They say that only two things in life are certain, death and taxes.

For the lucky among us will pass away quietly at an old age.

But why is aging and thus death inevitable?

And how do we even define aging?

Yes, you can define it by the ticking of the clock, but is there a biological way to define it that gives you a better shot at really understanding how the passage of time has worn away at your body.

If two people in their thirties can mix their old cells together to make a brand new baby, then why can't those same two people just start making young cells for themselves?

And shouldn't evolution favor living a really long time so we can make more babies and be around to help them grow.

Aging can be a counterintuitive phenomenon, and Daniel and I get many questions from our audience the extraordinaries about the aging process.

However, despite the furrows in my forehead that get deeper each year and that my son sometimes stares at, this biologist is not an expert in the science of aging.

But lucky for us, we were able to get doctor Venki Ramakrishnan, author of Why We Die, The New Science of Aging and The Quests for immortality to come onto the show to answer your questions.

Welcome to Daniel and Kelly's extraordinarily Old Universe.

Hi.

I'm Daniel.

I'm a particle physicist.

I round my age up two hundred.

Hello.

I'm Kelly Waidersmith.

I study parasites and space And Daniel, last time we talked, you rounded up to fifty.

Have you just decided that, now that you're fifty, yere rounding up to one hundred because that is not a helpful wait around.

I think that's totally consistent.

When I was forty eight, I called myself fifty, and now that I'm fifty, I got a round up to one hundred.

It totally makes sense, not to me.

Plus, I think I look pretty good for one hundred.

Yeah, you look great for one hundred, But I say you look good for fifty two.

But like, I don't.

Yeah, I know that that kind of rounding doesn't make sense to me.

But that's all right, all right.

So here's my question for you today, Kelly.

If you could take a pill that would extend your life to a thousand years or a million years, would you do you want to live a super crazy long life?

Umm?

Al right, So one, okay, So selfishly, I would need to know about the quality of that life, and if the quality of my life was going to be as good it is now, for all of that time, I would think about it.

But to be honest, the only reason I'm thinking that I might want to say yes is that I want to live at least as long as my son lives, because he's going to need care his whole life, and I don't want him to ever be alone.

And so if I could live as long as he lives, one hundred percent, So what about.

You, No, I see, life is like a hike.

You know, hikes are wonderful.

There's oneful moments you're glad you went on them.

You're also glad when they're over.

Nobody wants to be in a hike that lasts until the end of the universe.

And maybe sometimes the best part of a hike is when you get to sit down at the end, you're like, oh wow, what a nice walk done.

Especially at the end of a good hike, Yeah, you're like, ah, all right, I'm ready to be done.

Exact.

And my grandpa passed away recently, and I think he had that kind of life.

He hiked it was a good trip, and at the end he told everyone, he's like, I'm ready, and then he passed away into sleep, and I was like, man, I really hope that's in the genes somewhere, because that's pretty solid.

And I hope that listening to this podcast has improved that everybody's quality of life out there were making your hike through life more pleasant.

Maybe it will improve their quality of sleep, which at the end of the episode will discover is an important part of being healthy.

So we're doing our part.

You're saying that listening to the podcast could technically scientifically extend your lifespan.

Maybe maybe listen to our prior episodes about how you evaluate scientific statements and see what you think, dear listeners, and whether.

You should believe people who have skin in the game exactly.

Yes, all right, Well, so we get loads and loads of questions about aging from the extraordinaries, and so I pulled them all together.

We found an amazing expert to answer the question.

Amazing, amazing, he does such a great job.

How do you know this Nobel Prize?

Kelly Oh, thanks for pitching myte We both were on the short list for the Royal Society Book Prize.

Yep, Why We Die is thank you Rama Christnan's book, and A City on Mars was my book, and we both made the short list for the Royal Society Prize.

And you're just gonna omit those crucial piece of information that you won the prize.

So Kelly is the author of a book which edged out a Nobel Prize winning nonfiction science book.

I was not gonna mention that.

Thank you for ult over the years.

I appreciate it, all right, Well, this is a wonderful conversation with a deep expert who also has the unusual quality of being able to explain things clearly yes.

And being so nice, so nice.

Yeah.

Anyway, So I had so much fun.

I feel so lucky we got to do.

This interview before we bring on our expert, who want to know abel prize in this area.

We asked you guys what you thought was the reason for aging.

Here's what people had to say.

I underested it to be oxidative pressures where new copies of things just aren't quite as good as they used to be and there are errors throughout.

Short answer telemeres real answer, so that there's someone to say I wouldn't do that if I were you to the younger generations, it's not like the clouds are going to yell at themselves.

Certain proteins that mark ourselves or do something along the lines of maintaining how are unique gets repeated or transcripted deggregate.

Over time, the.

Body forgets how to make a new body the way that it once did.

We age as a consequence of too many gas station burritos, ninety nine cent big gulps and betrayal by Teilomeir.

At a molecular point of view, it's really hard to maintain consistency in the gazillion times molecules and the cells needs to produce these error skips that canap until the whole body the case, my.

Short answer is we age due to the passage of time.

I think we age because we need to die ultimately.

I think it's conducive, if not crucial, to the evolution of life itself, for organisms to have a finite lifespan.

Every beginning as an end.

So I believe I've read somewhere that the reason why we age is because there is a shortening of some kind of a protein or molecule within our cells.

And so for DNA current to fray and just gets left up to entropy.

Aging and death are just part of the evolutionary.

Process and processes that have brought us to where we are today.

It's just a fact.

Thanks everybody for your speculation on this concept.

Now let's talk to the expert and find out what we know and what we don't know.

Doctor.

