FoundMyFitness - #036 Judith Campisi, Ph.D. on Cellular Senescence, Mitochondrial Dysfunction, Cancer & Aging

Episode Date: April 28, 2017

Dr. Judith Campisi is a professor of biogerentology at the Buck Institute for Research on Aging and a co-editor in chief of the Aging Journal. As an expert on cellular senescence, the discussion involves a lot of talk about aging and cancer, where senescence plays a very important fundamental role. What are some of the strategies we might use in the future to prevent senescent cells? What causes them in the first place?  In this episode, you'll discover:  (00:00) Introduction (05:12) Fundamental molecular and cellular processes of aging (13:19) What is senescence and why did we evolve this cellular function?  (24:09) The difference between lifespan and healthspan (30:32) DNA damage and mitochondrial dysfunction promote senescence  (35:45) Prolonged fasting suppresses senescent cells and stimulates new cell growth (47:30) Exercise extends healthspan, partially by lengthening telomeres (54:03) Consumer tests for DNA damage and cellular senescence (59:58) NAD+ boosters, fasting mimetics, and aging in non-human animals If you're interested in learning more, you can read the full show notes here. Join over 300,000 people and get the latest distilled information on cancer & aging straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Welcome back to another scienterific episode of the Found My Fitness podcast. Today's guest is Dr. Judith Campizi, a professor of biogerontology at the Buck Institute for Research on aging, and a co-editor-in-chief of the aging journal. So about Judy, I've been a huge fan of her work, having read several of her publications and listened to her speak publicly. What excites me about her work is that she's exploring some of the central features of aging, especially when it comes to the role of cellular senescence in the aging process and development of cancer. Cellular senescence is so important when we discuss aging in cancer because as our cells accumulate damage, which naturally happens as we age, even as a consequence of the energy generating processes and immune cell activation,

there's only so many outcomes that we can expect. The first possibility is that cells can die. The next is that they can become senescent, where they stop dividing but stay alive all the while secreting molecules that influence surrounding tissue. Or the worst of all possible outcomes, the cells can really go off the rails and become malignant. What's interesting is that while accumulating senescent cells is inevitable, there are varying strategies of how to tackle senescence, and this is of great interest to the field of aging. There are ways to clear out senescent cells with drugs, or even dietary and lifestyle interventions. Not only are there ways to kill senescent cells, there are also ways to influence what sort of molecules they produce, possibly

limiting the inflammatory ones even without killing them. Finally, of course, we can also try to prevent them, which poses the question of what causes them in the first place. As we'll learn from Judy, there's more than one so-called phenotype exhibited by senescent cells, and they arrive at these different cellular phenotypes as a consequence of different types of cellular stress or dysfunction. In this hour-long conversation, we discussed a great number of very interesting things, including why diseases of aging, despite occurring in very diverse tissue types, all began to crop up simultaneously after 50 or 60 years of life, what the fundamental molecular processes of aging are, and what some of the ongoing research and general thoughts are surrounding these processes,

what senescence is and the evolutionary biology explanation for why we have the mechanism of cellular senescence in the first place. the infiltration of immune cells into our tissues that occurs as a function of aging, and the role of damaged or senescent cells in attracting these immune cells. The changes in gut permeability that happens with age, and how that may increase our susceptibility to chronic low-level inflammation. The role of senescent cells in cancer metastasis and progression. The clearance of senescent cells as a valid life extension strategy.

How mitochondrial dysfunction, even in the absence of DNA damage, can cause cells to undergo senescence. The interesting observation that senescence from damage versus energy crisis or failed mitochondria demonstrates a different and unique phenotype of cellular senescence. The effects prolonged fasting may have on the clearance of senescent cells. How periodic prolong fasts might mimic some of the effects associated with an mTOR dampening drug like rapamycin, how the secretions of senescent cells can affect the regenerative capacity of stem cells, the practicality of a consumer-available clinical assay for DNA damage and the challenge of assaying tissue-specific senescence without the use of an invasive biopsy, the effect of so-called

fasting memetic compounds such as hydroxycitrate, resveratrol, and spermidine on senescent cells, and believe it or not, much more. Okay, one quick mention before we get to the conversation. There's a few amazing things that make these podcasts possible. The first is the tremendous generosity of my guests that are willing to take time away from their research to bring us cutting-edge scientific discussions. This continues to surprise me and is in many ways a huge privilege since I get to meet some of the rock stars of the scientific scene. I feel very fortunate for this reason. The other thing that makes this podcast possible is a group of concerned listeners that secretly conspired to make the world a more informed place by contributing financially to the podcast.

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heading over to foundmyfitness.com forward slash crowd sponsor. That's found my fitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R. Crowd sponsor. Okay, enough of that. on to the podcast. Hello, everyone. Today I'm sitting here with Dr. Judy Campizi, who is a professor of gerontology at the Buck Institute for Research on Aging. Judy has made significant contributions to the field of aging, particularly for her research on cellular senescence, which I'm sure we're going to talk quite a bit about today.

I've personally been following Judy's work for several years, so I'm very excited to be able to have the opportunity to have discussion with her. So, Judy. Thank you. Thank you. I'm ready to just jump in. talk about all things aging. You know, most people when they think about aging, they think about the passage of time, a chronological number. But there's a lot of molecular changes that

occur with aging. Yeah. Well, it's a biological process. And it has its roots in evolution. It has its roots in actually gestation. But it is not just the passage of time, for sure. So can you maybe talk about some of the molecular changes that do occur that can contribute to the aging process? It's a good question. You know, right now I think it's safe to say that most people who work on aging believe there are a few fundamental molecular and cellular processes that drive aging in multiple tissues, which is why all of the diseases of aging, even though they're from very, different tissues all begin to rise exponentially after maybe 50, 60 years of age. But the truth is, we don't know exactly how many processes there are. And we don't really know precisely in each tissue

what the major driver is. So there are theories, the free radical theory of aging, loss of mitochondrial function, the accumulation of senescent cells, which I'm sure we'll talk about more. But for now, I think there are two things we can say that these fundamental processes almost certainly are driving tissue health. As for what actually drives lifespan, we really don't know. Yeah, I guess that's an entirely different topic, I mean, to some degree. I mean, they're related. Nobody dies of good health. Right.

