Dr Rupy: And I'm perfectly open about this. This is not about health. I want to die with abs. That's all.
Professor Richard Farager: I have a, you know, that's I'm just putting it out there. Okay. I am no longer in the closet. All right. If the devil came up to me and said you can knock 10 years off your lifespan for buns of steel and a six pack, it's where do I sign? And I'll be waving this outside most exercise classes saying, boys, you might want to get in on this. And I will spend nearly all of my residual lifespan flexing in the mirror. Okay.
Dr Rupy: Six conditions cause the majority of deaths in the world. These include dementia and cardiovascular disease. And traditionally, we've looked at these conditions through the lens of what goes wrong individually, such as blocked arteries on the heart or tangles of protein that impair electrical signalling in the brain. But the common denominator is actually ageing. And as grandiose and as esoteric as that sounds, ageing and the processes that govern ageing are what we need to be tackling if we want to better manage or even prevent these conditions of older age. And with me to discuss why and how we age is Richard Farager. He's professor of biological gerontology at the University of Brighton and has dedicated his career to understanding the ageing process and what we can do to improve this inevitable phase of life. And as you can tell from today's episode, Richard is a passionate advocate for older people and can wax lyrical about the history of the gerontology field. I think it would be important to go through a few definitions before we dive into the episode that will be helpful for folks who are new to the research. Now, there are agreed what we call hallmarks of ageing that are descriptions of processes such as metabolism that can go wrong and DNA repair functions. These can go awry as we grow older. Ageing is caused by these changes at the molecular level that can lead to downstream effects like disease and degeneration. Cell senescence is what happens at the end of a cell's lifespan where they become dysfunctional and they essentially need to be removed by your immune cells. However, in older age, it can become more troublesome for your immune system to clear away these senescent cells and increasing inflammation ensues. Senolytics are compounds or drugs that have been designed to selectively eliminate these senescent cells and the hope is that they can mitigate a range of age-associated conditions like arthritis, cataracts, dementia, and even more. Now, we are going to discuss senescent cells in a lot of detail and at one point, Professor Farager uses quite a graphic analogy for senescent cells using suicide, so I just want to give anyone a heads up who might be triggered or find that analogy uncomfortable. We also talk about the use of food and lifestyle and things that you can do today to prevent the ageing process. And one of the things that he said very nicely was that most of the foods and the fruits and vegetables that I use in my cookbooks are going to be key to healthy ageing. And if you're interested in recipes that are geared towards keeping you healthy and fit, you should definitely check out the doctorskitchen.com and the Doctor's Kitchen app. We have put so much effort into ensuring that you can find recipes that fit your needs, that fit your dietary requirements, your preferences, and recipes that your family will love to keep everyone in the household fit and fighting in their older years. And one of the best features and one of the features that we're most proud of at the Doctor's Kitchen is the ability to just type in a recipe ingredient, sorry, an ingredient, and you'll be given lots of recipes. We have hundreds to choose from that you can pull out of your fridge or pull out of your pantry easily. We don't use any weird ingredients and if we do use some unfamiliar ingredients, we always provide swaps as well. People are absolutely loving the app and I'm sure you will too. There is a free trial if you want to check it out for free, no questions asked. You can check it out at the Doctor's Kitchen. And remember, you can also watch this episode of the Doctor's Kitchen podcast on YouTube. Just go to YouTube, type in Doctor's Kitchen and you'll be able to see me and Professor Farager wax lyrical about everything to do with ageing. He is a real bundle of energy and I really had a great time chatting to him. So without further delay, please enjoy my conversation with Professor Richard Farager.
Dr Rupy: Professor, I've got a really important question to ask you right at the start of this. Is ageing spelt with or without an E?
Professor Richard Farager: If you're an American, it's agging, and if you're British, it's ageing, as God intended.
Dr Rupy: I'm glad I've clarified that because I've seen it spelt, you know, on papers and different ways and I'm always wondering which is the way that I should be spelling it.
