Professor, Buck Institute; Scientific founder of Unity Biotechnology; Member of the National Academy of Sciences and a fellow of the American Association for the Advancement of Science
Dr. Campisi received a PhD in biochemistry from the State University of New York at Stony Brook and completed her postdoctoral training in cell cycle regulation at the Dana-Farber Cancer Institute and Harvard Medical School. As an assistant and associate professor at the Boston University Medical School, she studied the role of cellular senescence in suppressing cancer and soon became convinced that senescent cells also contributed to aging. She joined the Lawrence Berkeley National Laboratory as a senior scientist in 1991. In 2002, she started a second laboratory at the Buck Institute. At both institutions, Dr. Campisi established a broad program to understand the relationship between aging and age-related disease, with an emphasis on the interface between cancer and aging. Dr. Campisi is a member of the National Academy of Sciences and a fellow of the American Association for the Advancement of Science. She has received numerous awards for her research, including two MERIT awards from the National Institute on Aging and awards from the AlliedSignal Corporation, Gerontological Society of America, and American Federation for Aging Research. She is a recipient of the Longevity prize from the IPSEN Foundation, the Bennett Cohen award from the University of Michigan, and the Schober award from Halle University, and she is the first recipient of the international Olav Thon Foundation prize in Natural Sciences and Medicine. Dr. Campisi currently serves on advisory committees for the Alliance for Aging Research, Progeria Research Foundation, and NIA’s Intervention Testing Program. She is also an editorial board member for more than a dozen peer-reviewed journals. Dr. Campisi is a scientific founder of Unity Biotechnology, a California-based company focused on developing therapies for age-related pathologies. She has served on the scientific advisory boards of the Geron Corporation, Sierra BioScience, and Sangamo Biosciences.
Do senescent cells make a difference? If we eliminate them, is the disease either postponed, which it often is, or ameliorated, meaning it’s not so severe. And once in a while for a few diseases, it actually can reverse.
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 at the cellular 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 – all these questions and many more… On this podcast we discuss & discover the future of aging with some of the brightest scientific stars on the planet.
We’re not getting any younger…yet!
Hi, everyone. I’ve just taken a walk from my office about six yards to another office and in that office is Judy Campisi. Judy’s research is amazing and known way across the world. It’s the study of the way that cells in our bodies change with age and the impact it has on human disease. I’m very excited that you’re going to get to experience what I experience every day on this episode.
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Gordon: Judy Campisi. It’s absolutely delightful to have you here on this podcast. And, it’s such a delight and pleasure to have time to actually talk to you for like a protracted period of time. So let’s get into it! Let me get your definition of what cellular senescence is. And this is something you’ve been studying for like 20 years or so.
Judy: A little more. [laughs]
Gordon: A little more maybe. But give us a definition, first of all.
Judy: So, a senescent cell is a cell that has entered a state — a new state. And that state has three compartments. The first compartment is the cell doesn’t divide anymore. So it starts out where it can divide if it wants to. But now, it’s blocked. And it will never divide again so far as we know. The second is: the cells resist dying. They stick around both in vivo and also in culture when we study these things in human and mouse cultures. And the third thing, which we think is even most important, is they start secreting a lot of molecules that affect their neighbors. We call this a tripartite phenotype, three parts to what the cells are all about. And that defines the senescent cell. Cells with those characteristics increase with age. They’re present at sites of age-related pathology in both humans and mice. Uh, we think that they’re driving aging, and in the mouse, we’ve proven that. We have not proven it in humans yet.
Gordon: So, these cells are accumulating during normal aging.
Gordon: I know that you believe there are beneficial effects. I want to ask you about that.
Judy: So even the molecules that they secrete, happens in very young organisms in those few instances where senescent cells are good for you. And they’re good for you when you’re young. So why? One is during embryogenesis. There’s a wave of senescence in certain structures. And the secretions are actually what’s driving the fine-tuning of certain morphological characteristics of the embryo. Second is in the placenta. So in both humans and mice, there’s a wave of senescence that precedes labor. And in women humans who undergo early labor, that wave is early. And in women who undergo late labor, that wave is late. And we even think we know some of the molecules that are driving labor that’s starting the whole process of birth. And senescent cells secrete those molecules. And the third example is during wound healing. So when you cut yourself you have what’s called an initial transient inflammatory reaction. If you don’t have that, you will never heal that wound. And how does that go about? Something about the cut, the platelets that are released causes senescence in the support system, say in the skin. That’s called the dermis.
