The Nature of Aging

Aging appears to progress similarly across species, from worms and flies to mice and humans, and involves pathways related to early development. Guest Linda Partridge talks with Gordon while visiting the Buck Institute to discuss the evolutionary trade offs of aging mechanisms, the role of nutrient-sensing pathways, and how we might get the most benefit from preventative interventions in midlife.


Linda Partridge

Linda Partridge, born in 1950 in Bath, England, studied and graduated in biology at the University of Oxford. After three years of postdoctoral research at the University of York, she was Demonstrator, Lecturer, Reader and finally Professor at the University of Edinburgh. After many years in Scotland, in 1994 she became Professor of Biometry, University College London. She is both a founding director of the new Max Planck Institute for Biology of Ageing in Cologne and Director of the UCL Institute of Healthy Ageing. Linda Partridge’s research is directed to understanding both how the rate of aging evolves in nature and the mechanisms by which healthy lifespan can be extended in laboratory model organisms. Her work has focussed in particular on the role of nutrient-sensing pathways, such as the insulin/insulin-like growth factor signaling pathway, and on dietary restriction. Her current work is directed to developing pharmacological treatments that ameliorate the human aging process to produce a broad-spectrum improvement in health during aging. She is the recipient of numerous awards, including a DBE for services to science. She is founding director of the new Max Planck Institute for Biology of Ageing in Cologne as well as the Director of the UCL Institute of Healthy Ageing.

Show notes




Episode transcript


 We’re not trying to make people live longer. That’s been going on for decades anyway, without the intervention of people like us. The problem is that healthy lifespan isn’t keeping up with lifespan. It’s that that we’re trying to tackle.  


 Aging. None of us can escape. Like gravity, it pulls on each of us. Why do some of us age gracefully and others don’t? How do our bodies and minds experience aging the cellular and molecular level? Why do we even age to begin with? And maybe most importantly, can we do anything about it? My name is Gordon Lithgow, and here at the Buck Institute in California, my colleagues and I are searching for and actually finding answers to these questions and many more. On this podcast, we discuss and discover the future of aging with some of the brightest scientific stars on the planet. We’re not getting any younger yet.  


Hi, everyone. Welcome to the show. I’m delighted to have Linda Partridge here today and Linda sitting right in front of me as she visits the Buck Institute. Linda is an evolutionary biologist by training, Fellow of the Royal Society, and got into aging about 20 years ago and has been really interested in all the different types of interventions: genetic, nutrition, drug-like molecules that have the potential to improve human life. So I’m so delighted you’re here. Linda. Welcome. 

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Gordon:  Uh, is this your first trip post-COVID?

Linda:    Uh, no. It’s not. But it’s probably my most exciting trip. So it’s just fantastic to be here again. I visited the Buck, for a conference, I think, a few years ago.

Gordon: That’s right. That’s right. Yeah. Well-well, welcome back. When we look at the different ways in which people age, there’s great hope there. Right. I mean, we’re talking about clinical trials. And, uh, there’s dozens of companies flourishing, uh, uh, you know, with this idea of targeting aging. What is — wh — describe the plasticity of aging in-in humans and what’s possible.

Linda:    Well, I think the most compelling evidence for malleability of people’s lives and their length and the health during them is really historical.  I mean, beginning in the middle of the 19th century, as places began to industrialize, there were lots of improvements in living conditions you know: clean water, better housing, uh, better aeration of houses so a bit less infection. And then along came antibiotics, immunization, and so on. And the result has been an  increase since then in those countries of about 2.5 years – — of life expectancy. So that’s six hours a day — — maintained over, you know, nearly 200 years now. I mean, uh, what a testament to the malleability of human lifespan — — human life expectancy. It’s just increased so much. And it’s also told us some of the interventions that can improve people’s health. But as I say, people are living longer because, for a given age, they’re healthier. So — and it’s often said that today’s 80-year-olds are the 60-year-olds of —

— some decades ago.

