Healthy Ageing: The hype and the hope - Dame Linda Partridge - 25th March 2026

Now to the main business tonight which is uh tonight's lecture. [clears throat] Um I am absolutely delighted to invite uh Linda Partridge to give us a lecture this evening. Linda is an internationally known researcher who works on the biology of aging and in particular healthy aging which is of course a big societal concern. I won't say anything about it being a concern to those of us in the audience. Uh Linda, Linda started her research career studying uh the behavior of birds and she then moved on quite quickly uh to start studying aging. She was at the University of Edinburgh and then she moved to University College London where she became the Welen Professor. She was also the founding director of the Maxplank Institute for the Evolutionary Biology of Aging in Cologne. Now, Linda's had lots of awards and honors for her research. I'm not going to run through them. Uh she's also a fellow of the Royal Society. She's a fellow of the Academy of Medical Sciences and a fellow of the American Academy of Arts and Sciences. And she is a Dame of the British Empire. and she's cringing at that. Um, so, uh, please, uh, Linda's title of Linda's talk is healthy aging, the hype and the hope. Thank you, Linda. >> Thank you very much, Pat, for a nice introduction. And you know, it's a real honor to give a lecture to the Royal Philosophical Society. Thank you very very much for inviting me. So I thought I'd start with Billy Connelly, uh, famous Glasgian, of course, um, because he really covers the two sides of what I'm going to be talking about because in many ways he's a very healthy ag. He's 83. He's enjoying life in Florida. He's a very active artist. But on the other hand, he had a brush with prostate cancer a few years ago and for many years he's been dealing with Parkinson's disease. So both of those have lowered the quality of the later part of his life. Two classic age related diseases. So the sort of thing that I do and many others including one or two people in this room I notice is to think about how we can push back the age of onset of the bad things that happen with age related diseases but also more general loss of function. Can we somehow squish that period of ill health at the end of life? So that's the name of the game and we've certainly been very good at making ourselves live longer. So this is by now a classic um illustration of the historical trend. So it started way back in the middle of the 19th century and has sort of continued to the present day. So what you've got there is life expectancy at birth. So that's the length of time that the average person is expected to live against the year in which the birth took place and it's plotted for the country that was the world leader at the time. So to start with that was mainly the Scandinavian countries. Latally it's been Japan, South Korea, um the East Asian countries and the causes have been different at different times. To start with, a lot of it was to do with infant mortality, infectious diseases, antibiotics, immunization and so on. But lately, the increase has been mainly in the older section of the population basically because of much better medical care as well as uh better living circumstances. The horizontal lines are just the predictions of various um individuals and organizations about where the trend would top out, what the intrinsic limit on human life expectancy uh would turn out to be. And it basically shot past all of them. That was the point of the publication at the time. So it's two and a half years per decade the slope of the that line six hours a day. So quite extraordinary increase in life expectancy over that period. And of course it's led to some extraordinary lifespans. I think these two are interesting. They're always women. Um on the left is the uh as far as we know the world record holder. So she was a French lady. There was a suspicion for a while that something had happened there that we know does happen in other cultures, which was that her death had been concealed and it was in fact her daughter collecting her pension. Um, but I think that one's been quashed now. Although certainly some, for example, the idea that people in Okinawa in Japan live a very long time seems to have been attributable entirely to that phenomenon. But hers seems to be a genuine uh record. So, she made 122 and a half. And the lady on the right is the oldest living person at the moment. Um, she's actually English. Um, she was an Opair in Hong Kong and she attributed her long life um to never getting into arguments with anyone. She says, "I just listen and then I do what I want." And also having an optimistic attitude. She actually survived COVID when she was 110. So really quite remarkable. Carmel I think is is even more mysterious with that great record. She smoked until she was 117. So and that's quite true of these extraordinary centinarians and super centinarians. It's not obvious from their lifestyle uh why it's them. But clearly this is you really something to celebrate. We've improved our living circumstances over this very long period. So, we're staying healthier at a given age and we're living longer. Very positive feature of civilization. But if we look a bit more closely, there are some wrinkles and and you know, granularity makes the picture a bit less pretty. So, I've been looking for some of the statistics in Scotland. And these are the very recent figures uh for life expectancy. This is from Scottish government uh records. So this is between 2000 and 2022 on the right. Again, it's life expectancy for women and for men. So the women in yellow, the the higher line. So everywhere women live longer than men do. That that's a global uh phenomenon, but they're not healthy extra years. So women have a longer period of ill health and loss of function at the end of life than men do generally. And also if you look at the trend here uh what you can uh see is that the early part up until about 2010 you see the increase continuing but then it plateaus before co and it hasn't recovered and if anything it's actually coming down again now in both sexes and also healthy life expectancy in Scotland has actually declined since 2014. So that's defined as the age at which the first age- related disease occurs. So it's the dis age related disease-free period of life and that has decreased steadily um since 2014. So what's happened as lifespan has increased is really illustrated by these figures which is you know although we're living longer actually that period of ill health at end of life is getting longer as well. And the big picture here of course is one of um degrees of social deprivation. It's really socioeconomic uh this kind of trend. Um so again these are figures for Scotland. And what's shown here is life expectancy for the most second most and second least and least deprived areas of Scotland. This is actually rather coarse. I'll show you in a minute. These are quite quite large areas. But what you can see is the very clear relationship. something like five or six years of life expectancy difference between the most socially deprived and least socially deprived areas of the country. This was how they actually cut the cake in into different areas. If you actually look um more fine grains, this is typical in London as well over very short distances, you can get huge variation in the life expectancy of the people living there. So this is really the the one of the huge things that needs to be tackled if we want to improve people's health as they age. But however you look at it, we're living much much longer than we did in our evolutionary past. And that means that natural selection hasn't had a chance to mold the later parts of life. We've basically evolved to function well when we're young, but not as we get older because natural selection hasn't had a chance to modulate things later in life. And that's why we see this late life loss of function. It's because of the huge increase in life expectancy. And what that means is that we're starting to see this