But the truth is that we don't really understand. understand, for example, why a mouse lives three years and a human lives over a hundred years, if you're lucky. And what it is that evolution had to do to take these two organisms, which are genetically pretty similar, but have a 30-fold difference in lifespan. Right. Yeah. Just kind of on the same topic, did you ever see that paper that was published? Maybe it was like 2015, I believe, it was out of Japan. And, the researchers had looked at a variety of different cohorts of aging individuals. So they looked at people that were considered elderly.

So these were like 80-plus-year-olds. They looked at centenarians. They looked at the semi-supercentenarians and then the supercentenarians. Right. And they looked at a variety of different biomarkers. I believe it was something like 12 different biomarkers. They were looking at immunosiniscence in the immune system. But they were looking at telomere length.

they looked at blood glucose levels, instant sensitivity, inflammation markers, and kidney function, like all sorts of things in each, you know, age group. Yeah, in each cohort. And what was found, sort of to my surprise, but not too much to my surprise, is that the only, you know, biomarker that was indicative of successful longevity in every cohort was suppression of inflammation. Yeah, I did read that. I did read that, yeah.

Whereas, like, T liver length affected if you could live to be, I don't know if it was 100 or 80 group, one of the group, one of the, you know, earlier groups. But so that was kind of interesting because it sort of, to me, you know, this whole idea of inflammation, which causes. Inflammaging as Claudio Franceschi. No, this is the term that was coined by Claudio Franceschi. Yeah, I heard of. Yeah. And it really refers to the fact that, well, if a pathologist were to take a liver sample, say, from a 15-year. year old and a 50-year-old. Here she could probably instantaneously tell you who was young and who

was old. One would be just looking at the structure of the tissue, but the other is he or she would look for what we call a low-level sterile chronic inflammation, meaning infiltration of low-level infiltration of some immune cells, but no evidence of a pathogen. And so this is a characteristic of almost all aging tissues is this is low-level inflammation. Most people don't really, I mean, I think they hear the term inflammation. They don't quite know what it means. Yeah. So they're two important.

Well, actually, there are two major modes of inflammation, right? So one is acute inflammation. So you cut yourself, turns bright red. That takes 24 hours. And you'll die without that. I mean, that's the acute response of your innate immune system that's going to try to protect you from infection, but also start the healing process. That acute inflammatory response has to die down after a few days because it's destructive. The innate immune system isn't very intelligent.

It's designed to kill non-specifically. So these innate immune cells make hydrogen peroxide, nitric oxide, bleak, bleat. Right. You know, right. Exactly. The whole idea is just to kill non-specifically until your adaptive immune system can figure out what precisely needs to be killed. So that's your T cells and antibody response. But that takes a few days.

So you need both. Chronic, low-level chronic inflammation or sterile inflammation is similar to acute inflammation in that many of the players are the same. But, of course, it's at a much lower level, if it were, that fulminant, you would probably die very quickly because your tissues would fall apart. But nonetheless, with aging, there's this constant increase in these innate immune cells that infiltrate your tissue. And after a while, the tissue does begin to degrade and lose its structure and lose its function. Yeah. So it's not only, you know, affecting the tissue.

It's affecting, you know, DNA. It's affecting... That's right, because these are damaging. agents, and so it becomes like a feedback loop. You have, you know, cells that are being exposed to these mostly oxidants, and yet then DNA gets damaged, and then the cell responds to the DNA damage, and it makes things worse, and you get into these feedback loops. So the question is, what is the cause of that low-level chronic inflammation? Of course, the short answer is we don't really know. But we have some clues. We have some ideas. Some people have argued that with age, the barrier in your gut breaks down slightly, not enough

to cause bacteria to invade your tissues, but enough to enable bacterial products to leak into your bloodstream. And then, of course, your body is going to respond to go, oh, my goodness, is this an infection? And so you get this slow buildup of immune responses. The other hypothesis, major hypothesis, is that damaged cells, which are what we now think are mostly senescent cells, produce as part of their response to the damage, cytokines, which then attract the immune system. And those are not mutually exclusive, probably both. Right, absolutely. Can you explain what the people who are listening and watching, you know,

what exactly a senescent cell is and how. how, you know, it's obviously that you just mentioned, it's producing more of these inflammatory cytokines in which to me sounds like it accelerates the aging process. But sort of just what is a senescent cell? Why do they form? Yes, good, very good question. So we now, we meaning the field, now I think, would agree that senescence can best be understood as a stress response. It's the way cells have evolved a program to respond to certain types of stressors. And the result of that response, that stress response, is twofold.

The first is that cells will lose the ability to divide, essentially irreversibly. So what happens is tissues begin to accumulate stressed cells that can no longer divide. The curious thing is that they also tend not to do. die or they don't very easily die, so they accumulate with age very slowly and gradually. They're always at pretty low numbers, but they go up with age. The other part of that stress response is the cells turn on a program that causes them to secrete molecules that we classify as being bioactive. And the reason why that term is vague is because there are probably 50, 60, maybe 70 molecules.

that these cells begin to secrete. And so they have many, many activities. Some of them are attract the immune system. So there are cytokines and chemokines that are immune attractants. Some of them are growth factors that will alert the neighboring cells because maybe now, if you have a need for proliferation, the senescent cell itself cannot divide, but it may want to tell its neighbors, hey, start dividing.