Judy: And those senescent cells secrete growth factors that help the wound close. So evolution selected for this phenotype, for embryogenesis, for birth and for wound healing.
Gordon: Okay. Okay. So this is, this is something that’s under natural selection. And we had this opportunity to talk to Steve Austad recently. And we talked about the origins of aging, through evolutionary biology. And Steve’s very much of the opinion that this is almost like an [epi] phenomena that happens —
Judy: Aging is.
Gordon: — for sel —
Gordon: — for — you know, for, selection for early — just as you’re describing, early biology that’s important —
Gordon: — for, you know — for reproduction and growth and so on is really the driver. So, now, you haven’t mentioned cancer yet. And isn’t that one of the major ideas? That cellular senescence also protects us against cancer early in life?
Judy: I mean, it’s important to remember, for 90 something percent of our Homo sapiens’ evolutionary history, there was no aging. Nobody died of cancer or —
Judy: — Alzheimer’s disease.
Judy: Uh, everybody was dead of infection or starvation or predation. I mean, we still die of predation. But, uh — [laughter] Yeah… So many, many years ago, when I was, you know, really a totally naïve undergraduate, people discovered that there were mutations that we knew were present in cancer cells that were also present in extremely young tissue. Really, in a five-year-old, you take a look at those cells. You have to look hard. There are not that many. But those mutations are there. So how do we manage not to get cancer before we’re 15 and able to have babies? Well, evolution took care of that. Evolution put into place two very powerful tumor-suppressor mechanisms. And one of them was cellular senescence. A cell that can’t divide can’t go on to form a tumor. So we think this was one of the major drivers — evolutionary drivers behind getting a cell to undergo senescence when it was in danger of proliferating or being damaged in some way that you don’t want that damaged cell to proliferate.
Gordon: Mm-hmm. Mm-hmm. That makes perfect sense. So, how do we identify senescent cells in either mice or people and in what tissues?
Judy: We have, by now, maybe two or a little bit more than two dozen, markers that are commonly used in the field. That’s the good news, that we have a bunch of markers. The bad news is absolutely none of them are truly specific for senescent cells. And so this — we discovered the first marker, the senescence-associated beta-galactosidase. But even in our very original paper, we showed that there were exceptions. There were times when a non-senescent cell would express this enzyme. But the beauty of this enzyme is you take a chemical. And you put it on a cell that is expressing this enzyme at high levels. And the cell turns blue. So it’s beautiful. Now, you can get human tissue or mouse tissue and look for blue cells. And that’s when you realize that there are so few of these cells. And then, they have other markers as well.
Gordon: When you take a section of a tissue and you look down a microscope, can you recognize senescent cells just by the way they look even without doing the beta-galactosidase thing?
Judy: If you have been working with them for the 20-plus years that I have been, probably but maybe not initially because they do get a little bit larger. But cells are heterogeneous. It took us a while to have some confidence that we could say—80 percent chance that cell is senescent. But then, we used the markers. Then, we used the blue color. We use some of the protein markers that have been discovered.
Gordon: What are some of those markers? What are some of those proteins?
Judy: Well, two of them are very famous tumor-suppressor proteins. One of them is called p16. And the other one is called p21. And we know that those stop the cell cycle. And we also know there are people with mutations in those genes. They die of cancer. Mice — they don’t have those genes. They die of cancer. So those are two markers. They’re pretty good. But you also have, for example, some stem cells in your body, good stem cells, they’re quiescent. They’re not doing anything. They’re not dividing. You don’t need them right now. But you wound yourself, or you have some kind of trauma where you need to have new tissue. Those stem cells wake up. The reason why they’re quiescent is they express low levels of these tumor suppressors.
Gordon: So they’re kind of like senescent cells.
Judy: They’re kind of like —
Gordon: — they can be woken up.
Judy: But they can be woken up. And senescent cells, so far, cannot.
Gordon: Mm-hmm. Mm-hmm. Wow. I guess I’m a little confused as to what happens — and maybe you can go back again to development and embryogenesis and so on. And tell me what happens to those senescent cells? Do they — do they remain senescent and become part of the new organism? Or do they — do they die? And it leads on to the question about why don’t these cells just die?
