Why We Die with Venki Ramakrishnan

0:07 [Music] I wanted to ask you a question but you preempted me. We were talking about how you were born in India. How you have traveled the world, how you grew up with scientist parents. But you derailed my question which was supposed to be profound about the impact on your impression on death to tell me you went to an all Catholic girl school. How did that happen? Well, it started off as a co-ed school. It was the only English school in town. And then this is in India. In India and it was a southern India, I'm sorry. My parents My parents were from the south and they'd moved to Gujarat where they didn't speak the language. I didn't speak the language. So, they sent me to an English school and the only English school was run by Catholic nuns and it

0:54 was a co-ed school. Then when I was in third grade, a Jesuit school opened up an English school for boys. So the nuns said, "There's an alternative for boys now. So we're not going to take any boys anymore." So from third grade on, no new boys were allowed to come enroll in our school, but boys would leave. Their parents would move or they'd flunk out or something. But new girls kept coming in. And so by the time I graduated, three grades below me, it was all girls. And my own class was like four four to one, girls to boys, you know, the ratio. So I didn't know how good I had it at that time. Well, you've traveled the world and yet despite having experience with Hinduism,

1:42 Buddhism, Catholicism, you still describe your attitude towards death as that of a rational scientist. Yeah, I want to pre I want to preempt anyone's aspirations that we're going to get spiritual here. Some sometimes I joke that I selfidentify as a as a Victorian a white Victorian gentleman scientist, you know, because my one of my heroes is Charles Darwin. So I think of myself as a Darwinist and you know, so very very rational I I think. And yet you you have this interest when in your book you discuss um how pervasive it is culturally for people to rail against the finality of death and there are these sort of plans people have for how to resist. It is true. I mean if you

2:29 look at human culture uh so much of it has been driven by the fact that we're aware of our mortality. And I I like to think, you know, I I point out that we may be the only species that's aware of mortality. Animals may be aware of death. In fact, there's going to be a book come that may have come out already about how animals perceive death. It's called playing possum. I think and and but but I don't think they animals there's no evidence that they know that they have an expiration date on them. It's the inevitability. They don't know the inev inevitability and the and the finitness of that lifespan. They don't they don't know. Humans know about it because of language and gen, you know, our ability to generalize and pass on

3:16 information to our children and so on. And that's driven human culture. For example, if you look at all religions, they all view death as a transition of one sort or another. For example, the Abrahamic religions from the Middle East believed that you would be corporeally resurrected at some point in time. So they traditionally insisted on burial. Cremation was considered a no no. And similarly if you look at eastern religions they believe that oh well your body may decay but you have a an immortal soul that will occupy some new body or or eventually achieve nirvana. And the Egyptians somehow conflated everything. They had corporeal resurrection which is why you had

4:02 mummification of uh the pharaohs but you also had they also believed in this immortal soul which they called ba or something. So you know that's been the case ever since uh human and if you look at how we you know talk about death even now very few people say you know my father died they say oh my father passed on or passed away or things like that. Mhm. And do you think that there was any adaptive value? You describe it as somewhat of an evolutionary accident that we're aware of the inevitability of death. Do you think there was adaptive value or did it simply come along with everything else? Language, consciousness, selfare. I think I think

4:47 more likely the latter. I think we simply happen to as we evolved uh you know larger brains and language and and ability to generalize and also ability to disseminate information in a systematic way through language uh when we started realizing that oh everybody's dying and you know so this means that it's inevitable we passed on that idea and I think we've been uh we don't we don't live in terror of death I mean We we all act in our daily lives as though we're immortal. Uh but deep down that knowledge of our mortality h does affect us and it it it has an impact. And as you said in uh this is Greenwood

5:34 Cemetery which is in our sort of Brooklyn neighborhood and we collaborate with Greenwood sometimes. Um in these Abrahamic religions they still thought eh maybe the body's important so let's bury it whole. That's why cremation is is uh is part of the Hinduist philosophy, right? And the the idea that reincarnation means the body's just the body is not relevant anymore once it's died. Right. Right. Do you do you think that uh even our awareness of death, so maybe it's not adaptive, it's just incidental, but do you think it drove some of these notions of the soul and uh and Oh, definitely. I think the idea of a soul may well have come about as we thought of ways to escape death. You

6:21 know, I I like to quote uh philosopher Steven Cave's idea. He says that, you know, ever since we became aware of mortality, we evolved four strategies. One is uh not to die, you know, try to and we're going to talk about that later. Try to avoid dying. The other is okay you may die but your body will be resurrected so you'll come back as yourself more or less and a third is well maybe the body won't will decay but you've got this immortal soul that will uh you know perpet be perpetual may occupy other bodies or or escape into some infinite space. And then the fourth idea of immortality is you live on through something else like your works

7:07 or your monuments. If you're rich, if you're very talented, you live on through your works. If you're very rich, you live on uh through monuments or buildings uh named after you. And if you're neither, you still have the option of living on through your offspring. And so uh that's uh you know, the four choices. But of course, it all always boils down to you know, choice A because ultimately we know those other things aren't quite the same. And you know, I think Woody Allen said, you know, I don't want to live on in the hearts of my fans. I want to live on in my apartment. You know, so that was Well, let's take a slightly more scientific approach um to the idea of

7:52 death. Some biologists have said biology can only be understood through the lens of evolution. It's really the only way to understand anything about biology. And so, it's a fair question. Uh why do we die? uh if if evolution wants us to survive, right? if that's how you gen it's a little it's kind of paradox and you know when Darwin proposed his natural selection theory it wasn't really understood it wasn't understood until the early 20th century uh actually not even that early in the sort of 30s and you know normally you would say well if the whole purpose what evolution optimizes for is fitness which is in in a biological sense fitness means the ability