Thank you.

Rama Krishnan was initially interested in physics, but I'm going to go ahead and give a point to biology because he transitioned to focusing more on this field and the biology stuff worked out well for him because in two thousand and nine he received a Nobel Prize for his work on ribosomes.

He was President of the Royal Society from twenty fifteen to twenty twenty and recently wrote the book Why We Die, The New Science of Aging and the Quest for Immortality.

And today we'll be talking about the science of aging.

Welcome to the show.

Thank you, and thank you for having me.

Yeah, we're super excited to have you.

We get so many questions from our audience about aging, and every time I'm like, look, I know when you look at me, I look like the right person to ask about.

Well, they should look at me then, and there's so much discussion out there about aging and how to prevent it and if it's possible, and so much snake oil being sold out there.

It's so important to cut to the chase.

It's certainly having a moment, and I'm a little bit cynical.

I think it has to do with my generation, the boomer generation, that's used to having everything it wanted in life, suddenly coming to terms with getting old, and so, you know, there's a lot of anxiety in the air.

Although having said that, you know, this fear of death and fear of aging is simply as old as humans, you know, because ever since we learned about mortality, we've fretted and worried about it.

And I like to say we may be the only species that's aware of mortality.

Other animal maybe are aware of death, but they're not aware that they all have a finite lifespan and everybody is going to die.

I'm not sure that other species have that understanding that we do.

And when we somehow obtain that understanding, perhaps as a result of cognitive development, language and so on, ever since then, it has become it became a theme and if you look at most religions.

They're all about, you know, how to deal with death and what happens after we die.

I don't know if it's a blessing or a curse that our species is aware of that.

Yeah, I mean many species aren't even aware of death, you know, it just simply happens.

Well, can I start us off with a very broad sort of philosophical question, which is, how do you define aging biologically?

Because as a physicist, I might think, well, you have a clock and it starts and it stops, and that's your age.

But we're interested in more than that, right, It's some sort of like decrease in the quality of life.

You're gradually moving towards death.

It's this fact that you don't just like live for sixty two years and then poof, you're done.

Your body degrades.

How do we define aging in a crisp way scientifically?

Yeah, so it's not.

It's definitely related to the chronological clock to time, but the rate is very different, not only for species, it's vastly different for species, but it's also different for individuals within a species.

If you go to your high school reunion, you will immediately be aware of that the fact that people don't age at the same rate, and I think aging molecular biologists would define it as the gradual accumulation of changes and damage to us over time that can happen different rates in different individuals.

And it's not just damage.

Some of it has changes that occur with time.

It may occur at different rates in different individuals, and these changes may have a purpose early in life, for example, modifications of our DNA, but they cause us or at least they're strongly correlated with aging later in life.

So that's how I define it.

And this accumulation of changes in damage leads to a gradual loss of function, and when that loss of function reaches some point where some critical system fails, then you have death.

And so a death is a result of aging, but its exact moment can't be predicted because in a complex system, you can't predict exactly when a critical component will fail.

Aging and changes, but that must mean very different things to different parts of your body.

You're talking about your nerves or your skin or your eyes.

Are there ways we have to measure it?

It happens at every level.

It happens at every level.

But I would say fundamentally it happens at the molecular level, and that then manifests itself and each increasing level of complexity.

So you can go from molecules to collection of molecules in our cell, to components of the cell, to cells themselves, and then entire tissues, and you know the way cells communicate with each other, like our immune system.

So you can see that, you know, it happens at the molecular level, but it starts manifesting itself at increasingly higher levels, you know, until the point that you know, we see aging as various forms of frailty, you know.

So in fact, a very good measure of aging is actually something called the frailty index.

They'll measure things like can you get out of bed?

How fast can you walk you know, fifty yards?

What's your grip strength?

How good is your eyesight?

How good is your cognition?

You know, how good is your memory?

So all of those things are indications of frailty at a macroscopic level, at a level that you and I experience.

But ultimately the underlying causes are molecular.

Okay, and is aging universal.

So we're getting to one of our first listener questions right now.

One of our listeners noted that they had heard stories about immortal organisms and they wanted to know are they actually immortal.

Yeah, I had to say, there's a lot of hype.

What happens is people will study an organism that ages very slowly, and suddenly they'll say, oh, this has no sign of biological mortality.

Let me back up and explain what I mean by that.

So, in normal species, the likelihood of that we are going to die at any given time keeps increasing exponentially.

So for example, that chances that you'll die when you're ten are very small, but the chances you'll die in the next year when say you're ninety five or one hundred or almost fifty percent, okay, so the chances keep going up.

Now, in some organisms, it appears that that likelihood of dying you know, of aging events, not of being eaten by a predator or starving or anything else.

Those are called external causes.

But you know aging, just dying of aging, that probability doesn't seem to go up with time.

And so there are some species, like a freshwater species called the hydra.

There's another species called the immortal jellyfish, and these tend not to show any signs of biological aging.

That is, the likelihood it's going to die just doesn't seem to change with time.

But in fact what is happening is it's probably aging very very slowly.

So if you looked, if you simply followed a hydra in the wild, it'll die of some other cause, not of old age.

But if you kept it safe and followed it long enough, you will find that it too, gradually ages because no regeneration is perfect.

You know, the reason hydra and jellyfish appear not to age is they constantly regenerate their tissue using specialized cells called stem cells.

In a way, they're like plants.

You know, plants have stem cells all over themselves, and that's why you can take a cutting from a plant and you know, grow an entirely new tree with it.

Right, we can't do that, but you know, some animals regenerate, like starfish.

You know, it cut off an arm and it'll regenerate an arm.

