Nobel laureate alarmed by over-hyped longevity research

Could we one day cheat death? Are we hurtling towards a time when science will be so advanced that aging can be prevented or halted in its tracks? Nobel laureate Venki Ramakrishnan takes a skeptical view in a fascinating exploration of longevity research. In Why We Die: The New Science of Aging and the Quest for Immortality, the acclaimed scientist delves into the complexities of aging and the pursuit of extending healthy lifespan.

A former president of the Royal Society in London, Ramakrishnan is a group leader at the Medical Research Council's Laboratory of Molecular Biology in Cambridge, England.  He shared the Nobel Prize in Chemistry in 2009 for his work uncovering the structure and function of tiny cellular particles called ribosomes and was knighted in 2012.

In this interview with Peter Bowes, the molecular biologist provides a critical perspective on the dilemmas of aging research; questions the hype and financial interests linked to some aspects of longevity science; delves into the concept of compressed morbidity and its challenges, and explains his belief that dramatic life extension is not imminent.

Read a transcript:  LLAMA podcast website
Photo credit: Kate Joyce and Sante Fe Institute

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Transcript

Venki Ramakrishnan: 0:24

I don't think anyone has solved the problem of keeping lifespan fixed, but keeping the healthy part, extending the healthy part. Usually both of them get extended. So the part that you live in with you know all the aches and pains and diseases of all days, that fraction hasn't actually changed, and so I think that is a serious dilemma or paradox in the field.

Peter Bowes: 0:51

Why we die. The new science of ageing and the quest for immortality is a fascinating new book by the physicist and molecular biologist and Nobel laureate, Venki Ramakrishnan. Hello again, welcome to the Live Long and Master Aging podcast. My name's Peter Bowes. This is where we explore the science and stories behind human longevity.

Peter Bowes: 1:15

Born in India, Venki Ramakrishnan has enjoyed a distinguished career. A former president of the Royal Society in London, he shared the Nobel Prize in Chemistry in 2009 for the work he and others did, uncovering the structure and function of tiny cellular particles called ribosomes. Over the years, his career interests have shifted in emphasis from theoretical physics to trying to understand how our bodies work at a molecular level and the process we call ageing. Why we die addresses that question, but also explores why we live, why some of us enjoy longer lives than others, and whether some of the more recent efforts to extend lifespan live up to the hype.

Peter Bowes: 2:01

Venki, welcome to the Live Long and Master Ageing podcast. Hello, pleased to be here. Yes, it's really good to talk to you and we will dive into the subject of your book, but I would like first of all to do a little romp through your career, and that's a phrase I get from your book, which you describe as a romp through recent molecular biology. But let's just start by talking about you and your extremely long and varied career. You grew up in India.

Venki Ramakrishnan: 2:30

Yes, I grew up in India, except for about a year and a half that I spent in Adelaide, australia, when I was eight and nine, and then I left India at the age of 19 to get a PhD in physics in Ohio, in the US, and in Ohio is also. I like to joke that the only notable thing I accomplished in my graduate school in physics was that I met and married my wife. But because it turned out that I really wasn't so thrilled about the problem I was working on, and even during my graduate work, I became very interested in molecular biology, and so I know you introduced me as a physicist, but no physicist with assault or her assault would consider me one, because I left right after graduate school and never did any work in it. And the reason was that I used to read articles in molecular biology and realized, you know, molecular biology was undergoing this huge revolution. You know DNA, the structure of DNA had been done in the early 50s and based on that we had this huge explosion in molecular biology. We were learning about the structures of molecules, of cell membranes, and how the immune system worked, how the nervous system, you know, was constructed and so on. So I thought, well, this was a good move. But I didn't know any biology. So I went to graduate school all over again at the University of California in San Diego, in La Jolla, california, and I had the option of getting a second PhD. But after two years I realized I'd learned enough biology. I had acquired a background in biology and I knew how to do lab work, and so, based on another article I read, I went to Yale University as a postdoctoral fellow to work on the ribosome, which is this enormous complex? They're tiny by everyday standards, but they're really enormous in that they have about half a million atoms and they're the machines that translate our genetic information into the proteins that those genes code for. So all the thousands of proteins in ourselves that actually make life, actually do its thing are made by the ribosome using genetic information. So every gene codes for a particular protein, and so that got me into the ribosome. And then, throughout most of my career, I've worked on one or other aspect of the ribosome and eventually we and others ended up solving the atomic structure of the entire ribosome, and that allowed us to figure out how it actually worked. So of course it's an ongoing process and we're still working on the ribosome.