Gordon: So obviously, we’re going to talk about aging. But you didn’t really start there. Right. I mean, evolutionary biology was your first love.

Linda:    Yes, very much so. I think, at that stage, I slightly had my hobby, uh, mixed up with my profession. I was a very keen bird watcher.

Gordon: [Gasps] Me, too. [Laughs]

Linda:    So, I actually did my PhD on bird behavior which was very enjoyable but, uh, you know, not obviously increasing the sum of human happiness. So after that, I-I turned much more to what had been a core interest, genetics and evolutionary biology so more population genetics and became very interested in the evolution of life histories. You know, why is it that different organisms mature at such different rates, have huge numbers — uh, different numbers of offspring, you know, have very variable delays before they start breeding as adults and then, of course, very different breeding lifespans as well. So, I was interested in that whole diversity of lifespans and actually did a lot of experimental work with the fruit fly, drosophila at that point because you can exploit the natural genetic variation that’s just present in a fly population just like it is in a human population. And so what we did was to select for a slower rate of aging in these flies. And the question was, how does aging evolve? Is it a side effect of genes that are beneficial in youth, in young adults? So you can imagine there might be genetic variants that, for instance, uh, make a young adult better able to reproduce, more competitive with others perhaps.

Gordon: Yes.

Linda:    But the kind of mechanisms that you need to achieve that competitiveness trade off with maintaining your body, looking after yourself, uh, you know, m — protein clean-up processes, all the sorts of things that cells do to keep themselves going over time. Maybe you can’t do that quite so well —

Gordon: Hmm.

Linda:    — if you’re rushing around being competitive. So there would be a tradeoff between performance and youth, the ability to survive and produce offspring then but at the expense of a higher rate of aging later on. And actually, that turned out to be true in these flies. So we could artificially select for flies that lived a long time. And they lived a long time because their, uh, rate of death went up more slowly with age. So we really seem —

Gordon: Hmm.

Linda:    — to have hit the aging process itself. But both the males and the females were less fertile when they were young adults.

Gordon: So I want to unpack some of this. So you started by saying artificial selection. Uh, and-and this is contrast to natural selection, I guess, uh, Darwinian natural selection. So these are laboratory-based experiments, how do you do this? You go out and capture tons of wild flies and bring them into the lab?

Linda:    Well, it only works if you’ve got a base population from which you’re going to do your selection which has got genetic variation in it. So yes. That’s typically what we do. We would bring in wild flies to the lab. So they were carrying all the natural variation that you see out there in nature itself. And then, you do a process which is very like the way that you make new breeds of dogs —

Gordon: Hmm. I see. Okay.

Linda:    — or select cattle to either be beef cattle or dairy cattle. You, in each generation, choose as parents the individuals that have got the trait that you want. So in this case, it was long life. So the way that you do it in practice with flies is that you just let them, uh, sit in their population cage where they live. The males and females — they produce eggs. And you let them get old. And there’s death in the period leading up to the time —

Gordon: Mm-hmm.

Linda:    — when you collect the eggs. And only those flies that have survived to the time when you collect the eggs and that are still fertile when you collect them 

Gordon: Yes.

Linda:    — are going to contribute to the next generation.

Gordon: So there’s a really big idea in what you’re saying here, and I think the big idea is that selection for other facets of life influence aging. And that maybe gets at the idea that, well, aging isn’t a process that is necessary or isn’t an outcome of Darwinian natural selection. Is that — is that —

Linda:    I think we can say fairly confidently that, in the vast majority of cases, aging is just a side effect of something else. So as far as we know, no genes have evolved to cause illness, loss of function, frailty, death. There is no positive selection in favor of aging. In fact, it’s very bad for individuals. It’s rather odd actually that Darwin never talked about aging and this is possibly why- because it’s a real evolutionary paradox. You know, why, when you can, uh, y — go through the remarkable feat of development and produce an organism in the first place with all its incredible features of survival and function —

— wouldn’t it be just much simpler to keep it going? And then, it would — it would have a higher Darwinian fitness.

