture all these things right so this is also one of the interesting things about maybe working epigenetically that you're not completely annihilating the organism or starting it over you're really taking it where it is memory is intact let's say if you're working with an adult mammal like a mouse and then you're trying to repair something that's been damaged can you tell us about this exam example of the uh the optic nerve damage because I think this is also a remarkable um result it's a it's it's a similar kind of experiment a Eureka

moment in uh in the lab what we're looking at are two optic nerves um running horizontally what we wanted to do was to ask the question so the eyeballs oh the eyeballs on the eyeballs to this audience's right brain to the left correct M and it's a bit longer than this this is just the beginning part probably the the brain would be beyond that wall and we've stained the nerves orange so if the nerves are sick or dead it will be blank um and you can see there's a big difference here what we did was

um and this was in collaboration with uh with zi gang her lab at Children's Hospital in Boston where they're expert in this and what they did was they pinched the optic nerve of these two mice and one of them was just left to its own devices after a few weeks we had a look and that's what you see across the top the top optic nerve is has been pinched at that at that point up there and you can see most of the optic nerve has died right that Mouse is now blind it's the same as

if you break your back you're not going to walk again not currently but the one on the bottom was treated with our three yamanaka Rejuvenation genes the oct Force socks 2 KLA 4 and we reversed the age of those neurons so that they were neonates these were old mice but we made them so young that they could grow again and you can see they're they're now growing back to the brain and the longer we leave it the longer those nerves grow somehow they know where the brain is that I don't understand but they know that

they have to go that way and they eventually connected with the brain and that was the first result that we had that we could truly reverse aging and rejuvenate tissues in an animal that's pretty astounding and it's you brought this up earlier you don't know how they know where to go is that kind of what you mean here as well why don't they wander off and go there so many something else well they they could grow into a a tumor but they didn't they knew that they needed to go back and form that so similar

to what Ali said before I think we're we're tapping into an ancient mechanism of tissue Rejuvenation and restoration in the same way that the the jellyfish can regrow its body and if you cut the liver of ourselves it will regrow somehow to the same size as the original liver how it knows how big to grow we have no idea might be electrical signals but the similar processes that are going on in your systems at early in life we believe are going on in these nerves when we turn on these embryonic genes even in the adult

uh Ali are you surprised that this kind of progress can be made without introducing stem cells specifically this is a beautiful experiment by the way which I think is going to might represent the future of the way we're going to move forward if we believe that re Rejuvenation is a natural process upon which stem cells act to replace old cells in every organ in our body or cells that are dead or dying then the future of clinical applications in my opinion it will not no longer be based on coming up with a drug or a

compound or some treatment to fix something that's already broken it will be almost based and I know it might sound fictional to you but I I really can see it it will be based on returning time to the damaged tissue and that's the beauty of this experiment that David has done it's like in the adult organism you can create the emonic Orin of the lineage that has been damaged so you reverse time you don't try to to fix something that's broken you just replace it by turning time backwards and that's aging directly about that I

think in the future we're not going to try to go to chemotherapy or radiotherapy or all these insulting ways of dealing with tumors and other issues we are just going to find a way to reverse time on the cells that are not behaving whatever that means within the context of the adult and I really think that's the way it's going to move forward that that was very well said I just want to add that this was the first experiment the next experiment we did with Bruce Cassandra's lab and he studies glaucoma and you can give

my my glaucoma by putting pressure in their eye and then we cured them of blindness and then I said to Bruce let's just do old mice and he said that can't work you know you can't restore blindness in Old mice no one can do that and just try it and he called me at 10:00 at night one day and said guess what we unblinded the data and it worked we've cured blindness for the first time now how how long ago was this phone call uh that would have been 2019 and what do you think the

time scale is for people to see this in actually human subjects uh well so in 2019 we formed a company to raise money to do this um it's been repeated many times now in mice it's been repeated in non-human primates and uh human trials are slated to begin as early as next year to treat blindness in people um gives you pause that's for sure I I know that so many people are interested in uh what you do scientifically but also how you influence lifestyle choices I know people will kill me if I don't ask you

about lifestyle uh choices and decisions but I want to play a little game to do this um uh that I like to call or no and so we're going to review some like kind of Health Nutrition claims because I actually have a bit of a pet theory that I think a lot of Suspicion towards science in general comes from the fickleness of at least reporting on Health Sciences and nutrition it changes just too rapidly and so we're going to do a little no what were you going to say nothing go ahead okay no red wine

can reverse aging damn it um Ali antioxidants are the secret to the Fountain of Youth Fountain of Youth I don't know okay okay good um I'm going coming back to you Ali zombie cells tell us what those are also cause aging zombie cells cause aging what do you think about zombie cells again I have a hard time defining Aging in the context that I told you about relativity of time what do you think David uh you know these zombie cells I hear about sess cells they cells yes do we have to clear them out yeah