incidence steady increasing incidence of age related diseases. And I can illustrate that with some work that was done recently recently at UCL. Um this is actually looking at national health service records primary and secondary care so hospital admissions as well as GPS. And the two people who did this um Val Khan um extraordinary person she did a degree in maths. She then became an actuary um got bored with that. So became a trader on the stock market floor. Um decided she didn't much like that. So she trained as a medic and became a GP. And by the time I got to know her, she was doing a PhD on these National Health Service data. She's actually now a GP in New Zealand. So extraordinary um life story, but she analyzed three million national health records. And what she asked was which diseases how many diseases are age related in their instance. So she looked at these 278 high burden diseases ones where a lot of people get them and simply looked at the rate of instance and how it changed with age. So incidence is the first occurrence in someone's life of the disease. And she came up with these nine clusters. So when she looked at the instance rates, they fell quite naturally into these nine different patterns. And you can see that the first four of them, the three at the top and then the left hand one in the next row, they're all age related. So they basically progressively younger incidents as you go through the four groups, but all of them uh go up in instance with age. So the first group, which really only comes on very late, hardly has any diseases in it. So um delirium, hip fracture are in there. Uh cluster two actually is u mainly cardiovascular disease pretty late onset generally. Uh cluster three most cancers are in cluster three and four is a bit hetogeneous um but there are a lot of digestive disorders in there for instance and those three between them account for 207 diseases. So 207 of these 278 are age related in instance. So advancing age really is the major risk factor for most diseases. And what that also means is that you start to see a lot of people who've got more than one disease which is called multimorbidity. Um these are actually data for Scotland because they illustrate it um particularly well. These are data for men. um women look pretty similar and it's a pretty general picture um for other places. So again as you go through advancing ages uh what you see is that so for instance by the time you get to 70 uh most people have got at least three diseases and almost nobody is disease-free at that age. And multimorbidity is complicated because often there are conflicting requirements for treating uh different conditions and also you start to see interactions between drugs and so on. So it's a real challenge often to treat multimorbidity. So what this means is that the major burden of ill health in our society is falling on the older section of the population and there really is a global challenge to try to do something about it. And what we would like to do, as I've mentioned, we've seen this big increase in lifespan. We've got the unhealthy period at the end of life. And as we've increased lifespan, we've actually also increased the unhealthy period. So health span has increased, but not as much as lifespan. And we're seeing this longer period of ill health. But what we'd like to do is this. We'd like to have the increased lifespan but with a squish of that red period at the end of life. So is that even a realistic goal? I think it's important to realize how malleable aging actually is. So there are some creatures that don't age at all. Um these are three of them. Um we've got a sea anemone on the left. um little freshwater hydra in the middle and a plenarian worm on the right. And as far as anyone can see, they don't get any more likely to die or any less able to reproduce as they go through their lives. They just flatline the whole way through. And an interesting thing about them is that they are more or less bags of stem cells, these dividing cells that can regenerate. They have great powers of regeneration these animals. And the stem cells can also give rise to the germ line, the sperm and the eggs when they reproduce. So they've got an evolutionary future. And this may be the key to why these things don't age at all. But there are clear existence proof that aging doesn't have to happen. And also if we look more broadly out there in nature, there are some amazing lifespans that seem to be independent of other characteristics. aging seems to be um a feature that can evolve to different values. So I think the bowhead whale is the um mamalian record holder at 200 years. Of course it's it's very big. So you might say well of course it's long lived because it's big but very small things can live a long time too. So if you look at the bottom row uh the ocean quah hook little balve molllesk it can make 500 years. Naked mole rat is a rodent. Very interesting social life. And it's about intermediate in size between a mouse and a rat. They can live 30 years whereas a mouse can only live three. And this little branch bat I find the most amazing. Um you can see it's just sitting on the tip of someone's finger. It only weighs 8 g and it can live nearly 40 years. So you've got aging here evolving quite independently of body size. I just put the Greenland shark up because it's just it's such a crazy creature and it lives quite deep in the Atlantic. It can live for 400 years and it doesn't even start reproducing until it's 150. So, it wouldn't make a great fishery. Um, but clearly you've got aging, the rate of aging evolving out there quite um independently of other characteristics. And these differences are genetic. somehow these different rates of aging are being encoded in the genomes of these different creatures. So an obvious way into looking at you know what we can do about aging is is to think about the genetics. Can we find some of the genes that actually influence the rate of aging? There are some genes in humans that do the opposite. These are the um premature aging system syndromes. Motively they're extremely rare but they do actually tell us something about mechanisms of aging. So these are the two main ones. Um Hutchin Hutchinson uh Guilford pgeria on the left is the most extreme. So the children are born ostensibly completely normal but at the age of about 18 months or two years they start to um show the symptoms you start to see loss of hair um loss of subcutaneous fat. Those are the obvious um superficial things. and they generally go through to about 13 years of age. Um and as I say mercifully it is extremely rare. Verus syndrome um is less extreme. It has an onset in the teenage years and usually they they make about 50 years of age and the Hutchinson Guilford children um get cardiovascular disease. Veres syndrome get uh both uh cardiovascular disease and cancer. Those are the main causes of death. And eventually the single genes that were mutated in both of these diseases were identified and interestingly they're both to do with maintaining the fidelity of the genetic material. So Hutchinson Guilford that the gene actually encodes a protein that's present in the nuclear envelope and it's very important for maintaining the structure of the nucleus and the arrangement of the genome in the nucleus. And that seems to be what goes goes wrong in that syndrome. And in Vera syndrome, it's actually something called a DNA helilicase. It's a molecule that's involved in um replicating the genetic material. And when it's mutated, um there are mistakes in the way that the DNA is copied. So I think that's telling us that it's very important to maintain the fidelity of the genetic material if you want to age healthily. But of course ideally what we'd like to find is mutations that improve health during aging not that uh make it worse. And for that really this cast of characters have have been the key. So these are the uh laboratory model organisms sure familiar to many of you but we're talking about yeast um the neode worm at the top right cenorabditis elegant uh my own favorite