Gordon: — during aging?
Judy: Yeah. Yeah. Well, in the embryo, it’s only been described by a few labs in the embryo, not by us. Uh, and in those embryonic states, usually the senescent cells disappear. And it looks like what might happen is these very primitive immune cells might just gobble them up. And immune cells are doing this all the time in both the embryo and the adult. You have cells that somehow the immune system says you don’t need them anymore. These little primitive cells called macrophages will go up and gobble them up. So we think that may be what’s happening —
Gordon: I see. Mm-hmm.
Judy: — because they’re not needed —
Judy: — anymore. In the adult, why doesn’t the macrophage or other immune cells get rid of these? So we — again, we don’t know the answer to that question. But what we do know is that the older you get the poorer your immune system works. So, it could just be that the cells are being made at the same rate. But they’re disappearing more slowly because the immune system is declining for other reasons. But it is also possible that they’re made at a faster rate because there are things happening during aging that accelerate, for example, DNA damage.
Gordon: So DNA damage is one of those initiators of —
Gordon: — cell senescence. What-what are other initiators?
Judy: Mitochondrial dysfunction — so things that cause mitochondria to not deliver what is needed for the energy of a cell in a proper way — things that, for example, cause a mutation in an oncogene. So most people think, my gawd, an oncogene. It’s going to cause this normal cell to become cancerous. That’s rare. That’s very rare. Usually, the cell senses, uh-oh, there’s this gene. It’s signaling in the wrong way. The cell shuts down and becomes senescent. So many oncogenes will actually induce senescence. Most people have these little black things on their skin.
Judy: These are almost certainly melanocytes —
Judy: — the pigment-producing cells in your skin who have picked up an oncogenic mutation.
Judy: And the oncogenes are known. It’s usually one of two or three different specific oncogenes. The cells start to proliferate inappropriately because this oncogene is saying grow, grow, grow. The tumor-suppressor mechanism of senescence kicks in. And everything stops. And they stay little. Most people die with these things. They never convert to melanoma. Once in a while, they do of course.
Judy: But that’s rare.
Gordon: It’s kind of fascinating. You know, you mentioned the fact that these senescent cells are so required in developmental processes and embryogenesis and so on. And-and you said they disappear. And I guess we have this mechanism, apoptosis, which is a-a cell death or cell suicide that seems perfectly adequate to get rid of cells. And we also have the immune system that-that m — you know, chops up cells as well. And it’s just weird that this doesn’t happen, you know, during aging. Uh, wh-why-why-why don’t these mechanisms that we know can eliminate senescent cells kick in and-and-and prevent disease?
Judy: Well, in your body, cells are dying all the time. So it’s not as though apoptosis is embryonic and then, as an adult, senescence takes over. They’re both going on all of the time. But the short answer to your question is we don’t know why certain cells are susceptible to death and others are susceptible to being eliminated, for example, by the immune system.
Judy: But we can guess.
Judy: It may be, for example, during embryogenesis, you want to make sure that those senescent cells have done their job before you eliminate them. And therefore, you call on another cell type, an immune cell, who can survey the whole structure and say, okay. Now, we can get rid of senescent cells. You don’t trust them to do it on their own —
Gordon: Mm-hmm. Mm-hmm.
Judy: — because they’re not surveying the tissue. So that may be one explanation. We don’t actually know for sure. But we do know that there are diseases that are caused by too much apoptosis and diseases that are caused by not enough. And we suspect that, you know, apoptosis, like senescence, is a double-edged sword. And so cells have to make a decision. I’m going to stick around until something else tells me to go away. Or I’m going to stick around until I decide I need to go away.
Gordon: Mm-hmm. Okay.
Judy: And there may be circumstances —
Judy: — where one is better than the other.
Gordon: How do you study this in the lab?
Judy: We study mice where you can also manipulate the genome. And we also study human tissue. So we have a number of collaborators who are clinicians, for example.
Judy: And we collaborate with them to look at human tissues.
Gordon: But you can induce cell senescence in a dish with radiation? With —
Judy: Yes. Anything —
Gordon: — mitochondrial dysfunction —
Judy: Yes. Exactly.
Gordon: — all-all these things.
Gordon: I see.
Judy: So the question is, why do these cells accumulate with age?