Professor Richard Farager: I think possibly the biggest boob of the British Medical Journal many years ago was to omit the E in ageing. And as far as I and some of my peers were concerned, the abomination of desolation was in the holy place. So, yeah, it it's it's a bit like colour or harbour.
Dr Rupy: Yeah, yeah, yeah, yeah. Always with the U. Um, great. Why don't we kick off this conversation with the why and the how? So, why in your opinion or, you know, from from your your studies, why do we age?
Professor Richard Farager: There's something of a consensus about why we age now. And in order to try and do this, it's worthwhile providing some context. Ageing probably evolved at least a billion years ago. So it's very old. And there are also some species that do not age. By which I mean, if you are a member of an ageing species, your chance of death increases exponentially every year. All right? If you are a member of a non-ageing species, you have a low chance of death and it doesn't rise. So, if anybody who's listening has ever had clam chowder, they've eaten, then you have eaten a non-ageing organism. Arctica islandica, the clams in your bowl of clam chowder were probably older than you are. And the oldest Arctica are so old that Shakespeare could have had them in a bowl of stew. And these are quite complicated animals. You know, you've got muscles, they have a nervous system. And you could say that everything we do in the field of the biology of ageing is really breakable down into two things. Trying to understand why some species, or most species, show this exponential increase in the chance of dying or getting sick. And any theory that purports to explain that also needs to explain why you see exceptions like Arctica, and there are several other species that I'm sure people will have heard of. And so, the best way to think about it is actually the way the early evolutionary biologists did. The the best entry point is a gentleman, a very famous British scientist, Peter Medawar. And what Medawar said was, if you look in the wild, what we call extrinsic mortality is very, very high. That's not dying from inside, you know, being predated, falling off a cliff, this sort of thing. And so Medawar did a little thought experiment where he said, consider a population of organisms that will not die from inside. They can be killed, but otherwise they will just go on and on and on. If you follow them over time, you will be able to pick up a death rate of those organisms. And by an analogy that he used was actually coffee cups or glasses. And there is a paper from the 1950s that measures the death rate of glasses in an American university canteen. It bids fair to be the most boring paper written by anyone on anything, but it establishes the point and the crucial distinction that hardened glasses have a lower death rate than unhardened ones. But it shows that, you know, in things that will not die from inside, you see this death rate. And so Medawar said, let's consider a cohort that have been around for say a year, where there may have been a hundred of them, but there's only one left. And now the new cohort, some eggs have hatched and we've got a hundred of those. And we let those two cohorts reproduce. You will always get more offspring from the newly emerged cohort rather than the old one. Not because there's anything wrong with our glass here. He's plugging away with the best of them, but all on its lonesome. And so you always get less offspring from organisms that have been around a long time because you've seen this culling. And so, and this is known in the jargon as the declining force of natural selection with time, which as an undergraduate was a phrase I shook my head at and could not understand at all. Um, and it part of the reason I labour the explanation was because it took me so long to get it. And so what Medawar said, and it's remarkably prescient given that he's working in the 50s, was, imagine that in these creatures, mutations develop that will kill the organism, but won't kill it until after the point in time at which it's reproduced. Said, natural selection can't remove this because all that natural selection really measures is number of offspring. And he ran with this and said, maybe what we see as ageing is just the accumulation of all of these what are called fitness neutral mutations that can't be weeded out. And one of the things that fascinates me is that I actually carry one of these. I I found a few years ago that I carry a quite common mutation that predisposes me to high blood pressure in mid-late life. It is completely environmentally insensitive. And during the time in which I would have been alive in the wild, to say, I've I've lived with some of the last hunter gatherers on earth, the Hadza in Tanzania. And there, about half the Hadza are dead by the age of 40. So I would have, I would actually was mapping my own life history onto that while I was there. I would have died of appendicitis at the age of 14, had I been born with the Hadza. You would never have seen the effect of that mutation.