Gordon: You’d imagine, yeah

Linda:    It would produce more offspring in its lifetime. But no. And, uh, you see aging regularly in nature. It’s been documented in a lot of birds and mammals and insects now that, even out there –you see an increase in death rate and a loss of fertility as creatures get older.And it does seem to be a side effect of this selection for high performance in youth.

Gordon: And this idea of tradeoff, I think, is probably really important, right, because, most of what we’re talking about in this entire series of podcasts is — or our ability to manipulate aging, to intervene in some way to extend lifespan and model organisms and then, you know, extrapolate to humans. But this idea of tradeoff is a bit of a challenge there, no? I mean, is there a sense in which, if we extend lifespan, we must be doing something else during early life, during development and growth?

Linda:    I don’t think that has to be true. I mean, part of the reason is that a lot of the interventions that we’ve got into the aging process — so we can make genetic changes. We can change diet. We can change lifestyle, for instance, the amount of exercise an organism does. Or we can manipulate processes with chemicals. A lot of them work quite well if you do them for the first time when the organism is already middle-aged —

Gordon: Mm-hmm. Yes.

Linda:    — or even old.

Gordon: Yes.

Linda:    So the important thing is not to impair the performance of young adults. That would, uh, just be a crazy thing to do. What we’re interested in is what are these side effects exactly and — of the fitness in youth?And can we interfere with them? And I think the huge discovery of recent years, because this is a field that’s really exploding at the moment, and I think the major discovery has been this underlying regularity of the things that do go wrong during aging — that’s this evolutionary side effect. And they’ve become known as the hallmarks of aging. But we know now, because of lots of work on these model organisms that we all work on in the lab — so yeast — you work a lot on worms —

Gordon: Mm-hmm.

Linda:    — on mice. I work a lot on drosophila — and mice. And of course, some of us also work on humans as well. We know that, across all those organisms, there are regularities in the way that they age. So if things go wrong at the genetic level, there’s damage to the genetic material, the way it’s packaged in the nucleus of the cells, the way it’s expressed. And that knocks on to things going wrong in cells, proteostasis. The proteins are the real workhorses of cells. And the way that they’re produced and broken down when they become old and dysfunctional is very important for maintaining the health of the cell. And both processes go wrong during aging.

Gordon: Yeah. I’d-I’d really like to get to that-that-that process actually.  So I think what — part of what you’re saying is that, yes, tradeoffs are real. Uh, these are genetic-driven processes, benefits in early life, detriments in late life. But the interventions are-are also real, that we can come in, in midlife once all those things have happened in growth and development and still make a difference that’s going to be beneficial.

Linda:    Increasingly, happily, that’s how it’s looking.

Gordon: Mm-hmm.

Linda:    Aging is a malleable process. We can get at it.

Gordon: So, you’re studying population genetics essentially of drosophila and life histories. And you have this interest in lifespan as, uh — as one of the life-history outcomes. Uh, but at some point, you suddenly become a molecular cellular biologist? [Laughs]

Linda:    Yes. It-it was quite a long walk, that one. And it was really started by someone who I think it’s a heroine in our field, uh, which was Cynthia Kenyon –who is very close by us here. She’s, uh, in San Francisco at Calico, originally at, uh, University of California at San Francisco. And she did what retrospectively seems like a blindingly obvious experiment. But I think it was really important. It was based on earlier work by others including Tom Johnson. But what she asked very simply is, if I do a mutagenesis experiment — so if I just zap the genetic material of the worm — can I alter it in ways that give me a long-lived mutant? And she found that she could.

Gordon: Mm-hmm.

Linda:    She got this extraordinarily long-lived worm. And it was, very importantly, wriggling around and healthy long after the normal worms were dead. So it wasn’t just an extension of the moribund period at the end of the life because because I think a very important principle — this is a bit of a digression, but I do think there is a very important principle here about what it is we’re trying to do with this kind of research. And what it is is to reduce that period of loss of function and ill health —

Gordon: Mm-hmm.