Judy: Is it damage? Is it mitochondrial dysfunction? And the short answer is we do not know.
Gordon: [sighs] That’s tough, right?
Judy: We do not know.
Gordon: I mean, you know, uh —
Judy: Well —
Gordon: — i-if you —
Judy: We’re going to find out. And I’ll tell you why. Because this new grant that was funded by the National Institutes of Health is going to allow us to take human tissue. It’s all human. And what we will be able to do is to detail exactly what genes individual cells are expressing. And what we’re hoping is that we go to — in culture. We induce senescence, say only with radiation, and we get a certain pattern of gene expression. Now, we look for that pattern in human tissue. And we look across the age spectrum. And so we think we might be able to get at that issue of what is driving senescence in vivo, in people —
Gordon: That’s —
Judy: — during aging.
Gordon: — fantastic. No. That’s really exciting. Maybe just talk about different tissues for now. Do you think that a senescent cell in skin fibroblast, as you have studied a lot of, is the same as a senescent cell in the liver, the same as a senescent cell in the brain. And maybe you could talk about the brain a bit —
Gordon: — because I think that’s something that really evolved, at the Buck Institute.
Judy: Yes. Absolutely. So I am not a neurobiologist [laughs] just like I’m not a real doctor. I’m not a real neurobiologist. But of course, we all care about our brains. And so it was really one of the-the benefits of coming to the Buck Institute and being able to collaborate with the real neurobiologists like Julie Andersen and Lisa Ellerby to begin to understand, does senescence occur in the brain? (The answer is yes.) Is it the neurons? Or is it these other cell types in the brain? And it turns out it’s probably both, but it’s definitely the other cell types, things that are called astrocytes —
Judy: — or microglial cells.
Judy: And —
Gordon: And this is based on the same set of markers that you originally established —
Gordon: — for-for skin —
Gordon: — cells, for example. You go into the brain.
Gordon: You look for the self-same proteins. And wow. They’re there.
Judy: Yes. Exactly. And we’re hoping to get new markers now because we know — we’ve done, for example, somewhat sophisticated comparisons between say fibroblasts from the skin, as you mentioned, and astrocytes from the brain. These are human. And we compare them. And there’s overlap —- for sure. But there are also things that are fibroblast specific and things that are astrocyte specific.
Gordon: Okay. So a senescent cell in one tissue isn’t necessarily identical to a senescent cell in a-another tissue.
Gordon: So let’s talk a bit about disease. We’ve talked about cancer. And that-that-that is clear that, you know, preventing cells that have DNA damage from proliferating is a good protection against cancer. Now, in the older animal or human, these senescent cells are driving aging.
Gordon: I think you-you would agree with that. But then, what diseases are they particularly associated with?
Judy: So the most shocking answer is cancer. [sighs] Yeah. So it-it really is a double-edged sword.
Judy: So we know that a cancer cell is responding to its environment. And we know that senescent cells can produce a tissue environment that actually promotes the growth of a cancer cell that has already overcome senescence. So that’s the key. In the young animal, the cancer cell is made senescent because it has an oncogene, and the cell shuts down. But in the older organism, as more mutations accumulate, the cells either escape. Or they’re made new. We don’t know the answer. But now, the tissue environment is fueling the growth of those cells. And we know that we can at least suppress the development of age-related cancer — not childhood cancer but age-related cancer by eliminating senescent cells from mice.
Gordon: I definitely want to talk about this amazing technology to eliminate cells and- all the potential that that-that brings with it. But, just mention some of the other diseases. And I think —
Gordon: — I think what we’re going to get into here is inflammation —
Gordon: — and-and the role of inflammation —
Gordon: — both in aging and normal disease. But-but the fact that senescent cells appear in the brain is driving some neurodegenerative diseases, right?
Judy: Yes. And-and that’s been shown in co-culture models. For example, if we take senescent astrocytes — so they’re a support cell within the brain — and incubate them with neurons, healthy human neurons, those two cell types will exist — coexist just fine until we give a little bit of a signal that is common between neurons called glutamate. And what we know is senescent astrocytes but not non-senescent astrocytes down-regulate the transporters that get rid of excess glutamate. Excess glutamate kills neurons. And so we just published this a year ago showing that, at senescence, the down-regulation of these proteins that get rid of excess glutamate will cause a neighboring neuron to die in the process of experiencing that glutamate. And that does not happen in a young brain because there are so few senescent astrocytes.
