Live Long and Master Aging podcast

Episode

246

Nobel laureate alarmed by over-hyped longevity research

Venki Ramakrishnan | Molecular biologist

BY PETER BOWES | MONDAY MARCH 11, 2024

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 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.

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Topics covered in this interview include (time stamps go to YouTube)

  • 00:00 Intro
  • 02:00 Career Journey: Ramakrishnan shares his career trajectory, beginning with physics and transitioning to molecular biology, focusing on the ribosome’s structure and function.
  • 06:34 Shift to Aging: He talks about his interest in aging, which grew from his ribosome work, and his concerns about the hype and financial interests surrounding aging research.
  • 11:43 Personal Interest in Aging: Ramakrishnan explains that personal concerns about aging partially motivated his book, aiming to demystify aging research for the general public.
  • 14:57 Analyzing Death: He discusses why defining death is crucial to understanding aging. The ambiguity in defining the exact point of death leads to a range of ethical and social questions.
  • 17:51 Compressed Morbidity: Ramakrishnan explains compressed morbidity, the idea of staying healthy throughout life and experiencing ailments only shortly before death. He expresses skepticism that science has yet found a way to achieve this balance.
  • 24:11 Studying Centenarians: He discusses supercentenarians, who appear to have achieved a compressed morbidity, suggesting research into their genetics and lifestyle could provide insights into healthy aging.
  • 27:00 Caloric Restriction: Its scientific backing compared to the more accessible concept of moderation in diet.
  • 33:39 Evolution and Aging: Ramakrishnan explains why evolution has not resulted in humans who live longer, citing the balance between lifespan and reproductive success across species.
  • 37:00 Views on Extreme Longevity: He shares his opinion on the prospects of dramatic life extension, siding with those who believe our current lifespan is relatively fixed without future breakthroughs.
  • 40:02 Impact of Longevity Research: The potential benefits of longevity research are not necessarily in extending life dramatically but in alleviating the disabilities associated with old age.
  • 48:10 Personal Takeaways and Retirement: Ramakrishnan reflects on the age-old advice for a healthy life—moderation, exercise, sleep—and his personal plans for retirement, advocating for passing resources to younger scientists.

Connect with Venki Ramakrishnan: MRC Laboratory of Molecular Biology | Nobel Prize | Profile

Read: Why We Die: The New Science of Aging and the Quest for Immortality

Photo credit: Kate Joyce and Sante Fe Institute


Discounts & Affiliation disclosure: This podcast is supported by sponsorship and affiliate arrangements with a select number of companies. The income helps to cover production costs and ensures that our interviews, sharing information about human longevity, remain free for all to listen.

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TRANSCRIPT – This interview with Venki Ramakrishnan was recorded remotely on January 16, 2024 and transcribed using Sonix AI. Please check against audio recording for absolute accuracy.

Venki Ramakrishnan: [00:00:03] 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 old age, that fraction hasn’t actually changed. And so I think that’s a serious dilemma or a paradox in the field.

Peter Bowes: [00:00:30] Why We Die:The New Science of Aging 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 is Peter Bowes. This is where we explore the science and stories behind human longevity. 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 aging. 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. Venki. Welcome to the Live Long and Master Aging podcast.

Venki Ramakrishnan: [00:01:45] Hello. Pleased to be here.

Peter Bowes: [00:01:46] 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: [00:02:09] Yes, I grew up in India, and 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 when 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, you know, 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 as a physicist, but no physicist worth his salt or her salt would 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, you know, was constructed and so on. So, so I thought, well, this was, you know, 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 had 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 that in our cells 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 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. Of course, it’s an ongoing process. And, you know, we’re still working on the ribosome. 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, you know, 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, you know, protein turnover and quality control. It’s very, very central to my field of how the ribosome does its thing. So 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 this is distorting the field and leading to wild claims. There’s also a lot of money in aging. As people get older, you know, they’re worried about getting old and and dying. They want to sort of postpone it and and stay healthy. So they’re susceptible to, you know, all sorts of, you know. All sorts of things, you know, people that people want to sell them. So I think, you know, I thought I’m close enough to the field, but not in it. So I don’t have I don’t come with any particular biases. And, and, but 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, I, in my last couple of chapters, are 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 what got me into the book and what the book is about.