organism drosopha down in the bottom left and also the mouse and they've really been um engines of uh discovery of mechanisms in biology. um things like how the gene uh genetic material is replicated, how it's expressed, how the nervous system works, how metabolism works, they've all been discovered using these organisms and it works because of the very strong evolutionary conservation of this kind of biology across big evolutionary distances. But I think people thought, well, is that going to work for aging? These things live very different lengths of time from each other. Um the worm lives about 3 weeks, fly about 3 months, mouse about three years and they face very different kinds of challenges as they go through their lives. Fortunately all those worries turned out to be unnecessary and the track really started here uh with work on the worm senior abdabitis eleans. So this was a very famous experiment uh by Cynthia Kenyon which really kicked off a lot of the modern science of aging and what she did was a very simple mutagenesis experiment and she said can I isolate a genetic strain of worms that lives longer than the normal wild type worm and you can see it here with the black dot so this is a survival curve now we're looking at the number of worms alive as they go through their lives at different ages and you can see that the mutants living much much longer than the wild type and very importantly they were still wriggling around and healthy looking long after the controls were dead. It was certain it was not just an extension of the morand period at the end of life. So that was in itself quite a dramatic uh finding at the time but it took quite a long time to figure out uh what this actually was and it turned out to be a mutation in the single worm insulin insulin like growth factor receptor. So this is a molecule that sits in the uh membranes of the cells and responds to insulin or to growth factors at the time much better known in mammals insulin because of the whole role in diabetes. um insulin like growth factor because of the role in growth and wound healing. And I think nobody even suspected it would be present in worms at all. But it turns out that just mutating tamping down the activity of this receptor improves the health of the worms during aging and makes them live longer. And quite interestingly also there are number of worm genetic models of human age related diseases. So neurodeeneration, cancer and so on. And it turns out that these mutants if you combine them with the disease mutants can often rescue a lot of the pathology. So this was one experiment that was done uh with sea elegans. So this is actually an Alzheimer's disease worm. So it's expressing one of the proteins that's important in Alzheimer's disease but in the body wall muscles. And you can see that it induces a sort of paralysis. The whole of the back end is paralyzed and there's just this rather feeble uh moving around at the front end. But if you combine that now with that DAFF 2 mutant that I've just shown you, you get a nice healthy worm again. And this is also true with worm models of cancer. So th this mutant is really powerful. It can improve the health of the wild type worm and rescue this disease pathology. So just what the world needs a really healthy worm. But happily it turned out to be evolutionarily conserved. So first of all people looked at Drosophila uh when the whole pathway came to light there and then eventually in the mouse. So these are mutants in the fly and the mouse that are very closely related to that worm mutant and you can see the nice extension of lifespan and just as in the worm they could often rescue disease related pathology and in the mouse there was a very uh thorough look at the phenotyping and I think what was really surprising about this story was the very broad spectrum improvement in health in different systems. So they had better glucose homeostasis, better immune profile and I should say the person who did this work sitting in the room Colin Salman and uh better motor function. They maintained uh their coordination better with age and they got less osteoporosis and cataract and you can see the ulcerative dermatitis on the right time mouse that's the control mouse about 40% of them got it as they went through aging. Uh the mutants were completely rescued. So I think what's really interesting here is is the broadsp spectrum improvement. And it seems that that what's happening here is that exactly what I've said about us functioning well in youth. The same is true with these animals. They're laboratory model organisms. They're living in a protected environment. They're living much longer than they do in the wild. And it turns out that this signaling system, which is what it is, works fine when they're young, but it drives too strongly at older ages when other things have started to go wrong. So if you tap down its activity, it helps. The way that this um has been followed up in humans is just by looking at natural human genetic varants. So you can look at the human equivalents of these interesting animal genes. um look for um variant sequences in them and ask if they're associated to survival to great ages in humans and there's been quite a bit of that and it really supports the idea that this whole mechanism is probably also in present in human aging. So these are just various papers that that came out on it over the years. You can see some of the titles. These are all bits of this um signaling network. Foxo3A, the top left one, is very interesting because this is a key. It's called a transcription factor. It's a molecule that turns on and off the expression of genes. Um, in the DAFF 2 mutant, when you knock down the activity of the receptor, it's activated and it turns on the expression of genes that are involved in in defense and stress resistance and so on. So in a sense what these mutants are doing is tricking the animal or the human into thinking there's a problem, there's a shortage of nutrients or there's a stress when actually everything is okay and that improves health later in life. So this is just one of the um whole mechanisms of aging that have come out in that short period since the early 90s. But there's been a huge burst of other work in parallel and that's come up with these hallmarks of aging. These are the basic mechanisms of aging that the their contribution varies between different tissues and cell types and to some extent between different types of organisms, but they're there in the aging process and they've all been shown to be causal in producing the problems. So you could actually show that interfering with them or modifying them in some way improves some aspect of health during aging. So it I think everyone thinks it probably kicks off with things going wrong with the genetic material as I've already mentioned the top three so mutations nibbling away at the end of chromosomes um the molecules that stick on to the DNA uh going wrong and that means that cells gradually lose control of their function. So the the important um aectors in cells are the proteins that whole domain starts to go down. There are mistakes in their sequences. They they form aggregates and so on. I've talked about the nutrient sensing with insulin. Uh the powerhouses of the cells the mitochondria start to malfunction. Um you get this phenomenon called cell scinessence. Basically when DNA damage happens in cells they often stop dividing. They don't die. they sit there and they spit out damaging molecules into the rest of the tissue and sometimes at a distance. Uh so they cause a problem. Stem cells don't do what they should do. They don't divide when they should or they divide uh when they shouldn't. And you also get a lot going on at the whole system level particularly immunologically. there's a major increase in inflammation during aging which is very common and also the immune system stops functioning as well as it should and they aren't independent these mechanisms but they interact with each other it's a complicated process but I think the real achievement of the last