The Joy of Why - Why Do We Get Old, and Can Aging Be Reversed?

Episode Date: July 27, 2022

Everybody gets older, but not everyone ages in the same way. In this episode, Steven Strogatz speaks with Judith Campisi and Dena Dubal, two biomedical researchers who study the causes and outcomes of aging, to understand how age works - and what scientists know about postponing or even reversing the aging process.

Daniel and Jorge Explain the Universe is a podcast about, well, everything in the universe. Do you want to understand what science knows about how the universe began and what mysteries remain? Are you curious about what lies inside a black hole? And if we'll ever know, Daniel is a physicist working at CERN who actually knows what he's talking about. And Jorge asks all the questions that pop up in your mind as you listen to make sure everything is crystal clear. Listen to Daniel and Jorge Explain the Universe on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts. I'm Steve Srogatz, and this is The Joy of Water,

a podcast from Quantum Magazine that takes you into some of the biggest unanswered questions in science and math today. In this episode, we're going to be talking about aging. Why exactly do we age? What's happening at the cellular level as our bodies get older? Scientists are still chasing many of the answers, but there have been some important advances in understanding the distinctive changes we call aging. Someday, that progress might not only help us live longer, but live better, too.

After all, living many years may not be much of a bargain if it means suffering from diseases like Alzheimer's or Parkinson's. We'll ask, what role do our genes play in aging? And why do women tend to live longer than men on average? And also, what is research finding out about the ways we might slow down the process of aging? Later in this episode, we'll be hearing from Dr. Dina DuBall, Associate Professor in the Department of Neurology at the Weill Institute for Neurosciences at the University of California, San Francisco. But first, joining me now is Dr. Judith Campisi, a biochemist and cell biologist and professor

at the Buck Institute for Research on Aging. Her lab there focuses on cellular senescence, a concept that we'll be unpacking very shortly. She is co-editor-in-chief of the Aging Journal. Judy, thanks so much for joining us today. My pleasure. I'm very excited to be talking to you about this. Well, of course, all of us are getting older, and we all feel it. It raises so many questions, though, like why is it happening?

Is it something that nature is doing on purpose? Is it that our bodies are kind of wearing out like an old machine? How should we think about it? on purpose? Is it that our bodies are kind of wearing out like an old machine? Or how should we think about it? I think the way we have to think about it is in the context of evolution. If you think about humans, our lifespan over the course of our evolution, aging never happened. There was no Parkinson's disease, no Alzheimer's disease. There was no cancer. There was no Parkinson's disease, no Alzheimer's disease. There was no cancer.

Everybody was dead by the age of 40 or 45. So evolution put into place ways of keeping young, reproductively fit organisms healthy for only a few decades, certainly not for the larger number of decades that we're living through now. Many of the processes that happen during aging really happen as a consequence of the declining force of natural selection. That is, there was no natural selection for these diseases. The process we study, cellular senescence, it's now clear, certainly in mouse models, that this process, this cellular process, drives a large number of age-related diseases, everything from macular degeneration to Parkinson's disease, cardiovascular disease, and even late-life cancer.

But it evolved to protect young organisms from cancer, so we certainly don't want to stop it when we're young. It also helps fine-tune certain structures during embryogenesis, and it initiates labor in women in the placenta. So these are the things that evolution selected for and this is why we have to be careful in how we intervene. And that's true for almost everything that happens with age. Evolution didn't try to make us old.

Evolution tried to make us young and healthy and sometimes that came at a cost. It's a fascinating perspective, actually, that the things that are healthy for us when we're young and that would be selected by evolution can have this inadvertent consequence that as we've been able to extend lifespan, I suppose, through better diet or medicine, all kinds of things, that now what used to help us can hurt us. Yes, this idea that what's good for you when you're young can be bad for you when you're

old. It was proposed in the 1950s by a guy named George William, an evolutionary biologist named George Williams. There was no molecular data at that time. No genomes had been sequenced. He pointed out evolution never had to fine-tune the prostate. If you don't have a good prostate, you don't have good babies. So you don't make good babies. On the other hand, almost inevitably with age, over the age of, say, 50 or so, the prostate begins to enlarge, and of course, it becomes a possibility of developing into cancer.