They secrete proteases that remodel the tissue that would also help with regeneration and repair. And they also, now we know, very new data from our lab, they secrete bioactive lipids like prostaglandins and leukotriens, which are very important for modulating inflammation, fibrosis, but also, again, tissue repair. So the way we now think of the stress response is that it's a double edge. sort. There's tons of data that go back two decades or more, showing that the arrest of cell proliferation is extremely important for preventing cancer. So that stressed cell is in danger of becoming a cancerous cell, and the stress response intrinsic to the cell says, no way, you will never divide again, and therefore you cannot form a tumor. So there are mouse models now,

and even some people with mutations in the genes that regulate that growth arrest. And those people die in early death due to cancer. And the mice die in early death due to cancer. So we know the growth arrest suppresses tumoragenesis. The secreted factors we also now know can be beneficial for tissue repair and wound healing. So we've shown, for example, in the skin, senescent cells appear at the wound. and they produce growth factors that help the wound heal. That's the good news.

The bad news is, as these cells gradually accumulate with age and don't disappear, they begin to drive this process of chronic inflammation. And that chronic inflammation caused by senescent cells is also a double-edged sort. On the one hand, it attracts the immune cells that will eventually begin to cause tissue destruction and degeneration. On the other hand, the cytokines that attract the immune cells can also have an effect on neighboring cells and cause them to not function properly. So, for example, some of the cytokines that senescent cells produce cause what's called an epithelial to mesenzyme transition. So what is that? Most of the organs in your body are composed of epithelial cells, and these are cells that absolutely must talk to each other.

Mezenkimal cells are the support cells, like in the skin, the epithelial cells are the outer layer. The support cells are in the dermis. Those are the mesenchymal cells. They don't need to talk to each other. They need to signal. They're basically telling the epithelium what to do. Now, when an epithelial cell becomes more meson-like, it stops talking to its neighbors. And that means the tissue is going to start losing function. And so senescent cells can change epithelial behavior so that the tissue doesn't function very well, and it can attract the immune system, which will cause then the destruction of the tissue, do the innate immune cells. So that's the bad side.

The good news is there are very few senescent cells in young people. And below age 50 or 60, you don't see very many of those cells in tissues. But after about the midpoint of our lifespan, they become detectable. And now you can imagine that those cells, as they build up, they start to drive the pathologies that we associate with aging. probably also start to cause more, yeah, cellular senescence. So a couple of questions sort of popped up when you were talking about sort of the double-edged sword and how cellular senescence on the one hand, it's a, you know, it's a function of a stress response that occurs to protect you from cancer. And so the cell stops dividing.

You know, and then the senescent cells, of course, are then making all sorts of various different secreted proteins like you mentioned. And that can have, sometimes it can have good effects if you're talking about wound healing and things, but also it can attract the immune system and cause, you know, more, basically activate the immune system to make more of these hypochlorite hydrogen peroxide, you know, warfare things going on in the cell, which can also damage a cell even more. But the other thing is the growth factors that you mentioned that they're secreting. And, you know, let's say as you are aging, you do have, you have accumulated more damage. And let's say now that that damaged cell is, you know, supposed to undergo senescence because

that's the stress response to protect you from cancer. But in the presence of excess growth factors, that doesn't actually always happen. No, it can start the process of cancer. So it's kind of ironic that the very thing that it's protecting you from, it's also now at some point, possibly now, making you more susceptible to, at least as you get a little bit. So it's just, I mean, there's very good data now in mice from our lab and other labs that the presence of senescent cells can drive late-life cancer, especially those cancers that are pre-malignant and poised to become cancers, but they don't have the mutations that are needed for a full-blown cancer. But under the stimulation, the growth stimulation of a senescent cell, these cells

can now start proliferating, they pick up more mutations, and then eventually they become fully malignant. Exactly. I think I read, you did some experiments out of your lab where you guys injected these free malignant cells into animals with and without the senescent cells. That's exactly right. And with senescent cells, they converted to full-blown malignancy and, you know, eventually kill the animal. So, you know, you should be depressed, right? If you don't have this process, you die of cancer. If you do have this process, you're still going to get cancer. So, you know, what, I mean, we've struggled with this. We in the whole field has struggled.

What do we do about this problem? And the good news is there are now mouse models. We don't know if this will work in humans, but in mice, we can selectively cause senescent cells to die. So finally, we can make them go away. And when we do that, there are health benefits. I should point out not necessarily an extension of lifespan, but definitely an extension of health spans. So our lab has done this. Our colleagues lab at the Mayo Clinic has done this.

There are now a number of labs that are working on the strategy of causing senescent cells to die. And this was initially done with transgenic mice. Of course, we can't make transgenic people. but there's an army of people looking for drugs that will do what the trans genes can do. And some prototype drugs are now, have been published in mice. They're prototypes because they're not yet ready for people. But, you know, and there are companies that are working on these things. So the good news is I think the strategy of tuning down the bad effects of senescence is on the way.

That's on the horizon for sure. We will still have to be careful how we apply those drugs, right? If you're going in for surgery, you don't want to take drugs that will kill off senescent cells because you need to heal the wound from the surgery. So there's going to have to be some intelligent discussions about when it would be appropriate to take these drugs. The good news about the drugs, though, is that from the mouse models, it's not as though senescent cells, you know, blossom at some point after some age. They just gradually accumulate.

So what that means is you don't have to take a drug that kills senescent cells every day. You may have, in mice, you can apply them every few months. And in people, maybe every few years. So this could be interesting strategy to improve health by incrementally knocking down senescent cells every so often. Yeah. So you said that with these studies that cleared away the senescent cells, the health span was improved, meaning I guess, the tissues, the organs aged better and things like that. But I thought I remember a study, maybe it was the Mayo Clinic study, where there was a mouse model, perhaps it was an accelerated aging mouse model, where they did have a lifespan extension of like 20%. No. So that was an increase in median lifespan. median lifespan, but not an increase in maximum lifespan. Sorry, and I should have distinguished between median lifespan and maximum lifespan. So the increase in maximum lifespan was not significant. The increase in median lifespan was significant. So that's what we call health span.