uh very few decades has been to understand these fundamental mechanisms and a lot of interest is therefore being directed now into saying well can we interfere with them uh to improve human health during aging. Um so just a couple of examples of of very recent work. Um muscle weakness, sarcopenia, it's a very important um loss of quality of life during aging. You know, it very often leads to falls and and just general lack of mobility. And there's a very nice piece of work going on at the moment from the lab of Helen Blau in the US. She's discovered an enzyme that can restore the way that the nerves communicate with the muscles, the neuro uh muscular junction and also the muscle strength and size. She's done this experimentally in mice. And that's basically acting through three of these uh mechanisms of aging particularly important stem cells and mitochondria. So you can see on the right that the neuromuscular junctions which are the yellow that they've beautifully arborized and restored uh by this enzyme and she's now in phase two clinical trials in humans uh with this enzyme. So I think that's very promising. Something else that regularly goes wrong during aging is intestinal dysfunction. The structure of the gut goes down. Um it also becomes leaky and that may be an important source of age related to inflammation. And there's a drug called rapamyin which I'll say more about later which induces a cellular cleanup process called autophagy and that turns out to be able to restore both the structure and the function of the gut and it's also looking as though it's really important in reducing age related inflammation in humans. So and there are a lot of trials going on with that drug. So I think these basic mechanisms of aging are now starting to feed through into looking at how we can interfere with them. And there's an even broader idea out there now uh which is generally known as the geroscience hypothesis because those underlying mechanisms of aging are present in the eeology of age related diseases often several age related diseases. we might be able to interfere in just one of these mechanisms of aging to prevent multiple things that go wrong later on. So the emphasis is on prevention and one into many. So as a sort of parody of current very successful medical approach, we tend to go organ by organ, disease by disease, medical speciality by medical speciality. But maybe geriatrics could develop more in into a science where we actually interfere with the mechanisms of aging to prevent diseases in several systems simultaneously as in that mutant mouse earlier on. So could that idea apply to humans? Is there any evidence at all that it might work? and it's something that we've been doing a bit of work on uh recently mainly uh using data from uh the literature and from patients. Um so these two were the ones who led the charge here. Helen's PhD student in the lab with Melena who uh specializes in computerized uh reading of the literature and what they did was to machine read uh almost two million abstracts in the biomedical literature. So that vast literature out there and what they did was to look for mentions of those 207 age related diseases which I talked about earlier from the work of Valon and a mention of the nine aging hallmarks. So they were looking for a co-occurrence in the abstract of a mention of the mechanism of aging and a mention of the disease. And that let them do for each of the nine aging hallmarks to produce a list of the 30 diseases that were most commonly mentioned in association with that hallmark. And this is what that looked like when summarized. It turned out to be actually only 83 diseases because many of the hallmarks were present in several diseases. And in the boxes here, what you have is the strength of the association between the hallmark and the disease. So dark red means mentioned together a lot. Yellow means sometimes mentioned, white means not mentioned together at all. And it's all very non non-random. Um and it made a lot of sense. So for instance, mitochondria cropped up a lot in the context of neurodeenerative disease. And we know that that's the case. So this seemed to be picking up a good strong signal. So we've now got 30 diseases that are associated with a hallmark. say stem cell exhaustion, we can actually go back and look at those medical records, the National Health Service records and say if diseases are associated with a single aging hallmark, are they also more likely to occur together in patients in multimorbidity? And the answer was yes, they are for several of the hallmarks quite remarkably. So we've got these age related diseases from from Kuran. um we take four decadal networks in the patient. So we start at age 50, late middle age and look at 50 to 60, 60 to 70 and so on. And we can make a network of the 30 diseases associated with the hallmark. So this is shown here for the 30 diseases associated with stem cell exhaustion. Um so what you've got again is the color coding the strength of the association with the hallmark and the thickness of the black line is the extent to which the diseases co- occur in patients the pairs of diseases. So thick black line means those two commonly occur together in the same patient and we can say well are these networks for the diseases associated with a hallmark stronger than we would expect by chance given the structure of the overall network. I mean clearly there's a lot of statistics in there but it can be done and it turned out that for five of the hallmarks so nutrient sensing mitochondria cellular scinessence stem cell exhaustion and altered intercellular communication the densities were higher. So what that's telling us is that there are some patients who have a predominance of mitochondrial dysfunction and so they are getting the age related diseases associated with mitochondrial dysfunction. getting them together in multicorbidity. So therefore, if we could tackle the mitochondrial dysfunction, we would take that group of diseases down simultaneously. So I think there's real promise here that we may be able to take this kind of approach to age related diseases. And of course I mentioned at the beginning the real importance of um socioeconomic situations and it seems that quite a lot of the variation between individuals here in whether they get particular sets of hallmark diseases or not is associated uh with social deprivation. Again, this is something that one can do particularly at UCL because so many of the longitudinal cohorts and including UK bio bank um are present there. Um so for this we uh collaborated with MKA who's the professor of epidemiology there and he simply looked at um in his data sets including UK bio bank whether these um hallmark related diseases were associated with particular aspects of social deprivation and what he found was that deprivation related diseases are very strongly related to these aging hallmarks much more so than ones that aren't and Again, it's the same cast of characters. Stem cell exhaustion, nutrient sensing, intercellular communication, and mitochondrial dysfunction. These seem to be the ones that are really associated with so social deprivation and therefore bring down the diseases that are associated with that mechanism. In some ways, I find that quite an optimistic bit of information because it implies that if you can interfere, you might particularly help people who are in socioeconomic bad circumstances because they're the people who are getting these hallmark related diseases. So, what interventions have we got apart from the usual diet and exercise? I should say there's a great deal of snake oil associated with this area. Um it sort of started almost immediately um in the 90s once the uh you know papers on mechanisms of aging started to reappear and one of the first appearance on the uh scene was this stuff resveratrol uh which is present in red wine and there was an almost ponzi scheme of papers talking about the wonders of this stuff. There's absolutely no solid evidence at all. And the same is true for many of the drugs that appear in in