Venki Ramakrishnan: 5:45

Now the aging thing came about for two reasons. One is the ribosome is very central and you can think of all the proteins in our cell, the thousands of proteins in our cell. Each one is doing its part and they all have to work together and proteins have to be made in the right amount and they have to be made at the right time. If they're no longer needed, they have to be degraded. So you think of it as a complicated orchestra and there's a lot of things in the cell which control when the ribosome starts making proteins. It checks the quality of the proteins made by the ribosome. There are all kinds of checks and balances. If the wrong thing is made or if it's defective, the cell has ways of getting rid of it and it turns out this process breaks down during aging and one of the chapters in my book it's called Recycling the Garbage and it's about a field called proteostasis which is about protein turnover and quality control. It's very, very central to my field of how the ribosome does its thing.

Venki Ramakrishnan: 6:58

So I had this peripheral interest, even though I myself don't work on aging. The other is that as a molecular biologist I became alarmed by the increasing amount of hype in the aging field and I think a lot of it is driven by money. You know there's lots of private money. A lot of billionaires are worried about aging and dying and they're investing heavily in aging research and this is distorting the field and leading to wild claims. There's also a lot of money in aging.

Venki Ramakrishnan: 7:31

As people get older they're worried about getting old and dying. They want to sort of postpone it and stay healthy. So they're susceptible to all sorts of things. People that people want to sell them. So I think I thought I'm close enough to the field but not in it, so I don't come with any particular biases and at the same time I can actually read the primary literature and so on. So I thought I would distill what is going on and try to give the reader a sense of you know, what are the things that make us age and what, if anything, can we do about them. And finally, in my last couple of chapters they're a bit philosophical about what would be the implications if we just prolonged life and so on. So that, in a nutshell, is sort of what got me into the book and what the book is about.

Peter Bowes: 8:31

Yeah, and that's really interesting. And I'm also wondering if the aging process, as it is affecting you as an individual, like it affects all of us, has also helped focus your mind. Yes, you've got your theoretical, you've got your scientific background and, as you say, you are able to dive into this subject in a certain amount of depth. And I'm thinking also from a purely personal perspective.

Venki Ramakrishnan: 8:56

Oh yeah, I say in the beginning of the book that you know one thing that would perhaps well let me back off a bit. There are lots and lots of books about aging, and they fall into many categories, you know. So a number of books are about how to age gracefully and how to accept the end. You know things like that. So that's one sort of category. Another is you know about, you know how to stay healthy, you know exercising and doing things that help, and you know those are sort of self-help books. Then there are books about, you know, the biology of aging, and these also fall into a couple of categories, you know somewhere.

Venki Ramakrishnan: 9:38

Written by journalists, you know, and some of them have done a good job, but they're not sort of equipped to be very critical about the literature or really digest it and see what its limitations are, and so they often rely on interviews and chats with people you know to get a feel for what's going on. And of course, those people they talk to may have their own biases. And then some of them are written by scientists. But these scientists often have some vested interests, they have companies, they have anti-aging companies, and so they're pushing a particular point of view, you know, and often I would say, they're somewhat biased towards their own. You know, whatever it is that they're sort of stunning.

Venki Ramakrishnan: 10:32

So I say in the book at the beginning that you know one thing you can say about me is I don't have any skin in the game. I'm not I'm neither directly an aging researcher, so I don't have preconceived biases. And you know scientists also, once they have you know certain theories and stuff that they've published, they're reluctant to back off. You know from them. You know they become sort of vested in their own beliefs as well. And but the other is I don't have any financial interest in aging. So I said I have no skin in the game. But then I point out of course that's not true for the reason you mentioned, which is we all have skin in the game because we're all worried about aging and dying. So in that sense you know, like everybody I have, I'm concerned about it.

Peter Bowes: 11:21

And the fact that, as you say, some scientists have and not all scientists. Some scientists in this field are very pure, if you want to use that word, but some do have vested interest and of course that only adds to the to the layperson, and I like to think that this podcast is aimed at absolutely everyone. I try to not use the acronyms and boil everything to a level that we can all benefit from.

Peter Bowes: 11:44

But yeah, there are so many vested interests. It just adds to the confusion of people who are genuinely interested in their aging process and their longevity but then think, well, which direction do I go in? Do I go down this very specialist diet route, or do I adopt this kind of exercise, or do I need a certain exactly?

Venki Ramakrishnan: 12:03

there's so many things being pushed, and so what I've tried, you know, just to give you an illustration, in the last 10 years alone there've been over 300,000 papers published on aging okay, primary paper now, nobody could read any of them. You know all of those because you know, just to read a scientific paper, even if you want to just read through it without really thinking about it, takes at least a couple of hours, you know, and probably longer if you really want to digest it. So of course, I've had to be highly selective, and so what I've tried to do is ask, you know, what are the key advances and and what are the key factors involved in aging. And I've tried to construct in my book, you know, to try to go from the very simple. So I start at the molecular level. So start with, for example, dna, you know, which contains information that really, you know run is responsible for the program, the program of life, the program to sell.