The animals still died, but they were healthier in many respects. You know, it's interesting. So what did they die of? It's not as easy as it might seem to do. determine what kills them out. Actually, even in people, sometimes, you know, pathologists put hearts stopped. Yeah. We don't know. Yeah. We don't know. Okay. So there was an increase in the median lifespan, which is still very important because now you're having more of these animals, which are living longer, but they're living healthier. And of course, for humans, this is amazing. If you, I mean, what people dread about old age is those last. years of life when you know you go through a nursing home and people are they're

barely mobile and you know they can't hear and they can't see and and they're depressed for good reason but you know I think the the image now of being able to be vibrant and then who knows what will do you in the end but you know we will die but it's I think what we mostly fear is those last few years of life where the quality of life is very poor. Where you're degenerative and, you know, a lot of these diseases that are degenerative diseases aren't necessarily like going to kill you right away or, you know, so like you said, you could have, you know, maybe macular degeneration or sarcopenia, something where it's just

slow and miserable and you can't function as well. And then brain, you know, degeneration of the brain is, I mean, dying of cancer is no fun, But I think many people fear even more this loss of cognition. It's like you lose yourself and then the incredible burden on the family. And so the idea is to try to compress that period of morbidity so that the last years of life, you know, you die maybe of a heart attack on the tennis court and you're winning. There's a lovely quotation from Thurgood Marshall. he was our first black Supreme Court Justice.

This was in the 1960s. And someone had the nerve to ask him, how long he plans to live? Lifetime appointment, right? There, you know. And he said, I plan to die at 110 from a bullet wound from a jealous husband. That's pretty funny. But talking about the brain, you just mentioned the brain, I kind of, I've always been curious about what tissues, if certain tissues accumulate more

senescent cells than other tissues, including in the brain. Yeah, so we and others have looked at senescence in the brain. Based on the markers we have, so I should also preface this by saying we don't have perfect markers for senescent cells. There are many markers, and so we tend to. have some confidence that we say a cell is senescent if we look at multiple markers and we say, well, it's a good chance this is a senescent cell. So the best markers that we have have been used in the brain by a number of laboratories. And it seems that the cells that are more likely

to become senescent in the brain are astrocytes. Sporting cell. Exactly. And so that's interesting from two points of view. The first is there are probably more astrocytes in your brain than neurons. There are, absolutely. Yeah, people don't realize that, but, you know, there are lots of astrocytes. The second is it's the astrocytes that give rise to brain cancer. So, again, consistent with the idea that the stress response protects us from cancer, at least for a while. We've studied human astrocytes, and I can tell you,

they amount to classic senescence response, including producing all those pro-inflammatory cytokines and growth factors and proteases. And we even have new evidence that astrocytes, as you know, help protect the neurons from certain types of toxicity, like neurotransmitter toxicity. And we can show that when astrocytes become senescent, they become less effective in that protective response. Really? Yeah. Yeah. So again, you know, being able to get rid of those senescent astrocytes could be beneficial for preserving brain function. Now, once neurons die, that may be too late.

So we have to distinguish between the ability to prevent degeneration in the brain versus reversing it. I think reversal is going to be much harder. It's always much harder, for sure. Is the senescent cells that occur, in the astrocytes, do you think that also, you know, because as we age, brain inflammation also increases. Do you think it's a contributing factor? Yeah, we definitely think that's a contributing factor. It may not be the only factor, but definitely. Well, there's now, you know, lots of evidence

showing that, you know, a lot of cytokines in the periphery can cross the blood brain barrier, a variety of mechanisms. Including this newly discovered lymphatic system that's connected to the brain, the meninges or something. That's right. So, so that's, so that's, interesting. So you don't necessarily even have to have astrocytes senescence to help contribute to neurodegeneration. It could be in your liver or your skin. Exactly. Exactly. So it's sort of like just sort of all connected. Maybe we can talk a little bit about the mechanisms that lead to cellular senescence. I mean, we mentioned inflammation sort of, you mentioned it's a stress response. It's just to stress. But, you know, specifically. What are those stresses? What are the main, like I know the main

mechanism I always think of when I think of cellular senescence. Is DNA damage? DNA damage. Yes, yes. For sure, anything that causes severe or persistent damage to the genome will drive cells into senescence. It makes sense because that puts you at risk for mutations, mutation puts you risk for cancer. So the cells want to shut that damage cell down. But there are other stresses now that we know. We recently showed, for example, that having bad mitochondria in the absence of DNA damage. So this is just mitochondrial dysfunction, if you will. And we could show that you could cause mitochondrial dysfunction by any number of

means, five or six different ways of causing the mitochondria to fail to produce the energy that they need and to produce more free radicals, even in the absence of those free radicals getting to the nucleus, cause the cells to senes. So they will senes in response to bad mitochondria. What's interesting is the cell senes, they stop dividing, they do start secreting molecules, but it's a different complement of secreted molecules. So we can now pretty much determine whether a cell has become senescent due to DNA damage versus bad mitochondria based on their secretory profile. There's overlap.

Don't get me wrong. There's overlap. But there's also distinct features that the mitochondria, are responsible for, bad mitochondria are responsible for versus damage DNA. What's like the main, what would you say the main distinctive? So one of the main distinguishing features is with DNA damage, there's a pathway that increases cytokines like IL-6, IL-8. These are very prominent pro-inflammatory cytokines.

That doesn't happen with bad mitochondria. So that loop is pretty much not, activated, but then other molecules are activated that can also be pro-inflammatory, but through a different pathway. Wow. So this kind of is very extremely interesting. I wonder why that is, and I wonder what, like, if they have different, if there's different, you know, functions of these senescent cells.

But the secretion of some of these pro-inflammatory cytokines and the attraction of immune cells to that, you know, to those, that area. one would think would then cause that senescent cell to be cleared away. Yes, yes. And it probably does happen, but it probably doesn't happen efficiently enough or with age maybe we make senescent cells at a higher rate. So several labs, not our lab, but several other labs have shown that senescent cells express molecules on their surface that can target them for being killed

by the immune system. And the immune system can do that, and it does do that. Nonetheless, we still see this increase with age. But the immune system declines with age, right? Function of the immune system, does, do you think that may contribute? Well, that's a big unanswered question. So what happens when we, what happens with so-called immune senescence is primarily the adaptive immune system. Oh, that's actually the good part of the answer. Exactly, exactly. And this is why you become more susceptible to certain types of infections with age. So the adaptive immune system tends to decline with age.