drugstores and chemists on the supplement shelf. They haven't been through clinical trials. There is no evidence at all that they help, but it's a very very profitable industry. Personally, I would never take any that has not been through a clinical trial. And the latest development is these uh longevity clinics. I'm not sure if any of you have come across them. They started in the US. They're real big business here there. Uh but they're appearing here now. They're basically for the wealthy worried well who can get everything measured. Um get told to you know eat a decent diet and take exercise and uh pay pay a lot of money for it. Um and this actually appeared in the Guardian. I think it was last week. People are turning themselves into lab rats. There's an injectable peptide craze. Well, that's really dangerous. You could just go into anaphylactic shock. So, you know, it it's amazing what people will do to themselves. And there's now this idea of biohacking where you do your own personal self treatment, decide what's wrong with you, what you're going to have, and and inject yourself with peptides. So it there there's an interesting fringe there but there's also a lot of very sensible stuff going on. Um so these were the sponsors of the standard um annual meeting aging research and drug discovery. You can see the enormous number here. Um some of them doing in silicico stuff the stuff on skin and the stuff on rejuvenation and and pushing back uh biological age in the um markers on the DNA. And a lot of this is actually financed um by extremely uh wealthy people. So for example, Altos is partly financed by Jeff Bezos u which has led to the idea in the field that we've got a new new model organism the billionaire but there's a lot of activity. I'm particularly interested in the prospect for gerrotective drugs um either existing or new drugs. I know that people often and and perfectly reasonably don't terribly like the idea of taking a drug for a disease that has not yet happened. Uh but there's plenty of evidence that it works. I mean the huge decrease in cardiovascular disease over the last decades has largely been down to drugs that lower blood pressure or statins that control the lipid uh profile in the blood. And it's been an incredibly successful campaign and millions of people are taking these drugs. So there's plenty of precedents uh for that basic approach. And our own work's been concerned with this nutrient sensing network, the whole um DAFF 2 story. Um so there it is in turquoise at the bottom of the wheel. This is just a picture of what it actually looks like in the fly. Um so we've got the receptor at the top here. So this is DAFF 2 and then a signaling cascade sort of pile of dominoes that signals down into the cell. This is fauxo. I mentioned the transcription factor that turns on uh stress resistance genes. And there's also this RAS pathway. Um terribly important in cancer. About a third of human cancers have a mutation in a RAS gene. And it's very much part of this network. And then also this talk uh complex in the center here uh which uh senses nutrients and stresses. So it's quite a complex network. And we're very interested in the idea of can we drug it uh to improve health as as are many other people. So two drugs here rapamy and tmetanib. Um tmet rapamycin disrupts this torque complex. Tmetanib inhibits this mech kynise here. So rapamy is an interesting drug. It's a natural product. It was discovered on Easter Island uh with an exped expedition there that was looking for drugs that inhibited the growth and cell division of mamalian cells. It's actually used um to uh suppress immunity at very high doses to stop kidney transplants being rejected and it's also used as a cancer chemotherapeutic um and to prevent reinosis after cardiac surgery. And um interestingly, it turns out to be gerrotective. It's the drug that's furthest down that route at the moment. So it was the first drug that was clearly shown to extend lifespan in mice. Um this was in the US as part of the intervention testing program. And you've got the survival curves of females and males exposed to increasing doses of the drug. And you can see the very nice dose dependent increase in lifespan. and it seems to interfere with multiple hallmarks of aging. It disrupts that talk one complex but with consequences for several of the other hallmarks and it's currently in several clinical trials. I mentioned this in the context of the gut structure and leakiness. Um but one of the published ones I think is very interesting. Um this is the work of Joan Manik. Older people respond poorly to immunization against flu and because of the effect of um rapamy on age related inflammation Joan decided to look at whether it could improve the response to vaccination against flu in older people. So she didn't actually use rapamy she used proprietary drugs with the same effect um because this is you know part of a pharma program. So what she did was to take people who were about to be immunized, pre-treated them with her drugs, withdrew them and allowed them to clear them and then immunized. And she found both that the direct immune response to the immunization uh was better and also there were fewer viral infections in the ensuing winter. In fact, it looked as though not only did the drug uh potentiate the effect of the vaccine, but it was also having a direct effect on viral infections because they didn't only get less flu. So, I think this was a very neat clinical trial saying that quite a short treatment with this drug can have an immediate benefit. It's actually a very interesting drug because it has really long-term effects. you can have a short treatment early in life in both flies and in mice and and see an effect much later in life on health during aging. So it looks as though it can be used in short sharp bursts which is what you want for a drug like this. Um the other drug I showed you the mech inhibitor a tmetanib that that's a standard pharma drug. was developed by GSK uh to treat malignant uh melanoma and uh we initially found that it was gerrotective in flies. It turns out also we found recently that it's geroprotective in mice. So these are two different uh doses of the drug here in females on the left, males on the right. We were being super cautious with the amount that we used. I'm sure we can go higher than this but you can see already we're seeing the increase in lifespan and because of that complicated signaling network with the RAS pathway the pathway kynis pathway talk to one and so on it's quite likely that this is a signaling network where actually more than one drug could be very useful because it would prevent the many feedback loops and also those transcription factors that the different branches talk to actually target slightly different sets of genene from each other. So we were able to look at the combination of rapamy and tmetnip in mice and the results of that are shown here and you can see that you by my standards uh this is quite a an impressive increase in lifespan in both sexes. So the orange curve here the right hand one is the two drugs when they're administered together. and looking at the we're still working on on this project but looking at what seemed to be causing it there was a very strong reduction in age related inflammation. So there was a clear immune effect as as turns up repeatedly with this drug but also at least two organs show considerably reduced incidence of tumors. So it would be very nice now to be able to push this forward into clinical trials. This type of um clinical trial in humans is not without its challenges. Um this is one that's been proposed in the US for a long time with metformin which is the first line of defense against type 2 diabetes. It's an extremely um safe drug which is taken by very large numbers of people and there are reasons for thinking it might well be gerrotective. And the important advance here was that the clinical indication was for aging. So is this is this is the FDA in the US actually allowing aging to be an outcome of a clinical trial. What