as part of a process for a long life and health span so you've asked two questions do they do they cause aging yes and do we have to clear them out no okay the the reason is my people say people might say why why what are you talking about David if they're causing AG of course you have to get rid of them but what we'll be we've just published and we'll be publishing more is instead of killing the zombies what if they're your family you don't want to kill your family you don't want to kill

senescent cells in your brain necessarily so we're working on a cure foressence so that we can get those cells to Grow healthily Again by using the same Rejuvenation similar technology yeah uh that's yeah so you're bringing the zombies back uh that's a Twist to the classic zombie film um shorten telr are the cause of Aging Ali do you want to talk about shorten telr oh David no uh if is five out of five stars I'd give it a two and a half a two and a half on the scale it's it's exaggerated in it's exaggerated

but you think it has some it it play it it's significant or tells you about the aging process somehow it's one of many things that changes and and it plays a bigger role in cells that divide a lot like the immune system so let's talk about um lifestyle things so uh no eat only meat fat and cheese while also being a vegan that sounds like my diet I'm a struggling vegan you're a struggling vegan Ali what do you think about I love meat um I I will I will go on record saying that the completely

meat and cheese diet that is not going to extend your lifespan that part is that part is BS um so I I used to eat cheese and drink red wine every night I stopped doing that completely and I'm much much healthier um and biologically younger since you're disappointing me terribly with the cheese and the wine sorry for the bad news I'm just a scientist I'm just tell the facts uh is there a pill that exists today I'll start with you Dave and then M go to Ali that can extend your Life resveratrol and aen rap

ayin met Foreman we don't know okay mhm I would say possibly I don't want to ask Ali about what pills he's taking oh you shouldn't okay Ali tell me this actually this is for both of you cold plunges Stave off dementia you know I mean I I I feel this command that I me about all this this no question you're asking me but I'm not exactly sure what we're trying to answer I mean is this are you talking about like living longer is that good yes so well okay that's that's an awesome question that's an

awesome question is that good so I think we've been talking about uh is a cure for aging viable why don't we come back to our original questions we should ask those questions um is aging a disease if I were to ask you again would your answer be different Ali than it was in the beginning you know again I need a more precise definition of Aging well then how would you define it precisely for us if we Define aging as a lifespan of an individual then I will immediately will have to add this other variable of

quality like what do we mean like do I want to be 120 years old and not recognize my kids or not know who I am or where do I live is that what's worth what we're doing and remember life is a cycle within Cycles right it seems to me like Evolution has selected us for the ability to be adaptive to the environment where we find ourselves that we did not choose nobody decided where they were born what culture what parents what language what religion none of this was our choice we just par shooted here and

if that wasn't bad enough we don't even choose our DNA so what am I trying to do here leave an extra 20 years gooo Gaga not knowing not knowing what I am I prefer to leave half of that with total awareness of my environment and total contribution to it I don't want to be here just to be here so I think that's why I don't think aging is a disease I think aging is actually a necessity for evolution I think in every single species may you be a plant or an animal that's part of the

natural cycle you will not develop adaptive trait if you didn't die and if you didn't age this is a fact for all species as far as I'm concerned making it longer or shorter you can ask the butterfly who lives only for one day she will tell you is a beautiful life beautiful Al so I think that beautifully brings us to the question before I open for for Q&A uh Ali I think you bring that question in really um in a very elegant way which is uh with N9 billion people on this planet what what do

we really what will we bring on if we really do delay aging significantly amongst large populations and and is this something we should want is this something we should really desire David do you have a a thought on this uh I have a a whole book on this actually uh I fundamentally disagree that just because something's natural that it is acceptable I do not believe that aging is acceptable in the same way that 100 years ago we thought cancer was a part of life the life cycle don't mess with cancer don't mess with heart disease

how many of us would just tell our relatives don't take a uh a medicine if they had cancer any of you would you let your your uh your parents die from cancer no you would fight it with every dollar and fiber of your body why is aging any different it is a natural process yes but so are all the other diseases and scourges we've fought and uh and misfortunes that we have in the in the wild we don't live in a world where we freeze to death anymore or starve to death anymore and we fight

against these diseases that we call cancer heart disease and Alzheimer's why not tackle the root cause of all those problems are you afraid of having too big an effect are you afraid of people being too healthy take my parents my mother didn't look after herself she died at 70 after suffering like hell for 20 years after Contracting lung cancer that's a world I don't want for anybody my father took a took care of himself he started taking uh some supplements he started exercising he started eating two to one meal a day he's now 85 healthier