The innate immune system, if anything, increases in activity with age. And it's the innate immune system that clearly targets senescent cells for clearance. So, for example, senescent cells express on their surface ligands for natural killer cells, and natural killer cells will then attack those senescent cells and kill them. Nonetheless, senescent cells still accumulate with age. So we're considering several possibilities. So one is maybe you're just making them too fast. The immune system can't keep up.

The other is that although the innate immune system doesn't do, decline with age per se, it does change and it could change in a way that it becomes less efficient at clearing senescent cells. So that's a big open question. We don't know the answer to that. And the third possibility is that some senescent cells may develop mechanisms to protect themselves from immune clearance. And we're sort of still studying that now. And we think maybe all possibilities are still open. Geez, I have so many things that popped in my head that I want to talk about, which order because I'm going to forget.

So talking about these changes in the adaptive versus the innate immune system sort of reminded me of Dr. Valtralongos research, who I interviewed a few months ago. And he was talking about how this prolonged fasting in mice, which is about 48 hours, or translates to like four days in humans, which is quite a long fast, but was able to just very robustly clear away damaged cells, presumably senescent cells as well, also caused cellular death, but followed by a massive and robust increase in stem cell proliferation, sort of replenishing the population. But what was so interesting was that it seemed to, at least in aging mice, if you did this in aged mice, it normalized the difference between the

innate and the adaptive. So like you were mentioning, the adaptive immune system declines with age, but this fasting sort of like replenished somehow, I guess the adaptive, maybe some of the stem cells. In the bone marrow, yeah. Yeah. And so you maybe have more of a 50-50 ratio like you do when you're younger. Right. So what would be interesting is if you like somehow did that experiment where you caused, you know, did some fasting and, you know, sort of regenerated that adaptive immune part arm, I guess, of the immune system. And then like gave some chemical to cause silenicin essence and see.

if there's any change in? Well, you know, a lot of Volter's work also has to do with the side effects of chemotherapy, right? So he was able to show that with this intermittent short-term fasting, even in humans, he could not only improve the efficacy of chemotherapy, but prevent some of the side effects. Right. So we've shown very recently using mice, a transgenic mouse model, that, Some of the so-called genotoxic chemotherapies, chemotherapies that damage DNA definitely causes senescence.

And if we eliminate those senescent cells in our transgenic mouse model, we can eliminate several of the side effects, several of the bad side effects of chemotherapy. So one possibility is that what the fasting does is it might eliminate senescent cells more likely what it might do, we think, is dampen mTOR activity. So just to remind you, mTOR is a kinase, which is highly conserved from yeast all the way to humans, and it's a nutrient and growth factors sensing kinase. So high nutrients, high tor activity.

And what has been shown in yeast and worms and flies and mice is that if you dampen, you, you can't, get rid of Tor activity, you need it for life. But if you dampen Tor activity, either genetically or with the drug Rapamycin, which is known to target one arm of the Tor pathway, you can extend lifespan. And what we showed recently is that what rapamycin does, or dampening tour activity does, is it also suppresses primarily the inflammatory arm of secretory phenotype of senescent cells. So it could be that fasting and rapamycin and the secretory phenotype of senescent cells all come together around the tor pathway and that it's really torp activity that's driving both the aging phenotypes, the side effects of chemotherapy,

and may explain, partly explain, the benefits of the short-term fasting that Valtors is a proponent of. Interesting. So if it's dampening the secretion of these cytokines from the senescent cells, but it's not actually getting rid of the senescent cells. It's not, so far as, well, we've shown that either genetically or pharmacologically with drugs like rapid myosin suppresses the secretion of senescent cells, but it doesn't kill them. So unlike some of these other drugs, these so-called senolytic drugs, that actually kills senescent cells, the mTOR drugs,

the mTOR dampening drugs, suppress the ability of senescent cells to secrete. And the effects are last longer than the application of the, the drug in the sense that we know that part of that secretory, pro-inflammatory secretory phenotype is due to a feedback loop. And what dampening mTOR does is it breaks the loop. And the loop takes time to reestablish. So even after you withdraw the drug, you still get suppression until eventually the loop reestablishes and then the cell starts secreting again. So you might think that if you were to fast for four days, you know, every few weeks, you might have more benefit, certainly more benefit than taking a drug like rapamycin, which has side effects.

Right. Because you're not only, you know, when you're fasting, you're also clearing away the damaged cells in theory. I mean, we, you know, we don't know how much of that's occurring in humans yet. Yes, but we do know in mice. That's right. And then the other thing, when this kind of goes back to the mitochondria-induced in essence that we talked about a minute ago, is that we know that fasting increases NAD levels. Yes, so the NAD plus NAD ratio. And that sort of is very interesting because this mitochondrial-induced damage

I think has something to do with declining NADs. It does, actually. So that's what we've shown is that this mitochondrial dysfunction-induced senescence. We call it mitochondrial dysfunction-associated senescence or midas. So we call it the mitus phenotype. It really has to do

with this altered NAD, NADH ratio, and that's one of the drivers. Interestingly, so when you change that ratio, you activate a kinase called AMP kinase. AMP kinase is a major regulator of P53. P53 is a major regulator of both senescence and apatosis. So that could be the link of why in Volta's paradigm you get reduced inflammation. that could be due to suppressing the secretory phenotype, but also increased apoptosis because you now have activated P53. Right, exactly.