And you know, some of these species can regenerate, you know, any tissue, and but it's not perfect.

And so I would say to your listener that yes, everything will die, but they die at different rates.

I mean, they age at different rates.

And so everything ages.

It's universal across organisms.

Do we understand why we age?

Like, is it an inevitability of like thermodynamics or molecular copying or something, or is it an evolutionary advantage?

Well, there there are two ways of looking at it.

One is, you know, the physicist way would be that you know, second law wins and there's always increase in entropy and disorder and eventually things sort of degrade.

And you know, life is not a you know, equilibrium system.

The problem with that is that life is not a closed system, and if you apply enough energy and enough resources you can reverse damage.

And in fact that's what we do.

So why is it then that we age and die?

Well, I'll tell you the evolutionary argument.

The evolutionary argument is resources are limited and throughout our history and in fact, until recently, resources were limited for humans as well.

You know, we had to struggle to have enough food to live and so on.

When resources are limiting, the organism has a choice to make.

Does it put more of the resources into maintenance and repair, which requires energy, requires food, et cetera.

Or should those resources be put in too rapid growth and development?

Now, if you take a mouse.

For example, a mouse lives about two years, whereas a blue whale lives a few hundred years.

So why is it that there's this vast difference.

Well, the evolutionary argument is that evolution doesn't actually care how long you live.

Evolution simply cares about how successful are you going to be at passing on your genes because it's selecting for those genes, it's not really selecting for you as an individual.

And so in the case of a mouse, there's no point in spending a lot of resources getting a mouse to live to be forty years.

And the reason is that long before that it'll be eaten, or it'll die of starvation or in a drought, or all of a zillion external causes.

And so in the case of a mouse, it's more advantageous from an evolutionary point of view for a mouse to grow very rapidly, produce lots of offspring, and then you know, it doesn't matter whether it dies, Whereas with larger animals, their metabolism is also slower, so they take longer to mature, their offspring take longer to produce and grow up and mature, and so in there it does make sense for evolution to have selected for longer lifespan in order to ensure fitness.

Okay, because otherwise it may men not actually have the chance to reproduce, or not to reproduce enough.

And it gets worse than that.

It's not even that evolution doesn't care what happens to you after you've produced your offspring.

Evolution also will select for traits that are advantageous early in life that will get you to maturity and reproduction, even if those exact same traits will cause you to age later in life.

And there are many examples of that in my book.

For example, certain mechanisms that cause us to age may have evolved as anti cancer mechanisms.

Now, of course you want to prevent cancer early in life, but later in life they may cause aging, and ironically, cancer itself increases as we age the likelihood of getting cancer.

But that's a different story.

Can you give us an example of an anti cancer strategy that causes aging?

Leader Yeah, sure so.

One very classic example is that most of the cells in our body can only divide a certain number of times, and then they reach a state called sinesence.

Senessen cells are these dysfunctional cells that can't divide and they actually secrete inflammatory compounds.

And as we age, we accumulate more sinescent cells and that becomes a problem and inflammation becomes a problem.

Now, why do cell stop dividing?

Well, it turns out that our chromosomes are linear DNA molecules and their ends are specialized struck.

It is called telomeres.

Now, the copying mechanism for DNA, every time it cell divides, that DNA has to be copied.

The copying mechanism is such that our chromosomes get slightly shorter every time the cell divides.

Okay, and these ends have a special structure.

Now, when they become too short, that structure unravels.

When it unravels, the end of our chromosomes looks to the cell like a broken piece of DNA.

That the cell has evolved mechanisms that if there's a DNA break, it will either try to repair it, or if it can't repair it, it will send the cell into Sinessence.

Why, because a cell with a defective genome is at cancer risk because it's about you know, it could do all kinds of you know, abnormal things, and it's much better to send that cell off to sinessence and have it be removed by the immune system, then have it continue with a DNA defect or a chromosome defect.

Right, So the cell has evolved as DNA response damage response in order to get rid of cells that are problematic in this way.

But of course that same thing is causing senessens and increase in senescent cells as we get older and causing us to age.

So that's a very you know, clear example of how something that may have evolved as an anti cancer mechanism early in life really is a cause of aging later in life.

All Right, I want to hear a lot more about that, but first we have to take a break.

Okay, we're back and we're talking about aging.

So you mentioned that as cells go on and replicate the telomeres, you get shorter.

But we and this is another listener question, but we're able to, you know, combine our gam meets with somebody else and make a fetus that has all new cells.

And you also mentioned that starfish, can you regenerate an entire arm using stem cells?

So why is it inevitable that our cells will break down when we seem able to set the clock back if we want to so we.

Have evolved so that most of our cells have lost that ability to regenerate, probably because you don't want all of the trillions of cells in our body to be able to keep dividing at will, because that is also a cancer risk, okay, because they could acquire mutation and then they could become cancerous.

So we have specialized cells called stem cells, which can keep regenerating.

They don't go into senescence, and these specialized cells their role is to regenerate tissue.

Now where do these stem cells come from, Well, they came from the fertilized egg.

The fertilized egg is the ultimate stem cell because it's what is called a toty potent stem cell.

That means it can make everything in the body, including the placenta.

Okay, then that separates off into placental cells and the cells that actually form the fetus and the body, you know, and the organism.

Early in development, those cells are called pluripotent because they can make any kind of tissue.

They could make kidneys, they can make lungs, they could make brain cells, they can make anything.

But as the fetus, as the embryo I should say, develops, the stem cells become more and more specialized.

And then you have amatopoetic stem cells, which can make anything in the blood system, and that includes all of our immune system and our red blood cells, et cetera.