Venki Ramakrishnan: 13:07

And so I start with DNA, then I talk about how DNA can be modified, then I talk about things that affect DNA, then I talk about what DNA makes proteins and how these proteins interact and how the proteins have to be recycled and how, if proteins clump together, you get diseases or aging like Alzheimer's. You know so. And then I talk about things inside cells, like large organelles, like mitochondria, which really it's amazing when you and I try to also give a lot of history, how we found out about this. You know characters who you know, some of them really weird characters who made big discoveries, and so the hopefully the reader will go on this voyage and by the end come out with some broad understanding of the whole sort of broad background of biology of aging.

Venki Ramakrishnan: 14:05

And the idea is that next time they see a report on some huge advance in aging according to the headline, they'll be able to judge, because they can relate it back to the biology that they picked up from this book and they can tell is this a real advance or have there been others like this before which have sort of fizzled out, or is this just one more thing or is it incremental? You know they'll have a much better sense of how to navigate this. You know constant, constant.

Peter Bowes: 14:39

You know drumbeat of, you know aging advances and what was interesting to me is, essentially, this is a book about living. It's about living as well as we can within the constraints of, let's say, an average lifetime. It's not about eternal life, it's not being immortal, it's not living forever. It's about living, but you actually start by analyzing death and what it is to die.

Venki Ramakrishnan: 15:05

I'm just curious as to why you took that approach yeah, because you know, if you want to talk about dying and aging, you have to actually ask what do you mean by death? You know, and what do you mean by aging? And just to give you a very trivial example, when you die, you know you have over a trillion cells in your body. Most of them are still alive at the moment of your death. That's the amazing thing, you know so. So what do you mean? You're dead, you know all those cells are still alive. In fact, after you die, somebody could take your heart or your kidney and and donate it to some recipient who needs it right, and people have done that, you know. People go and liver transplants, kidney transplants, heart transplants, etc. So you know what do we mean when we die? Well, what it means is that we die as an individual. An individual is somebody who functions as a unit. So the collection of the cells that make you function as an individual, that collection, is no longer working as a coherent whole, and so that's when you die.

Venki Ramakrishnan: 16:17

And typically nowadays, most places define death by brain death. Okay, in the old days, you know, if your heart stopped, you were considered dead, but then people figured out how to resuscitate you, you know with CPR and so on, and so they felt, oh, that's not a good definition. So then it went to brain death and even brain death. You know, the exact details are slightly different and I point out in the book that those cases where, especially in the United States, the definition of death in one state is not the same as in another state and there was a very famous case of a young woman who died and I think in California, she declared death but her family she was not dead by the standards of New Jersey and so her family, you know, appealed and got her body transferred to New Jersey and kept her alive by New Jersey standards. And then, you know, eventually she died and you know, she was in a coma.

Venki Ramakrishnan: 17:15

And I think you know it just goes to show you that defining death is not not trivial and it's also, I point out, at the other end, defining, you know, when a person's life begins. It's also quite complicated, you know, is it at the moment of conception, is it at the moment of implantation? Is it when the embryo reaches a certain stage? You know, is it when the fetus is viable? I mean, these are not necessarily scientific questions, they're, you know, social and cultural questions as well, and that's why we have this. You know, big polarization about abortion.

Peter Bowes: 17:54

It's about arguing about when life begins, you know and you write about compressed morbidity which as an expression, as a, as a phrase, I think is crucially important.

Venki Ramakrishnan: 18:05

If you understand and get what it means and I look to just explain your understanding very interesting concept, and so the idea of compression or morbidity is that you live healthily for nearly all your life and the period when you're sort of suffering debilitation and decrepitude of old age is very, very short. So that period of morbidity is compressed to a very short period. And so the idea is you stay healthy all your life and then suddenly, you know, collapse okay, within a very short time. And the person you know who first coined the phrase freeze, he said that look, this is a little bit like the one horse shea. He quotes a poem by Oliver Wendell Holmes, from the thing from the 19th century. A shea is like a is a one or two horse carry, one or two person carriage. And he said, the one horse shea in the poem is constructed so that all its parts wear out at about the same time. So nothing ever, it's never defective, you know, because all the parts are going along at the same time. And this farmer is riding along, and one day he's riding along and suddenly he finds himself on the ground in a heap of dust because the entire carriage is disintegrated in front of him, right under him.

Venki Ramakrishnan: 19:38

Now that would be the equivalent of compression of morbidity, because it has a paradox which is if you're healthy, why would you suddenly die? You know all your organs are healthy, you're feeling great, well, why would you die? And the reality is that almost everything that has helped us stay healthy for example, statins for cholesterol or blood pressure medication to prevent high blood pressure, or, you know, diabetes drugs, you know metformin and things like that All those things that have helped us against diseases of old age and helped us stay healthy they have all effectively prolonged our lives. So the period that we are actually, you know, suffering from the disabilities of old age has not changed as a fraction of our lives. So, in fact, because we're living longer, you could argue that we're actually spending more years, you know, with all these aches and pains and disabilities of old age, and you can see that. You know nursing homes and care homes for older people. It's a booming business, you know, because more and more people are going into them and they're going, you know, living longer.