Linda:    — at the end of life. It’s not just to make things live longer. We often use lifespan as a rather crude output of the work that we’re doing because it’s a very useful first indicator of what’s going on. But we’re not trying to make people live longer. That’s been going on for decades anyway without the intervention of people like us. The problem is that healthy lifespan isn’t keeping up with lifespan- it’s that that we’re trying to tackle. So the fact that these mutant worms were very healthy late into life was important.

Gordon: Mm-hmm.

Linda:    And I think, at the time, we all looked at it and thought, gosh, that’s interesting. But it’s probably just a worm thing. And as a group, we thought, well, perhaps this is going on in drosophila as well —

Gordon: Right.

Linda:    — because what Cynthia had found eventually, it took a long time to figure out what her mutant was, but it was a lesion in the nutrient-sensing network. So there’s a whole system in multi — in organisms that consist of more than one cell, and actually in single-celled organisms like yeast, for detecting their current nutrient status. You know, how much food have I got? Am I infected? Have I got other kinds of physical or biological stresses?

Gordon: Mm-hmm.

Linda:    And then, they set their metabolism according to what can be afforded so their growth, their reproduction, their metabolic status. And here it is in the worm apparently affecting the aging process.

Gordon: Did you read Cynthia’s paper and suddenly go, boom, this is what I want to be working on? Or was it more a series of conversations with people? Or —

Linda:    I think it was a quite long series of conversations —

Gordon: Yeah.

Linda:    — with people because, at the time, I was still very interested in kind of evolutionary aspects but getting more interested in the effects of nutrition itself —

Gordon: Mm-hmm.

Linda:    — so dietary restriction and so on.

Gordon: Mm-hmm.

Linda:    We were doing a lot of work on whether, when you decrease the food supply of an organism and it responds by an increase in healthy lifespan —

Gordon:     Yeah.

Linda:    — which is a very common finding . . . 

Gordon: Yeah.

Linda:    We were interested in wh — in what it was in the food that was important. Was it just the amount of calories that the creature was —

Gordon: Mm-hmm.

Linda:    — eating or the nutrients itself? So I was always — already interested in the systems in the organism that sense nutrients. And Sally, who was part of our little group of scientists who were having conversations, uh, had just discovered the equivalent of another mutant in this network that extends worm lifespan affected growth and cell division in —

Gordon: Mm-hmm.

Linda:    — drosophila. The whole network came to light in the fly not because of —

Gordon: Mm-hmm.

Linda:    — anything to do with aging or metabolism. It was the control of growth and cell proliferation. And she, of course, was working in a cancer institute. So this was of —

Gordon: Uh —

Linda:    — great interest. So we then, as a group, said, well, why don’t we just try some of these mutants for their lifespan? And lo and behold, it turned out the effect was conserved in the fly.

Gordon: Which is amazing and — well, uh, going back to the-the initial discoveries — uh, you mentioned Tom Johnson. And-and he published this paper with a 70 — seven zero — percent increase in lifespan in this tiny roundworm, nematode C. elegans. The impression I got later on was that people actually didn’t believe this.   Was there a tension in any way between that sort of discovery and Cynthia’s discovery with the sort of population genetic theories of aging that you’d been steeped in for years? In other words, I’m asking you, did you believe it?

Linda:    Yes. I think I believed it. I mean, the data were just too compelling. I mean, the lifespan increase was enormous. I mean, you c — I —

Gordon: [Laughs]

Linda:    — just cannot see how you could possibly get that as an artifact. But I think, you know, people said, “oh, it’s..” they called them things like refrigerator mu-mutants.

Gordon: Mm-hmm. Yes. Yes.