that means in practice is several diseases. Uh but it's an advance to allow that. But the challenge of these trials is that even if you're repurposing an existing drug like rapamy, it's off patent and it's cheap. So nobody's going to make any money out of it. And if you're starting to use it for a new indication and especially if you're using it in older people, then it's going to have to go through clinical trials again. And if you're looking at multiple disease outcomes, it's going to be very expensive because you're going to need a lot of subjects. So really pushing this forward, I think with all those kinds of challenges, the fact that you need long-term drug treatment, a lot of individuals, you have to go through safety again because it's a different target population. you know, the regulators are going to be very interested in that and the pharmaceutical industry aren't going to touch it because they can't make any money out of it. So, you're really looking at charities and governments for this. But on the other hand, it's clear that if we could get it through the the valley of death, that the health economic benefits, even if you look at it in brute economic terms, would be enormous. And of course, in terms of individuals, it would be huge. So let's hope that is the promise and that that we can get some of these drugs into clinical trials. So to finish I think there's a real global challenge with reducing the burden of life diseases. Social deprivation the elephant in the room when it comes to this there's a opportunity to prevent multiple age related conditions simultaneously by targeting these mechanisms of aging. May many existing drugs target mechanisms of aging and show promise for repurposing and I hope one day we're going to see this broadspectctrum preventative intervention for aging. So thank you very much for listening. Okay. Uh now we have some time for questions. Uh and we have two microphones. Uh please don't ask a question without using the microphone because that means that the people who are listening online can't hear what you say. So just put your hand up if you'd like to ask a question. >> Thank you very much. Great talk. Um, from an evolutionary point of view, um, animals life has been subject to toxins and has presumably in the environment and and maybe from its own, uh, internal mechanisms for, you know, that's the way it is. Um, and have developed mechanisms for dealing with them. We are in a new world with all sorts of new toxins. Can you say something about that and how that could affect aging? >> Yes. Um so as far as the evolutionary side of goes um there's quite a lot of evidence that for instance foxo that transcription pack factor part of the um cast of characters that it activates is actually the detox pathway. It's the standard you know phase one phase two. So it it seems clear that in defending cells that and defending cells during aging that whole process is very important. As far as the model in modern environmental pollutants go there's been very little work on it so far partly because I think sometimes we just don't know what's going on. So you know there's this rise this is not an aging related thing. It's the opposite. there's this rise in colctal cancer in the younger section of the population, but I think there's a strong suspicion that that has to be some sort of environmental pollutant, but nobody's got any idea what it is. And we can certainly use some of the ones that we know about and start to look at their effects on, you know, organoids and whole organisms, but I would say that whole line of inquiry as far as aging goes is really in its infancy. But I think it's really important quiet audience. Richard Adam wants to ask a question. Thank you kindly. It's a bit weird being on this side. My understanding of aging is that it primarily connects to telomeirs. I believe it's pronounced as in the protective caps of the chromosomes. Now feel free to say if this is going more into the side of snake oil. My understanding is that this is affected by free radicals and it's to do with oxidation and all this jazz. Uh could you weigh in on that by chance? >> I'm sorry. >> For some reason, Adam, it's quite tricky to [clears throat] hear your question. Do you want to uh come down and ask it from the microphone at the front? >> Yeah. Sorry, I didn't hear. >> Is this any better? No. Yes. >> Yes, that is. >> And my question was to do with telomeirs. I know how to use my microphone. Thank you. My question was to do with uh the protective caps of chromosomes, i.e. telomeres. My understanding is that as we age, they get more and more damaged. Uh, from there, this is going maybe more into the snake oil idea, isn't it? That as we get older, there's more free radicals, there's oxidation and all that jazz. Could you weigh in on that? I mean there's certain tie sorry >> there's certainly tieumir erosion um you know particularly in in types of cells that divide during aging and it's a very important cause of cellular scinessence because once the tieumir is eroded to the point where it's starting that actually to nibble into the chromosome itself and the genes then you get the cell tipping over into cellular scinessence And then you start to get the tissue damage. And there's a lot of experimental evidence now that if you remove scinsesscent cells from tissues, this is in mice now um either genetically or with a drug then you improve the tissue health and you can also actually make the mouse live longer. So it's very clear that the ones that accumulate during aging are damaging. One size doesn't fit all. um cellular scinessence is very important in wound healing. So the real role of these cells during development and wound healing is that they appear and they remodel the tissue. That's why they can destroy tissue because often to remodel it and heal a wound you need to kill bits as well as make bits. But the problem is they appear during aging and normally when they're functional they're removed by the immune system. But for some reason these ones that appear during aging don't get removed probably because of some sort of immune deficit and so they accumulate and and definitely tie erosion feeds into that. I I'd like to ask you a question, Linda. Um, in connection with the graph you showed at the beginning of your talk where you mentioned that women live longer than men, but their healthy lifespan is shorter. Um, I wondered to what extent the menopause in women might play a role in that deteriorating health without shortening lifespan. Do we know that? And we we know the menopause doesn't do you any good. Is it the case that the kind of damage we associate with the menopause is not actually linked to lifespan? >> I'm not sure if we know because we'd need to have individuals who didn't go through the menop. You know, you'd need to have some sort of comparison. But certainly the sorts of um things that are associated with menopause I mean osteoporosis you know muscle weakness these are all bad things that happen during aging. So certainly some aspects of of age related ill health in women are related to menopause. >> So you might then think it it would reduce lifespan in women but they live longer. >> Yes. So I I don't think anybody knows what the I mean there are about five different hypotheses to explain that difference and I don't think anybody really knows you know what what the right ones are. Um there's one interesting bit of of biology which is that there are some organisms and humans are one of them uh with a long post-reod lifespan in females. And there's this idea of the grandmother effect that actually it's an advantage to have your grandmother around and in hunter gatherer societies in humans um which is what we've evolved from. There's some evidence that that's the case. Actually having grandma around can either increase the reproductive success of daughters or the survival of grandchildren. But a particularly clear case is actually killer whales. Killer whale females have a very long uh post-reroductive lifespan. And it's absolutely clear from the numbers