Not everyone ages in the same way. Many people have a decline in health brought on by age related diseases. Women live longer than men around the world, and there are people who are still young. What is that? In this episode, Steven Strogatz talks with Judith Campisi and Dena Dubal, two researchers who study the causes and outcomes of aging to understand how it works.
If you want to listen to it on the go, you can either use one of the aforementioned platforms or stream it from Quanta.
Steven Strogatz is the host of The Joy of Why and he takes you into some of the biggest unanswered questions in science and math. We are going to talk about aging. Why do we get older? As our bodies age, what is happening at the cellular level?
Some important advances in understanding the distinctive changes we call aging have been made by scientists. Someday, that progress could help us live longer. Living many years may not be a good idea if you suffer from diseases like Alzheimer's or Parkinson's. We want to know what role our genes play in aging. Women are more likely to live longer than men. What research is being done about slowing down the aging process?
We will be hearing from Dr. Dubal later in the episode. Dr. Judith Campisi is a researcher at the Buck Institute for Research on Aging. We are going to unpack the concept of cellular senescence very soon. The Aging journal is co-edited by her. Judy, thank you for joining us.
Judith Campisi said that she was happy.
Strogatz is excited to talk to you about this. We all feel like we're getting older. Why is it happening? Nature is doing something on purpose. Our bodies are starting to wear out, is that the case? How should we respond to it?
The way we think about it is related to evolution. Over the course of our evolution, aging didn't happen. There was no Parkinson's disease or Alzheimer's disease. Everyone died before the age of 45. Evolution puts into place ways of keeping young, reproductively fit organisms healthy for a few decades, not for the larger number of decades that we are living through.
Many of the processes that happen during aging are a result of the decline in natural selection. There was no choice for these diseases. It is now clear that the cellular process drives a large number of age related diseases, including Parkinson's disease, cardiovascular disease, and even late-life cancer.
We don't want to stop it when we're younger. During embryogenesis, it helps fine- tune certain structures. It starts labor in the woman in the uterus. These are the things that evolution is trying to find. This is why we have to be careful. That is true for most things that happen with age. It wasn't evolution that tried to make us old. We were made young and healthy by evolution. Sometimes it came at a price.
Strogatz says that the things that are healthy for us when we are young can have consequences. What used to help us can hurt us now that we have been able to extend lifespan.
This idea that what is good for you when you're young can be bad for you when you're old is true. A guy named George Williams proposed it in the 1950's. There wasn't a lot of data at that point. There were no genomes that had been done. He said that evolution didn't have to fine- tune the prostate. You don't have good babies if you don't have a good reproductive system. Good babies aren't made by you. With age, over the age of 50 or so, the prostrate enlarges and is a possibility of developing into cancer. That wasn't the case for most of our evolutionary history.
Wow, Strogatz! It is so rich and wonderful that you and your students and colleagues have discovered at the cellular level. What does it mean for a cell to be senescent?
The cell enters a state in which it adopts three new characteristics. The ability to divide is one of them. It will be resistant to death. It tends to produce a lot of molecule that can affect other cells and the circulation. When cells become senescent, not a lot of cells have been studied. As we learn more and more about different cell types and different ways that cells enter senescence, everything else we know about it is starting to change as well.
So they stopped dividing? That would prevent cancer. They're resistant to cell death. They stay around. This could explain why they grow older. People have looked in many tissues. The more senescent cells are present, the more old the tissue is.
There are still very few of them in old and sick tissue. A small amount at the most. People think this has something to do with aging. The third thing that happens when cells become senescent is that they start to produce a lot of molecules that are outside the cell. senescent cells can call immune cells to the site where they are and cause neighboring cells to fail to function Chronic inflammation is a situation that is caused by it. Chronic inflammation is a risk factor for age related cancer. Childhood and age related cancers are not the same.
A small subset of cells that stopped dividing hang around for a long time, don't die, and still produce immune cells or other parts of the immune system. Are they signalling to come and kill me? What's happening? They are secreting for something.
They are secreting a lot of molecule. Some of them are related to growth. When you make a wound on a mouse, senescent cells form within a few days, and they produce growth factors.
This is the reason evolution was chosen. It's not terrible. It is possible that a cancer cell will wake up and form a tumor if you have a pre-cancerous cell next to it. Good for you when you are younger, bad for you when you are older.
Strogatz asked about some basics while we were talking about senescent cells. Is it a good idea to think of them as having started out like any other kind of cell and been set on a path to senescent? We are born with them. What is the best way to think about this?