Dr Rupy: Yeah, because we were talking about that just before we started recording. I don't think many people appreciate the the survival rate of the Hadza. Everyone sort of talks about the Hadza from the perspective of their diverse microbiome, you know, how it's untouched by external pharmaceuticals and how it's rich with diversity and this is what we should be aiming for. But actually, if you're looking at survival, they're not faring too great, are they?
Professor Richard Farager: Well, if you look, I mean, and the story is, I think, the same across the piece for most modern hunter gatherer groups. Now, you have to be a little bit careful. A modern hunter gatherer group is not a living fossil. But they are the closest examples we have culturally and physiologically to the way in which early humans would have lived. And what you can see from memory with the Hadza is one in five babies die before they reach their first year. Um, at least a third of people are dead by 14. And one of the things that entertains me is, you know, I am the man because Hadza names are quite difficult to pronounce if you're a Westerner. And Western names aren't exactly easy if you're Hadzabe. And so you're looking at the man they nicknamed Baboon Ninja. Now, Ninja is what happens when you mix a modern hunter gatherer culture with pop culture. And Baboon means granddad. And that's because I'm in my early to mid 50s. And I was with perhaps one exception, the oldest person they'd seen. And so that's what extrinsic mortality looks like. And so of course, the mutation I'm carrying would never have come into play. Now, so one reason why we age is this accumulation of fitness neutral mutations. A couple of years after Medawar, a gentleman called George Williams took this idea, kind of flipped it round and put it on steroids and said, imagine in the situation of very high extrinsic mortality, predation and accidents, you have a mutation emerge that makes you better at having offspring. That will not just coast, that will be really heavily selected for. And it will be selected for even if it is associated with bad stuff happening later on. Because for most organisms, there is no later on. And so, I am kind of a mixture of those two things, as are you, because this what I've just given you is a very good example of something that I work on called cell senescence. Um, and in every species that we've looked at, ageing evolved through a mixture of these two processes. The same theory allows for the evolution of non-ageing, the organisms like the clams, under very specific circumstances. The simplest explanation is, if you get better at making offspring, the longer you are around, then any selection early on in the life course is is pretty small. And so that at least opens the door to that going on. There are things we don't understand, but that's basically the why.
Dr Rupy: Okay. So, what I'm hearing, and forgive me for summarizing, uh, what is quite complicated, natural selection doesn't really care about your long-term survival. It's purely optimising for reproduction. As long as you get to a reproductive age and you pass on your genes, you create offspring, thereafter, it doesn't really care about, um, extension of life. Is that, have I summarized that?
Professor Richard Farager: That's all natural selection measures is a trait we call fitness. And fitness is a combination of two things, the capacity to survive and the capacity to reproduce.
Dr Rupy: Okay. Okay. All right. That's that's clear in my head now. You mentioned cell senescence. Why don't we clarify what that means? Because I think people have heard about cell senescence in the context of these compounds called senolytics that are going to help them live forever. That's what you're hearing, uh, at least if you're getting the adverts on Instagram and Meta. Um, what what do we mean by cell senescence?