that if you've got a post-reroductive grandmother in the pod, the young males survive much better than if she's not there. So that there may be advantages to a post-reroductive lifespan under certain restricted circumstances, but certainly the menopause is not good news for overall health. Uh, does reducing inflammation increase lifespan? Sorry, does what? >> Reducing inflammation. Inflam inflammation. >> Inflammation. Yes. Yes. That that there's uh plenty of evidence for that in experimental um studies with the model organisms. I mean this age related inflammation is not is not because they're becoming more infected. There's nothing adaptive about it and if you tamp it down I including with rapamy it it's clear that that it's advantageous. Yes, it's a it's a negative feature of aging and it's accompanied and it seems it may even sometimes be causal in making the immune system work less well in a functional context. So it damages the system itself and a lot of it is to do with immune cells getting into the wrong places. So for instance, one of the reasons that obesity is so dangerous is that the fat becomes in invaded by inflammatory macrofasages and then starts releasing lipids into the bloodstream and that's very damaging. So yes, it it's definitely a good idea to tamp it down. I wonder >> that's an incredibly important question. Um I think a lot of the question mark over that is to do with dosing. So the doses of rapamy and tmet that are used in the mouse studies um are a lot lower than the doses that would be used clinically and the dose of her proprietary drugs that Joan used in that immunization project induced no side effects at all. was working at doses way way below what you'd use as a cancer chemotherapeutic or to prevent kidney rejection where you do get quite major side effects. But I think what we do not know for any of or either of those drugs at the moment is what the consequences of taking them for a long period are. We don't know about you know chronic treatment and the kind of side effects that might appear with long-term use. That's why I think the fact that rapamy can be used in very short bursts is is really important. Um the metformin trial I think would have been very interesting and if they can get the finance for it I think it will be really important because many people have taken metformin for very long periods and it clearly is a very safe drug with long-term chronic treatment. So I think it it's a prime candidate in a sense for the first long-term clinical trial in humans because we already know how safe it is. But the question of side effects is obviously crucial. Your mention of obesity reminds me that I was at a talk recently by Navidid Sata showing the effects of weight loss drugs um that are actually reducing protecting against uh a whole range of what would be age related diseases. Is that another promising um pathway for >> it's absolutely clear that they you could almost describe them as dera protectors. I mean, they they've only been around for such a short time that we can't possibly know. I mean, nobody's taken them for for long enough to know what the consequences there are. But I find it really easy to believe that they would be uh very protective during aging simply because of what we know about the um socioeconomic deprivation story and the hallmarks. So you can go on from those kind I didn't have time to mention it but from those epidemiological studies we know that almost any measure that you use of social deprivation is associated with acceleration of the hallmark related diseases and if you go on and say okay let's look at the characteristics other characteristics of the individuals in those studies which ones are associated with the acceleration number one is obesity come straight out number two is current smoking. Number three is low level of education but education is almost certainly acting as a mark for health seeeking behaviors other things but obesity is always top of the list. So if you can reduce that you're going to reduce a lot of age related diseases. >> Hi thank you. Uh great talk by the way. You mentioned a lot of interesting experiments uh on the effects of drugs on mice and expanding their healthy lifespan. And I guess that's good because mice don't typically live very long. So those studies can complete quite quickly. But in terms of moving this on to a human clinical trial, my assumption is that we'd need to wait for all of the humans in your clinical trials to pass away to assess the effectiveness of those drugs in humans. And so I guess I'm speaking a bit more practically in that assuming these clinical trials in humans are successful, how soon could we have these drugs be available for humans on a commercial basis? And secondly, speaking as someone who's felishly young at 27 years old, do you think those drugs will be available for me in time? >> I'm going deaf. I didn't hear the last bit. What was it? >> 27. >> Right. Um, yes. Uh, so what was the first bit of your question? Sorry, I was there were three bits. When when should you start? I think we'd all hope that you wouldn't have to start at least till middle age. I mean that a lot of these things that go wrong during aging are basically life course effects. I mean it's clear that even effects in uterro can be important on how people have an important effect on how people age later on. And some of them at the moment we don't know how to reverse. Um so um it would be nice to think it's never too late but probably it sometimes is a bit too late. Um but ideally what we'd like is interventions that we could make in you know start in late middle age and would be beneficial from then on. But I think for a lot of these we don't actually know and I remember the first bit of your question. Now you're right about the long-term nature of the clinical trials in humans. One of the things that um nobody none of the regulators will allow at the moment and I think there are good reasons but it may change is the use of biomarkers rather than a disease outcome but if we can do enough work uh with the model organisms that we've got a clear indicator a molecular indicator that we're hitting the right target and that therefore a particular disease is less likely to occur. It is possible I think that in the future we'll be able to use predictors in clinical trials rather than having to wait for the final outcome. But at the moment, you know, if you talk to any of the regulators, they don't want anything to do with it. And I think that's absolutely fair because I don't think the biomarkers are accurate enough at the moment. But I think they will get more accurate. I mean, that's the huge benefit of these long-term studies where you collect samples and plasma and so on all the whole way through and you can then see what happens to the person but go back and looked at whether you could have predicted it when they were young. So, there's a lot of that going on at the moment. Hi, thank you. Um, I just wondered that when you mentioned these promising developments which sometimes companies won't look at because there's no money in it. Um, and I just wondered is there any campaigning organization or is there any agency that's trying to work at developing more integrity in the pharmaceutical world? That that's a very interesting question and it's something we have it's something we have a lot of discussions about is is how to how to deal with the lunatic fringe. Um, so you know they they come together at that Copenhagen meeting which incidentally been cancelled this year by the university. So watch this spot. But that that's where there's a lot of serious science but also some more dubious stuff and who is actually financing it. it it's it's where you know the whole boundary of what should and shouldn't happen sits and I think how you actually negotiate that in terms of trying to you know keep keep what people do as respectable as possible and make absolutely clear the distinction between scientifically rigorous work and puff and things that have been through a clinical trial and things that haven't