The field is starting to realize that senescent cells are not the same. So you are correct, you begin with a normal cell. Where it doesn't divide would make it enter this weird state. We tend to associate stress with both cancer and aging. Anything that damages the genome is now called the Epigenome. Damage to the nucleus can cause a cell to go into senescent state.
On the other hand, there are also stresses that we don't associate with cancer as often as we would like. The chemical reactions that take place when glucose levels are too high can be found in advanced glycation end products. This is a problem for people with diabetes or pre-diabetes. Those chemicals can cause the cell to stop functioning. It is more appropriate to refer to it as a stress response.
Strogatz wants to talk about the mouse experiments that you and your group have done, where you used the technique in the creation of genetically modified mice. You should tell us what they are and how you use them as a testbed for how to get rid of bad senescent cells.
Campisi says that right now in biology it is easy to insert DNA into a mouse and have it make babies. The mouse that we made was trans. A transgene is a piece of DNA that is made when a cell becomes senescent. There were three parts to that foreignprotein. We were able to see the cells in a living animal because of a molecule called luminescent. We were able to sort senescent cells from the tissues of the mouse because it had a fluorescentProtein. It had a genes that would normally be benign. senescent cells will die if you feed a drug with a foreign gene.
We made this mouse a long time ago. Alzheimer's disease, Parkinson's disease, cardiovascular disease, age-related cancers, osteoporosis, osteoarthritis, et cetera are some of the diseases being studied by academic labs. The results are simply amazing.
If you eliminate senescent cells, you can either make it less severe, or you can delay the start of the disease.
Strogatz said, "Oh wow."
Campisi knows. So far, that is the case for osteoarthritis. This has given rise to the idea that we can develop drugs that can do what our transgenes can do. It's too late for adults to get their transgenes. It is1-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-6556
Strogatz sees where you're going with that. That is a big can of worms, isn't it?
It is too political. It has been completed.
Strogatz asked if it really was.
It has been done. In China, it has been done. Yes, right?
Strogatz says that you are saying that the fetus is before the uterus.
Campisi says that is correct. It was made. It's true. The Chinese man who did it was condemned by the community because there weren't enough controls. There was no oversight. It is doable. There is no reason why we can't make people with certain genes. I think it's not just China.
Strogatz: Okay, in terms of what you did, you and the other people, make sure I get that. It sounds like there are two parts to the transgene that are for detecting. There are two parts, the luminescent and the fluorescent. The bad senescent cells could be killed off by drugs in the future. There was a genetic mechanism that you had.
That is absolutely correct. Humans are not genetically modified so the drug we use to kill senescent cells in the mouse wouldn't work in them. New drugs would be developed now. They are being worked on. There are some that are being used in mice, and 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.
Strogatz said that if this really comes to pass, it will give us hope for, as you said, postponing, ameliorating or in some cases maybe. That's what you said to us. I agree. Wow!
You'll die on the tennis court at 112. You will be the winner.
Strogatz said thank you very much to Judy. This has been enjoyable.
There are more science mysteries in the book Alice and Bob Meet the Ball of Fire. You can find it at Barnesandnoble.com or at your local bookstore. Tell your friends about The Joy of Why and give us a positive review. It makes it easier for people to find this show.
Two of the biggest mysteries about aging are why we age and what happens to our bodies as we get older. Sex differences are one of the mysteries. Men live longer than women. People say they live three to five years longer. Some places show that women live more than 10 years longer. Being female makes women more resistant. A woman who is 70 years old may be younger than a man who is 70 years old. An epigenetic clock is different for each person.
We may be able to develop therapies to help everyone if we can understand why a woman's brain ages differently than a man's. Sex chromosomes and hormones are related to research into this question. The goal is to comprehend all of this. Is it possible to slow down the aging process.
Dr. Dena Dubal is here to talk about this. She is an associate professor at the University of California. The aging brain is studied in her lab. Is it possible that it is resistant to cognitive decline? The Simons Collaboration on Plasticity and the Aging Brain is led by Dr. Dubal. Thank you so much for joining us.
I would like to thank you for the invitation.
Strogatz said he was pumped up by the news. I think about how sharp some of the women were when I was a child. I had an aunt who was 100 years old. She had been smoking her entire life. She was quick. I don't know how she lived so long. The men were all dead.