Professor Richard Farager: I mean, I I would preface that. I always end up, as I was saying, I I seem to get kind of two responses rarely if I'm talking to a general audience. One is I'll we'll finish a chat like this and somebody will turn around and say, I don't want to live forever. And I always say, that's great because you don't have the option. And they always get angry. And I don't know why. You know, I I liken it on occasion to imagine I'm a waiter and I wander over to you and show you the menu. And you turn around and say, I don't like oysters. And you say, well, you're in luck, sir, because oysters are off today. You then bang the table, demand I convince you that oysters are food of the gods, and then get upset because you can't have some. So on the one hand, I get that. I also occasionally get the, you know, I want to live forever. And my response is always, have you considered the fact that forever is a bugger of a long time? In fact, you know, an argument can be made that it's the longest time there is. This isn't a long time as you and I can't time. You know, the the universe is predicted to come to an end, I think in, I forget whether it's about three or five G-class stellar lifetimes. Oh gosh, right. So, yeah, that that is a long time. You know, a long time as solar systems count time. You know, and and if in fact what you mean is I don't want to die, then I think we're all kind of in that boat. So, what then with that kind of clearing of the decks is cell senescence? And the story is really interesting because the fun thing about being interested in ageing as a process is you don't need a huge amount of starting information to ask really profound questions about it. And I have often started to think as I've got older that the more obscure the answer you get from somebody, the less likely they are to actually have ever thought about the larger question. And one of the largest questions you can think about in cell biology or cell physiology, how tissues and cells work, is, is the base setting of cells to divide forever or to have limits to division? Because you can see, depending on how you've set that up, that will have profound implications for lots of physiology and lots of pathology. So, if the, you know, if the ground state of cells is that there are no limits to division, what are tumours? You then have to, your whole sense of what a cancer is would be very different. And really until the 1950s, the idea that was going around was that the base setting of cells was to grow forever. And the reason for this is kind of historical. Tissue culture, which is of course how you would kind of test these things, was extremely difficult to do. Very few labs could do it. So effectively, you're trying to grow sterile populations of cells in a world without antibiotics and sometimes without electric light. And so it was difficult to duplicate this stuff. It was hard enough to get it to work at all. And really, the seminal name in, I would argue, cell biology and certainly in ageing is a gentleman who recently died, Leonard Hayflick. And Len Hayflick had a job, which was he was to make normal populations of human cells in which you could grow vaccines because there was a and intention to clean up the vaccine production pipeline for the United States. Previously, animal cell populations had been used and there were valid concerns about animal viruses getting into the human population. And so Hayflick took cells from the human fetus. And the reason fetal tissue was used was it was assumed that the fetus would be shielded by the mother's immune system. Um, and what happened was he tried to get them to grow forever as the established doctrine said they would, and they resolutely refused to do it. And Len did a whole series of experiments which showed that this wasn't bad tissue culture technique or the medium was missing things. And the simplest one that everybody can understand is he took male cells that had stopped growing and female cells that could still grow, and female or female cells that had stopped growing and male cells that could still grow, mixed them together and just looked at the proportion that had a Y chromosome, which you could stain for. And what you saw was the cells that could still grow would continue to grow, whereas the ones that had stopped growing were resolutely non-growing in the same dish, with the same medium, in the same chamber. And so this is intrinsic to the cells. And he realized that what he'd found were fundamental limits, which he called cell senescence. And he realized, I think, also two things. The first one was that this dramatically simplified the then current understanding of cancer. Because if there are finite limits to division, it's easy to see that a lot of cancers will have arisen by escaping those limits by mutation. And the other thing that he realized was, if there were finite limits to division and cell replication, those limits had the potential to play a role in ageing. And so that's what I think probably made him pick the term cell senescence. It's an unfortunate term, but it's stuck. Um, you know, it's open to multiple meanings, but no more so than the word bark and bark. You know, tree barks and dogs are very different. Um, and so long as we're clear which one we're talking about, it it doesn't matter too much. And a lot of my work personally has been on this process. And to cut a long story short, the way in which we think it causes ageing is this. The normal course of your life, you lose cells. That loss is balanced by cell division. Cell division is actively monitored as an anti-cancer mechanism because you pick up most of the damage to your DNA when your cells are dividing. Most and most of the time in most of your tissues, your cells aren't dividing all the time. Okay? But so when you do decide to go into cell division, you need to keep a very close eye on it. After a number of divisions, and a lot of human tissues, for example, cells from human tissues, um, the number of divisions is monitored by the shortening of the ends of chromosomes or the telomeres, which some people may have heard of. After a variable number of divisions, exit from the cell cycle is