Yeah. So I just got sort of loss on the question I was going to ask you, but the... So, okay. No, one other thing I was going to, yeah, I don't know if you're going to ask this question, but it's worth discussing, is the stem cell, the regenerative process that Volta has seen. So we also know that the secretions,

of senescent cells can have very profound effects on stem cell proliferation and function. So it could also be that by dampening the secretory phenotype of senescent cells, you now release those stem cells from the suppression that was due to those secretory phenotypes, and therefore allow them now to do what they do best, which is to proliferate and regenerate tissue. So all of these things really probably tie in to each other. I mean, they're all interrelated. So the growth factors that are actually secreted by the senescent cells do help with stem cell growth? Because I always thought of senescent cells, like, if this happens in a stem cell, you're depleting the stem cell pool and it's contributing the stem cell aging. Both are probably

true. Both are probably true. So we have shown in the skin, for example, that with AIDS, senescent cells do accumulate, but if you clear those cells, you don't get much benefit. And that's because by old age, you've depleted the stem cells. So, you know, you can't, once you've depleted that stem cell pool, you can't go backwards, or at least you can very easily go backwards. But two labs have now shown that senescent cells can also produce growth factors or factors factors that help neighboring cells reprogram to stimulate regeneration. And they do it, again, by their secretory phenotype.

So it's, again, this double-edged sword. Some of the secretions of senescent cells dampen stem cell activity, and others promote stem cell activity. What about the mitochondrial-induced to senesin cells? What's their function? And I know the DNA damage-induced ones are, you know, obviously you're protecting from cancer. What's the purpose? What is the evolutionary purpose?

Well, if you have a cell with bad mitochondria, you probably want to clear that cell, prevent that cell from propagating because then you're going to have clones of cells with bad mitochondria. And we know that that causes all sorts of degenerative diseases. is neurodegeneration as well as muscle degeneration. And so it probably is also protective, but not so much against cancer, but against accumulating degenerating accumulation within a tissue. We know, for example, that people who are born

with mitochondrial DNA defects, eventually the bad mitochondria expand. And so that's not good for an organism. there probably is a protective mechanism to prevent the propagation of cells with bad mitochondria. Okay. Well, that makes more sense. Yeah. I guess, you know, at a certain point, your mitochondria, if you don't have, you know, a really bad defect in mitochondrial DNA, you or mitochondria will repair themselves through mitochondrial fusion. Yeah, I mean, right? Isn't fusion also part of how they sort of exchange all their mitochondrial content, the damage one sort of fixes itself? to some degree. Although I guess that gets diluted.

The bad ones also get eaten up by the lysosomes. Right. Yeah. So I guess there's multiple mechanisms. Do the mitochondrial-induced senescent cells, they produce the growth factors that affect stem cell growth? They produce some growth factors, yes. They produce, for example, amphiregulin, which is a EGF-like growth factor. So they do. They do. So we're still struggling with trying to understand. You know, what aging phenotypes are caused by genomic damage? Yeah, that was my end up.

Yeah, that was my end up. Muscle atrophy? Do you find more in muscle tissue, mitochondrial induced? Well, we find more senescent cells. We don't know. And we find them in the heart, but we don't know how they got there. It's a big unanswered question is to, when you see a senescent cell in vivo, which we do in human tissue and mouse tissue with age,

they accumulate, but what caused them to become senescent? Is it mitochondrial damage? Is it genomic damage? Is it metabolic imbalances? Right. We really don't know yet. It's still one of the big unanswered questions. Yeah, that sort of leads me into the preventative sort of questions I had, and that is, you know,

we do know that there are lifestyle factors that affect mitochondrial health, that affect DNA damage, that affect telomere length, you know, and these things are obvious to a lot of people. I mean, a lot of work out of Elizabeth Blackburn's lab with Alyssa Appel. Yes, yes. They've done some really great work. I mean, a lot of it's associative studies where they're looking at telomere length and various lifestyle factors, but they've shown, for example, you know, that exercise is very important and people that are sedentary have shorter telomeres than people that are physically active.

People that are stressed have shorter telomeres. actually people that have low vitamin D have shorter telomeres. Omega-3. Sugar accelerates the aging process at the level of telomeres. So all these factors. And telomere length also is a major regulator of cellular senescence. Oh, yeah. I think the best way to think about telomere length is that when the telomeres become too short,

so telomeres form a structure that caps the ends of the chromosomes and makes sure that the cell doesn't mistake. that chromosome end for broken DNA, because the cell will try to fix that broken DNA by fusing it to another broken end. And you don't want that to happen with your telomeres. So when the telomeres become too short, that cap structure then is disrupted. And now the cell thinks it has a broken DNA end. It will try to fix it if it can, but if it can't, it will cause in essence. So short telomeres are in a way a subset of DNA damage, which again is a major driver of senescence. So that's, I mean, telomeres tie in exactly.

They're so connected. And don't telomeres sort of take the hit for DNA damage as well? Well, they have a fairly high proportion of the nucleotide guanin. Right, right. And that base is pretty susceptible to oxidative damage. So it becomes like a sensor for damage. It's not the only thing that will cause DNA damage that is oxidized guanin. But telomeres are good sensors of whether there's oxidative damage.

So do you agree that things that would at least have been associated with DNA damage and telomere length in humans and associative studies, but may likely be the same things that help prevent the accumulation of cellular senescence. Yes. Yes. Yeah. Yeah. Yeah. To some degree.

Exactly. Right. I mean, I don't want to oversell the idea that senescence can explain all of aging, just like telomeres can't or DNA damage can't. But we think it's an important process, and it's tied in to other things that may intersect with the senescence pathway, including things like telomere length and genomic damage. damage, but also things like exercise. So there are, there's a recent study that I thought was really interesting. This was a study that looked at lifespan, longevity, in obese people. So both groups were obese, but they compared obese people who was sedentary with obese people who were moderate exercisers. And there was something like an eight year difference in lifespan.

kidding. No. Even with the obesity, moderate exercise in general protected the longevity of obese people. And so imagine what it does for people who are not obese. I think exercise is probably the single most important intervention that cuts across multiple diseases. So sarcopenia, which is, you know, muscle loss with age, and major cause of, you know, see people sitting in wheelchairs like this, horrible. The only intervention, effective intervention, is exercise. And we don't know. We know that exercise can have some effects on senesin cells in vivo, but we don't know how it works. We don't know precisely what it does. What about the stress response pathways it activates? I mean, exercise is a type of hormetic stress. That's right. So it's a little bit stressful

and activating all these. Yeah, so that's one idea is that it's hormetic stress, meaning it's low-level stress that then primes everybody else, all your other stress responses to be hypervigilant. And so then when a bachelomere comes along or an insult from radiation or high sugar because you just couldn't resist that last brownie, you're better able to deal with that stress.