Another kind can make anything in the nervous system, you know, neurons, glia, all of those cells.

Others can make skin and hair and so on.

So you get the picture.

The stem cells are becoming more specialized, but those stem cells have a balancing act.

They have to reproduce so that they maintain the stem cell population, but they also have to differentiate and produces more of the tissue.

So there's always this switch going on.

Do they reproduce more of themselves so you have more stem cells, or do they make the tissue keep regenerating the tissue they are, and there's always this balance.

But as we get older, our stem cells get depleted because they also get defective.

They also age, they also become sinescent, and so you get this depletion of stem cells.

You also get the remaining stem cells are not optimal.

They become what are called clones.

Instead of having a diverse population of stem cells as when we're young, you get these clonal stem cells which are suboptimal.

They're selected for being able to reproduce rather than being effective at generating tissue.

So these stem cells also decline.

So that's why we can't keep going forever, you know, by regenerating tissue.

Now, the other question your listener had was, you know what about our germ cells.

You know we can you know, we keep producing babies that are age zero.

They're not.

You know, in my book, I point out that a forty year old woman doesn't give birth to a baby that's twenty years older than a twenty year old woman.

They're both zero right, born at a time zero.

So that's a combination of two things.

One is our germline cells are highly protected against damage.

They have better repair mechanisms for repairing DNA damage.

They're shielded against DNA damage, et cetera.

So that's one aspect.

The others there's a brutal selection process.

You know, a female is born, a female human is born with about a million or so eggs.

But you know, if you look at the number of menstrual cycles and a woman over a lifetime, it's only maybe a few hundred.

So why do you need a million eggs?

You know, when you're really only going to use at the most a few hundred, right, So that's because there's a lot of selection in the process of going from the germline's precursor cells to the egg that's actually eventually selected for ovulation.

There's a lot of selection.

Sperm, of course, you know, is highly selected.

I mean, you know, each fertilization event there you know, I don't know how many I would had to guess and take a guess, but maybe it's a million sperm cells or something, and out of that is only one is selected, you know, So they have to raise and they have to you know, win the competition.

So they are also selected for fitness for health.

And then after the fertilized egg is formed, you know, it is also checked.

So if the developing embryo is at all defective, there'll be spontaneous abortion.

Often a woman won't even know it, you know, the very early spontaneous abortion.

Later abortions are what we call miscarriages, and that's another selection.

And even within the growing embryo, cells are selected against if they're defective.

The embryo keeps growing, but it kills off cells that are defector, which I found remarkable.

So it's this combination of selection and protection that ensures that, you know, the child that is born is has its aging clock soon reset, okay, at each generation.

But is it technically possible for us to reset our own clock?

Is it just like a bad idea evolutionarily, or is there something that prevents us from just like constantly being at teko zero.

I don't see how you would reset your entire clock.

You know, in the whole organism there are people.

So if I were to back up just a little bit, there is an example of taking a fully grown adult cell and making a whole new animal from it, Okay, And the first time that was done was by John Gordon who received the Nobel Prize for it when he cloned a frog from a skin cell.

So he took a skin cell from an adult frog and implanted the nucleus of that cell into the egg of another frog and then just grew it up and it resembled the frog from which the skin cell had been taken, you know, so it was essentially a clone.

And then people asked could they do it to mammals?

And that made big headlines when Dolly the Sheep was cloned.

Now Dolly the Sheep turned out to be very sickly sheep and died at about half the age of a normal sheep.

So everybody said, ah, this is because Dolly the Sheep was cloned from a fully grown adult cell which was already kind of old and damaged and didn't go you know, wasn't a normally produced sheep.

It was done by this weird cloning procedure.

But it turns out that there are many other cloned animals, and in fact, with Dolly, the other cohorts like Daisy and Debbie, they're all females that had d names and these sheep though by and large, had normal lifespans.

And so that means that you could actually, you know, reset the clock to substantial degree by erasing all the marks on the DNA.

Okay, it's not perfect, because the cloning itself involved lots of selection.

You know, it is very very inefficient.

It only works small fraction of the time, and most of them end up in miscarriages or or they don't take and so on.

So at least in theory it's possible.

Now, could we do to cells in a more systematic way what Dolly the sheep or John Gerdon did with his frog, Because they just treated it in various ways, but they didn't have a clear idea of what was what was it?

What were they doing to make that adult cell go back to resembling a fertilized egg and start growing a new animal.

You know, it's like going backwards in time, right, And so a Japanese scientist named Shinya Yamanaka asked, could you take these stem cells that are in the final stage, or even the final cells like a skin cell or you know, lung cell or whatever, and have them go all the way back to pluripotent stem cells so that they could then, you know, become any kind of cell.

And remarkably, he found that if you take four genes and introduce them into one of these adult cells and turn them on, you could change the genetic program of the cell and have it go backwards all the way back to pluripotence.

Now, this has created a big industry in the stem cells because stem cells are going to be useful for all kinds of things.

For example, if you want to replace damaged tissue, you know, let's say you want to replace pancreas in diabetics so that they can produce insulin.

There are all kinds of things being talked about, and they're you know, cartilage and a guy like me with very bad joints.

So or for a guy like me with you know, very little hair, you could imagine stem cells stimulating new hair growth, Okay, and that would be a billion dollar industry.

Yeah, if you could develop some like gun you pointed a part of your body and you're like, make this younger.

Exactly, So people asked, now, the problem with going all the way back is that you have the risk of cancer, you know, because it's you're taking these cells.

They're not quite exactly the same as a normal embryonic development is it's the somewhat artificial process that you're using to go backwards in development.