Gordon: Let’s talk about inflammation.
Gordon: So it seems like this the senescent cells are producing inflammatory factors —
Gordon: — uh, which I think you coined the-the secretory phenotype of the —
Gordon: — the-the SASP. Uh, so talk about the relationship with that process with the general picture of inflammation in aging and disease. I know it’s a huge topic. You could probably speak on that for a couple of hours.
Judy: Yes. But just to remind you, m — also, many, many years ago, an Italian scientist, Claudio Franceschi coined this term: inflammaging. And his point was, if you take a 16-year-old and do a liver biopsy and you take a 60-year-old and do a liver biopsy and then you give those biopsies blinded to a pathologist, the pathologist doesn’t really need to do very much. The pathologist will pretty much tell you, “This is young. This is old.” And what the pathologist will look for is low-level infiltration of certain immune cells. And that’s what Claudio called inflammaging.
Judy: And it is a general feature of aging and a general feature of aged tissues. It is not all driven by senescent cells. There are drivers that are senescent cells because they’re producing molecules that call these cells to the tissue. But there are other things that will cause, in — for example, a leaky gut will release certain fractions of bacteria. And that will attract immune cells. And that will cause inflammation. So there are multiple causes of inflammaging. Senescence is one of them. We think it’s a pretty important one. But it’s not the only one.
Gordon: You mentioned bacteria there. And I think that’s where most of us in-in high school learn about inflammatory processes is —
Gordon: — in response to bacteria and viruses and so on. But I think you’re hinting that-that the fact that this can happen also in the absence of pathogens —
Gordon: — that this is something that’s happening, sterile inflammation.
Judy: Exactly. So the type of inflammation that’s caused by senescent cells has been called sterile inflammation. There’s no evidence for a pathogen. But the immune cells are there. And-and-and these immune cells are destructive. So many of them are part of the more primitive part of our immune system called the innate immune system. These guys evolved to get rid of pathogens. And they do it by initially secreting toxic molecules —
Gordon: Mm-hmm. Mm-hmm.
Judy: — hydrogen peroxide, hypochlorite, bleach —
Judy: — you know — until the more sophisticated part of your immune system called the adaptive immune system can now make the antibodies and be s — the-the other types of proteins that we associate with sophisticated, immune function. So senescent cells attract mostly innate immune cells. But of course, these two immune systems talk to each other. So eventually, you get a full-blown inflammatory response.
Gordon: I think this takes us perfectly into discussing how to manipulate cell senescence.
Gordon: And earlier, you mentioned a mouse where you had eliminated senescent cells.
Gordon: How do you do that?
Judy: Well, we can manipulate the entire genome of the mouse! I mean, the whole genome has been sequenced. And we can put genes in. We can take genes out. We can make some of them mutant. So it’s-it’s time consuming and expensive. But you can manipulate the genome of a mouse pretty well. And we’ve done that by causing one of these senescent markers to drive a foreign gene that is a killer basically but only in the presence of an otherwise benign drug. And so using that mouse, we’ve shared that mouse with many laboratories, all of them working on a different age-related disease. And that’s why the list of diseases that we know can be driven by senescent cells is so long.
Gordon: How long? How many?
Judy: The list is enormous! I mean, brain aging including the famous disease of, brain aging, cardiovascular disease, skin aging, macular degeneration, hypertension, kidney failure — the list just goes on and on and on. And-and each lab is working on a different disease. We get them our mouse. And they test the hypothesis. Do senescent cells make a difference? And if so, if we eliminate them, is the disease either postponed, which it often is, or ameliorated, meaning it’s not so severe. And that often happens. And once in a while for a few diseases, it actually can reverse. So for example, osteoarthritic joints — when you eliminate senescent cells from those joints, now the joint begins to make some of the proteins that are needed to lubricate the joint. So you no longer have bone rubbing on bone.
Gordon: So that’s rejuvenation, right?
Judy: That’s sort of rejuvenation at least in that tissue. Yeah.
Judy: It doesn’t work that way in all tissues —
Judy: — at all.
Gordon: But, I mean, that list of diseases, these are like the chronic diseases of aging. This is like really — you know, you get to the point where you think, is this — is this particular process, cellular senescence, a driver of most of what we see in aging in humans in chronic disease?