It's one hypothesis. I think there's still, you know, an ocean of ignorance around how exercise seems to be so beneficial for so many indications of aging. Again, aging, not necessarily maximum lifespan, health span. Yeah, it does seem to affect many different diseases of age as well, in addition to circropenia. Cardiovascular health, I mean, you know, cardiorespiratory fitness is also very tightly correlated with... And there are some groups now that are studying the effects of exercise. on side effects of chemotherapy and showing benefits of, again, mitigating some of those side

effects simply by an exercise regimen. And we're not talking running marathons. We're talking sort of moderate but persistent exercise. I think that's... It's fascinating. I've read a couple of the studies, at least the animal studies, where they can sort of force them to run a little bit more on this running wheel. Yeah. And it was like, there was a very robust response in terms of, at least in combination, I think, with the standard of care treatment. That's right. Where I want to say something like 50%. It was something very, like, really?

You know, like, that's very, you know, I've always thought about it as sort of when you're exercising, you're forcing your mitochondria to work harder and you're producing more reactive oxygen species. And cancer cells don't like that. I mean, they're, you know, so who knows? Yeah. Yeah. I think, yeah, mechanism so far unknown, but lots of possibilities.

Right. What about the hope for a clinical assay for measuring things like cellular senescence or at the very least DNA damage in people? Yeah. So that can be done. I mean, I know of at least a couple of companies that are doing this. Usually they use peripheral blood. And there are very good antibodies that will detect persistent DNA damage, so you can stain these blood cells and get a sense of what your DNA damage load is. There are good markers for senescent cells. Now, we always recommend that you use two or three, but we can probably assess the load of senescent cells. The difficulty lies in tissue specificity. So peripheral blood is easy. You know, bucle swabs are easy because

they're accessible, but you know, you really probably want to know how many senescent astrocytes you have in your brain and, you know, brain biopsies are not going to be approved very soon. So that's the difficulty is it's, we can get a general idea from those easy-to-access tissues, but there are tissues we might want to know about that are not going to be easy to biopsy. Is there a correlation between, let's say, if you were to look at cellular senescence in white blood cells or leukocytes between that and the heart or the brain? Yes, yes, there is. And of course, the work that really exemplifies that the most is the work on telomere length, where you take peripheral blood. That's mostly what's being used now

to assess telomere length. But you look at the data, and of course there's enormous scatter in the data. There's always a young person, you know, who's down with a length that's equivalent to a 90-year-old and a 90-year-old who's up there with the equivalent of a 16-year-old. And part of that, I'm guessing, is due to the fact that you're measuring one tissue and you don't know what the history of that. You know, when was the last time you had a cold? That's going to affect, you know, how many T-cells you have with bathealomeres or not. And so human data tends to be messy. It's very messy. Yeah.

I've actually seen this quite a bit because I've done a lot of work with Dr. Bruce Ames. And I've measured DNA damage in people and lean people, obese people, after a certain, you know, giving them an certain intervention. And I do this by measuring phosphorylated H2AX, Gammon H2X, right? Yes, yes, yes. But I've seen, even looking at different age groups, like, you know, sometimes, like the 20-year-olds will, like, look like a 70-year-old. And you're like, what happened, you know, here? Sometimes the obese people look really great, but most of the time obese have higher levels than lean.

But there's certainly, it's, there's a lot of variation. There's a lot of variation. And I think that variation is twofold. The first is, you know, we're people, we're not genetically identical, the way our mice are. So there's going to be individual to individual variation because we're not genetically identical. But the other interesting aspect is that we've taken, in our mice, we have transgenic

mice in which senescent cells activate a protein, a luciferase, that we can then measure by luminescence in the whole animal. So we can follow the appearance of senescent cells in living animals by looking at this luminescence signal. So we start with, say, 12-month-old mice. So that's a 35- or so-year-old person, very low signal. And then as these animals age, the luciferate signal goes up and up and up. Then you look at the ara bars, genetically identical animals, sometimes in the same cage,

and the arabs get larger and larger and larger. So that says there is stochastic variation that's not due to. genetic differences. That causes identical animals to have some with a high burden of senescent cells, some with a low burden of senescent cells. And this is true for virtually every aging marker that has been looked at. The ara bars get larger and larger and larger. So we call this stochastic variation. We don't know whether it's malleable, meaning we don't know whether you can make things less variable or more variable. We don't know whether it correlates with health of the animals,

but it is a very common feature of aging is that things that go wrong do it almost randomly. And there's no idea of what's causing it. It's just... Well, I mean, you know that if you take a bunch of cells, identical cells, genetically identical cells, and you apply some toxin, and then you look at damage, you get a Gaussian curve, meaning there are some cells that don't respond very well. Most of the cells respond a certain way, then some cells that are super responders. And so it probably is just the messy nature of biology. We have all these pathways that are intertwined, and by chance, one configuration makes the

cells super responsive and another configuration makes a cell less responsive. And if that's true of cells, and it's definitely going to be true of something as complicated as a mouse, much less a person. Right. So I have just a couple more questions, a couple more wacky, but just to circle back real, since I have you here, I know we've been talking for a while, but back to the, the, the, the, NAD levels that reminded me of this whole new field as sort of something. semi-new, I guess, on, you know, different precursors of NAD that you can give like nicotinamide riboside and nicotinamide my nucleotide. I know nicotinide ribicide, at least in humans, has been shown to increase NAD levels,

at least at very high levels. What do you think, do you think that any of those, and I know that there's been some animal studies showing it increased health span so that the tissues were aging better and certain organs were aging better? Yes. Do you think that any of those effects of the increased NAD had to do with lower cellular senescence? That's a good question. As I mentioned, we know that this mitochondrially driven senescence.