Venki Ramakrishnan: 20:57

So my I say in the book, compression of morbidity is a very worthy goal, but it's not clear yet how we can achieve it. Okay, because you know what we may do is simply prolong life and at the end, everything's not necessarily going to break down at the same time and, you know, as things start breaking down, well, then you have your morbidity, okay, and so it's a complicated problem. The one thing that suggests that there's some hope for it comes from studies of centenarians. So I communicated with Tom Pearls, who's a world leader in this area, and he has his studies show that people who live especially 105 or 110 these are what are called super centenarians.

Venki Ramakrishnan: 21:50

You know even centenarians of people who live to be a hundred. So, but these semi and semi, super and super centenarians, they turn out to have very short periods when they're actually sort of ill or, you know, frail, and they they often tend to have almost none of the diseases that many people have as they get older. So they're very healthy for most of their lives and have a very short period of sort of what I call illnesses of old age. So that suggests that maybe, you know, if we can find out why these people have somehow managed to live healthily for a very long time and then, you know, suddenly die, that would be something that would be worth looking into.

Peter Bowes: 22:42

And I think, just to emphasize the point, the best example I can think of of someone achieving a compressed morbidity in modern times was Queen Elizabeth. She died, yes exactly she was working right to the very end.

Venki Ramakrishnan: 22:57

Yeah, and actually you know her husband, prince Philip, was also very healthy until you know, just the last few years of his life. So perhaps you know people should sequence their genomes and see in their lifestyle.

Venki Ramakrishnan: 23:14

Of course you know, you have to realize they also had the very best environment and medical care and so on so it's perhaps not a very fair comparison, but, on the other hand, it does say something about, and they didn't live past a hundred. Neither of them live past a hundred, so they're not, in a sense, the most extreme of the cases, but it's a good point.

Peter Bowes: 23:39

And I think it's also interesting just non-famous people that I have known of who've got to a great age. What's interesting to me is that they often achieve that, most times achieve that without thinking about it, they just get to a great age and they live their lives.

Peter Bowes: 23:54

But then you, sometimes you dive into the way that they've lived their lives, whether it's being their diet, their exercise regime or, in many cases, their social connections, their social circles and the people that they've had around them at a great age. I think these are all the things that play into that ability to live long and to live well.

Venki Ramakrishnan: 24:14

Yeah, so I point out in my book that Tom Pearls has a website called living to 100.com and you can fill out all sorts of things about yourself and your habits and you know your health history, and it'll tell you, you know, how long you can expect to live. And I do fairly well, because one of the things apparently is if you have a parent who lived very long, like in their 90s, that somehow improves your chances for genetic reasons alone. I have a father who's 98 years old. He's well, he's going to turn 98 this Saturday and he's still going strong. He, he does his own laundry and is cooking and until a few years ago he would go off, you know, on long walks and shopping and so on. And he still walks, you know, a couple of miles. So you know, I don't know exactly what it is about him, except I think he has a zest for life. I think maybe you know that's quite important, but of course a lot of it is due to some combination of genetics and diet and habits and so on.

Peter Bowes: 25:28

I think that factor that you mentioned of people that do their own gardening and laundry and household chores until they achieve a as they're achieving a great age, is important. I mean you could characterize it as movement. It doesn't really matter as much as you do. Yes, absolutely.

Venki Ramakrishnan: 25:43

And using your brain. I mean when you're cooking or doing, you know somewhat complicated tasks. You know it's more active than you know if you're simply passively receiving. You know watching television or something, and you know. So of course this is all anecdotal, but I think you know these people who study centenarians, like Tom Pearls. They're looking systematically at you, know what are their habits, what are their health histories, and then they're also going to sequence their genomes and also sequence their you know, methylation methylones because DNA methylation is a modification of DNA that's somehow related to aging, and they could see other methylation patterns, these tags on their DNA as they age, but they're different from people who don't live as long. So there's a lot of information to be gained and we'll learn more about that as these studies progress.

Peter Bowes: 26:46

You cover in the book, caloric restriction, which I think, if you look at the science, there's perhaps some of the most solid science behind the idea that a certain amount of caloric restriction, reducing the amount of calories that you consume on a daily basis could help you live longer and better. And the dilemma, of course, for a lot of people here is that many people prefer quality of life, and quality of life does not involve caloric restriction over quantity. Ultimately, the number of years I point out, you know.