8:38 to pass on your genes, the likelihood of being able to pass on your genes. So that's what evolution cares about because it's selecting genes. It's so it's it's really about if your genes survive, they're selected for. If they're not if they don't survive, you know, that's it. So you might think that the longer you live, the the more likely you are to pass on your genes. And so you should be selecting for a long lifespan. But it doesn't work that way. And there's a reason for that. The reason is that in real life resources are limited. So it's only recently that humans have solved the resource problem. And we now have at least in developed countries we have

9:24 plenty of food. Actually too much. But throughout most of our existence and certainly for all other wild species, resources are limited. And so you have a you have to make a tradeoff. Do you spend those resources in maintenance and repair of the individual uh animal and that takes energy and resources? or do you spend those resources in rapid growth and maturation in order to uh make sure that you have offspring? And the trade-off works differently depending on the animal. So if you're, for example, if you're a a mouse, there's no point of in a mouse having evolved to live for 40

10:11 years naturally because in the wild it would be eaten by a predator or die of starvation or drought or something long before that. So there evolution has selected for a species that grows very rapidly and reproduces quickly. Now, if you're a large animal, take the other extreme. A Greenland shark or a boowhead whale. They live for a Greenland shark, you say? That's right. They're 400 years old. So, so if you're if you're that kind of animal, then you know it does. The Greenland shark has extremely slow metabolism. It's also true that metabolism is faster in small animals and slower in large animals. There are some physical reasons for

10:57 that. And so Greenland shark can live up to at least 700 years. There there's a Greenland shark that's been dated that to live that long. And there because it's a slower metabolism, it matures more slowly, etc. The equation's different. Now, one interesting example are bats. So bats are the same size as mice, but they live about 20 times as long. Why is that? Well, bats can fly around and and so they can escape predators much more easily and they also can forage over a much wild wider area, so they're not as likely to starve. And also, when they rest, when they roost, they roost in the ceilings of caves. So, they're also relatively immune to

11:43 predators. And so bats can live 20 to, you know, 10 to 20 times as long as as mice because there it pays because bats will live long and produce more offspring over a longer lifespan. And the Galopagus tortoise is another example. Galapicus tortoise is same. It's slow metabolism. It's very well protected by its shell. It's not likely to be the subject of predation and and so there it lives longer. And I like to joke, you know, Galapicus tortoises could live to be maybe 200 years, at least 170s documented. And so there could be a Galapagicus tortoise around today that encountered Darwin when he was visiting the Galapicus Islands,

12:29 right? That's quite amazing. Um, you make an analogy in the book between death and bankruptcy. You reference um Hemingway's the sun also rises and a character is asked how did you go bankrupt? And the reply is two ways. Gradually then suddenly. Yes. Is death like that? I I like to think so. So if you you know when we think of death, the death is really the end product of aging. So if you think of aging, what happens is that it's a gradual accumulation of defects at every level from our molecules to our com the components in our cell to cells to tissues and organs and then eventually the whole individual. And at every level

13:16 you're accumulating defects or changes. Some of them are not necessarily defects per se. They had a purpose. And so um you get this accumulation and it you lead leads to gradual loss of function and that's the gradual phase of bankruptcy. you're losing money, you know, you're you're you're you're in negative revenue and you're burning through your cash reserve and that's the gradual phase and then suddenly something comes to a head for example some critical system fails like uh your brain or your heart or your kidney and so the whole thing uh just can't work and this gets to the definition of

14:01 death. What do we mean by death? Well, while we're alive, millions of cells in us are constantly dying. In fact, the many of them have to die for us to continue uh living. And the paradox is at the moment of our death, most of our cells are still alive, you know. So, uh it's it's you know, that's why you can donate organs to uh transplant recipients. But what we mean by death is the death of the individual their ability to function as a whole individual and the you were saying that even though we are living much longer than we used to back when we were on the savannah um that there's still a maximum age it feels like that that hasn't moved. We were talking about um sorry actually I'm

14:49 going the wrong way because we got excited about the Greenland shark. Um, we were talking about this woman who is purportedly that's John Calmon. Yes. Tell me about her. She's a very colorful character. She lived to be No. She's smoking and drinking. She was smoking and Yeah. smoking. She had a a cigarette and a glass of port every day after lunch well into her until she was over 100. And she used to bicycle I think until she was 100 or so. And um she lived to be 122. And one little anecdote about her, once she would reached say 105 or something, reporters would gather uh around her house every anniversary, every birthday. And at one of them, uh a reporter said to her,

15:37 "Well, see you next year, I hope." And she said, "Why not? You look pretty healthy to me." And so, and she also, by the way, ate 2 and 12 pounds of chocolate. And I could get behind that. I daily. No. No. A week. Sorry. 2 and a half pounds a week. So, it's interesting that we're living longer and we're healthier, but the maximum age hasn't moved that much. Yeah. And we think that because she died in 1997 and since then, no one has lived over 120. And so you know although our lifespan you might say it's not true that our lifespan is increased what is

16:22 increased is our life expectancy which means what is the probability that you will reach that age when you're born. And our life expectancy has increased gradually over the it's doubled actually over the last 150 years. And that's because of improvements in sanitation uh vaccines no matter what the US government may think and um uh better uh nutrition uh antibiotics. So a number of things helped to and food supply even things like the harbor process for fixing nitrogen has dramatically increased lifespan by improving food production. And so that's resulted in the doubling of life expectancy because

17:10 many of those dis previously people would die early in life often in infancy or in childhood. So that's been gradually uh not eliminated but really dramatically reduced. But what hasn't increased is the maximum lifespan and that's probably about 120 at the most. But even anybody over 110 is an extreme outlier that very very few people live that the super centigenarians in some sense. So you have said nonetheless that there is something about us that is teetering towards the immortal and what aspect is that of our biology that doesn't die. Sure. There's a there's a

17:55 couple of things. So each of us came from a living cell you know actually two living cells. one from our uh father and one from our mother. And each of those parents came from a pair of living cells. And you can go on all the way back to the very first cell. And that was a few billion years ago. So you can say that you know we have not come out of nothing. We've each cell has given rise to other cells and has so there's a an element of us that goes all the way back to the beginning of the first cell and so in a sense that cell lineage has been immortal even though the body dies and so there's a distinction you know I