than he was in his 50s he's healthier than me he's fitter than me for sure loving life he's educating his grandkids he travels around the world spending money boosting the economy training people he started a new career he's 85 he's running out of friends his age it's that's the one issue of getting older if your friends don't stick around but I would tell you which kind of world do you want for yourself or for your family members do you want my mother's experience where we just say ah good enough let's take what God or Evolution

gave us it's natural fine or do you want to fight against this like we have with every other thing that has plagued us as humans and give more people the kind of life my father is experiencing and let me tell you what when people get healthier for longer the byproduct is longevity the primary goal of my research is not to live longer it's to avoid the diseases that make us suffer and die and having witnessed my mother die basically in my arms I do not want anybody to have to go through that if they don't

have to wow all right awesome I mean I could keep asking you questions all night but I want to open it up to Q&A before I do that please join me in thanking Ali and David for such a prop positive conversation so I guess my question is I think most people would agree that the thing that differentiates us from mammals right is our cognitive ability and and the effects of compounded knowledge and on contribution to research like AI is the result of compounded knowledge of humanity and contributions over time right for better for worse rip

the environment um so I guess my question is why in kind of like this pivotal moment around Public Health are we as a species kind of refusing to Grapple with what I think today is probably one of the biggest contributors to what we would describe as aging or damage to our organs our cells which is co research comes out every single month about vascular damage neurological damage as well as like you know the effects on dementia early onset is your question about Co it is about Co and I guess our species ability to reckon with

aging when we know what could help prevent it so I think the question is are we you know using our cognitive leverage to really manage these complexities like Co which have taken their toll tremendously and we know long Co really takes its toll and and related to aging but Ali did you want to try this um um not sure if I um understand exactly the question but if there was a issue about about AI being part of this also I think it's important to remember that our cognitive abilities are also evolutionally evolving so I don't

believe that other animals do not have the same cognitive abilities it happens that covid is a species specific virus so it affects us and we react to it in the best way that we can scientifically socially psychologically but I think is in one of those elements and you you point perhaps correctly that influences aging but is a nonautonomous influence so it's a factor that comes from the outside world to influence our survival versus the kind of thing that David and I are talking about today which is what is the autonomous influence in moving time forward

in the way we perceive it so a virus also has a lifespan a virus also has aging so the job of the virus is to survive and go as far as it can and our job is to try to block it for our own but I don't think they're detach mission to be honest with you just a few thoughts on Co very briefly um one is that if if we could make people younger their bodies younger we wouldn't have had so many deaths due to co that's fact one the other is we have published that

in humans when you get covid-19 the levels of NAD drop dramatically and this is the fuel for the C and defenses and so you do accelerate aging when you get Co and it's not surprising we're seeing these long Co symptoms that resemble aging especially cognitive um and then lastly with AI uh I think we're entering a golden phase of pharmaceuticals uh and medicines and wearables so that we can detect diseases earlier uh and find cures much quicker and it's an exciting time hi um I want to preface my question by saying that there are dangerous

implications to manipulating our genomic timing as you know um one implication is that certain humans may want to prevent aging altogether which is something we've sort of touched on um in this talk so as a scientist myself I would be remiss to not acknowledge our history of eugenic ism how might your research impact the lives of the most dis possessed and how do each of you fulfill your scientific practice with that in mind thank you for that question it's a good one do you want to go first or um I'm cognizant that these Technologies like

the one that I showed today are expensive and will be um for a while this is a gene therapy that we're talking about we introduced those three genes with a a drug activatable uh virus it's a domesticated virus called an aav and these can cost a lot of money they can be over $100,000 which is probably worth it if you want to recover your hearing or your eyesight or avoid uh serious other diseases but in my research we are working on bringing the cost down from $100,000 down to $100 and this is work that we

are working about half my lab is now devoted to is bringing the cost down of these medicines so that hopefully everybody on the planet will have access to them how do we bring down the costs well we've found just very simple molecules that could be taken as a pill um and swallowed to have the similar effect so imagine taking a pill and curing deafness and blindness that's what we're working on and it cost maybe $10 maybe I will expand on your question because it's a very important one and I will zoom out from David's correct

argument about addressing that I would just ask what do you think is the benefit for Humanity to have people who age longer or ultimately never die regardless of how much it costs do you think that's a good idea for Humanity as a society not to die and you can pay $1 or $100,000 but then what then what do we accomplish at the at the social scale level not at the individual level how does it how does this do good for our planet how do we manage this so detach from the price and I totally recognize

your question and I respect it I would say there's a dimension that's bigger than that if it was for free do we still want to do that I know that part of your uh lifestyle protocol involves an excellent single malt and absolutely and um I just want to toast the choice to the single malt and thank you both for an absolutely glorious evening and I'm going to buy you one now thank you everyone [Applause]