Venki Ramakrishnan: 27:20

So the evidence for caloric restriction is quite good, which is caloric restriction is when you give an animal or a person just enough calories and nutrients so they're not malnourished. So just enough and no more. And that in studies on many different species, all the way from worms and flies to mammals, has shown to improve lifespan compared to an ad-limitum diet where they're fed as much as they want. You know the food they can eat as much as they want. But some critics have pointed out it's not a fair comparison because an ad-limitum diet is basically unnatural. You know, the idea is we never had an ad-limitum diet until modern times when food became plentiful. And so they say well, you could just as well conclude that an ad-limitum diet is really bad for you, you know. And that if you don't, you know, if you restrict your calories it's better, but it doesn't have to be so extremely restricted. And there are also studies on intermittent fasting. You know people say if you fast for 16 hours at a time or eat only in a five-hour window, that that can, you know, that can help, and that too has been contested. So I point out, in the book, for many of these claims there are also counterclaims, and we need to be a little cautious about how good it is. However, there's no question that, at least compared to an ad-limitum diet, which is eating a lot and eating as much as you want, a calorically restricted diet does better. And so the question is then why?

Venki Ramakrishnan: 29:15

And this has led to the discovery of these nutrient-sensing pathways. Well, actually I'm saying that wrong, because the nutrient-sensing pathways didn't all come out of aging research. Only one of them did, but the other one was a complete accident, which is the Tor pathway. And it turns out that this pathway senses nutrients, and if nutrients are plentiful, it does one thing it turns on protein synthesis and it shuts down degradation and recycling of proteins. On the other hand, if nutrients are reduced, and even if very specific nutrients are reduced, so you may get a lot of calories, but you're missing certain amino acids, that too can have an effect.

Venki Ramakrishnan: 30:02

And what it does is it shuts down what I call initiation, the beginning of protein synthesis, so it prevents the ribosome, which is my molecule, from starting to make proteins, and so you stop making more proteins and at the same time, you turn on these pathways which are involved in removing what I call the garbage garbage recyclers of the cell, these things called phagosomes, which take things to the lysosome, which is an organelle which is like a giant recycling center where things are broken down and recycled. So there's lots of things to connect the biology with these broad studies, observational studies like what does diet do to your health? And that's another fascinating thing how we're able to connect the underlying molecular biology and the detailed physiology of the cell to broad things like diet.

Peter Bowes: 31:37

And I think what it is valuable to look into and to analyze is that some of these interventions whether it's a calorically restricted diet or something else that may emphasize may impact your longevity, the number of years that you live, and it also has an impact on how you live now, which could well influence how you live in years to come. But I think for a lot of people, living now is crucially important and just by speaking personally as an element of caloric restriction makes me feel actually good, makes me feel better, makes me feel a little bit lighter, makes me feel more energized, and I think that could potentially help me live longer.

Venki Ramakrishnan: 32:19

Yeah, so the fact is that these animals on calorically restricted diets they're not lethargic, they're actually quite active. I think you're frozen, I'm not sure. Are you hearing me?

Peter Bowes: 32:34

So I had indeed frozen the internet letters down. So we're actually picking up this conversation 24 hours later, internet restored. Thank you for sticking with us. So, let me just return to the point that you were Actually just making. We were talking about calorie restriction and the impact on especially laboratory animals. When we look at mice, those calorie restricted mice are not lethargic, they're very energetic. And you see it, don't you in the mouse wheel in terms of how they, and it's the same.

Venki Ramakrishnan: 33:06

It's the same with worms. You know, when these first mutants, these aging mutants, were discovered in worms Again, the worms were. You know Cynthia Kenyon called them frisky. You know they were moving around and they behaved a lot like younger worms, so it wasn't as if they were kind of living longer, but sort of in a doddering state. And so there is something about it also being fairly healthy.

Venki Ramakrishnan: 33:38

I wouldn't say caloric restriction comes with no effects. You know people under extreme caloric restriction that is a very rigorous kind, which just enough to keep you alive and not malnourished they do have things they feel cold, they have loss of libido, they're slower to heal wounds, typical things like that. So it's not entirely, I would say, without cost. And the most important thing is very hard psychologically to keep it up. And that is, if you take mice that have been caloricly restricted and they're doing fine, you would think they'd be happy doing fine, but as soon as you allow them to eat as much as they want, they gorge away. So there's something about our evolution we didn't grow up in a time of plentiful food, so we somehow want to put away that food. And so I think there is a question of how viable is this as a strategy?

Venki Ramakrishnan: 34:55

There is also the question of people are always comparing caloric restriction diets or these intermittent fasting diets with a sort of more liberal, almost all-you-can-eat diet. Certainly, with animals it's an all-you-can-eat diet. Now it could be that all you can eat is one extreme and that's not great for you, but it could also be that maybe eating in moderation and eating healthy food, balanced food, is perhaps almost as good. I don't know if anybody has done that comparison. The one comparison is with studies on chimpanzees. There was a group at NIH and a group at Wisconsin. The Wisconsin group definitely felt that the restricted chimpanzees were better off, the NIH group not so much, and the main difference was that the control diet of the Wisconsin monkeys was much richer, and so the control animals there did develop all the symptoms of overindulgence. I forget all the details, but they did have many of what we call diseases of excess and not so much in the NIH group. And that suggests there may be a happy medium and moderation and not overindulging is probably and having a healthy diet.