Linda:    You know, this is just a creature that’s not doing anything. It’s just existing. It’s not dead. But it’s not really alive either, though. And I think that, from the evolutionary community, there was suspicion because it was clear that, you know, the aging process, to the extent that it’s controlled by genes at all, genetic variation between individuals, lots of genes are involved. So I think, to them, it seemed unintuitive that just throwing a spanner into one gene would be enough to produce such an enormous effect. I think what we all had a blind spot about was something called phenotypic plasticity, which is you can get hardwired genetic differences between individuals that affect their lifespan for sure in these little invertebrates, but you can also get huge plasticity in lifespan – you know, depending on nutritional status depending on, uh, physical stresses, depending on whether the creature is infected, what it’s eating. You know, all of these things can cause these tradeoffs that the animal is making to be reset. And what this mutant was doing was, resetting things in favor of survival and self-protection.

Gordon: Right. And-and obviously, we’ll get to humans and why this is important for us. Uh, but it seems like the discovery that the same pathways or the same networks, as you describe them, in worms were also determining lifespan in flies was a major, major landmark, right, because it’s no longer just a worm thing.

Linda:    Yes.

Gordon: This could be conserved. And then, why not maybe mammals? And why not maybe humans?

Linda:    Yes. Uh —

Gordon: Were you conscious of that at the time?

Linda:    I think I was a bit surprised at the size of the impact that it had actually. I mean, I knew it was interesting. And I knew it was quite important. Obviously, that was why we’d done the experiment. But I mean, the paper was, you know, practically grabbed by science in a way that I hadn’t experienced before. And, uh, it-it caused huge interest. I mean, it was very highly cited.

Gordon: Yeah.

Linda:    And I think, at that point, people really did start thinking, gosh, you know, if it’s conserved over the large evolutionary distance between these two, could it be going on in mammals as well —

Gordon: Mm-hmm.

Linda:    — as the same [signaling] — because it’s a terribly conserved network.

Gordon: Right.

Linda:    You know, most of the fundamental components, the molecular components in the cells, are present pretty well throughout multicellular organisms.

Gordon: Right. And as it’s played out over the years, we have now realized it is important in mammals and probably in humans as well.

Linda:    Yes.

Gordon: You got interested in — I guess the next question you asked was, uh, are there particular issues or are there particular systems within the flies you were working in that were important for this-this process? Uh, we should say that many of these genes encoded for proteins involved in the response to insulin, which was very confusing at the time, right, because we felt well, you know, loss of insulin signaling is associated with diabetes. Why would this be beneficial? But you got interested in how different tissues might interact in the response.

Linda:    Yes. And that turns out to be quite a surprising story. So a lot of tissues in mammals and in flies are sensitive to insulin. So we’re talking about both insulin and something called insulin-like growth factor, which is important in the control of growth and wound healing. So there’s two rather separated functions in mammals. In the invertebrates, uh, it tends to be just one single, molecule on the surface of the cell that basically serves both functions. Uh, but  they’re both there and important. And what really interested me about a lot of work that we did quite painstaking over a number of years looking at different tissues in the flies that were responsive to the in — circulating insulins in the fly was that they all responded in different ways. So the signaling cascade, you know, the basic, uh, bits that communicate with each other once the signal gets into the cell are there and conserved. They’re similar in different tissues. But then what happens is that they control things called transcription factors which are molecules that are either always around the genetic material or move in and out of the nucleus where the genetic material lives. And they switch on and off genes. And what we were finding was that the actual genes that were switched on and off were very different in different tissues. Yet each tissue in its different way was contributing to the overall health benefit of this reduced insulin signaling. So it’s as though the whole system can modulate what’s going on in different tissues in different ways according to, you know, what molecules are expressed there, what things can go wrong in those tissues during aging, which is quite different for different tissues. And somehow, it tamps down the damaging activity in all of them, whatever that damaging activity has —

Gordon: Mm-hmm.

Linda:    — and ups the protective responses.

Gordon: Mm-hmm. And one of those protective responses is a process called autophagy. And you mentioned protein conformation and shape and damage earlier on. Can you tell us what autophagy is?