When I was young, I noticed that women lived longer than men. My parents took me to India every summer when I was a child. Immigrants from India. We went to a small village in western Gujarat. It was amazing that the elderly were mostly females. Rumba was my great-grandmother, who was not educated, but smart. She lived to the ripe old age of 90. Despite being very smart and robust, my great grandfather died in his 40s. Her lifespan was more than twice that of his. I always wondered why the women lived longer than the men and this was seen throughout my family.
Strogatz said he was sure that many of his audience were thinking the same thing. It is a common experience that the women live longer than the men. It isn't universal. It is an amazing general trend and there are exceptions for all sorts of reasons.
Women live longer than men in every society. Japan and Sweden have lifespans that are much longer. At times of famine and epidemics, the girls will live longer than the boys and the women will live longer than the men.
When there is high and equal stress in the environment with high mortality, the girls are out living the boys. The Irish famine is one example of a sad and remarkable time in our world history.
It does feel like there is something biological going on, but it is fascinating to think that it is so innate. I don't know if we could get into that. Is there something going on in the body that could explain the differences?
Dubal says there can be four main reasons. Sex differences and human longevity can be explained by this. Sex chromosomes, our genetics, our genetic code, and every single cell in our body are all related. Female mammals and female humans have two X chromosomes in their cells. The sex chromosomes complement of women and girls is dependent on one of them being inactivated. Men and boys have the same number of X and Y.
There is a very clear and striking difference in our genetics at the beginning. There are reasons for the sex differences in longevity. The presence of a Y in males is thought to have a negative effect on the body.
Strogatz said that an idea was amazing. Why do living things last so long? We shouldn't live forever. Is there a cause for aging in the first place.
Dubal says that is a very simple question. The passage of time affects the biology of cells. There is a change in the function of the body's cells. Genetics is one of the main causes. Our genetics becomes more unstable over time. There will be some changes that will happen. Transposons are parts of our genes that jump around. Epigenetics is the change on top of our genes that affects the way our cells express themselves. Over time, that becomes more and more malfunctioning.
The story of why we age then is a very multi-faceted one.
Dubal says that there is the loss of what is called homeostasis. What that is is the housekeeping of proteins. How they are turned over, how they are modified, how they are folded. There is a decline in the housekeeping of these genes with age. There is a build up of gunk that contributes to aging and jams up cellular processes. Mitochondria are the powerhouses of our cells and have more function with age.
The mother's curse is a possible reason for female longevity. All of the cells in Steve and I are descended from our mother's. In the process of cellular division, mothers pass on their genes to their offspring. Mitochondria can only evolve in a female body. Men won't pass their genes on.
It is predicted at the end of the day that the function of the mitochondria is more evolved to females. When things start to go wrong, this may make a difference. The female cells may be more fit due to the fact that their mitochondria are more evolved to the female cells. That would be a curse for men.
It might be a mother's blessing for females. It's interesting. This is something that is fascinating. Wow! That gives me a good idea of what is happening. We will be discussing other aspects of what we are discussing here. The issue of living better is also there. We all associate with getting older, but not in the case of people.
Dubal said yes. Well, lifespan is one thing. How long does it take one to die? The oldest person in history is currently 122 years old. Health span is a measure of how long a person will live. We want to have a good healthy health span, where we don't suffer from cancer, cardiovascular disease, neurodegenerative diseases, like Alzheimer's, and more as we get older.
If you have a good health span, you can live a healthy life without these chronic conditions until you die from pneumonia. Health span is what that is. Life lived without diseases. The things that help us to live longer tend to make us live better.
If we can understand the molecules that work together, we can harvest them to fight diseases. That is the reason why we are interested in the topic of women living longer than men. Is there a way to discover and learn the biology of aging so that it can be used to improve health span in males and females?
Let's get into that, then. Our common sense tells us that it has to be about sex hormones. Estradiol is associated with women. Is it the hormones that protect here? Let's get started with that. This is a story of hormones.
It is a golden question. There are four reasons for sex differences in lifespan. Is there a correlation between the presence of a Y and increased mortality? Is there an extra X in females that lasts longer? Is it a mother's curse that only affects males? Sex hormones are fourth. It's possible that testosterone is decreasing in males and that estrogen is increasing in females.
Considering sex differences in biology and longevity, this is an important possibility. There are some intriguing clues from natural human and animal experiments.
The removal of testosterone prolongs life. Korean eunuchs were castrated by the Korean Cho Sun dynasty. They were members of the dynasty and the court. On average, they lived 15 years longer than men of the same socio- economic status that lived at the same time.