Peter Bowes: 36:32

Moderation is always the word that I come back to when I'm discussing this, and to some people it might be a boring word. Moderation doesn't sound exciting like intermittent fasting or no, but it's something we can live with. Well, yes, exactly Something we can live with.

Peter Bowes: 36:48

Exactly, and I think the point is that, yes, there are lots of fasting regimes. Some may be difficult to sustain long term. There is some evidence that a certain amount of caloric restriction could be beneficial for us. But if you look at, if you apply this to humans and you look at the way most people, especially in the Western world, eat these days, if you look at the extremes, the fast food, look at television advertising, billboard advertising of food, that is the excess extreme.

Peter Bowes: 37:20

Which points to me. It shows to me that, yes, there is a happy medium, there's a moderation, and the challenge seems to be to persuade people that moderation which isn't extreme is potentially very good for us.

Venki Ramakrishnan: 37:34

Yeah, and also I feel moderation is much more sustainable than having an extreme calorically restricted diet, which would be much harder to follow. I mean even and I think moderation also carries fewer risks of some of the downsides of a highly restricted diet.

Peter Bowes: 37:55

Let me just change direction a little bit. The whole principle of evolution is or at least one of the principles is survival of the fittest. Evolving over many, many years, it's the survival of the fittest principle that governs the way that we evolve. So I'm curious why evolution hasn't created a human being that evolves to live longer and stay healthy for longer.

Venki Ramakrishnan: 38:20

Right, but that's because we think of fittest as the fitness of the individual. But you know, fitness is, in evolutionary terms, is defined more as being successful at passing on your genes, and so every species has to have this balance. They have to have a balance between being able to procreate successfully, producing enough offspring that their genes live on in their offspring, versus living longer. And at some point there's no. If you've succeeded in living long enough to pass on your genes, evolution doesn't care how long you as an individual live, because the genes survive, and that's what's selected for. Of course, genes, you know you select for the Genes are what are selected for. But of course genes don't exist in a vacuum. They exist in individuals. So the individual has to survive and be successful enough at procreating, and this is perhaps why different species have very different lifespans. So I'll give you a broad rule of thumb among mammals the larger the mammal is, the longer lived it is on average. They're outliers and I discuss them in the book because the outliers are actually very interesting. We could learn from them. In fact, humans are an outlier. We live much longer than would be expected for someone, our species, our size.

Venki Ramakrishnan: 39:55

But you take mice. Mice live for about two years. Now why don't mice live for 300 years, you know, like a whale or a shark or something? And it's because there's no advantage to a mice, because mice would get eaten or starved long before that. So there's no advantage for evolution to allow mice to evolve, mice to live very long or to age more slowly, because they'd die of external causes that have nothing to do with aging, like predators. And so smaller animals also have a higher metabolism and in fact it's metabolism that's more correlated with age. So faster than metabolism, the shorter the life.

Venki Ramakrishnan: 40:42

So I think my chapter is called Live Fast and Die Young, or something like that. And so evolution is, for each species, optimized fitness. So if you have a chance to live very long, then your metabolism is slower, then you take longer to procreate. There's an advantage to living longer If you're a short animal, fast metabolic rate, fast growth, very quickly get to puberty and procreation. There's no particular advantage in terms of evolution in having that species live longer. Now there's a curious thing I point out in the book about bats. So bats are about the same size, or even some of them are even smaller than mice, and yet they live. You know, a bat has lived for 40 years. I mean, that's an amazing record for such a small animal, and that too has an evolutionary basis. So bats can fly, so they're more easily able to escape predators, and it turns out that animals that can fly are generally longer lived than comparably sized animals that are terrestrially bound, and that again makes perfect evolutionary sense.

Peter Bowes: 42:06

So in human terms and we kind of touched on this at the beginning of the interview there are those in the longevity industry, if we can call it that, that aspire to live to a very great age, whether it's 120, 180, or even much, much longer than that, and there are some that believe that within our lifetime. So let's say in the next couple of decades that the science is going to evolve so quickly that it is going to make that dramatic life extension possible.

Venki Ramakrishnan: 42:37

What do you think? Well, I don't think anybody can know. If you were to ask me my opinion, I would side on the. I would come on the side of people like Jay Olshansky and others who believe that Our current lifespan is pretty much fixed and to overcome it will take much longer. Okay, it'll take some real breakthroughs in aging research, and part of the problem is aging is not one thing.