Peter Bowes: [00:08:10] Yeah. And 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. But I’m thinking also from a purely personal perspective.

Venki Ramakrishnan: [00:08:35] 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, 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 that help. And, you know, that’s 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, some are written by journalists, you know, and 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 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 studying. 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 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. 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. Yeah.

Peter Bowes: [00:11:00] 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 interests. And of course, that only adds to the to the lay person. And I like to think that this podcast is aimed at absolutely everyone. I try to not use the acronyms and boil everything down to a level that we can all benefit from. But yeah, that 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. Absolutely. 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 access exercise, or do I need a certain.

Venki Ramakrishnan: [00:11:41] Exactly. There’s so many things being pushed. And so what I tried, you know, just to give you an illustration, in the last ten years alone, there have been over 300,000 papers published on aging, okay, primary papers. And 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 as I’ve constructed 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, is responsible for the program, the program of life, the program of the cell. 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 of 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. 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, you know, drumbeat of, you know, aging advances.

Peter Bowes: [00:14:23] 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. I’m just curious as to why you took that approach.

Venki Ramakrishnan: [00:14:47] 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 donate it to some recipient who needs it. Right? And people have done that. You know, people have given liver transplants, kidney transplants, uh, 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 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. 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 there’s 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 in, I think, in California, so declared dead. 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. 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. You know, it’s about arguing about when life begins, you know.

Peter Bowes: [00:17:37] And you write about compressed morbidity, which as an expression, as a, as a phrase I think is crucially important if you understand and get what it means. And I’d love to just explain your understanding.

Venki Ramakrishnan: [00:17:50] Very interesting concept. And so the idea of compression of 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, within a very short time. And the person you know who first coined the phrase Fries, he said that, look, this is a little bit like the one horse Shay. He quotes a poem by Oliver Wendell Holmes from the I think from the 19th century. A Shay’s like is a 1 or 2 horse carriage, 1 or 2 person carriage, and he said the one horse Shay 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 has disintegrated in front of him, right under him. 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, 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 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. 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 Perls, 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 supercentenarians, you know, so even centenarians are people who live to be 100. So but these semi and semi super and supercentenarians, 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: [00:22:21] 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 at the age of 96. She was working right to the very end.

Venki Ramakrishnan: [00:22:36] 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 and their lifestyle, of course, you know, you have to realize they also had the very best environment and medical care and and so on. So it’s perhaps not a very fair comparison, but but on the other hand, it does say something about and they didn’t live past 100. Neither of them lived past 100. So so they’re not, in a sense the most extreme of the cases. But but it’s a good point.

Peter Bowes: [00:23:18] 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’ve lived their lives. But then you sometimes you dive into the way that they’ve lived their lives, whether it’s been 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 at a great age. I think these are all things that play into that ability to, to live long and to live well.

Venki Ramakrishnan: [00:23:53] Yeah. So I point out in my book that Tom Perls has a website called livingto100.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 improves your chances for genetic reasons alone. And 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 his 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 that’s quite important. But, but of course, a lot of it is due to some combination of genetics and and diet and. And habits and so on.

Peter Bowes: [00:25:07] Well, I think that factor that you mentioned of people that do their own gardening and laundry and household chores until they achieve a or as they’re achieving a great age is important. I mean, you could characterize it as movement. It doesn’t really matter, I suppose, what you’re doing. 

Venki Ramakrishnan: [00:25:22] Absolutely. And using your brain, I mean, when you’re cooking or doing, you know, somewhat complicated tasks, you know, it’s it’s more active than 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 Perls, 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 methylomes 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. Are they different from people who don’t live as long? So there’s a lot of information to be to be gained. And we’ll learn more about that as these studies progress.

Peter Bowes: [00:26:25] 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, over the number of ultimately the number of years.