Yet that didn't happen for most of our evolutionary history. Wow. So let's go into cells because it's so rich and wonderful what you and your students and colleagues have been discovering at the cellular level. So could you please define what it means for a cell to be senescent? It is a state that the cell enters in which it adopts three new traits. One of them is it gives up almost forever, almost forever, the ability to divide. It will tend to resist dying. And most important, it tends to secrete a lot of molecules that can have effects on neighboring cells and also in the circulation. Not that many cells have been studied when they become senescent. And almost everything else we

know about senescence is slowly changing as we learn more and more about different cell types and different ways that cells enter senescence. Okay, so they stop dividing. And that makes sense that that would prevent cancer. The other thing is they become relatively resistant to cell death. That is, they stick around. And this could explain why they increase with age, and they do. Many people now have looked in many, many vertebra tissues, and it just seems that the older the tissue, the more senescent cells are present. The caveat to that statement is that there's still very few of them, even in very old and very diseased tissue, a few percent at the most. So why do people think this has anything to do with aging? That has to do with the third thing that happens when cells become senescent,

is they begin to secrete a large number of molecules that have biological activity outside the cell. And that means that those senescent cells can call immune cells to the site where they are. It can cause neighboring cells to fail to function. And it basically causes a situation that is classically termed chronic inflammation. You know, and of course, chronic inflammation is also a great risk for developing age-related cancer, not so much childhood cancers, but age-related cancers. So certain small subset of cells that stop dividing, hang around for a long time, don't die, and yet secrete molecules that call immune cells or other parts of the immune system to come and what? I mean,

are they signaling come and kill me? Or what's going on? What are they secreting for? Yeah. So they're secreting a large number of molecules. So some of them are growth factors. And we reported some time ago that at least in a mouse, if you make a wound, like a skin wound, just a little punch biopsy on the back of the mouse, at the site of that wound, senescent cells form within a few days, and they secrete growth factors that help the wound heal. This is why evolution selected for this phenotype. It's not all bad. On the other hand, if you have a precancerous cell nearby, and those growth factors are now being secreted, and this cancer cell sees them, it's

possible that that cancer cell will wake up and start to form a tumor. So again, good for you when you're young, bad for you when you're old. Well, let me ask some basics while we're talking about senescent cells, because I think there are some things I'm curious about. For instance, should I think of them as having started out like any other kind of cell and something set them on a pathway to become senescent? Or are we born with them? Or what's the right way to think about this? I think that where the field is right now is we're beginning to realize that all senescent cells are not equal. And so then the question is, why would

what starts out as a normal cell, so you're right, you start out with a normal cell, what would make it enter this strange state where it doesn't divide and it's got all these molecules it has to make and secrete? that we tend to associate with both cancer and aging. So, for example, anything that damages the genome or even damages what we now call the epigenome, the way genes are organized within the nucleus, anything that damages that has the potential to drive a cell into this senescent state. On the other hand, there are also stresses that we don't think about as normally associated, certainly not associated with cancer, but things, for example, like advanced glycation end products, the chemical reactions that take place when glucose levels are too high. And so this is a big problem with people who have diabetes or pre-diabetic

conditions. So those chemicals can also cause a cell to become senescent. So it's more appropriate to call it a stress response, except not all stresses result in senescence. Let us, if we could, talk about the mouse experiments that you and your group have done, really pioneering experiments where you've used the technique in molecular biology of transgenic mice. Maybe first you should tell us what they are and then how you use them as a kind of test bed for how to get rid of bad senescent cells. So right now in biology, it's pretty straightforward and easy to insert DNA into the genome of a mouse and then have that mouse develop into a full-blown adult mouse and have that adult mouse make babies. And so the mouse that we made, this transgenic, so that's called a transgene.