18:42 call it the immortal gene and the disposable body so the what persists is information the information on how to build an entire cell or an entire organism from a single cell that has sort of persisted over the over over time. And it's quite stunning to think that we all share genetic information all the way back to the first multisellular organism billions of years ago. Yeah, no question. I mean even bacteria there are lots of genes that we share with bacteria you know and and so that just shows you how you know basic genes have been conserved all the way from bacteria to humans for example

19:27 ribosomes are which translate the genetic information into proteins and that's what I am known for working on ribosomes are incredibly ancient and bacteria have ribosomes and we have ribosomes and core of the ribosome is the same in bacteria and in humans. And is it also the case that um viruses can inject their this is not a virus by the way it's a jellyfish. Viruses can inject their DNA, their code into our DNA that we have remnants of viruses. I think viruses probably evolve from very early life form. So almost every species has viruses that will attack it. There are viruses that'll attack bacteria. There

20:13 are viruses that will attack archa which is another very old form of unisellular organisms. Yeast has viruses. The all species have viruses. And so that means they evolved along with uh you know independently living cell forms and viruses are basically small codes. They can't survive or reproduce without a host cell. And so they've learned how to be sort of parasitic and in infect host cells and and and dei multiply inside the host cell and make copies and so on. I just want to pause for a second to talk about the immortal jellyfish because the immortal jellyfish seems to be really spectacular in that it seems to be as there are a few other organisms

20:59 like it um almost technically immortal. It doesn't show scinessence. It doesn't it's its likelihood of dying does not increase over time. Yeah. So the the way biologists have defined mortality is that if you look at most species the probability it will die increases exponentially with age. So for example in humans the likelihood that a 10year-old will die I mean of aging not of I don't mean in an accident or infection or something like that. Um the probability a 10-year-old will die very very small, tiny and and then as you get older the likelihood keeps increasing. By the time you're in your late 90s, the chances you will die in the next year are over are 50% or so. So it increases

21:47 exponentially. But in the case of the jellyfish, it turns out that the likelihood of it dying at any given time doesn't seem to increase with time. It seems to be steady. But I think what it is is it's actually very slow. So if you really followed a jellyfish, eventually you would see there's so many cases where biologist said, "Oh, this is a immortal, you know, species that doesn't show signs of mortality." And in fact, you know, like the naked mole rat was a classic example. An old nickel mole rat or or the Galapagus tortoise. They thought that was biologically immortal. But actually, they age. they they look just like we humans do when we're old you know and bad skin and you know bad eyesight and on the whole and baldness

22:34 and the whole works you know so so I I think that's u that's an issue but the jellyfish does its thing by the fact that it has regenerative cells called stem cells and they're distributed throughout so it can regenerate itself and it's even bizarre that if a jellyfish gets injured or does something, it can actually go backwards in development which you know we certainly don't do naturally although there are people trying to do it with molecular biology tricks and that is almost the equivalent of a butterfly turning into a caterpillar you know that's the kind of thing I mean but in some sense that jellyfish ceases to be

23:19 right if it had a complex enough it doesn't have a central nervous system but it would be a do. Yeah. Jellyfish. Yeah. And and as I say, jellyfish do die. It's just that because they age so slowly in in in the wild, they die of other reasons, starvation or predation rather than aging. Fascinating. So let's talk about the cell. Your book is very much very compelling story of really the biology of the cell is everything. And this is a famous photograph 51 uh which is the discovery essentially of the double helical nature of DNA. Yeah. So well you know DNA is a a double helix and um it's a each strand contains a

24:10 sequence of building blocks. uh and there are four types of building blocks and the order of the building blocks is is what specifies the information and so you can think of DNA as a very very long sentence that needs to be uh understood or decoded and as we age a number of things happen. So, uh, just to back up a little, sections of DNA are essentially units called genes. And typically what a gene has is information on how to make proteins, a particular protein. Each gene codes for a particular protein. And proteins are the are the workh horses of life. They really carry out all the

24:55 reactions, the sensory reception, the building the structure of the cell and so on. And so uh you can have damage to the DNA and that would be like corrupting the sentence in the DNA and that then would lead to loss of function because you're not making the right protein anymore. Or you could modify the DNA so that you're changing the way in which proteins are made and when they're made or how much they're made or maybe you're shutting off uh making proteins. So there are lots of ways in which you can change this very complicated program uh that that you know our genes represent. And so that's one of the ways

25:41 in which we age. M and you said uh that that's sort of overrated though too. I felt in your description of the book that yes DNA has wear and tear but in some sense there's no gene for dying. We're not programmed to die. You've said we're not programmed to die. There are genes that affect aging. For example, in worms uh they've found mutant worms that live twice as long as uh wild type worms. But if you took those mutant worms that live twice as long in a petri dish and put them in a petri dish with wild type worms, within two or three generations, they're out competed, which means that they're at a disadvantage. There's some there at some cost to

26:26 living longer. Now, it turns out that the genes that make you live twice as long, those were not aging genes. they were genes for various growth pathways and so on. So they were selected for other reasons. The aging was just an unexpected consequence of um this you know selection for growth and so and and other processes. This goes back to the evolutionary question. So evolution as I said doesn't care how long you live. It cares only that you can live long enough to uh grow up and multi and and produce offspring. And so it will select for things that optimize that process. And

27:15 that means optimizing growth, maybe preventing cancer early in life. Uh and uh many in many cases those very same things cause aging later in life. But evolution doesn't care what what you what happens later in life. Do you think in some sense that most things simply died for other reasons that nothing made it long enough to die from the negative effects of genes that were exactly and in fact you know many for example uh you know why weren't why wasn't Huntington's disease selected against in humans or because for most of our history we'd be dead before Huntington's disease manifested itself and we would have in any case passed on our genes