Linda:    Yes. That’s turning out — I mean, it’s turning up in so many people’s studies in different organisms and different interventions. It’s a process — it’s a cellular clean-up process. So cells are often metabolically very active. They produce damaging molecules as side effects. Uh, you know, oxygen and handling of oxygen can be a problem. And, uh, what autophagy does is to recycle damaged bits of cells. So there are organelles in cells, you know, the powerhouses, the mitochondria, other bits that do different functions. And they eventually become dysfunctional. The molecules in them are damaged in different ways. And what autophagy does is to grab them and recycle them. So it’s an interesting process because it has a basal level that just goes on all the time. Cells need cleaning up. But it’s also increased a lot during food shortage because then, during starvation, the cells need to rejig themselves to make sure that they keep the absolutely vital processes going and shut down anything that’s not essential for life. And that’s achieved by recycling- by autophagy. And a lot of these interventions including reduced insulin signaling activate autophagy — in a similar way to starvation.

Gordon: I see.

Linda:    So what happens is the process increases —

Gordon:    Mm-hmm.

Linda:    — and there’s more recycling. And cells become more functional. So for instance, in the fly, we find, with reduced insulin signaling, there’s a big effect on gut health. The intestine is a very important organ in aging. And, uh, that’s achieved as a result of increased autophagy.

Gordon: Should we be looking at ways to activate autophagy chemically or in other ways? Is that of general benefit?

Linda:    Well, I’d be interested to know what you think about this. So I mean, yes, we would like to increase autophagy, but only in some tissues.

Gordon: Hmm.

Linda:    And that turns out to be the answer to many of these kinds of questions about aging biology. Somebody discovers that something is really useful either in the context of a particular disease or in just people who are aging reasonably normally. But usually, the effect is tissue specific. Uh, so for instance, in the fly, you would not want to increase autophagy in muscles. So, there’s a lot of interest –

Gordon: B-because that’s like sarcopenia, like a —

Linda:    Exactly. 

Gordon: — human disease and muscle loss.

Linda:    Exactly. So the question is, how can — this is a much more general question than the sort of thing I do. How can we make drugs that are only going to target particular cell types? And I’m aware of some work on this where you can coat the drug so that it gets into a lot of cells, but the coat is only removed in the cell type where you want it to act. And that’s done by tuning what’s in the coat to what’s in that cell type. And you make it something that would be broken down if that coating got into that cell type. And I think that’s the way things are heading.

Gordon: That’s super exciting. Yeah

Linda:    But it — you know, that-that’s not my bailiwick at all.  But I’m assuming that we’re going to see more and more of that —

Gordon: Yeah

Linda:    — as time goes by.

Gordon: Let’s talk about-about drugs, uh, and, uh, the idea that we can pharmacologically intervene in aging. And this is something that, again, another phase, uh, of-of-of your career that you moved into. And I’m curious again about what was — what was the-the, uh — what was the inspiration to do that? Was it a realization that what we were doing was really important for human health? Or was it just another way to study aging?

Linda:    I think the reason that I switched into becoming much more of a molecular, mechanistic kind of scientist, uh, was partly that I felt that I understood in principle how aging had evolved. It had been a bit of a puzzle. But I felt I got more of a handle on it. And it was clear that research into aging at the mechanistic level was going to go on to a very, very steep trajectory of increase. I mean, that original insulin — conservation of insulin signaling paper, the finding that went on in the worm, went on in the fly —

Gordon: Hmm.

Linda:    — went on in the mouse eventually – made it clear — uh, and the general health was improved –

Gordon: Yes.

Linda:    — in the mouse during aging. So if you look at a mouse that’s lost one of the insulin-receptor substrates, then what you see is a mouse that’s got better glucose handling so not the opposite, which you might expect with a lesion in insulin signaling. But actually, as they get older, they-they were better able to handle glucose  than the controls were basically because the beta cells in the pancreas that produce the insulin had more than compensated. Uh, but they also had, uh, better agility, you know, just coordination. And they got fewer cataracts, less osteoporosis, the skin was better, they had a better immune profile. So all of those things going on as a result of one lesion — I mean, that looks as though you’ve really hit the underlying aging process.