signalled. That cell will never divide again. And the cell then takes on a very different set of behaviours. It changes as profoundly as say a white blood cell changing into a liver cell. And what it does are a range of things, but the ones that are most interesting from our point of view is, first of all, the cell will never divide again. And secondly, it starts to throw out a whole lot of inflammatory agents and agents that break down collagen or extracellular matrix. And we used to joke in the lab and call this the Lord of the Rings hypothesis. Why does it do this? You know, if you remember the Lord of the Rings, Gandalf says to Frodo, remember Frodo, the ring wants to be found. Senescent cells want to be found, which is why they're doing this. So they're a little bit like, I don't know, a man who's decided to commit suicide but in a very peculiar way. He gets into a rowing boat and rows out into shark infested waters. He then slashes his arm and puts it in the water, and then uses the knife to punch a hole in the boat. The blood in the water are the pro-inflammatory proteins, and the knife in the bottom of the boat are the enzymes that break down collagen. Why? The pro-inflammatory cytokines attract immune cells, particularly the NK cells, the natural killers, and punching the hole in the collagen allows them to get to where they're needed to kill the cell. Now, this should work perfectly. The problem is your immune system is made of cells and it is ageing. And so if you're in your early 20s, almost certainly as soon as you make a senescent cell, it's cleared. By the time you're my age, it's more like being on the phone to the car insurance company. You know, we are experiencing an extremely high call volume. Please stay on the line. And the number of callers builds up. And what you see is something that I'm sure will be familiar to to listeners, which is you see this increased grumbling low-grade inflammation. There are other problems as well. For example, my laboratory showed some years ago that when vascular smooth muscle cells become senescent, they forget they are vascular smooth muscle cells that are forming the outer layer of your blood vessels. They think they're bone cells. And so they throw out these inflammatory molecules, but they also start busily building little bits of bone in your blood vessels, things called vascular calcifications. And as you you know, you really want a blood vessel to be a nice kind of springy little rubber pipe. What you don't want are lumps of concrete in there. And there's a number of different tissue specific problems that can start to emerge. How do we know that this isn't a just so story? And there's a number of pieces of evidence. If you look in mice, calorie restriction, which is feeding the animal a diet complete in all regards, but rather deficient in calories, restriction typically to 60% of what we call basal metabolic rate, reduces the rate at which senescent cells appear. Long-lived mice have lower numbers of senescent cells and they are less inflamed. I work on a very rare human genetic disease called Werner syndrome, which is characterized by the accelerated senescence of cells from some tissues but not others. If you are unfortunate enough to have Werner syndrome, then that will knock the best part of 40 years off your life expectancy, and you will start to show a range of age-related problems, cardiovascular disease, for example, you'll start to show diabetes, things like this, osteoporosis. And probably the experiment that launched an entire field, very, very interesting work from Jim Kirkland and Jan van Deursen and Darren Baker, which is if you make transgenic animals, and these are mice that are made from a single cell, carrying a very clever what we call genetic construct, you can directly test the effect senescent cells have. And the construct is really easy to understand. It just has a piece of DNA at the front that turns on any genes behind it when the cell becomes senescent. So, every time a cell goes senescent, this construct snaps on. And what does it, behind it is a gene that will kill the cell, but only when you add an external trigger. One of the easiest ones to understand is actually a construct that does this. And so in mice, it then these senescent cells then start expressing the receptor for diphtheria toxin. Mice can't get diphtheria because they don't have the receptor for this toxin, humans do. And if you then put diphtheria toxin in the mouse's drinking water, only those senescent cells will die. Another one uses the common reagent that we have in medicines for cold sores, drug called ganciclovir. And so you can do two kinds of experiments with these special little mice. And the one you like most is an almost perfect function of how old you are, I've found. You can remove senescent cells throughout the lifespan. You can let the animal fill up with senescent cells, then delete them and see what happens. And in both cases, you get improved health, which is the key thing. And because the animals are much healthier, they live longer. They can live up to 35, 36% longer, depending on sex and genetic background. And there's loads of data I could cite, but the data I like most are voluntary wheel running. These mice will run about twice as far and about twice as long as their littermates who haven't had the senescent cells removed. And they are running because they're just enjoying life. And if anybody doesn't believe me, I would urge them to find what I think is one of the most fun scientific papers ever published, having mentioned one of the most boring ones, which is it's in the proceedings of the Royal Society B, and it's a group of researchers who went to pet shops and got those wheels you have for your hamster and just put them outdoors and had them with camera traps. And wild mice will take time off from foraging for food to have a run on the wheel. So when you, if you own a hamster or a mouse and it's running on its wheel, it isn't bored. It's this is as good as life gets if you're a rodent. And so the holy grail with things like senolytics is can we do for our older people what we're doing with those mice? And I think there's every chance.