And when they try to grow those plur iportent stem cells, they often would get these tumor like growths called teratomas, and so there is definitely a cancer risk.

But what a number of scientists asked was supposing you turn on these Yamanaka factors transiently, you know, just turn them on and then figure out a way to turn them off after a while, then what would happen.

Well, astonishingly, they tried this in mice and they found that the mice, you know, resembled younger animals.

They suddenly had better fur and muscles, and you know, by various markers they seemed younger.

So this idea of cellular reprogramming is a big area in the longevity field, but it's still in early stages.

Even though there's a lot of excitement the idea that tomorrow you're going to go and get a treatment that will suddenly make all yourselves younger, it's really not going to happen anytime soon, and it's because there are lots of problems.

One is, you know, you have to get the right dose, you have to make or it's safe.

You have to make sure it goes to the tissues and just the right amounts.

These are all big challenging problems.

And you know, of course a long term cancer risk is another problem.

So I think it's very exciting and promising, but it's not something that's around the corner as it's often hyped.

I mean that's my opinion.

Of course, you know, people will disagree with me those but remember a lot of these people have quite a lot of skin in the game.

They have financial interests, they've founded companies and so on.

So you have to slightly take what they say with a pinch of salt.

So you've mentioned that one of the reasons that we age and die is because it has something to do with resources.

And with evolutionary choice.

Basically.

Yeah.

So now many humans like me live in an environment where there are too many resources maybe, and we should take in fewer resources, and we live in an environment where we're better and better at being able to treat cancer, because it seems like we keep coming up across you know, cancer is the thing that's holding us back.

So if we were in a high resource environment and we could figure out how to cure cancer, do you think we might be able to get our life spans up one hundred years or something.

Well, somebody did a calculation.

Demographer named Jay Olshansky from Chicago, who's a leading expert in this area, did a calculation a number of years ago, maybe twenty five thirty years ago, which suggested that if there are four major causes of major diseases of old age that caused death, one you mentioned cancer, the other one is diabetes, a third one is heart disease, and the fourth one is dementia.

Neuer degenerative diseases and of course the newer degenerative diseases are among the hardest to treat.

But let's say you could eliminate all four of them.

The suggestion is you're only gain about fifteen years of lifespan if you eliminated all of these four causes.

And the reason is that they will not affect the normal process of aging, you know, which leads to frailty of you know, system wide frailty.

And there's always this argument, is aging a disease And people say, well, you know, all of these major things like diabetes, cancer, etc.

The risk goes up with age.

In fact, the biggest risk factor is age.

The older you are, the more likely you are to get one of these things, or more or several of them.

But the other argument is that, well, these diseases don't happen to everybody.

Not everybody dies of cancer, not everybody has heart disease, and also young people get cancer, so it's not directly related.

And aging, on the other hand, is something that happens to every single person and it's inevitable.

So how can you call something that's both ubiquitous and inevitable a disease.

It's simply a process of life.

And I tend to agree with that.

But the reason they want to call it a disease is because then it's easier to get approval for clinical trials.

Well, I think they ought to try some other thing.

For example, they can choose a target, a disease target that's strongly correlated with aging, for example ostere arthritis or loss of various functions and so on, and then they could use that as the measure of success of their drug.

So there are ways to get around it.

But I don't think that just eliminating these diseases will increase lifespend that much.

And in fact, even people who in the aging field who have bet so.

Olshansky was on one side of a bet with another gerontal just named Stephen Ostad.

Stephen Ostad made a bet with him that the person who lives to be one hundred and fifty has already been born, okay, And that bet was made some time ago, and they bet it so that in one hundred and fifty years, you know, the amount would be worth that a billion dollars or something.

Of course, you know, maybe it'll cost a billion dollars to buy a sandwich, but by that time.

But anyway, but they made this bet.

Now.

Stephen Ostad also doesn't believe that it's just going to be because of eliminating disease.

Rather, what he thinks is that we're making progress in slowing down or arresting aging itself, and that's the reason why we may end up living longer.

And for example, you know, there's a drug called wrappamicin which is somewhat is related to caloric restriction, which also allows animals to live longer.

That, for example, can increase lifespan in mice by you know, twenty or thirty percent.

Well, if we live you know, ninety years, you know, thirty percent of that would already get us to one hundred and twenty or so.

You see, So maybe he's counting on on things like that.

I tend to be on the Olshansky side.

I think that I'm really fundamentally increasing lifespan, and especially healthy lifespan.

Is not going to be as easy as they say, because it's highly multi factorial.

There's so many things going on.

Well, how do we know you're not just a shell for big death?

You know?

Are you being paid by the death industry?

All right, well, take a break, and when we get back we'll talk.

More about aging, and we're back.

So we have another question from a listener, and here it is, I'm curious why immune systems seem to decline with age.

Shouldn't they get supercharged because by then, when you're old, you've basically seen everything.

It is true that immune systems are exposed to more things as we age, but immune systems are essentially a collection of cells, and the cells themselves age, and so they don't respond as well as they do when we're younger or when we're in our prime.

And this has to do with molecular damage affecting higher levels like the cell and communication between cells, and so for all kinds of reasons, our immune system as a result of this accumulated damage doesn't function optimally.

So it's got a lot more wisdom, but like less energy and effectivity.

Yeah, and actually it doesn't function as well.

For example, it responds in an aberrant way.

It's not as well regulated.

You know, the immune system always has to be very finely regulated because you don't want to react against yourself or against harmless things.

You only want to react against truly dangerous entities.

So that fine balance is disrupted, and so you get essentially a dysfunctional immune system, and you also get a lot of inflammation as a result.