Judy: So in mice, yes. In humans, [laughs] we’re still finding out. We think so because they’re a smoking gun. We now know what they can do in a mouse. And when we see them in humans, again, in all of these diseases, we make the hypothesis that this is also true in humans that they’re drivers. But that has not been proven and won’t be proven until we have drugs that can do what our transgene can do in the mouse.
Gordon: Okay. So drugs —
Gordon: — great.
Gordon: Let’s talk about that. So, there are ways to reproduce what you can do with this mouse with chemical compounds?
Judy: There are some ways. So there are two classes of drugs that are being developed right now. So one of them is called senolytics. And these are drugs that are designed to selectively kill senescent cells but not the non-senescent counterparts.
Gordon: How do they do that?
Judy: Well, in some way — in some cases, we know how they do it. So in one sort of well-known case, senescent cells — the reason why they don’t die is they partially increase the proteins in a cell that are designed to keep that cell alive. So these are called anti-apoptotic proteins. So all cells have pro and anti-apoptotic proteins. Senescent cells have a little bit more of the “anti”. And that’s why they tend not to die. So these drugs then attack those proteins and drive them down. So now, the senescent cell can die. The non-senescent cell which has not increased the level of those anti-apoptotic proteins is mostly okay.
Gordon: I mean, that must really depend on the concentration of the chemical, no?
Judy: Oh, yes.
Gordon: I mean, this must be really important.
Judy: Oh, yes. Uh —
Judy: — the concentration and the cell type —
Judy: — because not all cells are protected from cell death by the same mechanism. So this is why I would say these senolytic drugs are on the horizon. They are being tested by companies. There’s been some modest success in what are called early-phase trials. These are trials where you just look to make sure the drug is not toxic, and the drug is showing some improvement in some disease — early, early stages.
Gordon: So that’s senolytics. And then, you mentioned another approach.
Judy: The other approach are called senomorphics. And what they do is they suppress what senescent cells secrete. We’re a little less enthusiastic about those drugs because what happens is you add the drug. The cell stops secreting. So the inflammation goes down. If you take the drug away, the cell starts secreting again because they’re still there. And the inflammation resumes. So we would argue there’s no such thing as a perfectly safe drug. So the shorter the period of time you can expose an organism to a drug, the better.
Gordon: Mm-hmm. So in other words, you can potentially, with the senolytics, clean out the senescent cells. And maybe you have to do that again and again. But you don’t have to be exposed to the-the chemical agent —
Judy: All the time.
Gordon: — all the time.
Judy: That’s correct.
Gordon: Yes. Yeah.
Judy: That’s correct.
Gordon: You know, I’m wondering, did you ever imagine that you’d be talking about clinical trials resulting from the research that you-you started as a basic question about cancer biology?
Judy: No. And I must tell you this is also true though, of many biologists. When I was a graduate student, we were not encouraged to think about the clinic. I mean, we were basic biologists, you know. You do the molecular biology or the biochemistry or the chemistry. And we were not encouraged — n — we were not discouraged, but we were not encouraged. I think now almost every basic biology lab has at least in the back of their mind how this could be applied in the clinic. And I think that’s great because it has now fueled this growth of companies that are, academic labs are not good at developing drugs. [laughs] And we’re not good business people.
Gordon: I know scientists are rubbish at predicting the future. But do you want to have a shot at this? Let’s talk about the commercialization first before the biology maybe. Do you think that we’re going to see drugs — safe drugs, being developed by these companies in the next five years and that is —
Judy: Five years?
Gordon: — making an impact in human health?
Judy: Yeah. I mean, it’s hard to put a timeline because there are always surprises. Right. I mean, you know, a drug you think is just great all of a sudden will start doing something you didn’t expect. I would say maybe, within 10 years, we’ll probably have drugs, with limited use. So the two most advanced drugs that I know of aside from the ones going into the joint are the ones going into the eye. And the reason why that’s good is because, if you apply something to the eye, it doesn’t get into the circulation. So if there’s bad stuff happening, you minimize that. But I think, within the next 10 years, there will be something out there that hopefully will be successful not for all of aging but certainly for individual age-related diseases. And then, there are drugs like metformin. This is a drug that’s been given to tons of people over many years for very specific indications. But there’s now some hints that metformin can suppress what senescent cells produce. And there are beginning to be clinical trials to follow these large numbers of people who have been on or off metformin and ask, do they have fewer diseases of aging? And if so, what are those diseases? Because —
Gordon: Mm-hmm. Mm-hmm.