Venki Ramakrishnan: [00:26:58] I point out, you know, so the 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. Okay. 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 libitum diet where they 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 libitum diet is is basically unnatural. You know, the idea and it’s we never had an ad libitum diet until modern times when food became plentiful. And so they say, well, you could just as well conclude that an ad libitum diet is really bad for you, you know, and that if you’re 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, uh, 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 counter claims, 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 libitum diet which is eating a lot and eating as much as you want, a calorically restricted diet is does better. And so the question is then why? 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 it turns on protein synthesis and it shuts down, uh, 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 two can have an effect. And what it does is it shuts down, uh, the 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 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. Recycled 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 with these broad studies, observational studies like what is diet do to 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: [00:30:46] 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, but 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 speaking personally, 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, yeah, that could potentially help me live longer.

Venki Ramakrishnan: [00:31:28] Yeah. So the, the, 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: [00:31:43] 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 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…

Venki Ramakrishnan: [00:32:15] 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. I wouldn’t say caloric restriction comes with no effects, you know, people. Under, you know, extreme caloric restriction. That is the very rigorous kind, which just just enough to keep you alive and not malnourished. They do have things. They feel cold, they have loss of libido. They have, they’re slower to heal wounds, you know, typically 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, you know, if you if you take mice that have been calorically restricted and you know, 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 they gorge away, you know. So there’s something about our evolution. You know, we didn’t grow up in a time of plentiful food. So we’re somehow, you know, want to put away that food. And and so I think there is. You know, question of how viable is this as a as a strategy? There is also the question of, you know, people are always comparing caloric restriction diets or, you know, 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, you know, eating in moderation and eating healthy food. Balanced food is 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, you know, better off. The NIH group, not so much. And the main difference was that the controlled diet of the Wisconsin monkeys was much richer. And so, you know, the control animals there did develop all the symptoms of, you know, overindulgence. I forget all the details. But, you know, they did have many of what we would call diseases of excess and not so much in the NIH group. And that suggests, you know, there may be a happy medium and, you know, moderation, and, and not overindulging is probably and having a healthy diet, you know, that.

Peter Bowes: [00:35:41] Moderation is is always the word that I come back to when I’m discussing this. And, you know, to some people it might be a boring word. Moderation doesn’t sound exciting, like intermittent fasting or no, but 

Venki Ramakrishnan: [00:35:54] It’s something we can live with,

Peter Bowes: [00:35:54] Well, yes, exactly.

Venki Ramakrishnan: [00:35:56] It’s something we can live with.

Peter Bowes: [00:35:57] 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, oh,

Venki Ramakrishnan: [00:36:27] That is terrible, terrible,

Peter Bowes: [00:36:28] Extreme. Yeah. 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: [00:36:44] 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, you know, of a highly restricted diet.

Peter Bowes: [00:37:04] 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: [00:37:30] 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, uh, enough offspring that they, 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 an individual. 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 is that the larger the mammal is, the longer lived it is. On average. There are outliers. And I discuss them in the book because the outliers are actually very interesting. We could learn from them. And in fact humans are an outlier. We live much longer than would be expected for someone our a species our size. 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 starve long before that. So there’s no advantage for evolution to, you know, allow mice, you know, to evolve mice to live very long, you know, or to age more slowly because they die of external causes that have nothing to do with aging like predators. And and so smaller animals also have a higher metabolism. And in fact, its metabolism that’s more correlated with age. So faster the metabolism the shorter the life. So I think my chapter is called Live Fast and Die Young or something like that, you know, and so that’s evolution has for each species optimized fitness. So you know, if you have a chance to live very long then, you know, and 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: [00:41:15] So in human terms, and we kind of touched on this at the beginning of the interview, there are those in the 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. What do you think of that?