Dr Rupy: Okay. I want to bring the listener and anchor them back to cell senescence. So this is around the fundamental limits to cell division. When you reach that fundamental limit, that's where things break down, like that graphic image of the person going out in the canoe, breaking down the canoe, and also signalling via the blood leaking into the shark infested water. That's all the inflammation spilling out. This is the cellular picture, if you like, of what's going on with the cell senescence. And when that occurs in a young person, they have the immune system that enables them to clear that senescent cell efficiently, so they don't hang around causing this inflammation or inflammaging. Whereas an older person whose immune system isn't as robust, can't clear those cells, those senescent cells as effectively, hence they have an accumulation of inflammation, just like the call centre and you you got the backlog of.
Professor Richard Farager: That's absolutely right. You don't need me.
Dr Rupy: I just wanted to re because those are some fantastic analogies around cell senescence that I haven't heard before and that that's that's brilliant. I love the honesty. I love the honesty. But you know, I think one of the things we should realize is people do train for an aesthetic and that can lead to overtraining. But carrying too much, you know, carrying excess weight can lead to an inflammatory burden. So that kind of needs to be cleared. But again, one of the things that matters when we talk about dose of exercise and things like that is everybody's motivation isn't the same and everybody's responses aren't the same. And the reason I I pick myself is, you know, I was lying in a hotel bedroom in New York one day, staring despairingly and thinking, why don't I look like Captain America? And rather than the obvious answer, which is if the actor concerned hadn't spent like 10 years being shouted at and living on a diet of chicken, he wouldn't look like Captain America either. And in despair, I turned to a professor of exercise physiology. And she said, have you considered the fact you might be a non-responder? And this is very important for people. So, if you look across the population, if you took say 100 people and you put them on a 12-week fitness class and you measured one measure of physical fitness we call VO2 max, okay, it's a nice measure of your aerobic capacity. About a third of those folk will over respond. A third will be kind of on point and a third will under respond. But the guys who under respond still get the health benefits. So this is a big problem because imagine, you know, us two of us and we're both untrained. After 12 weeks, you look like Captain America and I look like me. I am very likely to say, oh, you know, I'm out of here. Whereas if you can turn around and say, look, you're still getting the health benefits. And if you make any improvement at all, that's massive. Management of expectations really, really helps people. And one of the things that I look, I see, but and we are I think we're starting to do this, sequencing genomes, looking at different sub-populations. One paper I'm very fond of is just looking at the differences between weight loss on a high low fat versus a low carb diet. You can tie this down to three or four genetic variations. The simplest to understand is a transporter that moves fat across the gut. It comes in a variety of flavours, but the easiest ones to understand is some people have a very efficient transporter, some people don't. So if you have a very efficient transporter, you're shuttling fat across your gut very easily. That means you're getting a lot of energy from it. So if we turn down the fat, that will turn down the calories. Imagine you're carrying the low activity form. You're probably not getting much energy from fat anyway. Turn down the carbs and boom. And the difference isn't big, it's about twofold. But imagine it's the difference between losing a kilogram and losing almost nothing. You'll sit there, you're going to try and you're going to stick in if you can make big gains towards getting what you want early. And I think this is a really helpful thing for people to think about themselves. So in that sense, it's with exercise, just do whatever you can. The effects from the cyclist say it's got to be quite a high dose relative to what people can put in, but anything will help and it's really quite open.