Judy: — there’s not going to be a magic pill. You’re not going to go to Walmart and pick up your anti-aging pill and you know, take it once every five years and-and live to be, as old M — as Methuselah.
Gordon: Uh, that’s disappointing. But w —
Judy: I’m sorry.
Gordon: [laughs] Uh, no. It’s actually super exciting. And, it’s great to see the investment in the basic science now play out —
Gordon: – in commercialization, which is basically the way that we can bring drugs to to people in the end and that the whole field of the biology of aging, I think, is undergoing this kind of revolution where —
Judy: Oh, yes.
Gordon: — where we are seeing this happening across the board —
Gordon: — different mechanisms. I want to go back to this revolution in-in being able to study single cells and the genes that are expressed in single cells under certain circumstances —
Gordon: — including different stresses. And obviously, this is very much, connected to what you’ve been doing. Uh, is it — is it there’s normal cells, and there are senescent cells? Or are there other things going on?
Judy: Uh, there’s always other things going on. So there are normal cells, say in the skin. You look — and you look through the different layers, you know, the epidermis, which is the outside, the dermis, which is what gives you the springiness. And then, under that are muscle cells and fat cells and so all these different cell types. So there’s some cells that would look the same no matter what your age is. But there are other cells that definitely look different. And they may not be senescent cells. But what they could be — and we think we can mimic this in culture anyway. What they are are cells that are responding to senescent cells.
Judy: So now, they’re not quite normal.
Judy: But they’re not quite aged themselves. But they’re responding to all these molecules that are being secreted. And then, there are these senescent cells which are rare. But because they’re affecting a large area around them —
Judy: — uh, you see more of the second type than you do of the first or the third.
Gordon: And you’re studying humans now? How-how do you — obviously, you can take, I guess, tissue samples or —
Gordon: — biopsies and-and count cells the way that you’ve normally been doing. How do you establish the-the general load of senescent cells? I mean, can you — can you take someone and say, you get x percentage senescent cells, and that’s good or bad? Or —
Judy: We hope we can do that. We cannot do that now. But we’re hoping that’s where this will lead. Uh, we are also involved in another NIH grant to look for biomarkers.
Judy: And our emphasis is not so much biomarkers of aging but biomarkers of senescence. And the ideal would be to either take a small blood sample. Or even better, we have now one example. We can just take some urine, just pee in a little cup and get a sense of what the burden of senescent cells might be. And this will be important for industry because imagine you have a drug that you think is going to k-kill senescent cells and improve disease.
Judy: It’s going to take years before you prove that that drug is beneficial. But at least, you can take a little bit of pee and show that the drug works, that is that senescent
Judy: — cells are no longer there.
Judy: So that’s what we’re hoping —
Gordon: Amazing. Yes.
Judy: — hoping, hoping.
Gordon: Yes. [laughs]
Gordon: What’s your lab working on now? And what do you think are the major unknowns that you would like to-to continue to work on in the next few years?
Judy: What are the next big things that we want to solve?
Judy: So one of them is understanding cell-type-specific aging and senescence. Why is an endothelial cell different from an astrocyte, different from a fibroblast? And we need to understand that, not only in the context of the whole organism but in the context of individual tissues. I’ll tell you right now. Fibroblasts from your skin are not the same as the fibroblast from your kidney or the fibroblast from your cartilage. So we need to understand that because there may be times when you want senescent cells to be present and times when you don’t. So we need to understand that difference. And this new technology of looking at single cells and asking, “What is their pattern of gene expression?” allows us to pick out very rare cells and begin to formulate hypotheses. Ah, this cell is producing this molecule. This is what has been so powerful with my collaborations at the Buck. I’m really now optimistic that we’re going to be able to pinpoint — we’ve done this, for a couple of examples. For example, wound healing — we were able to narrow that down out of a thousand proteins to one protein that is mostly important for wound healing.
Gordon: What is that protein?
Judy: So that protein is called PDG — GF-A —
Judy: — platelet-derived growth factor A-A. It’s an understudied form of this growth factor. And senescent cells are making lots of it in the skin. And if you take a s — uh, our mouse model —
Judy: — eliminate senescent cells from a wound, the wounds heal much more slowly. They scar more. They’re more fibrotic.