28:02 uh before it took effect. So, so there are many cases like that. So, there's another quite amazing discovery beyond just the sort of immortal gene, which I I believe famously Richard Dawkins says this publicly. He he called his influential book the selfish gene, but he sometimes wishes he had just called it the immortal gene. He would have gotten less grief, right? Less hate mail. Um if you want to be amused, you can watch Richard Dawkins reading his hate mail on broadcast. It's it's really quite hilarious. Um but uh beyond the the discovery of the immortal gen is is a discovery of stem cells which strikes me as quite profound which which are cells that seem to be able to kind of reset the biological clock. Yeah. So let's talk about resetting the

28:48 biological clock first. Okay. So there is a biological process that resets the aging clock to zero and it happens to us every time a child is born. So when a child is born, it's born from uh cells that it got from its parents who are adults. Nevertheless, the child is born at effectively age zero or at least conceived effectively at age zero. So a child born to say a 40-year-old woman is not 20 years older than a child born to a 20-year-old woman. And so how does this happen? Well, you remember I said DNA can be modified as well as damaged. Well, these

29:36 modifications can be erased and that can then uh help bring the cell back to an earlier stage. Now to your question about stem cells, what happens is you can start with a fertilized egg. A fertilized egg is like the ultimate stem cell. It's called totally potent. It means it can give rise to everything including the placenta. This cell divides and then part of it becomes uh placental cells and the other part of it uh are pluropotent stem cells which can give rise to everything else in the body like skin and nervous system and blood and cartilage and bones and

30:22 muscle etc. And as this embryo develops the stem cells become more and more specialized. So later on you have stem cells. They can regenerate for example all of the cells of the blood system. They're called hematopoetic stem cells. Others can re generate all of the cells of the nervous system. But the nervous system stem cells can't generate blood cells. So they've already specialized a bit. Now you get to the final stage. Those cells can't generate uh for example a a white blood cell can't generate other types of cells. It can only divide and it can only divide a finite number of times unlike a stem cell which can divide almost indefinitely. And so stem cells are are

31:10 the cells that are involved in regenerating our tissues and organs. And you all know that if if for example you bruise yourself, you can generate new skin. If you damage certain organs, you can generate uh you know the organ will repair and and and regenerate. Others like your heart can't regenerate very well. That's why heart attacks are so dangerous. So if you damage your heart muscle uh you have a problem and uh neurons very few there's very little turnover of of neurons. Basically uh they don't really regenerate so readily. Now, as we get older, our stem cells also decline because they also age. So,

31:56 they become smaller in number, poorer in quality. And so, we're unable to also regenerate our selves as readily as we could, unlike the immortal jellyfish, which is where stem cells are there uh throughout its existence. It's sort of a a strange curious question. Uh if the neurons did regenerate, would they reorganize our memories and our thoughts? Is there something about preserving structure? Be very hard because it's not a question of generating just new neurons. For example, let's say if you have Alzheimer's and your neurons die, you're not when a neuron dies, it's not just the neuron that you care about, but it's all the connections it's made. So, how would you regenerate a new cell and form

32:44 those connections? I think you know I I point out that whereas you people are doing reprogramming of cells there are now tricks for making fully differentiated cells like a skin cell go backwards in development something that doesn't happen naturally and maybe even get back to being stem cells that can generate more of that tissue and people have tried this by there are four factors uh called Yamanaka factors These are genes that uh code for proteins that regulate other genes and called transcription factors. Anyway, uh these four factors can when introduced in a cell can make the cell go backwards. In

33:30 fact, it may go all the way back to pluropotent cells which is dangerous because then you could have development in ways that you can't control. But what people ask is can we make them go backwards just a little bit so that they can then regenerate more of that tissue and it's been quite successful in mice. But going from there to a safe procedure that's useful is very hard. And getting back to your question, how you would regenerate the brain that has aged and become damaged, that would be very hard because it's not simply a question of regenerating cells. It's also regenerating that network of connections. Yes. Be careful what you wish for. You could regenerate the brain

34:15 and no longer be you anymore, right? You might not be anything. That's that's the problem. Yeah. Fascinating. I've also heard um something about stem cells where uh women who've had pregnancies inherit the stem cells as well of the of the um fetus or and and that that can protect them throughout their life. Is that something that we see that stem cells that were uh from pregnancies are in women's bodies? Well, for example, germline cells you can think of as the sort of almost the ultimate sort of stem cell in that they're eventually going to produce fertilized eggs which reproduce the entire organism. And it's true that our germline cells are very well protected. They have you I talked about

35:01 DNA damage. Uh so they're protected more against DNA damage. That's really interesting. They're also selected again for so we You know, for example, uh a female, you know, human is born with a very large number of uh oites, you know, these precursors for for eggs, germline cells, but loses a huge number of them. And that's because at every stage uh before it becomes an egg, there's a huge amount of selection going on. So, anything defective is is essentially eliminated. and uh and and even after the embryo is formed there's selection

35:46 going on of defective embryos are naturally aborted and even without within a developing em embryo defective cells are are are eliminated. So there's a a lot of brutal selection but also a lot of protection to ensure this so this apparent immortality of the of this germ line. So you've described to us the nucleus of the cell a little bit and the DNA and how the DNA is the kind of control center. You describe in your book the cell is almost like a city and the organels are these different factories or playing different roles in the city and and we have to talk about the ribosome which is of course an area in which you've you had a picture of the cell as a city. Oh yeah it's over here.