It's definitely driven by this alteration in the NAD-N-A-D-N-D-H ratio. So it's possible. We haven't really studied those precursors directly on senescent cells. Yeah, it would be interesting. Yeah, it sounds like a grand, I should. Yeah. There you go. And then one more question about, before I get to the other wacky question was, what do you think about some of these, these, like, people call them, quote-unquote, fasting memetics. I don't like that. I think there's too many things going on with fasting, but, you know, that have been shown to clear away damaged cells, like spermating or the hydroxycitrate or serratrol.

Yeah. Do you think that's something? I mean, people are taking these to, like, clear away synestine cells. Yeah, we've explored some of those. Some of them have no effect on senescent cells, which doesn't mean that they might not have health benefits, but it just doesn't act through senescence. Resveratrol, for example, we don't see any effects on, say, pro-inflammatory cytokine secretion or anything that we think might be important. But that doesn't mean that it's not doing other things. I much prefer red wine.

Cells don't like it. Yeah. I don't like it. The other wacky question that just came to my mind was, so I'm thinking about cellular senescence, not the mitochondrial induced senescence, but, you know, the DNA damage induced cellular senescence as a protective effect against cancer. And that's why it's evolved. I mean, we have that because we don't want to dive cancer young.

What about animals like elephants that don't get cancer? They have a relatively long... I don't think it says that they don't get cancer. I think what's amazing is that they're so big, right? And they have so many cells. Yes. And so you would think that there should be ways, they should be super ways they have of protecting against cancer,

because it's a hell of a lot of cell division to go from a single elephant, egg, and sperm, you know, a zygote, you know, to an elephant, which is so big. And there have been some studies on looking at, for example, tumor suppressor mechanisms in some of these animals. Like P503, right? right, they have extra copies of P53. And so... Do they have any cellul senescence?

I was just wondering if anyone's looked at that. I don't know that anyone has looked, but I would be surprised if they don't. I mean, we've seen cellular senescence in, or we, meaning the field, has looked in a number of vertebrate species, and it seems to be common amongst all vertebrate species. Does it occur in lower organisms? They only live... Well, it does... Based on the markers we have, some people have looked in Cieligans and they don't seem to find it there.

But then Cialigans is unusual in that the only dividing cells in the worm is the germ line. But in Drosophila, you know, there is a small fraction of cells that undergo division in the gut. And there is some hints that there may be senescence that occurs in the gut. of the fly. And that kind of makes sense because one thing that happens with age in the fly is they get this gut hyperplasia. It's almost like colon cancer in the fly. But they don't have the vast number of dividing cells that say we have or a mouse has. So it's possible that it might be found in Drosophila. Okay. And what about that just now? One tricker to question. So do they, does cellular senescence occur in more rapidly proliferating cells?

Is that like the gut and the human? It can. I mean, the gut is different, I think, because, remember, those cells are programmed to die. Die, right. Kind of like the immune system, I guess. Or some of, yeah, some immune cells. I mean, but if you think about, say, something like the skin. So, again, those cells are programmed to die, but then there are these basal epithelial cells.

It takes a long time. So unlike the gut, where there's very rapid sloughing off of those cells, it takes longer in the skin. And, of course, people do get skin cancer, and they always come from the basal keratinocytes. This is certain types of skin cancer, right? Not all skin, I mean, not melanoma, for example, which comes from melanocytes.

So those cells can transform, even though they're programmed to die. And we do see senescence in the basal lens. layer of keratinocytes in human skin. So maybe. Does that contribute to collagen breakdown? Well, that's the idea is that it could because they're making a lot of proteases that will destroy collagen.

Yeah. But, I mean, we have, you know, nobody really knows. Yeah. Okay. And so with all your research that you found, you know, throughout the years on cellulosin essence and just aging in general, do you have any practices that you have, sort of gleamed from your own research that you incorporate into your own lifestyle? Yeah, so, you know, moderate exercise, although I always seem to be busier than I like to be.

You know, a good diet, you know, I don't smoke, eat your veggies. But then there's this genetic component which says you should choose your grandparents very wisely. And that's sort of difficult to do. Well, Judy, this has been a very illuminating conversation. I really enjoyed it. Thank you for your interest. Very interested. I look forward to.

Thank the audience for their interest. I'm going to continue reading about your research. I can't wait to learn about all the new things that you discover. But for people that want to learn more about your research, do you have a website or just the Buck Institute? Yes, they can go to the Buck Institute website. And, you know, there's websites for the individual faculty members. Right. I know if you just Google Judy Campeszi, the Buck Institute.

institutes like the top hit. So they can learn more about your research there. Yes, of course. Okay, well, thank you, Judy. Thank you. Thank you. Thank you, everyone for listening. I hope you learned something new from this podcast, perhaps a new fancy term like synolytic that you can throw around at a party to impress fellow revelers. A few quick reminders. This podcast has an amazing accompanying video. Want to know about a study that's being mentioned? Got lost on a word and want to know what it means. my team has put together an amazing supporting video which can be found on the YouTube channel. If you're a supporter, you paid for it. So don't miss out on that. Head over to YouTube.com forward slash found my fitness or just Google, Found My Fitness YouTube.

If you dig the podcast, help me keep it going and maybe even create new opportunities. You can learn all about a wide variety of ways to support the podcast by visiting foundmyfitness.com forward slash crowdsponsor. That's foundmyfitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R, crowd sponsor. Until next time, may your FOX-O-3 expression be strong, your telomeres be long, and your senescence mitigating strategy be multi-pronged. Dr. Rhonda Patrick, over and out.