This is incredible.
Dubal said, right?
Strogatz is amazing!
The suggestion is that decreasing testosterone prolongs life. We can see this. Animals that are castrated will live longer than animals that are not. There are some very strong studies in dogs. A castrated male dog will live longer than a non castrated male dog.
I have to tell you that this question was burning me for a long time. It's possible that the hormones contribute to female longevity. Sex chromosomes may or may not contribute to longevity. If this is a good time, I would like to explain the experiment we did to get to the bottom of the causes.
I like that you describe it as neat because I read about it in order to prepare for our discussion. I thought this was elegant and it was similar to science. The scientific method is to ask a difficult question and find a way to answer it.
Dubal was excited to do the experiment. The science would tell us something about the causes of sex differences in longevity if we followed the science.
We used an animal model called the FCG model to figure out if female longevity was caused by hormones or sex chromosomes. There is a genetic engineering that has been done in these mice. There is a testis-determining factor on the Y chromosomes that causes male differentiation and the production of testosterone.
SRY is removed from the Y chromosomes and added to any other non-sex chromosomes. The inheritance of the testicular determining factor, the SRY, can be given to males that are XY or females that are XX. At the end of the day, this genetic engineering enables the creation of mice that have four genders: XX mice with ovaries. Some mice have developed testicles. They can't be compared to other male mice because they have the testicular determining factor SRY and they are males. They have male reproductive behaviors as well. The animals fight in their cages. They are male mice.
Hmm, Strogatz I have it, so I have it. I want to make sure everyone listens because it is so amazing and you can make it. They look like males but inside they look like females.
Dubal said that was correct. Yes, that is correct. In males, we produce males that lack the testis determining factor and have developed as females, that is, that they are indistinguishable from other female mice. They have a uterus, they cycle, they have female reproductive behaviors, but their genetics are not X. There is a male that has developed a male trait.
There are four sex genotypes with males and females, XX and XY, that were created with either ovaries or testes. Which mice will live longer is tracked by this. Is it the mice that have the same reproductive system? Is it the mice that have female genetics even if they have testes?
Strogatz asked if you would reveal the answer before. I want everyone to think about the question and guess what the answer is. I think we have it, but it is difficult to wrap our minds around. I don't know which one of the four genders is called the male. Is it right for you to refer to a male as XY?
Dubal says he does. It's a matter of taste and style
Strogatz says that it is an organisms that is XY but has ovary. The organisms that are X are not organs. There is a mouse with testes.
This is a scientific type of game.
Strogatz is pleased with that.
Dubal said that they didn't have a specific hypothesis and would follow the science. The mice with two X chromosomes lived longer than the XY ones. The XX mice were the ones that lived longer compared to the XY because they had more testosterone and had more testes. For the first time, we know that sex chromosomes contribute to female longevity.
There was more to learn from the experiment. The hormones produced by the ovaries are thought to contribute to female longevity, as shown by the mice that lived the longest of all the groups. It's possible that testosterone is bad. Sex chromosomes have an effect on female longevity. The hormones had an effect in that area.
The traditional female seems to be the winner if you can keep referring to it as that.
Dubal lived the longest. I agree.
Strogatz wanted to know what the worst was. I don't know what to think about the person living the longest.
Dubal wanted to know if the XY had testes. The mice that grew up with testes lived longer than the mice that grew up with testes. XY mice lived less than XX mice.
That is a huge difference. I assume by any measure it was significant. Did your statisticians say that was right?
Dubal said yes. The sex chromosomes effect is very significant.
Thank you for that very inspiring and thoughtful note. This was an excellent discussion. Thank you so much for coming with us today.
Dubal said, "My pleasure."
What is happening at the frontiers of mathematics, physics, computer science and biology? There is an editorially independent publication supported by the foundation. Basic science and math research can be illuminated through public service journalism. We are at quantamagazine.org.
Steve Strogatz is the host of The Joy of Why. The selection of topics, guests, and other editorial decisions are not influenced by funding decisions made by the Simons Foundation. The Joy of Why is produced by two people. The editors are John Rennie and Thomas Lin. The theme music was written by a man. The artwork for the episodes is done by Michael Driver and Samuel Velasco. Steve is your host. Please email us at quanta@simons foundation.org if you have any questions. Thanks for taking the time to listen.
All Rights Reserved © 2024