36:32 Oh there it is. Let's go back this one. Yeah there. Yes. So, so you know for example what do you what do you have in a city? You you have a government which you can think of as a kind of command and control center. You have uh traffic uh you have subways and buses that transport you and and trucks and so on that transport you. You have road networks and you have uh you know electric electricity generating plants uh power plants. uh then you have uh and increasingly so you have border control that controls uh what comes in and out of the country and uh or who comes in and out of the country. So the cell has all of these features and so in some sense the cell is is like a city and and

37:21 the city has to work in a very coordinated way. uh all these things have to work smoothly together and almost in a seamless way and you you only notice that when uh for example in Margaret Thatcher's uh Britain you know there's this massive uh strike of garbage uh you know collectors and there's all this piles of trash you know building up on the streets and uh the whole system started to break down and so that's what happens if things don't work and that you know is also part of aging. If things stop working then the whole cell stops working. So it's more like a city. It's not like a machine you know which is sort of designed thing with one part. Cities were by and large

38:08 evolved uh you know of course we have city planning and so on but historically cities just sort of evolved for various uh reasons. You mentioned the garbage strike. I I was really struck by your description of the organal the lossome which is like a garbage dumping facility. The city has a garbage disposal system very sophisticated garbage disposal system. So you actually see it eating other organic matter breaking it. Yeah. So when when proteins for it it works at every level from proteins to even very large organels or even uh infectious agents that have entered the cell and been detected. And what what the cell does it it puts

38:54 markers on them and then encapsulates them and takes them to this organal called the lo. And in in the loome, the whole thing is essentially broken down into its component pieces. So it's like a great recycling center because then you can you reuse those components uh to build more of the cell. And so sometime when when certain cells stop functioning um you describe this as scessence or uh which doesn't when a cell goes into scinessence it's not dividing anymore. It still plays a role uh sometimes. Yeah. The scinessence evolved for for good reasons. For example, if if you if a cell has damaged DNA, you don't want that cell hanging around and doing its

39:42 thing and dividing because it might become cancerous and that would be detrimental. You can easily afford to get rid of one cell because uh you have plenty of cells and and you won't even notice it. Millions of your cells are dying all the time. So, so the cell the the you know life has evolved. So when a cell is stressed or damaged there are a couple of signals. One of the signals could send the cell to a state called apoptosis where it just dies commits suicide. But the other state is where it sends it into a state called scinsessence. In scinsessence, the cell doesn't die, but it can't divide in a normal way. And

40:29 it's no no longer functional. So if it's a skin cell or liver cell, it's not doing its normal thing. And it then also secretes inflammatory compounds. Why are why is it doing that? It's the inflammatory compounds are basically signals to the immune system to come there and repair the site and get rid of the cell. And because it might be the site of an infection or a wound, what caused the stress, you know, it's not always clear, but whatever it is, you want to get you want to fix the problem. Now, as we get older, what happens is more and more of our cells uh are under stress. more and more of them are damaged and so you start building up scinsesscent cells. At the same time,

41:17 our immune system is also aged. So it's not as efficient as at clearing scinesscent cells. So you get this buildup of scinesscent cells, buildup of inflammation. Inflammation then causes organ damage and more scinsesscent cells and and so it's a vicious cycle and so it's a real problem with aging. So, is there research into clearing away these scinsesscent cells? You say sometimes they're sent to go kill themselves and sometimes they're eaten by the lysosome, but sometimes they're just around causing problems. Yeah. So, there are there are people who are uh looking at ways to specifically target scinsesscent cells. So scinsesscent cells have certain pathways turned on

42:02 like non-eptootic pathways uh so that they don't die and they keep you know in this scesscent state and so there are markers for scesscent cells and people have asked can they target things that will go specifically and kill scinesscent cells and that's been promising in in animals and animal trials but of course going from there to a therapy is is is tricky because you have to make sure these compounds don't kill your normal cells, that they aren't toxic, they don't cause cancer over the long term, they don't have awful side effects, and it gets to a general. So, that's an ongoing area, but there are these they're called synolytics. These

42:48 compounds that kill scinsesscent cells, there are compounds in in clinical trials already. They are in human clinical trials. Yeah. But but the but the the general problem with anti-aging therapeutics is is the following. If you have serious cancer and you know you're going to if you don't take any drugs, you're going to die in months or maybe even weeks, you will then be willing to take even horribly toxic uh cocktails of of drugs in order to survive the cancer. You you'll take radiation treatment. and you'll have surgery to lop off organs. You'll do all that because the alternative is you'll die. But for

43:33 anti-aging therapeutics, what you're asking is you're asking a patient to take a drug uh for years to come in the hope that you know couple of decades down the line they'll get an extra 10 years of healthy life and that's a whole different proposition. So the the bar on safety and uh and and efficacy is much different for anti-aging therapeutics. Now we have to talk a little bit about the ribosome that I I believe I took this from your Nobel Prize lecture. Um you have said that the most important thing that the genome does or that the genes do is uh is is tell the cell how

44:19 to create proteins and proteins are everything. It's how we smell, taste, feel things. Even anti even antibodies that fight off everything viruses are proteins also we remember because of proteins. the proteins that strengthen neuronal connections which is quite a a startling kind of revelation that it all can be boiled down to the ribosome is the protein generating machine. Yes. And this is actually an image that uh that you created in the laboratory. Can you explain this a little bit to people? Both the image and the ribosome. So I told I told you that DNA is a string of letters that forms a sentence and it's in units called of called genes. So let's say each gene represents a sentence and DNA has a whole library of

45:05 sentences and but that information is not read directly on the DNA because DNA you can think of as an archival material. You don't want to mess around with it too much and it's in the nucleus in in our cells. So what the cell does is it it takes a gene only when it's needed. It copies the information in that gene to an intermediate molecule called mRNA. Now before 2020, nobody had heard of mRNA except for molecular biologists. And now all of you have had mRNA jabs in your arms. Uh well, not all of you. This is the United States after all. Uh but

45:50 uh you know you've had mRNA jabs that um are supposed to vaccinate you against COVID. Well, what is that mRNA that you're injecting in into yourself? That mRNA is simply the mRNA for the corona virus gene for the spike protein. So what what happens when you do that is the mRNA gets into your cells into cells of your immune system and then the ribosome latches onto that mRNA and makes the spike protein. The spike protein is then presented on the outside of these immune system cells or or fragments of the spike protein are. And