we made this transgenic, so that's called a transgene. The transgenic mouse we made carried a piece of DNA that had a foreign protein made when cells become senescent. And that foreign protein had three parts, a molecule that was what we call luminescent, that was what we call luminescent, meaning we could image these cells in a living animal. It had a fluorescent protein, which meant that we could sort senescent cells from the tissues of that mouse. But most important, it had a killer gene, a gene that would normally be totally benign. But if you feed a drug which is also very benign, that drug and the presence of that foreign gene will cause senescent cells to die. So we made this mouse quite a while ago, and we've shared it with dozens and dozens of academic labs that are studying different diseases of aging.

academic labs that are studying different diseases of aging. Alzheimer's disease, Parkinson's disease, cardiovascular disease, age-related cancers, osteoporosis, osteoarthritis, etc. And the results are just astounding. If you eliminate senescent cells, it is possible to do one of three things to an age-related pathology. You either make it less severe, or you postpone its onset, or, and this is, of course, the one we all love, in a few cases, you can even reverse that pathology. I know. That's true for osteoarthritis so far. And so this is now sort of given meat to the idea that developing drugs that can do what our trans genes can do. It's too late for any adult to get their trans genes, but if you have an unborn baby, it may be possible. Oh, I see where you're going with that. I mean, of course, that's a big can of worms for us, isn't it, to think about? I know. It's too political where you're going with that. I mean, of course, that's a big can of worms for

us, isn't it, to think about? I know. It's too political. It's already been done. Oh, really? Well, it's been done. It's been done in China, right? You're saying that fetuses, or before fetuses. That's correct, was engineered. Yeah, I don't know. The guy who did it, the Chinese guy who did it, was condemned by the community because there were not enough controls, there was no oversight, etc., etc. But it's possible. There's no intellectual reason why we can't make transgenic people. And my guess is it's not just China. Okay.

In terms of what was actually – we know that you've done and you and the other people doing transgenic mice. Just make sure I got that. You said there were three parts to the transgene, two of which it sounds like were for detecting. So there's the luminescent and the fluorescent part. But the killer part is the part that is playing the role of, in the future, drugs, I suppose, that could kill off the bad senescent cells. You had this genetic mechanism. That's exactly right. So the drug that we use to kill senescent cells in the mouse would not work in a human because humans are not transgenic. But the idea would be now to develop new drugs, and they are being developed. There are already some that are being used in mice and even

a few in early stage clinical trials in people with the idea that they would mimic what our transgene can do in the presence of this otherwise benign drug. And so the punchline here is that if this really comes to pass, this gives us hope for, as you said, postponing, ameliorating, or in some cases, maybe, again, we're dreaming, but like there's science behind this, or possibly reversing some of these many age-related diseases that you told us about. Yes. Wow. You'll die on the tennis court at 110, but you'll be winning. Thank you very much, Judy. This has been just a delightful conversation. My pleasure. Just a delightful conversation.

My pleasure. Explore more science mysteries in the Quanta book, Alice and Bob Meet the Wall of Fire, published by the MIT Press. Available now at Amazon.com, BarnesandNoble.com, or your local bookstore. Also, make sure to tell your friends about the Joy of Why podcast and give us a positive review or follow where you listen. It helps people find this podcast. Why we age and what happens to our bodies as we age are two of the biggest mysteries about aging. Another mystery has to do with sex differences. Women tend to live longer than men. It's often said that they live three to five years longer. But really, if you look at the global statistics, you see that in some places, women live more than 10 years longer. So what is it about being female that makes women more resilient?

The body of a 70-year-old woman may be younger than her 70 years, biologically, when compared to that of a 70-year-old man. Researchers on aging say that an epigenetic clock runs differently for each. If we can understand why a woman's brain might also age differently than a man's, we might be able to develop therapies to help everyone. Research into this question gets us into proteins and sex chromosomes and hormones. this question gets us into proteins and sex chromosomes and hormones. The goal is to understand all of this better. Can we slow down the aging process somehow? Joining me now to discuss all this is Dr. Dina DuBall. She's an associate professor of neurology at the University of California, San Francisco's Weill Institute for Neurosciences. Her lab studies female longevity and the aging brain. What makes

it resilient against cognitive decline? Dr. DuBall is also an investigator with the Simons Collaboration on Plasticity and the Aging Brain. Dina, thank you so much for joining us today. My pleasure. Thank you for inviting me. Well, I'm really pumped up by this. You know, I think in my own family about how sharp some of the women were in their 90s. I recently had an aunt who just passed away just shy of her 100th birthday. She had smoked her whole life, but she was sharp. And I don't know how she could have managed to live so long. The men were all gone. The husbands had all died. Yeah, I noticed something similar in my family of origin when I was very young, and that is that women lived longer than men. And every summer, growing up, my parents would take me back to