So, for example, I mentioned those sinescence cells.

The reason those sinessn cells secrete inflammatory compounds is as a signal to the immune system that hey, there's something wrong here, come and clear it up.

And so the immune system will come there.

It may be the side of a wound, or an infection or or some other stress, and it will deal with it.

But as we get older, not only do the number of sines and cells increase, but the immune system doesn't respond as well to the signals, and so you get this sort of auto catalytic or you know, you get this essentially, this explosion in the growth of sines and cells and inflammation.

And is this something that's understood across species.

One of the listeners asked why cats and dogs have the same age related diseases that we do, but they appear at a younger age, maybe smaller number of years.

That's simply the fact that this allocation of repair to maintenance and repair to growth and reproduction, that balance is different for different species.

You know, you could ask why do whales live so long?

Well, one reason is they have a slower metabolism than say animal like a mouse.

But the other reason also is but they have a large number of repair enzymes.

You know, if you look at just DNA repair enzymes, they have many different repair enzymes when they sequence the genome of some of these species, and elephants, for example, have many more copies of a DNA repair enzyme than mice.

Do because they live longer, so they need more repairs.

Yeah, and they have to they have to maintain that.

Also, there is a paradox They have many more cells, and so the chance that one of their cells could become cancerous and kill the whole animal is much higher in a larger animal than in a small animal.

But paradoxically it's mice get cancer more often than elephants, and that's because the elephants do have this additional capacity to repair.

So it's all evolution really just optimizing for fitness.

Remember, evolution does not optimize for long life.

It doesn't care about long life.

It cares about survival of genes because that's what it selects for.

This might be a little too far off topic, but I've seen articles that say, like green sharks never get cancer.

Are there actually species that never get cancer or it just takes them away and we don't see it often.

It is almost entirely that we don't observe them long enough.

So for example, I'll give you an example of Glapicus tortoises, right, you know, they live to be two hundred years old.

And I like to joke that there's probably a Galapicus tortoise wandering around now that might have actually met Darwin.

Oh you know, that's a cool thought, right, But anyway.

Let's have them on the podcast so exactly, so.

You know, if they could talk, they might be able to tell you quite a bit.

But anyway, No, it was thought for a while that these things, these tortoises don't age.

Well, actually they do age.

If you look at old tortoises, they have terrible eyesight, and you know, there's slow moving, there's skins, you know, old you know they have all these.

They don't know how to use the VC exactly.

They have all of the same problems, and it's just that it happens more slowly, Okay.

And I gotta say, Daniel, I think the VCR joke aged you more than anything.

Well, the fact that you laughed at it aged you.

Oh, you got me.

That's true.

That's true.

So let's jump back, if that's okay, to another example of folks trying to extend lifespan.

So I've heard of examples of like taking blood from young mice and giving it to old mice, and then I think there's a guy, Brian Johnson who's trying to limit aging by using his son's blood.

Is there any evidence that that's anything other than nuts.

That's an excellent question.

And it is true that when they connected an old rat to a young rat, the old rat benefited by the exchange of blood and the young rat actually suffered.

And then they were wondering whether it was really due to the blood itself, or maybe the young rat had better liver and kidneys to detoxify the blood, and so it wasn't just the blood, but it was just that it had better organs to clean up blood.

So they separated them and simply give them transfusions, and they found that, in fact, the effect was still there, but it was more that the old rat had things in it that were harmful to the young rat.

That was more the case than that the young blood was beneficial to the old rat.

But it did.

But there was some effect both ways.

Now this is true, and when the people discovered it, they caught all sorts of creepy phone calls from rich people asking, you know, whether they could get young blood and so on, and in fact, companies.

Where do babies?

It's kind of exactly.

And in fact companies sprouted up, and as you can imagine, mostly in California.

I think.

That's what I would get, you mean, the center of innovation and forward thinking and creativity.

That's why you said, ye, anyway, that's somehow obsessed with youth.

But but anyway, some of these companies would would get blood from young donors and sell them at a huge markup to rich people wanted them.

And in one case, the FDA actually tried to shut one a company down and then it opened up under a different name.

And in one case the CEO said, well, look, our people simply don't have the time to wait for clinical trials, you know, Oh my goodness.

It was really bizarre coming from, you know, a CEO of you know, a health based company.

But you're saying that there are real benefits to having transfusions of blood from young people.

Well, there's certainly seemed to be in animals, and so there's a big bar of research to find out what is changing in blood as we get older, and what do these factors do.

You know, if they're harmful in old age, what do they do?

Maybe we can inhibit them, or if they're beneficial in early life, maybe we can take advantage of that and introduce them into older people.

So I think that's a very legitimate and broad area of research and lots of very you know, top scientists from very well known universities are actually working on that.

But you know, this idea that you should just take transfusions, you know, it's not really going to help that much at this point.

And Brian Johnson whom you mentioned, actually did this experiment of keeping it all in the family.

He took blood from his son and gave his blood to his dad.

But he's also, I mean to give him some credit, he's obsessed with a you know, or not aging to be more precise.

He spends like a couple of million dollars a year on all kinds of longevity treatments and measurements, and you know probably has you know, fitness programs and all sorts of things.

Okay, Well, the thing that fascinates me about Brian Johnson is that he does take a lot of data, right, he is.

Exactly focused data on metrics, right, He's focused on metrics.

But he doesn't look young, Like even though he says he has all these metrics which are equivalent to an eighteen year old, he still looks like a vampire.

So he sort of captures this like, well.

I would say, no, I'll give him credit.

He's his late forties.

He looks pretty good for late forties.

But I'll tell you my son is in his late forties.