Dr Rupy: Yeah, I'm glad we double clicked on exercise because not only did I get an insight into how you exercise, but also I think the non-responder element is something that I haven't personally looked into myself. And particularly, you know, as people are becoming a lot more data driven and metric orientated, if you're not seeing those numbers improve, like your VO2 max or your ability to do zone two for long periods of time at a high wattage on a bike, for example, it can be quite disparaging. But the fact that you're doing something consistently is what's most important.
Professor Richard Farager: Yeah. The the most, the key thing, I mean, there's there's two things that kind of need to be passed out. And there are no right. It's what are you exercising for? When and you can lie to other people, but please don't lie to yourself. If you're exercising for the aesthetic, then that's fine. Okay? If you're exercising for health benefits, then um, you will get those. You, you know, um, and this will have, you know, this will have important effects on on motivation because the job, I think, your job in terms of, you know, incorporating fitness and lifestyle stuff into your average working life is, what am I looking for and how many hours am I willing to invest? I mean, with any of these kind of, you know, you you mentioned all the various, you know, wonderful pills and potions that come up. I always apply what I call the the gym membership test, which is, am I going to get more out of magic potion X, even if it works, than a gym membership? Because and there's a significant social element to that. It gets you out, it gets you moving, those sorts of things. But I think it provide, you know, and if I'm not willing to pay for a gym membership, why would I be willing to pay for that? You know. Um, and so I think it's, you know, I I'm very keen, you know, I'm I'm I like the healthy longevity elements of things, but I'm also a great believer that an extra two weeks living in a care home is not worth a lifetime without a bacon sandwich. You know, there there are, I think there is a question about what you can reasonably expect of yourself and for why. Because, you know, imagine that you're desperately doing all these things and it's making you miserable. That means that you were miserable for most of your life. And I fail to see that as a positive outcome, you know.
Dr Rupy: Yeah, yeah, yeah. Yeah, yeah. Yeah, it's a very, very important point. Um, let's move on to diet, uh, because obviously this is the Doctor's Kitchen podcast. Everyone's interested in diet and ingredients and and perhaps we could talk more holistically a little bit later on about what you refer to earlier as calorie restriction. But yeah, are there any diet and longevity diets?
Professor Richard Farager: I mean, there's some very interesting, provocative stuff. There there's some very, very interesting, provocative studies. Everybody focuses on calorie restriction. And I always remember it was a lovely thing because I I know, I'm not going to name names, but I have a huge amount of respect for one of the calorie restriction researchers in the US. And he was very good friends with a gentleman who tragically is no longer with us, um, Jim Joseph. And Jim Joseph is the man who first demonstrated the potential benefits of blueberries. And Jim was interested in an area which then was niche, but I think is broadening out now, which is, okay, what different kinds of foods have these different benefits? And in one famous joke exchange, the gentleman who worked on CR said to this friend of his, you know, all you do is feed animals different food. And he looked back and made the crushing reply, all you do is take their take their food off them. And yeah, I I think that, you know, we we do need to contextualize this. In terms of calorie restriction, I think what's going on is the restriction in nutrients correlates with something we see in long-lived mutant animals. So, there are long-lived mutant animals that are healthier because they carry mutations in nutrient sensing pathways. And that's probably because at the cellular level, being anthropomorphic, the cells think there are no nutrients out there. I will recycle. And the analogy I often use is kids with Lego, if you've ever been a parent. Kids love new sets of Lego. And as long as you keep buying them, they'll keep making them. And that means your house gradually fills up with built bits of Lego. And the analogy with that in a cell is de novo or new protein synthesis is energetically cheap. If I turn off the supply of Lego, my kid can only make something new by taking old stuff apart. And that's an investment of time that my kid doesn't want to make, time and energy. And cells are the same. Recycling damaged proteins involves investment of time and energy. And so if it's coming in new, why bother? Now, imagine I've got a mutation in a nutrient sensing pathway. I think there are no nutrients out there. I will recycle. If I'm CR'd, there really are no nutrients out there. I've got to make do with what I've got. Thus far, those elements sit in quite nicely. In the other end, the Jim Joseph end of diet, it's clear, for example, that