46:36 then other immune system cells recognize it and say, "Hey, this is a foreign protein. I've not seen this before." And it starts mounting an immune reaction. Makes antibodies, makes te- cells, which uh will kill any cell that has this marker. And so then when you get infected with real corona virus, the body sees the spike protein on the surface, but it's already prepared because its immune system has already been uh kind of pre-triggered and so it it quick to get rid of it. So quite amazing the vaccine um sends instructions for for how to defend yourself in some sense. Well, this vaccine in in the old the classical

47:23 vaccine is you would make spike protein in uh cell culture or something purify it and then inject the spike protein into your system and then your body would react to that spike protein and and mount the same immune reaction. And there was a very good vaccine called Novivovvax which did exactly that which is a classical vaccine worked very well but they were third or fourth in the marketplace and so uh you know they had very little uptake with mRNA the advantage is that if you get a new variant you don't have to make new protein all over again you can simply change the mRNA so that it codes for the new spike protein variant of if you have new corona virus this variant. So, you

48:09 can get a booster that uh protects you against a new strain. So, um I did want to talk about the research that's being done to try to uh if do what you described in the opening as plan A, the don't die version, right? Yeah. the don't die uh resistance to the finality of there there is there is a a tech billionaire Brian Johnson who wears a t-shirt which says don't die he he spends $2 million a year on longevity of of himself you know and and does all sorts of things to slow down his aging well um is there any evidence that he's reversed course

48:55 I I uh he looks very good he's in his late 40s He looks very good. But I should point out my son who's also in his late 40s looks just as good without any of that stuff. So, well, you also mentioned in this area of um research, anti-aging research or longevity research, um somebody said um our goal is that everyone should die young after a long time. Yeah. So, can you explain that sentiment? Yeah. So this has to do with something called compression of morbidity. So normally we live healthy lives until we age and then we start becoming less and less vigorous more and more problems. I get I have

49:43 osteoarthritis. I have pain in my joints. You might get dementia. You might get all sorts of issues. And so you get this long decline at the end. Now it turns out that as life's expecties increased that period that we spend with morbidities that is with problems of old age has not gotten less. In fact it's remained almost the same as a fraction of our lives. So in terms of number of years it's actually increased. In the old days you would get you got old you'd get pneumonia you'd immediately die. You wouldn't have this long sustained uh decline. And so the this idea of compression or morbidity is a lot of a aging research researchers

50:30 say and by say I don't mean that the researchers are aging when I say that I I mean longevity researchers. So these people uh basically say that we're going to increase health span so we're going to keep you healthy uh for as long as possible and reduce that period of decline. That idea of that reduction is called compression of morbidity. That's the term uh that they apply to it. And the question is is compression of morbidity actually possible because almost every advance that has increased life expectancy for example improvements in cancer treatment, diabetes, heart disease, all have increased our life

51:16 expectancy. But they've also increased that period of decline. It's not shortened that period of decline. And there's a poem called the one horse open sheay by Oliver Wendell Holmes which is quoted in the first paper that coined this term compression or morbidity. Now the sha a sheay is a carriage for one or two people. And this wonderful one-horse open sheay was constructed so all its parts would wear out at the same time at the same rate. So this farmer was riding along on his perfectly good shay and suddenly found himself on the ground surrounded by a heap of debris because the whole thing just disintegrated all

52:01 at once. And and that's sort of what we're expecting a asking uh for humans that you you live very healthily. And this is this quote that you said we want to die young after a long time was by Rick Clausner who's a chief scientist of Altos Labs which is one of the big sort of billion dollar investments in anti-aging and you know a lot of tech billionaires like Jeff Bezos and Yuri Milner have invested in it and so the question is if you're young why would you suddenly die you know so that's that's the conundrum that they I haven't quite explained but I should point out that these super centinarians that it's a term you used for people who live over

52:47 110 many of them live extraordinarily healthy lives and then suddenly decline and die. So there is there are at least some individuals who have achieved compression of morbidity but we don't know if these super centinarians have some general lessons for the rest of us. For example, they may have a particular combination of genes and life history and pure luck that allowed them to uh live that long and live healthily. They may have escaped various infections and just not got cancer purely uh by chance or some combination of their genes and lifestyle. It's not clear what lessons we can learn from them. Uh there may be things that we can but it's not yet

53:34 completely clear. My bubby was like that. She was 96. She called me to tell me she quit smoking. Yeah. And that she was doing meals on wheels for old people, you know. Yeah. The family joke was, "How old are they, Bubby?" You know, um and then she she lived alone, you know, argued about politics and um lived to be 101. Yeah. Just uh was exactly what you describe. It was then it was she was ready. She was like, "I'm done." So, it's very it's very intriguing um this idea that who's going to want to die at the peak of fitness, right, if they're told that it's a sudden switch off or really anything. There's an old joke in the aging uh field which is who would want to live to be 100 and it's someone who's 99, you

54:21 know? Right. Exactly. Um so but let's talk a little bit about protocols because I know a lot of people want to hear what uh regardless of all the warnings and the philosophical realities. Um what is being done in research and one of the things that's been very popular um among the people that you're describing who want to uh die young after a very long time. Um one of the things that's become very popular is caloric restriction and and um and how there's evidence that actually that kind of stress Yeah. leads to longevity in certain animal subjects. So the so there have been studies done in a variety of animals all the way from uh even small single cell animals like yeast uh to through flies and worms and

55:10 mice and even uh chimpanzees or or monkeys anyway. So, so you can you can have a whole range of of animals and in all those cases they found that if you take a group of animals and feed one group all they all all they can they can eat that's called an ad libitum diet. They can eat as much as they want of this food you give them. And the other group gets just enough food for them to live, not starve. So they don't decline in weight, but they can they have enough calories and nutrients, vitamins and micronutrients to live uh indefinitely. It turns out that the calorically restricted animals are often healthier