Yeah he does none of this stuff.

Yeah, okay, but he runs regularly and eats well, and he looks just as good as Brian Johnson.

And I'm not just being biased.

You could look him up on online.

He's a cellist.

So well, you're definitely biased, but I don't don't not believe you, But you know, I think it raises a deeper question, which is, like, is it possible to be young biologically by all of these metrics, as you say, you know, you're measuring the damage to whatever molecular mechanisms, but still somehow not be young in the sort of social sense.

That's that's a very good question.

You know.

So you know I mentioned the high school reunion and how we all look different.

Yeah, so that's led to this quest for biological markers of age.

Okay, yeah, because you want to know.

You know, your birthday may have been, you know, forty years ago, but how old are you really in biological terms?

Right, So the people have come up with different clocks, you know.

So one clock is this so called DNA methylation clock.

So these are little tags that get attached to our DNA from the time we're conceived.

Okay, it happens even in utero.

We're aging even in utero, okay, And that's apparently better correlated with with mortality than chronological age.

You know, So chances that you're going to die are more correlated with your data infilation than they are with your date of birth.

So so that's you know, used as a clock.

But does that suggest that if you could somehow adjust that you would extend your life?

I mean, is it causal or is it correlated?

That's the real question.

You know, we don't know the extent of causality.

The other case is that as we age, extra sugar groups get added to our proteins.

It's called lication.

And so you can measure this, you know, addition of sugar groups to our proteins, and when that happens to our proteins of our immune system, it also doesn't work as well.

So people think that it has some connection with this, you know, decay of the immune system.

But anyway, that's another clock.

Now people will sell you kits.

They'll tell your denim infylation kit or a glacation kit or a full blood you know library.

You know, they'll just analyze a bunch of stuff in your blood to give you a sort of biological age, and each one will say this is our thing, is the most accurate?

Okay.

Now, I think these are all very useful research tools because if you have a longevity intervention, like an anti aging intervention, you can see are these markers changing more slowly or are they changing at the same rate?

Okay, and they'll give you a good idea of you know, are you aging faster or not.

But people need to come together and agree on a panel.

You know, I don't think a single clock is going to tell you the whole story.

Yeah, okay, I think they need to agree on a panel and then say okay, here's a panel and this is what it represents, and it might be a complex thing.

There's no point in talking about your biological age because your liver may not be the same age as your kidney or your lung.

You know, you can imagine if you're an alcoholic, your liver might be older than other parts of your bodies.

So I think people need to have a more complex view of aging, of biological age.

But don't we also need to unravel this question of causality.

I mean, if you identify a marker, even or even a complex panel that indicates biological age, adjusting those results doesn't necessarily make you younger.

It's like I can turn back the clock literally and it will read a different number.

Doesn't make me younger.

And if this is just a comment, one more thing which is one of my favorite mechanisms that Brian Johnson keeps track of is that, and I love that he's totally transparent about his data, is that he measures his erection quality during the night and he posts this data online, which I think is hilarious.

But you know, just as an easy example, if the guy took a viagara every night when he went to you probably would have like glorious erections all night long.

It wouldn't make him any younger, right.

That's true.

But you know, let's take dinner methylation.

You know, so one of the things about those reprogrammed cells is that they have changed the methylation pattern as well, you know.

So I mean that one of the distinct things about going back to an early embryonic state is that the methylation pattern is different.

So there may be some element of causality, because methylation does change the program of our gene expression.

So if you're going back to an earlier state, you maybe you're going back to an earlier program.

But I agree that, you know, causality, you know, needs to be established by careful experiments.

You know, is is it sufficient to reverse methylation and without cause on automatic cause something to look younger.

There are some scientists who claim that they have reversed aging just by this process, but it's highly controversial.

So I imagine our listener is going to want to know, as an expert in aging who doesn't believe, you know, that there's a magic pill out there that's going to give us an extra fifty to one hundred years, what do you do to slow the aging process?

Yeah, yeah, I should say, you know, there's no theoretical reason why we couldn't all start living to be one hundred and fifty eventually.

Okay.

The thing that I'm what I'm saying is that we don't know how to do that at this point, and more importantly, we don't know how long it's going to take.

And that's where I differ with some of the more extreme optimists that the field is full off.

Okay, but what we can do right now before then?

I want to address one question.

If you ask most aging research, they would say, oh, we're not interested in extending lifespan.

We're really interested in extending health span.

Okay.

And this whole thing is based on an idea called compression of morbidity.

So as we get older, we start accumulating various morbidities.

You know, you could say diabetes is one, or heart disease or dementia, accounts, et cetera.

You know, frailty of various kinds or morbidities, and the ideal life would be that you're extremely healthy and then suddenly we have undergo a rapid decline.

Okay.

This is called compression of that morbidity into a very short space of time.

You have a span of time.

So that's the goal.

The question is is that even possible.

Well, in the last few decades we are all living healthier as a result of improvements in health, but it's also extended our lives, so that our period of morbidity has not changed.

Okay, so it's just postponed.

And in fact, you know, we're living more years and it's sort of decline than you know veras before, we might have died brutally quickly, okay, as soon as something went wrong, you know, would collapse and die, and now we're sort of prolonging it and have a long period of morbidity.

So it's not clear that as we improve things, we're going to somehow keep healthy and reach some fixed limit and then collapse.

It may simply be that we'll live a bit longer and still have that inevitable period of decline.

That's an unsolved question, no matter what people will actually say.

The one exception to this are super centenarians.

These are people who live to be over one hundred and ten and even over one hundred and five.

They tend to be extremely healthy.