Judy: You topically add PDGF-AA, and you can reverse that slow wound-healing phenotype.
Gordon: Hmm. [Yeah.]
Judy: I mean — yeah. We couldn’t believe it. But it —
Gordon: [That’s] —
Judy: — it’s true.
Gordon: So Judy, I don’t — I don’t know when the last time you did an experiment yourself —
Gordon: — in the lab. [laughs] A little while ago? Yeah. Uh, but, how do you conceive of like the next experiment? How does that happen?
Judy: It can happen in two ways. So one way is you read about something that’s going on. Cells are accumulating with age. Or they’re producing something or other. And you have — I-I can only describe it as a sense just like when you sit down to make pasta Bolognese. I mean, [laughter] you — how much of this are you going to put in? And how much of that? Y — it-it’s a sense. And so e-either you go into the lab and you do it, or you tell your postdoc to do it [laughter] or your student to do it. But there’s another thing that happens that is even more thrilling. And that is you talk about some experiment. The experiment gets done. And the results are totally unexpected. So of course, the first thing you say to your poor student or postdoc or to yourself is, what did you do wrong?
Judy: And you do it again. And, result is true. So let me give you a concrete example. The first biomarker of senescence, this senescence-associated beta-galactosidase.
Judy: — in those days, it was very common to take a bacterial gene similar to the senescence-associated beta-galactosidase and use it as a reporter of sequences that could turn on the expression of other genes.
Gordon: Mm-hmm. Mm-hmm.
Judy: And so what you would do is you would make a construct. You would make a piece of DNA where you had the regulatory sequences that you think was driving something and then the reporter, which was this bacterial gene.
Gordon: The famous lacZ.
Judy: LacZ. Exactly. And then, you would take that piece of DNA. And you would introduce it into human cells or mouse cells or whatever cells you’re interested in and then either watch them, or add a drug, or chain to the medium or do something and look for blue cells. So one day, we’re having a lab meeting. And my post-doc — very good post-doc actually — said, “Wow. I introduced this piece of DNA into senescent cells. And 100 percent of the cells picked up the DNA.”
Gordon: Hmm. Doesn’t sound right.
Judy: Very rare.
Judy: Very rare. This introducing DNA into cells — it’s better now. But in those days, it was a few percent.
Judy: And I couldn’t understand how this could happen. So we set up all these controls. Right. You know, we did enzyme — and I’m walking through the lab. And I open an incubator door just out of curiosity. And in those days, our incubators were set so that there was carbon dioxide in the air —
Judy: — to buffer the medium – and noticed that there were all these blue cells. And I realized that what carbon dioxide does is it, it increases the acidity of the medium. So then, I said to my post-doc, “Okay. Now, forget the incubator. Just make a bunch of buffers at different acidities and ask, do you turn on this enzyme?” And at some level of acidity, all the cells turned blue.
Gordon: And these are senescent cells.
Judy: And the non-senescent cells were not blue.
Judy: And that’s when we realized it had nothing to do with the DNA we were adding. It had to do with something the cells themselves were doing.
Gordon: So you’re telling me that one of your major discoveries —
Judy: [laughs] Was an accident —
Gordon: — published, I believe, in the proceedings of the National Academy of Sciences was down to pure luck — [laughs]
Judy: Yes. Yes.
Gordon: — but not so. And-and I-I say that because wh-what you’ve actually described is being prepared to see something that’s different from what —
Gordon: — you expect —
Gordon: — and then following up on it and reacting to it. And finally, you make this discovery.
Judy: I think it’s the most important part of science is being — first of all, being prepared to be wrong. You set up a hypothesis. I preach this constantly to my lab. If you prove your hypothesis is wrong and you’re really good, you’ve done all — that’s great! That’s fine. We’ve learned something.
Judy: Don’t worry.
Judy: And then being prepared to see something you were totally unprepared for and scratch your head a little bit and come up with some new ideas.
Gordon: Wonderful. Wonderful. Thank you so much, Judy, for your time. It’s been a real privilege to-to have this time with you —
Judy: Same here!
Gordon: — just to unpack some of these things. I’ve learned a whole ton today. So thank you.
Judy: Thank you. Thank you.
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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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