a diet rich in blueberries has very beneficial effects on the cognition, not just of older rats and mice, but of older people. The problem is, there's a paper from the Joseph lab that actually shows this. Um, and it's done in a very clever way. It has people running a maze that has been built in Minecraft, although it's written in such a colourless way that you would never um, never see this, this particular paper. And um, what I think happens therefore is, okay, what there's two things. What's going on there and how effective is this? Most of the work that I do, I would like to see benefit in the people who need it the most. The those older people who are social class D and E, they're they're my gran, salt of the earth, behind a counter, whole life, dependent on the state pension, many things wrong with her, not much income. Okay? At the other end, there are older people who are kind of like me, you know, 65 plus, their interests are their gym and their wine club and keeping up to date. And I have two of those interests and I'm not interested in keeping up to date. And folk like us are really so healthy and so well off that we should be doing a bit more to help our fellow citizens, frankly. They're my peers are not my problem. But with these folk who are kind of on the sharp end of ageing badly, turning around and saying, I think you should spend 2,000 pounds on blueberries when you're trying to choose whether you've got to have the heating on, thank you Kier Starmer, compared to getting a haircut, isn't helpful, it's actually insulting. And so, but the general thing with diet is, what is it with the blueberries? What is it with strawberries? What is it with a range of these different compounds? And what is provocative, and I use the word very advisedly, provocative, many of the compounds that we have identified that either kill senescent cells, or in the case of work from my own laboratories, safely reverse senescence, are derived from fruit and vegetables. Fisetin, a senolytic, is very heavily found in strawberries. And so, we also, linking this up to the rodent and human data, um, we know that removal of senescent astrocytes in the brains of these transgenic mice improves cognition. And maybe, and I stress maybe, what is going on is this. If you're able to eat a diet rich in fruit and vegetables, you are microdosing with senolytics and senoreverters, in amongst other bits and pieces. Are you clearing them yourself? Now, and I think the important thing to say is we don't know. But that looks plausible to me, and I think it would be very interesting to be able to take a look, because it would allow us to link together the data that we're getting from diet itself, all of these cross-cultural, nutritional studies, and the mechanisms of ageing that are coming out of a lab and saying, okay, what is it in the diet that's affecting this? You know, are there, you know, are there a bunch of senolytics that remain to be discovered? I think that the natural product area is going to be quite a happy hunting ground. Because one of the things that people I don't think realize, and it is central to some of the um, the discussions that we had earlier about hallmarks, people don't realize why plants make stuff. Okay? Um, you're an evolutionary biologist if you can look at a field of wheat from the wheat's point of view. You see the wheat as a food source. The wheat doesn't want to be eaten. And so plants incur, to to go back to where we started with this, large fitness costs in, they spend money that, you know, energy they could spend on reproducing, pumping out these chemical products. And some of these chemical products are intended to discourage the plant from you from taking a bite out the plant, like chili peppers. Others are intended to ensure that you're walking around talking to God and something else has eaten you because you decided to eat that mouldy bread. Um, so, you know, this shapes the repertoire of natural products, what they look like, as surely as a drug discovery problem does. And a lot of natural products are engaged, are have kind of been selected to engage multiple biochemical pathways quite weakly, because I don't know what's going to take a bite out of me, so I want to give it a rotten day. All right? And an example might be, for example, you've mentioned metformin. As listeners probably know, metformin is a less toxic version of a natural product called galegine. And galegine is found in goat's rue, and goat's rue is a traditional Western herbal remedy for diabetes. It's not there to fix diabetes. It's there to bung up a bunch of other stuff. And the interesting thing, this is a very live discussion within the drug discovery community at the moment, is there are different models of how we go after drugs. And one dominant orthodoxy is a good drug only targets one protein very precisely. Are we missing these products? How do we pick them up? Because it could be that something that engages, my colleague Richard Hartley at Glasgow refers to these compounds as network engaging drugs or Neds. And are we missing the Neds? And where we'll find the Neds is in the pages of your cookbook. And I'm reasonably certain of that.