India, their country of origin, their immigrants from India. And we would spend time in a very small village in Western Gujarat. And it was really remarkable that the elderly were really mostly women. And I had a great grandmother, whose name was Rumba, who was just a remarkable woman, not educated, but really smart. And she lived almost to her 90s. And her husband, my great grandfather, despite being robust, tall, handsome, and also very smart, he died in his early 40s. And so her lifespan was nearly double that of his. And this was seen really throughout my extended family that the women live longer than the men. And I always wondered why that was. I mean, I'm sure that many of our listeners are thinking the same thing. It's a pretty

commonplace experience that the women outlive the men. Of course, it's not universal. There are exceptions for all kinds of reasons, But it's just an amazing general trend. So in every society that records mortality across the world, women live longer than men. From Sierra Leone, where lifespan is lower, to Japan and Sweden, where lifespan is much longer. But here's a really interesting piece of information. When we look historically across multiple countries and societies at times of extreme mortality, like famine and like epidemics, the girls will live longer than the boys and the women will live longer than the men. And this really suggests to us that there is a biologic underpinning for female longevity because even when there is very high and equal stress in the environment with very high mortality,

the girls are outliving the boys and the women are outliving the men. outliving the boys and the women are outliving the men. There's some very, very sad and really remarkable times that demonstrate this, including the Irish famine and many, many other examples in our world history. It's really fascinating to think that it's somehow so intrinsic that there's something, you know, you mentioned the cultural aspects, but it does feel like there's something purely biological also going on. And I wonder if we could get into that. I mean, is there something happening in the body itself that could account for these differences? There can be really, I would say, four main reasons, if we think about this biologically, why there could be sex differences in human longevity. One has to do with sex chromosomes, our genetics, our genetic code in

every single one of our cells in our bodies. And that is that female mammals, and certainly female human mammals, have two X chromosomes in every cell. One of them is inactivated during development, but there are two X chromosomes, and that is the sex chromosome complement of women and girls. In contrast, boys and men have one X and one Y. have one X and one Y. And so here already at the outset, there is a very clear and striking difference in our genetics. And so with this difference in XX females compared to XY in males, there arises four biologic reasons for sex differences in longevity. One is that in males, there's a presence of a Y. And it is thought, although not experimentally shown, that maybe there are toxic effects or deleterious effects of the presence of a Y chromosome. Wow, what an idea. Well,

why do living things get old at all? Why don't we live forever? What causes aging in the first place? There is a change in biologic functions that lead to dysfunction and vulnerability to diseases. One major cause is genetic instability. So over time, our genetic code becomes more unstable. So mutations will occur. Parts of our genes kind of jump around. Those are called transposons and disrupt other parts of our genetic code. There are changes that occur epigenetic, that means on top of our genes, that ultimately change the way that our cells express themselves. And that becomes

dysregulated and more dysfunctional over time with aging. All right. Well, so there's the story of why we age then is a very multifaceted one, apparently. Yeah, yeah. And the loss of what we call homeostasis. But really what that is, is housekeeping of proteins, how they're turned over, how they're modified, how they're folded, what is done with the proteins in our cells, and the housekeeping of these proteins declines with

aging. And so then there's this buildup of essentially gunk of like clutter that really jams up cellular processes and contributes to aging as well. Mitochondria are the powerhouses of our cells, and they have more dysfunction with aging. This brings us back to another possible biologic reasons for female longevity. It brings me to something called the mother's curse. So all the mitochondria in all of your cells, Steve, and all of mine are inherited from our mothers. So in the process of cellular division and the creation of a zygote, mothers pass on their mitochondria, not fathers. And so this becomes really important because mitochondria can only undergo evolution in a female body. Males will never pass their mitochondria on.