55:55 uh and and and live long somewhat longer than the uh control group. And so this leads to the idea that maybe caloric restriction does something to our aging process. Now there is one caveat and one of the sort of fathers of aging research Leonard Haylick who discovered cellular scinessence. uh he complained that these studies just show that an all you can eat diet is bad for you, you know, because because there was another monkey trial where they didn't feed such an unhealthy diet to the control group. And there the differences weren't as striking as as another a different monkey trial where they gave the control group a rich all

56:41 you can eat diet. So anyway, but no matter what, it does mean that the level of calories you consume does have an effect on aging. And people have figured out at least some of the pathways that are affected by caloric restriction. Now, caloric restriction is very hard to do, you know. Yeah, I'm not into it. People who people who are in calorically restricted diets feel hungry all the time. They they're cold. They often have loss of libido. So, you know, you want to ask, you know, what is the purpose of life? You know, you got to be sure about those scientific studies is all I'm saying. Yeah. So, so, so people have asked, is there a way to cheat the system? And the idea is could you maybe

57:28 interfere with pathways that are affected by caloric restriction that might mimic the effects of caloric restriction? And one of the darling drugs of the anti-aging community is rapamy which inhibits a pathway called the to pathway which also senses nutrients and and and so reducing calories has a similar effect as this drug rapamy. But rapamy is also an imunosuppressor. That's why it was approved as a drug and it it was you know given to organ transplant recipients to prevent rejection of a foreign uh graft. So um whether you would want to give that

58:13 sort of drug for over a long period to and it has other side effects by the way. So would you take rapamy for a long period in order to uh age perhaps more slowly or maybe a bit more healthily? Uh you know it's not clear. I personally wouldn't but I can tell you there are a lot of longevity researchers who are quietly taking rapamy on the side off as an offtarget uh prescription. So I I guess they think the the control trials will take too long and they're aging in the meanwhile and they don't want it to age. So So uh they feel that the data are good enough for them. I think uh this just shows that science is

58:59 a very rational endeavor but scientists are humans and therefore not completely rational. Uh and in this research there there has as you warn um there have also been examples of sort of snake oil um things that were touted even companies that were exchanged with hundreds of millions of dollars at stake um where none of it actually played out and there's a sort of warning about things like was it certuins and maybe uh reserrol certuins came out of you know, perfectly legitimate research and in fact, you know, many of those papers uh you know, they're they're the original papers are probably did show uh the effect. Uh

59:46 certuins are are proteins. They're enzymes that modify their their they add acetyl acetal groups to other proteins. And there was this idea that maybe certins are involved in uh in aging. But then other studies showed contradicted those first studies. Then there was an idea that resveratrol an ingredient of red wine would activate certuins. And then it was shown that actually the report on activation had to do with a particular way in which they measured activation which turned out to be an artifact. So in in many ways

1:00:32 uh but but certuitans the whole concept was sold to Glaco welcome for $750 million and after many years of work follow-up work Grao Welcome basically shut down that division and so you know me most of the aging community does not believe uh in a sort of primary role for certain but I should tell you that many of the original investigators and some of them are quite famous uh still believe in certain and I like to joke that this is you know Max plank was a very famous physicist and he said that uh people don't adopt discard false ideas and adopt new ideas because they

1:01:20 change their mind scientists don't do that rather scientists just die and a new generation not if they can help looks at the data more objectively and moves on. And so the the short version of that statement is science advances one funeral at a time. But a lot of the research you think is legitimate and a lot of the the research you think is legitimate and quite a lot of it is is is is u based on very solid science. For example, reprogramming of stem cells, very promising, but not around the around the corner yet because of it from going from there to being able to have effective and safe therapy for humans in

1:02:06 a that has predict predictable outcomes. That's that's quite hard. Same with caloric restriction. Rapamy does work but can you find a safer version or maybe can you find a dose for rapamy that has the benefits without the unwanted side effects. So and metformin is another drug which is somewhat uh evidence on metformin is mixed. Some say that it actually uh does uh make you live longer and healthier. Others say that it doesn't make much of a difference and you need large-scale trials on healthy people not on diabetics who have to take metformin. So there are lots of things that are uh have a sound uh scientific basis and but

1:02:56 they need to be developed like synolytics these scinsesscent cell targeting or factors in blood. It turns out that if you connect a rat, an old and a young rat, so that their blood systems uh, you know, are exchanged, then the old rat benefits from the blood from the young rat and the young rat actually, uh, deteriorates or suffers from the blood of the old rat. And so this means there are markers, there are factors in blood that change with age. And that's a legitimate field of research. But when you talk about charlatans, uh it turned out that right from the time when these uh scientists at Stanford published their first finding, they started getting creepy

1:03:41 phone calls from you know rich people about where could they get blood and companies started sprouting up getting blood from young donors and then selling them up at some huge markup uh to rich old people. And of course these transmissions uh transfusions had really you know almost no effect because you know it's not the same as connecting uh two animals all the time and also you know you need to know what these factors are and how they work and how to administer them and that's long uh you know a long range research project. M um I I'm conscious of the time and I want to give people a chance to ask questions. Um but before I do, I I want

1:04:28 to kind of end on your own sort of philosophical disposition towards this. You also quote in your book um Barbara um Erin Reich who experimented with living in poverty. It was very interesting. Oh, it was a great book. I remember that. Yeah. And there's a you you quote this line which I'm going to shorten drastically um where she says you can think of living as a a temporary um interruption of an eternity of personal non-existence. Right. Right. Right. which is you know there's 14 billion years before we were born and there will be many billion years after you didn't exist for an infinite period and then you exist for a short time and then again you're you don't exist and that's