Venki Ramakrishnan: 43:10

I doubt that there's going to be a magic bullet which will say if we do this, we're going to solve aging, and I think aging is highly complex. There are multiple, almost parallel strands that go into aging, and it's going to take some time to sort of pick through all those strands and come up with a real solution to aging more slowly, Even in our individual selves, our organs age at different rates, as judged by various biomarkers and so on. So the idea that there'll be one magic bullet and that'll solve aging, I don't buy it, and so it's really a question of opinion, I admit. My opinion is that it's going to take a while, and long before that happens, we need a number of other advances to be made. Now, of course, the more optimistic people will say well, look at the rate at which knowledge is exploding and we'll have AI and genomics and we'll figure out all this stuff. I don't buy it, but I can't say as a scientist, I can't say they're absolutely wrong. Okay, that is not. I mean, there are a number of charlatans in the business, but this is not a charlatan-like question. This is a real question on which I think serious people could disagree.

Venki Ramakrishnan: 44:45

Now one serious scientist, Stephen Ostad, actually made the bet with Ostansky about whether a person who lived to be 150 years has been born already or not.

Venki Ramakrishnan: 44:59

And they made a bet and I think the bet was $150 or something which they calculated would become $1 million in 150 years, although I don't know what $1 million would be worth then with inflation. But anyway, I think they don't disagree about the fundamental biology. I think they disagree about whether these advances will come in time for someone born now, before they reach current life expectancy, and I think there are others who believe that there's a constant race. So we start aging, but science advances and by the time they get really old, we'll be able to extend their lives another 10 or 20 years and then, by the time that goes by, we'll be able to extend it again another 10 or 20 years, and that's how they'll do that. And the extreme view of this is that we could live a few hundred years already because of advances. I think those people are, to say politely, blind optimists. But that's, as I say, a matter of opinion.

Peter Bowes: 46:15

Yeah, and I think, and would you agree, that perhaps some of those serious-minded researchers who genuinely believe that we may have extreme life extension at some stage and are doing good work in that area, that at least some of their work might actually help us now and might benefit us in the next decade of our lives?

Venki Ramakrishnan: 46:38

I think the really big advantage to aging research is that it will help with what I call the disabilities or the decrepitude of old age. We have inflammation. I'm 71. I'm saying only because it's today. A generation ago I'd be ready to die, and so I'm 71.

Venki Ramakrishnan: 47:05

I have been fairly active most of my life, and now I have joint pain in my shoulder and knee because of osteoarthritis Clear disease of inflammation in aging, and I even describe it in the book.

Venki Ramakrishnan: 47:21

And so if somebody were to look at what causes this osteoarthritis and inflammation and came up with a treatment for it, well, that would extend my healthy, comfortable life and it might extend my life as well to some extent, to the extent that inflammation is a source of aging and death, and inflammation in fact is a major cause of aging. So I think the hope for aging research is to keep people healthy as they age. Now the problem always is that if you do that, will you also be prolonging their lives? Because if you're keeping them healthy, there's no reason for them to suddenly drop dead, and so that's always an issue. I don't think anyone has solved the problem of keeping lifespan fixed, but keeping the healthy part, extending the healthy part Usually both of them get extended. So the part that you live in, with all the aches and pains and diseases of all age, that fraction hasn't actually changed, and so I think that is a serious dilemma or a paradox in the field.

Peter Bowes: 48:43

So you say you're 71 years old. What do you feel that you've learned from your research into this book in terms of human longevity that you apply to yourself? Has anything changed in your viewpoint?

Venki Ramakrishnan: 48:58

No, because a number of things that, well, the age old advises, you know, eat in moderation. I think who was it who's I quote the person, but I've forgotten his name who said you know, eat moderately and mostly plants. You know, I think, eat food not too much and mostly plants? Okay, michael Pollan, who wrote a book called In Defense of Food Right, and what he was talking about was real food as opposed to food with lots of additives or highly processed food and so on. And so his thing was Eat food, meaning real food, not too much and mostly plants, and I think that's very good advice and that actually takes into account, you know, not too many calories. You know restricting your calories, eating a variety of food to have a healthy diet, and so on. And I think you know I've always led an active life.

Venki Ramakrishnan: 49:59

I bicycle every day to work five miles a day. If I get time. I go to the gym two or three times a week to do weights and some more cardio and sleep. Now, I should work on sleep. I'm actually terrible at it and my wife always complains because I'm on my what you call it, my stupid devices, you know, on my phone or iPad or something you know, while I'm trying to go to sleep, and those are really not at all good. You know, and I think sleep is very much underappreciated.

Venki Ramakrishnan: 50:35

There's a brilliant book called why we Sleep by Matthew Walker. You know who's a sleep expert, and it's amazing. We think of sleep as something you know, because we have eyes and we shut our eyes when we sleep. But actually all sorts of animals, from very simple organisms, actually sleep in the sense of going through a daily rhythm of inactive periods and active periods, and sleep is highly conserved and you would think we would not have evolved it because when we're asleep we're more at risk to predate, predators and so on. And so you know, it serves a very deep evolutionary purpose and we're only now uncovering all of the things that go on when we sleep, including repairing damage that happens during the day, and it's that kind of damage that means that sleep has an anti-aging benefit.