Venki Ramakrishnan: [00:41:48] 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. 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 the strands and come up with a real solution to aging more slowly, even in our individual selves, our organs, you know, age at different rates as judged by various biomarkers and so on. So, the idea that, you know, there will be one magic bullet and that will solve aging, I don’t buy it. And so so it’s really a question of opinion, I admit, uh, 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 we’ll figure out all this stuff. I don’t buy it. But, you know, I can’t say, you know, as as a scientist, I can’t say they’re absolutely wrong. Okay.That is not I mean, there are there are a number of charlatans in the business, but but this is not a, uh, a charlatan like question. This is a real question on which I think, serious people could disagree. Now, one serious scientist, Steven Austad, actually made the bet with Olshansky about whether a person who lived to be 150 years has been born already or not, and they made a bet. And I think the bet was it was $150 or something, which they calculated would become $1 million in a 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, you know, to before they reach you know, current life expectancy. And I think there are others who believe that this kind of there’s a sort of 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 this is, you know, the extreme view of this is that we could live, you know, few hundred years already, you know, because of advances. I think those people are are, you know, politely to say politely, you know, blind optimists. But, but that’s,as I say, a matter of opinion.

Peter Bowes: [00:45:24] 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. They might help us now.

Venki Ramakrishnan: [00:45:46] 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. You know, we have, inflammation. I, you know, I’m only I’m 71. Okay. I’m saying only because it’s today, you know, a generation ago, you know, I’d be ready to die, right? And, and so, you know, I’m 71. I have,been fairly active most of my life, and now I have a joint pain in my shoulder and knee because of osteoarthritis, clear disease of inflammation and aging. And I even describe it in the book. And so, you know, if somebody were to look at what causes this osteoarthritis and inflammation and came up with a treatment for it, uh, well, that would extend my,you know, healthy, sort of comfortable life. And it might. Spend my life as well, to some extent, you know, to the extent that inflammation, is a source of aging and, and, and death and inflammation, in fact, is a major cause of aging. So, so I think the, 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, you know, 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, you know, all the aches and pains and diseases of old age, that fraction hasn’t actually changed. And so I think that’s a that is a serious dilemma or a paradox in the field.

Peter Bowes: [00:47:52] So you say you’re 71 years old, what have you, 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: [00:48:07] No. Because you know, a number of things that, well, the age old advices, you know, eat in moderation, I think, uh, who is 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. Yeah. Okay. Yeah. Michael Pollan.

Peter Bowes: [00:48:33] That’s right.

Venki Ramakrishnan: [00:48:33] Who who wrote 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, to have a healthy diet and so on. And I think, you know, I’ve always led an active life. I bicycle every day to work five miles a day. If I get if I get time, I go to the gym 2 or 3 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 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. There’s a there’s a brilliant book called, Why We Sleep by Matthew Walker. who’s a sleep expert. And it’s amazing. We think of sleep as something that, you know, because we have eyes and we shut our eyes and 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 predation, 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. 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 what the book does is it talks about why they’re true. What is the biological basis that these age old advice at this age old advice is true. And I think in my life I have done that. Now my father is a is actually a record holder. He’s he’s 98 years old in our family. 98 until 92, he was walking 8 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 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: [00:51:55] 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 the energy.

Venki Ramakrishnan: [00:52:19] So 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: [00:52:44] 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: [00:52:56] 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, I could argue that I actually could have retired, even a few years ago. And I honestly don’t think it would’ve made a huge difference to, 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 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, 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, uh, 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 and but all the people who are doing the sort of more what you would call the, the utility, the 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. And I also think that scientists and, you know, people in leadership positions hanging on forever is a very bad thing. They’re they’re there’s a general intergenerational fairness issue there preventing younger people, uh, you know, from, 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 there’s just a huge imbalance of power. And at the same time, we’re also most creative when we’re young. And that’s not 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. When they’re young. So I think on the whole I would be for, you know, you know, retirement, 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 in their team. You know, it’s not they who are really driving it, you know? So. So I think we need to think about retirement as well as an issue.

Peter Bowes: [00:56:26] I’m with you on that. 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 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 and your writing. And and you know, whether you describe that as work or not, it is just you. And some of us, I think, some of us just want to continue doing what we do.

Venki Ramakrishnan: [00:56:51] 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 who are just starting out, you know.

Peter Bowes: [00:57:08] 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. 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.

The Live Long and Master Aging (LLAMA) podcast, a HealthSpan Media LLC production, shares ideas but does not offer medical advice. If you have health concerns of any kind, or you are considering adopting a new diet or exercise regime, you should consult your doctor.

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