1:05:14 one way to view it and another people other people have said that you know for example uh Mario Yosa Vargas the the Peruvian novelist he said that um that you know an immortal life would be just horrible because you would lose all of the incent incentives of life. If you knew that you you just had infinite time to do whatever you wanted, these are all philosophical. But I have to say the reality is if you ask somebody how do you feel about a finite life? They say oh yeah yeah it's fine. If you ask them would you like to die next year? How how about next year? They said h we don't want to die next year. And so if somebody came to you with a pill and said, "Look, this pill will make you

1:06:00 live an extra healthy 10 years." Most of us would take it. I mean, I'm taking statins and high blood pressure medicines. Uh why am I doing that? So that I can stay healthier and potentially live longer. So I think human nature is to want to exist because existence is all we know and we fear that loss of existence. Um beautiful moment. Please everyone join me in thanking Rama Krishna. At 96, I asked my mother how old she felt inside and she said after thinking

1:06:46 for a little while, she said not yet born yet. At 101, she left her body behind. What about the spirit with the energy that that Jenna's mother lived to 101? Grandmother. Yeah, Jan. Sorry. That's right. uh um what what do we what is that energy that keeps us running, keeps us alive, keeps us excited? There's a there are two interesting social sociological observations about death. One is that elderly people who have a community, they have a network of friends, of relatives or family, have connected to the community in general, they have a

1:07:33 lower mortality rate. A second is that older people with a sense of purpose in life tend to have a lower mortality rate. And so if they have some reason for wanting to live because they have a purpose, they want to do something. There's some, it could even be a hobby, it could be volunteering, it could be anything, you know, those people somehow seem to live longer. Whether that's just a correlation or cause, we we don't know, you know. Thank you. Thank you for your question. Next question. Thank you for the excellent conversation. Um you often hear anecdotes of people being aware of their own morbid morbidity. Um so you know grandma wakes

1:08:18 up one day and says today's the day and later that day she dies. Um or people who are on their deathbed kind of letting go and kind of dying shortly thereafter. Is there any scientific understanding of people's kind of mental connection or awareness with their death or is this all just kind of happen stance? I I think you know the letting go I I'm not sure letting go actually is causing them to die. Uh rather it may be that their body has reached a certain stage you know of suffering or decay. Uh that their brain has eventually accepted the signals from the rest of the body and said okay this is it. and and so we we may be mixing up cause and effect

1:09:04 there. Thank you. Yeah. I I keep on getting caught in this conversation with a dear friend of mine. I think he does this to annoy me, but he talks about this idea of the simulation and that we're all stuck in this thing. And I hope you don't agree with that. And uh I I kind of lose my cool when I talk to him about this. Yeah. So I'm wondering if you could supply me with some arguments. Well, I think you know this whole simulation, you know, maybe people have seen the matrix too often and uh so they think life is simulation. This is an old philosophical paradox like how do we know this is the real world and we're not in some sort of simulation of some other uh thing. And uh you know I I

1:09:52 don't I don't buy it. uh but there's no I mean there there's no real logical way uh to refute it and so I don't think of it as science uh in that in that sense because science is basically you have to have a hypothesis that you can you can refute so this is a domain of uh either sophomores in college or or or philosophers I I have to say I I think that you might be able to make a rational argument which is my computer's never gone that long without crashing. And I and I never get a 404 not found page, you know, in reality. And and in fact, there are mathematical proofs that you cannot make a bug-free code. So, if we were in a

1:10:38 simulation, it would have to have bugs unless it's not guided by mathematics, in which case we're not really in the realm of anything as interesting as even the matrix. I think I think people are pretty buggy. But thank you. Quick question. Since uh evolution wants us to live long enough to uh reproduce and have our genes carried and most everybody who does that is going to do that say by the age of 40, why do we live as long as we do? Why aren't we all dying at 40? Yeah, that's a that's a slight that's a slight paradox, but there there may be two reasons for that. One is that about 40,000 years ago, our uh lifespan uh dramatically increased

1:11:25 for reasons that are not completely understood. And so we may have evolved a lifespan that um sorry so we may really have a lifespan that goes well beyond our reproductive uh you know period uh because of that and it relates more to uh to women than to men because it you know women go through menopause and so they live long after they can reproduce. Men actually can reproduce not quite until death but you know for a much longer time. In that sense they're more like most other species. And you were saying that even whales um

1:12:12 can reproduce towards females can reproduce towards well orca whales are one of the few other species that go through uh humanlike menopause where u the female you know stops having the ability to reproduce and lives much longer. And there are all kinds of theories uh about it. The good grandmother theory, grandmother theory, the mother theory, mother hypothesis is you have to live long enough until your youngest child has grown up, be able to reproduce, otherwise it doesn't really uh count. And the grandmother hypothesis is that uh you it's better for you to stick around and help your grandchildren uh survive than for you to continue to

1:12:58 have uh babies. But evolutionary biologists don't really buy at least the grandmother uh hypothesis. And so um you know it could simply be that evolution hasn't had a time to catch up with this increase in lifespan. But social species have there there is something about the organization of social species that isn't just the survival of the individual at least you know. Yeah. But you know group selection doesn't really work out except group selection is where uh you evolve for say some trait that helps the group as a whole not not necessarily the individual. And that mathematicians have shown only works for

1:13:43 groups that are extremely related genetically like ants youocial species like ants or bees. Uh so naked mole rats which you mentioned naked mole rats which you mentioned earlier. Yeah. So it doesn't really work for humans you know and there are reasons for that because there's this thing called cheaters and if you if you have m mutation that goes against the benefits you but not the group it'll be selected for eventually. Um last question please. Hello. Thank you both for your insight. I was curious about your opinions on psychedelics and I know people have been using them for thousands of years and I was wondering from like a biological and evolutionary standpoint like why do you think they're here and why sorry about

1:14:29 psychedelics uh psychedelics like psychedelics like you know help me out here people mushrooms um if you think that there is a reason why human beings beings have um an a relationship with psychedelics. Oh, I don't think that I'm not sure that has that much to do with aging or death. I think I think it's simply uh you know

…