Gordon: Yeah.

Linda:    These are completely different things in different tissues. And I thought, well, if that’s really true, I want to go after it because that’s really important.

Gordon: I mean, this is an extremely powerful idea: the idea that aging itself is a driver of all these different kinds of pathologies in different tissues and then onto very different diseases — Alzheimer’s, Parkinson’s, osteoporosis, osteoarthritis, the large list.

Linda:    Well, that was a very quick thing that also impressed me a lot and-and h — the decision, which was that I think three groups simultaneously did a study where they took one of these long-lived insulin mutants in the mouse. But they combined it with a genetic model of Alzheimer’s disease. And what they found was that they could immediately — not just that they could make an ordinary mouse healthier as it was old, but that you could actually block some of the pathology in these mouse disease models. I thought that was particularly impressive. Cynthia actually — Cynthia Kenyon showed the same thing in the worm.

Gordon: Yes. Yes. And-and then, you’ve extrapolated that into human studies, right, where you’re looking at co-occurrences of multiple morbidities, uh, I guess is another way of saying it and aging mechanisms. I mean, can you talk about that?

Linda:    Yes. I think one of the huge problems with aging now with this growing period of ill health at the end of life is that actually the vast majority of diseases — you know, recognized clinical diseases with a proper disease code for clinical practice — most of them are age related.

Gordon: Mm-hmm.

Linda:    And what’s therefore happening with the increase in life expectancy is that clinicians are seeing more and more patients that have got more than one thing wrong with them, of-often a lot more than one thing wrong with them. And that’s horrible for the patient and the people who care for and about the patient. Uh, but it’s also very difficult to treat because, often, different conditions require some more incompatible treatments. And also, patients are often seen by specialists in the different things that they’ve got wrong with them who treat them somewhat independently with drugs. So you get these real horrible problems with drug interactions. So it’s a growing social and economic problem worldwide. It’s called multi-morbidity, the presence of more than one thing —

Gordon: Yeah. Yeah.

Linda:    — wrong in a single individual. And we, in collaboration with clinicians and artificial intelligence people and so on in London have done a study recently where we’ve looked at data from patients. So, uh, you know, it’s between three and four million patients from national health records. So these are people for whom we’ve got the primary record of their interactions with their general practitioner, also any hospital admissions, and what they were for. And what that means is that we can construct a huge network of all of these diseases that are age related and which ones are most likely to co-occur in the same patient. And if you do that, and then you look at the genes that affect those diseases . . . So there’s been a huge amount of work on genetic, just natural genetic variation between humans and how it affects their likelihood of getting different kinds of diseases.

Gordon: Yes.

Linda:    And if you look at what those genes do, it’s called their annotation. What you find is that genes that affect common diseases are likely to be annotated from one of these mechanisms of aging for instance, mitochondrial dysfunction, these powerhouses —

Gordon: Mm-hmm.

Linda:    — in cells that go wrong during aging. If you look at diseases that co-occur in a network, you can find that that particular group of diseases that tend to occur together have underlying them —

Gordon: Hmm.

Linda:    — this association with mitochondrial function. So it really does look as though these mechanisms of aging that we know about quite independently from all this research mainly with animals are the ones that — you can see that they’re present in the, uh, development of individual diseases. But they’re also explaining clusters of diseases. And that’s really important because it means that, if you could interfere with that mechanism you might be able to delay or even prevent that whole group of diseases simultaneously.

Gordon: The story of your career is incredible because you go from seeing some things happening in-in tiny m — one-millimeter-long worms to extrapolating that into a much more complex organism, drosophila, the fly, and finding the mechanisms that are conserved, and then going all the way into human studies, where you’re-you’re l — you’re looking at aging mechanisms in genes that w — are known to be tied to aging, and finding that they may be responsible for comorbidity

Linda:    Exactly.