And so at the end of the day, what that predicts is that mitochondrial function is more evolved to female physiology when compared to male physiology. And this may make a difference with aging. When things begin to go awry, the female cells may be more fit because the mitochondria are more evolved to the female cells compared to male cells. For males, that would be a mother's curse. And then a mother's blessing for females, maybe? Interesting. This is an interesting thing. Wow. So that gives me a very good big picture about what's happening. So living longer, though, is just one aspect of what we'll be discussing here. There's also the issue of living better, right? In terms of not, in the case of people, not experiencing the cognitive decline that we, reducing that that we all associate with getting older. in history has lived to approximately 122 years old. But then health span is really a measure of

how many healthy years of life is one living. That's what we really aspire to is really good, healthy health span, where we are not suffering from cancers, cardiovascular disease, cancers, cardiovascular disease, neurodegenerative diseases like Alzheimer's, cognitive decline, and more that happens with aging. So with a very good health span, one lives a healthy life without these chronic debilitating conditions until, let's say, 100. And then one dies peacefully in one's sleep from pneumonia, let's say. But that is healthspan. It's really life lived without diseases. And the reason that we are so interested in lifespan is that the things that help us to live longer tend to help us to live better.

longer tend to help us to live better. So if we can understand the molecules that work together to conspire toward longevity, we can harvest those molecules to help fight disease. And that's why we're so interested in why is it that women live longer than men? Is there some biology of aging that can be discovered, learned, and then harvested toward better health span in males and in females? Well, let us start getting into that then. I mean, I suppose our common sense would say that it's got to be about sex hormones, that we associate testosterone with men, estrogen with women. Is it estrogen that's the secret here, that that's somehow protective? Or let's start with that. Is this a story of estrogen? Yeah, it's a golden question.

So this brings me to the fourth biologic reason for sex differences in longevity. One was, could it be the presence of a Y that increases mortality? Is it an extra X in females that extends lifespan? Is it a mother's curse of mitochondrial inheritance from mothers only that works against males? And fourth, what about sex hormones? Could it be that testosterone is decreasing lifespan in males and estrogen is increasing it in females? I think this is a really important possibility in considering sex differences in and experiments in animals. There is some support

that removing testosterone prolongs life. The Korean Chosun dynasty had a population of Korean eunuchs that were castrated. They were useful and respected members of the dynasty and of the imperial court. And they lived a very long life, a significantly longer life than men of the same socioeconomic status that lived at the same time, on average, 15 years longer. This is amazing. Right? Wow. It suggests that decreasing testosterone prolongs

life. And we do see this actually. There have been animal studies in which sheep are castrated and will live longer compared to those that are not. And some very robust studies in dogs. Of course, we spay our dogs and castrated male dogs will live longer than non-castrated male dogs. But Steve, I have to tell you that this question that you asked was burning me for many, many years. Could it be the hormones that contribute to female longevity? Is it estrogen?

Or could it be sex chromosomes that contribute to longevity? And to that point, we did a really neat experiment to be able to dissect out those two causes. And I'd love to explain it if this is a good time. It's perfect. And I like that you describe it as neat because in reading about it to prepare for our conversation, I thought this was such an elegant and, you know, this is like primo science. This is the scientific method to ask this tricky question and find a way to get a good approximation to an answer to it. It was a really exciting experiment to do, and it mattered not what the results were. We were to follow the science, and the science would tell us something about the cause of sex differences and longevity. And so to be able to dissect out whether female

longevity was driven by hormones or by sex chromosomes, we used a really elegant, as you said, animal model called the FCG model, the four core genotypes model. And in these mice, there's a genetic manipulation, there's a genetic engineering that's taken place. And that is on the Y chromosome, there is this SRY or a testes determining factor. There's a gene that causes male differentiation and the production of testes determining factor. There's a gene that causes male differentiation and the production of testes and testosterone. So in this model, SRY is taken off of the Y chromosome and added to any other autosome, the non-sex chromosomes. And what this allows is the inheritance of this testicular determining factor, the SRY, the inheritance of it by males that are XY or by females that are XX. So at the end of