Many of them have never seen a doctor until they're one hundred or so, and then they suddenly go into a decline and die.

Now you could ask why is that, Well, it could be that they're selected and they're just there's a selection bias there.

First of all, they may be lucky in the combination of genes that they have, but they each combination, there's no fixed combination.

They may be different than each individual, but somehow these combinations give them that edge.

Another is that they may simply have been lucky in avoiding various diseases and cancer and accidents and so on.

And you're looking at the survivors, okay, and so it's not something that's translatable to the rest of the population necessarily.

So that's still debating.

And people are studying centenarians, which I think is a great idea, and trying to find out more or about their lifestyle and their genome and also their methylation patterns and so on.

Now you asked, what could WeDo, Well, I advocate the trio of diet, exercise, and sleep.

It's been known in many species that caloric restriction improves lifespan and improves health in old age.

And of course caloric restriction is extreme.

It means you're consuming just the bare minimum number of calories required to have a steady state.

In other words, you're not losing weight and starving, but you're just steady.

But that will leave you hungry and cold, and your loss of libido and all sorts of side effects which maybe not worth it.

Yeah, you know, it reminds me of that joke about the doctor who said, you know, if you do these things, you'll live live longer, and the patient said really, he said, well, I'm not sure, but it will feel like it so anyway.

So, but but you could have a moderate diet, you know.

And it is true that a healthy and moderate diet will help.

And exercise has all kinds of things, including, by the way, those regenerative abilities, regenerating muscle, and even regenerating mitochondria, which are these organelles in our cells.

So exercise has huge benefits that are only now becoming clear.

And then the third which I think Americans need to take more note off.

And by the way, I am an American who lives in Britain, although I'm now also a British citizen.

So Americans particularly ignore sleep.

Okay, and sleep is really important because that is when a lot of the repair and maintenance mechanism of the cell, the clear, clearing out garbage, you know, repairing damage, et cetera.

Much of that occurs when we sleep.

And there's actually a very nice book called Why We Sleep by Matthew Walker, which talks about all of the things about sleep.

So though that trio is extremely healthful.

Now, things like stress, cause you know, accelerate aging.

But you know, if you exercise and sleep, you will also be less stressed.

And if you exercise you'll sleep better, sleep better, you're less likely to overeat and you know, snack and so on.

So there's it's like a three legged stool that help you know, each one helps the other two.

But then let me ask you about that specifically, because it feels like as we get older, it's harder to sleep longer it is well.

And yet you're telling me that sleep is crucial for old age, and so it seems like a death spiral there exactly.

And that's why if you exercise and eat well, you're more likely to sleep well.

And and then it's a it's a kind of virtuous cycle.

They help each other, each each leg help the other two.

And then there are social things.

For example, again, Daniel, you mentioned causation versus correlation.

But there's strong evidence that people who are socially well networked in old age, for example, they have circles of friends, family, they're socially involved, tend to have lower mortality rates.

And people with a sense of purpose in life, independently of the social network they have a sense of purpose in life also tend to live longer.

And so this would argue for being socially involved and perhaps you know, contributing, you know, maybe volunteering and having some sort of purpose just beyond watching your Netflix Q, although that some people would argue that's a purpose too, but anyway, but having a real purpose in life might help.

Now again you might say, well, people who are healthier and you know, not as fast may be more inclined to do these things.

So there is this correlation causation issue, but I think it's it's well worth considering.

Is it time for the alien question, Daniel?

I think it is.

So we often wonder on this podcast not just about the scientific mysteries here on Earth, but scientific mysteries more broadly in the galaxy.

And so since we're in this moment where we you know, maybe on the cusp of discovering aliens on the other planets in the next decade or whatever.

Do you think that.

I'm very agnostic about that, by.

The way, as Ama, I sure, though enthusiastic.

But say that we're there, you're an astrobiologist, you're on a mission, you're landing on the planet.

Do you expect that life cycles on alien planets will also have the same sort of aging patterns that we see here on Earth.

I think so, because I think natural selection is a universal process.

You know, if you think of life as essentially the ability to reproduce, self, replicate, and evolve are two essential characteristics of life.

So if you have that, you will have natural selection, and so it will if inevitably have these trade offs of resource versus maintenance and repair, and and of course if it's carbon based, then you know it's more likely even to have that.

And and ultimately, ultimately the laws of physics, which you know are result in chemistry, which results in damage that's not going to change, you know, somewhere else.

So everywhere across the galaxy there are grumpy old aliens telling those young kids to get off their lawn.

That that that I would I would bet on that if I had to.

But I'm I'm somewhat skeptical about I think we don't know what the probability of life here is, and until we know that, we have no idea whether life elsewhere is very likely or whether we're alone or somewhere in between.

We just don't know.

I should say some of the enthusiasm for extending lifespan to very very long lifespan is by people who want to do extra galactic travel.

You know, there are people who feel that we may be the only intelligent species and we should go off and colonize not just Mars, which you guys have pointed out as extremely hard anyway, but you know, even other galaxies, and so they figure, well, if we have to do that, then we have to be able to survive the voyage, you know, and so we should you know, we need to start working on longevity.

So it seems like a crazy idea, but anyway, that's how it is.

I think for a lot of people, it's like, you know, they'll say, oh, I want humanity to do it, but what they mean is that I want to be the one who does it in particular.

So yeah, yeah, yeah, absolutely, yes, all.

Right, Well, thank you so much for being on the show.

This was fascinating.

I'm sure our listeners are going to be thrilled with all of the answers, and thank you for your time.

Thank you, it's been a real pleasure chatting with both of you.

And by the way, I really enjoyed your book.

Oh thanks, I loved your book.

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