Gordon: And then, at the same time, you’re coming in and saying we can pharmacologically interfere with this process.  

Linda:    These are all kind of in-principle things. I actually think a huge — I mean, lots of people are doing the kind of work that I’m doing, uh, you know, partly because it’s so exciting what’s happening in aging research at the moment. People are, you know, piling in and —

Gordon: Hmm.

Linda:    — and doing absolutely wonderful things, uh, worldwide. But I think the huge challenge is actually going to be the clinical profession because, quite rightly, you know, it’s very tightly regulated. Uh, you know, diagnosis of patients, the treatment options and the way that you implement them in clinical medicine, that runs on rails.

Gordon: Yeah.

Linda:    And that’s how you assure quality.

Gordon: Yes.

Linda:    Th-there’s very little latitude. But I think we need to get this geroscience thinking, the idea that  if you see an old patient with a lot of things wrong with them, you may be able actually to interfere at a rather basic level with several of them at once. I think medical students should be taught about this.

Gordon: Yes.

Linda:    And the, what we will find is that people who come through and treat old people, the geriatricians who are present tend not to be particularly research based — they’re much more involved in primary and-and secondary care of patients — I think we need a whole new [cadre] of geriatricians —

Gordon: Hmm.

Linda:    — who are interested in clinical research and who start to take some of these things into clinical practice.

Gordon: Well, hopefully, some of our listeners today are medical students.

Linda:    Yes.

Gordon: Uh, Linda, this is all fascinating. And, uh, one thing I’d like to ask you, is what are you most excited about now?

Linda:    Gosh, that’s a good question. [Laughs] And it’s one I hadn’t anticipated. I  think I’m still really excited by the nutrient-sensing network and the effects of diet. You know, it’s what I’ve been focusing on for years. But I think it’s still got a lot of mileage in it. I think we’re going to be able to produce some modifications to diet and when the d — that diet’s eaten, for instance, uh, that should be able to help with muscle weakness during aging. I’ve been thinking about this quite a lot. But we showed some time ago that the composition of protein matters, not just the amount of it. So a protein is made up of things called amino acids that are building blocks. There are about 20 different kinds. And it turns out that, if you alter the balance of those amino acids in the diet of a fly or a mouse to the overall composition of its own proteins in its body . . . So food doesn’t normally match the organism that’s eating it. There’s an imbalance between what’s in the food and the proportions of these amino acids  that the creature   wants to build its own body. And I’ve been thinking about that because one of the things that helps elderly people with muscle weakness is a gentle exercise regime combined with an intake of a protein shake. But people haven’t thought at all about the composition of that protein shake.  I reckon if you actually match that to the amino-acid composition of muscle, which is slightly peculiar, that you might be able to produce an enhanced response. So that’s something I’d really like to get involved with at the moment. Uh, it’s-it’s more applications to humans in-in —

Gordon: Yes.

Linda:    — small ways seeing, how can we take this stuff into people and help them? That’s the bit that really excites me.

Gordon: sounds like you’re ready to do a clinical trial on this.

Linda:    Well, I’ve been thinking about it. Yeah.

Gordon: Wonderful. Thank you so much for your time today, Linda. It’s wonderful to have you back at the Buck Institute.  

Linda:    It’s been wonderful to be here. And thank you for your interest in it all.


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 “We’re not getting any younger, yet!” is made possible by a generous grant from the Navigage Foundation. The Navigage Foundation is enhancing the lives of older people through the support of housing, health, education and human services. Our podcast is produced by Vital Mind Media: Wellington Bowler is here with me using sign language to keep me on course and recording the podcast. Stella, who I love spending time with talking about science, as you know, is our editor with the Creative Direction of Sharif Ezzat and the Buck Institute’s very own Robin Snyder as the executive producer.

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