the day, this genetic engineering enables the creation of mice that have four sexes. creation of mice that have four sexes. XX mice with ovaries, that is the typical female biologic genotype and phenotype. XX mice that have developed as male with testes. And that's, again, because they inherited the testicular determining factor, SRY, and they have differentiated as males, and they cannot be distinguished from other male mice except that they're XX. So they have testes, they have male reproductive behaviors, they ejaculate, they fight in their cages. They are male mice except they're XX. Huh. So I've got it. I want to make sure everyone listening has got it because it's so incredible, this way of doing things, that you can make – I mean, let me put it crudely. I think it's approximately right. Phenotypically, on the outside, they look like males.

But inside, in terms of their chromosomes, they look like females. That's right. That's right. look like females. That's right. That's right. And then we do the same in males in that we produce X, Y males that lack the testes determining factor and have developed by default as females. That is that they are indistinguishable from other female mice. They have ovaries. They have a uterus. They cycle. They have female reproductive behaviors. They are female mice. They have ovaries. They have a uterus. They cycle. They have female reproductive behaviors. They are female mice, except their genetics are XY. And then we have the typical male that is XY male that has developed a male phenotype. So this model produces four sex genotypes with males and females, XX and XY, that develop with either ovaries or testes.

And this allows us to really track which mice will live longer. Is it the mice that have ovaries, regardless of being XX or XY? Or is it the mice that are XX, that have female genetics, regardless of growing up with ovaries or testes? Before you reveal the answer, let me ask the question a different way, because I want everyone to mull this question over in their head and guess what the answer is. So the question is, you've created this thing that's a little hard to wrap our minds around, but I think we've got it. These four sexes, a traditional male, a traditional female, a male genetically, but I don't know which one you call the male. You refer to male as anything that's XY, is that right? I do, but it's a matter of

taste and style. Okay, but so it's an organism that's XY but has ovaries. Yes. Or you can have an organism that's X, not an organism, it's a mouse that has XX but has testes. It's Sudoku. It's like this is scientific Sudoku. That's great. Yeah. We actually didn't have a specific hypothesis.

We were going to follow the science and what we found very clearly is that the mice with 2x chromosomes lived longer than those that were xy so the xx mice regardless of growing up with ovaries and having lots of estrogen, or regardless of having testes and lots of testosterone, it was the XX mice that lived longer compared to the XY. So this was a decisive genetic experiment that showed us really for the first time, that sex chromosomes contribute to female longevity. Now, there was more that the experiment taught us too. The mice that lived the longest of all the groups were the mice that had ovaries combined with the XX chromosomes. Those lived to maximal longest lifespan, suggesting that the hormones produced by the ovaries, the ovaries and the hormones also contribute to female longevity. And that maybe testosterone is deleterious.

So the answer was the main statistical effect was that sex chromosomes contribute to female longevity. However, the hormones did have an effect in there as well. So of the four sexes that we could choose from in this Sudoku that you created, the traditional female, if I can keep referring to it as that, seems to be the winner. In living the longest, yes. What about the worst? What about the one living the shortest? Is it what I would guess? The XY with testes. The XX mice, whether they grew up with ovaries or testes, lived longer than the XY mice that grew up with ovaries or testes. XX mice lived about 15 to 20 percent longer than XY mice.

It's an enormous difference, really. I mean, I assume by any statistical measure it was considered significant. Your statisticians must have said. Is that right? Absolutely. Very, very clearly significant. A very clear sex chromosome effect. Well, thank you on that very inspiring and thoughtful note, Dina. This was a really just an outstanding discussion.

Thanks so much for joining us today. My pleasure. Want to know what's happening at the frontiers of math, physics, computer science, and biology? Get entangled with Quantum Magazine, an editorially independent publication supported by the Simons Foundation. Our mission is to illuminate basic science and math research through public service journalism. Visit us at quantamagazine.org. The Joy of Why is a podcast from Quanta Magazine, an editorially independent publication supported by the Simons Foundation. Funding decisions by the Simons Foundation have no influence on the selection of topics,

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