Venki Ramakrishnan: 51:34

So you know, getting your beauty sleep, people say you know it actually turns out to be true. So I think those three things are sort of key, and what the book does is it talks about why they're true. What is the biological basis that these age-old advice? This age-old advice is true? And I think in my life I have done that. Now my father is actually a record holder. He's 98 years old in our family 98,. Until 92, he was walking eight to 10 miles a day and he still does his own laundry and cooking and he can't walk by himself anymore because he's unsteady, but he'll go for a walk with me or with my sister. So I think you know that's another sort of thing, having that, you know, balance in your life. You know it sounds very trite but it actually does work and I don't think there's any real anti-aging medication or supplement that works as well as these things. You know.

Peter Bowes: 52:46

Yeah, I'm totally on the same page as you. I often say it comes down to I put sleep at number one because I think if you and like you I struggle sometimes to get enough sleep, but if you don't sleep well, you're less inclined to eat well the next day, or in other words, more inclined to cheat and less inclined to exercise, because you don't feel as if you have the energy.

Venki Ramakrishnan: 53:09

Yeah, it has lots of knock-on effects. Yeah, I mean I would. I might agree with you that it's actually one of the most beneficial things we can do, and our society is not geared to encourage it. You know even our sort of daily sort of schedule and you know the hours we keep. It's just simply not designed to encourage it, and I think we need to think about that.

Peter Bowes: 53:35

Well, let me ask you in closing. You say you're 71 years old. You're talking to me from your office. How do you feel about, as it applies to the aging process, how do you feel about retirement?

Venki Ramakrishnan: 53:47

Oh, I have a whole section on retirement in my last chapter and so I'm retiring at the end of next year, okay, and you know, I could argue that I actually could have retired even a few years ago, and I honestly don't think it really made a huge difference to science. We're still doing good work, but there are lots of people who are doing very good work in my area and so I do feel that people there's a balance. You know you can't kick out people arbitrarily if they're doing well and people age at different rates. So I think a fixed retirement age is not a good thing, because we're biologically age at different rates. The other thing I should point out is that different professions will have different requirements. I mean, if you're doing hard physical labor or even if you're doing, you know you're a trucker or some, you know a mechanic having to work all day long, or somebody who's on their feet all day, you know cooking in a restaurant, you can't expect them to keep going, you know, beyond retirement age and they wouldn't want to either. And a curious thing in my own institute is all the scientists want to hang on for as long as they can, but all the people who are doing the sort of more, what you would call the utility, the people who do the construction in the building, the electricians, plumbers, cleaners, even the IT people they all want to retire as soon as they can, you know, as soon as they're eligible. So there is a difference. And forcing everybody to work longer is not a good thing.

Venki Ramakrishnan: 55:38

And I also think that scientists and you know people in leadership positions hanging on forever is a very bad thing. There's a generation intergenerational fairness issue. They're preventing younger people, you know, from assuming that. And yet there's also a big imbalance of power. You can see in the US, you know you have Biden and Trump. You know two relatively old people, you know, probably going to duke it out for the election. You have guys like Rupert Murdoch in their 90s, even though he stepped down. You know he controls a lot of the world's media. It's just a huge imbalance of power.

Venki Ramakrishnan: 56:18

And at the same time, we're also most creative when we're young. That's not necessarily due to biological age, although I think we do decline cognitively, even from our 20s, you know we decline cognitively. But creativity is also about freshness. When we're young, we're seeing everything for the first time, we're approaching everything with fresh eyes, and that's why scientists, even writers, are very creative when they're young. So I think, on the whole, I would be for, you know, appropriate retirement. I'm not for people hanging on forever, as some of my American colleagues, you know. They hang on until their 80s because they're having fun. Well, they're having fun, but really all the creative work is being done by young people and their team, you know, it's not they who are really driving it, you know. So I think we need to think about retirement as well as an issue. I'm with you on that.

Peter Bowes: 57:18

I think it's a fascinating issue and it's very obvious to me as well that certainly one rule doesn't apply to everyone when it comes to retirement. And also, I don't suspect that you might officially be retiring at the end of next year, but I think you will continue with your thinking, your writing, and you know whether you describe that as work or not it is just you and some of us, I think just want to continue doing what we do.

Venki Ramakrishnan: 57:44

Yeah, that's quite true. But what I won't be doing is taking up resources, you know funding etc. Which would be better spent on younger scientists. You know people say half my age were just starting out.

Peter Bowes: 57:59

Well, Venki, this has been a really fascinating conversation. I thoroughly enjoyed your book. I would recommend it to anyone. I appreciate your time. Thank you very much indeed. Thank you, thank you. And Venki's book is why we Die, the New Science of Aging and the Quest for Immortality. There's a link to it in the show notes for this episode, along with the transcript of this conversation. This has been a HealthSpan Media production. We'll be back soon with another episode. Thanks so much for listening.