I think it's something the whole field actually needs needs to pay a lot more attention to and be a lot clearer about. First of all, uh thanks very much for the uh discussion. Um following on from the last question, um you you were somewhat dismissive of supplements etc. uh on the grounds that there had been no trials carried out to prove one way or the other whether they work. But later on in in the program you mentioned the same truth about um rapamy and the the the trials for the combination uh which seems to fall on the basis that as it's out of patent no pharmaceutical company can make money from it. Therefore there are no trials done. So I'm wondering just if you can give me a broad idea of what one of these clinical trials costs so we might maybe approach Mr. Bezos to put his hand in his pocket. >> Yeah, that's that's a good idea. Um I I mean you're up in the um hundreds of millions because if if you've got [snorts] to follow people say for 10 years and you're looking at a five disease outcome and you're looking at men and women and you've got the right ethnic mix in there. So the whole thing's stratified according to the variables that you know are going to be important in the way that people respond to a drug. You're looking at a very very expensive trial even by clinical trial standards. Well, I think hundreds of millions is quite expensive. No, you're talking seriously expensive. Bezos money. where it's said that 55 years old is old in Bridgton whereas there are many people in Bears's den who are 75 years young the difference between biological and physiological aging and I wonder to what extent the lit the literature you described spans both aspects of aging I'm thinking in particular that participation in trials and research is much less in deprived areas and you know you mentioned Bio Bankank which recruited 5% of the population and I'm just wondering whether there's a a gap there. >> Yes, I mean certainly there is you know the who volunteers for um you know a long-term study the longitudinal cohorts that's not going to be a random random section of humanity by any means. It's one of the reasons I particularly like the health record because there are some people who would never go near a doctor. I mean, there there is still a non-random aspect to it, but you've got a much better, I think, cross-section of the population if you're looking at GP and hospital records that if you're looking at people who volunteered to take part in a long-term study. So yeah, I think I think the issue that you rais is a very real one and it's one that increasingly um people are starting to address in clinical trials. I mean there's been a very serious bias there in the past. They've almost all been done with young men. So you know there is a problem and increasingly when people look you know these other variables age, gender, sex and so on um do affect how people respond to drugs. I've been diabetic too for 25 years. I take metaphor and etc. Simpatic. Last year I was diagnosed with prostate cancer and uh just got the result a few days ago that I'm clear now. I went through radiotherapy and uh the other treatment you know so I'm still here and uh can you give me any the re recommendation? I'm I'm I'll be 76. I'll be 76 in July, but sometimes I feel 26. You know, >> you see, it's what I was saying about Billy Colony, the zen and yang of, you know, there are these beastly diseases, but there's also healthy aging going on in parallel. So, let's get rid of the diseases >> on top of the the radiotherapy bit, hormone treatment as well. That's to calm down the testosterone. >> Yeah. >> Anyway, >> bless. >> I feel good. And I just I want every I want the world to know. >> Thank you very much for your uh very very important talk. H I just wonder whether in your view is it at all possible that uh by healing people in old age can recover from diseases because there are instances that they do report that somebody without any surgical operation has been cured or healed. I'm not I'm not sure I really have any wise words about that. >> Well, I I mean that with some people may stop all the diseases associated with old age as a result of religious belief or spiritual uh dimensions of their lives or healing as it is operated and practiced in many religions. Well, I mean it it's just to some extent believable because I mean all of these things, if they have any effect at all, are going to be doing it through biological mechanisms. And it's clear for instance that certain kinds of stress are really bad for you. Not all, but some. Um, not sleeping properly is really bad for you. So, if it's feeding into those kinds of things, then it could be having an affair. >> Just like to have that very wise. We've got time for one final question. Is there one over there? Yes. >> Thank you. It used to be the case that uh full dental clearance and the false teeth were a common 21st birthday present in Glasgow. Dental carries is a potent source of inflammation, chronic inflammation. Uh it's the most common cause of surgery. I think hospital admissions in the under 10 and it's closely related to social deprivation. So I've got two questions to you. How many times a day should I brush my teeth? And has there been any data strong data linkage between uh dental health? I don't know if the English they can actually can they link up dental records and and GP records. >> I I I think you've raised something really important. Dental health is so important not just for the teeth and the mouth but you know endocarditis for instance with you know infections and gum disease is something that um in mice is actually reversed by rapamy and it has a really dramatic effect. But what infuriates me about the whole thing is first of all the whole situation with national health or the lack of situation with national health dentistry I mean the standards of dental care throughout the British I think are absolutely appalling and actually I I have occasional fights with my own dentist about it and say why on earth don't you guys get involved in more clinical work why aren't there better records you know why why don't you get yourselves organized so that we actually have a picture of what's going on with people's teeth nationally and how it's affecting their health. They just seem to be not involved in research. Sorry if that I'm offending any dentists in the room. But I do find it quite extraordinary that there isn't more clinician science going on in dentistry. Well, >> perhaps on that uh not so happy note, [laughter and sighs] especially given that the west of Scotland has traditionally had a lot of poor dental health. Uh we should draw this to a close. Just one final thing I'd like to say. Uh, I won't ask Linda to comment on it, but there is data showing that baldness in men is not linked to lifespan. I say that looking around the room hesitantly, nor is graying of the hair. So, we're all Anyway, uh I'd just like to thank Linda so much for a very wide-ranging and informative talk on something that is very relevant to society. You probably know the Scottish government produced a report just in January on healthy aging and and what it society needs to do to try to get it to happen. and research of the kind that Linda's doing is very very important in this context. Uh whether we're all looking forward to taking a pill or not uh remains to be seen. But uh just before then we thank Linda collectively. There's two things I have to do. Actually, maybe three things. I'll just remind those that were getting the chocolate [laughter] that chocolate is these days considered to be good for you. So, don't forget uh to pick up your chocolates. Uh it's my pleasure uh on behalf of the society to present Linda with the society Graham medal in honor of Graeme the chemist who was very influential in our society and of course in the discovery of dialysis and then secondly to prevent present her of course with the Royal Philosophical Society paperweight. You're welcome. It's a really beautiful medal. Thank you so much, P. This is a real honor. The really beautiful paper weight.