- The speaker discusses the possibility of living longer and healthier lives
- He argues that aging should be considered a medical condition and that it is possible to delay diseases and live longer
- He introduces the idea of the "information theory of aging" and explains the role of genetic and epigenetic information in the aging process
- The speaker suggests that it is possible to slow down aging and live healthier lives, and discusses early experiments in resetting the aging clock of the body

- The epigenome, made up of proteins that wrap up DNA, plays a role in aging by switching genes on and off
- Changes in the epigenome can cause cells to lose their identity and function, leading to aging
- Research on mice has shown that inducing DNA cuts can accelerate aging and lead to increased dementia
- DNA methylation can be used to measure aging rate with great accuracy
- It is possible to reverse aging by manipulating the epigenome, as demonstrated in experiments with mice
- The work of mathematician Claude Shannon is referenced as a model for preserving and restoring information

- In 1948, Dr. Shannon proposed a set of diagrams and equations to preserve information between a sender and receiver, leading to the development of the TCPIP protocol and the Internet.
- His work on information preservation is now being applied to aging and the potential to reset the age of our bodies.
- By using a subset of the Yamanaka factors, researchers have been able to reset the age of cells in mice, leading to the regrowth of optic nerves and reversal of vision loss in old mice.
- Enzymes called TET1 and TET2 have been identified as key players in the process of aging reversal.
- NMN, a chemical found in the body, has been found to stabilize the epigenome and prevent aging, and can be activated with molecules like metformin and other substances.

- The speaker discusses the potential benefits of NMN and intermittent fasting for longevity
- Clinical trials are being conducted on a molecule related to NMN to raise NAD levels in people
- The role of insulin in aging and the importance of insulin sensitivity is highlighted
- The speaker's father has experienced improved health and vitality through a combination of NMN, metformin, exercise, and intermittent fasting
- The speaker discusses the information theory of aging and its potential to explain the hallmarks of aging
- Oxidative damage is discussed as both upstream and downstream in the aging process

- DNA breaks can be caused by oxidative stress, free radicals, cosmic rays, CT scans, and x-rays
- Antioxidants may not work as well as hoped because there are other causes of DNA damage
- Molecules in antioxidant-rich drinks can activate the body's natural antioxidant defenses
- Resetting cells to behave as though they are young again can help rid the body of damaged proteins through autophagy
- Intermittent fasting and certain treatments have shown promise in anti-aging, but more clinical trials are needed
- Epigenetics is not entirely digital, with methylization being the only digital part
- Research is ongoing to identify the deep observer in the biological clock and understand the levels of epigenetic modifications
- Mice with a scratch-taped genome showed symptoms of aging and a shorter lifespan, but more research is needed for statistical significance.

- The use of machine learning to predict longevity based on frailty measures shows promising technology
- The potential for a treatment to be developed within 5 years and approved by the FDA within 5-10 years
- Ethical considerations surrounding the choice to use anti-aging treatments
- Comparison of NMN and NR supplements for anti-aging effects
- The role of the CMYC gene in cell proliferation and aging
- The importance of taking risks and perseverance in pursuing career goals and dreams in the field of anti-aging research.

- Aging is considered a medical condition and can be delayed
- The "information theory of aging" and epigenetic information play a role in aging
- Research on mice has shown potential for reversing aging through epigenome manipulation
- The work of mathematician Claude Shannon is being applied to aging research
- NMN, intermittent fasting, and insulin sensitivity are discussed as potential factors for longevity
- Clinical trials are being conducted on anti-aging treatments
- Ethical considerations and the role of the CMYC gene in aging are also discussed

David Sinclair, professor of genetics at Harvard Medical School, discusses his new book "Lifespan", which distills his cutting-edge research findings on the biological processes underpinning aging. Sinclair describes lifestyle hacks we can undertake now to combat aging, as well as future scientific breakthroughs that promise to slow down—and even reverse—the aging process.

Moderated by: Sam Phippen

Get the book: https://goo.gle/2LXCd2P

I'm not sure I'm going to tell you how to live forever today, but I'm going to

tell you that we understand how to do it.

There's a few people here that helped make this book possible.

I want to thank them all personally, and also Sir Nick Platt for making this possible, and also Matt LaPlante, who also helped write the

Yeah, so this has been a long journey for me.

I'm going to talk for about 25 minutes, and we leave time for

I'm a fairly open book, so ask me any question and I'll do my best to answer it honestly.

So I've been working at Harvard for, well, since 1999.

I was 29 at the time, so I had no idea what I was doing.

So I just turned 50, which is good and bad.

The good part is that I now know what I'm doing.

that I'm a lot closer to being towards that edge where we all drop off in physical health and mental health as well.

Now, some of you are very young, and it's easy to pretend

All of us will get old, and we will all die.

It's also terrible to think that our parents and everybody we love will also face this.

The point is to actually try to prevent people from being sick for the last 10 years of their life.

And the hope is that our generations will be able to expect to live till 90 and play tennis and even make it to 100 and still have a career, a second, third, or fourth career.

Second, third, or fourth partner if you want.

But the important point here is that this isn't about living forever.

It's about changing the way we treat people in terms of health care medicine.

Right now, aging is not considered a medical condition.

Does anyone have any idea why we don't call aging a medical condition?

So the medical definition of a disease is something that happens over time that causes you to lose function and become disabled.

The reason that aging isn't a medical condition yet is because it happens to more than 50%.

But what we argue in the book is that just because something affects 51 or 50.1 percent of people doesn't mean it's any less important than a rare disease.

In fact, I would argue that it's more important.

And I hope that after you have a chance to read the book, you come away realizing that it has been insane to regard aging as something that is separate from a disease or a disorder.

Now the World Health Organization has declared aging for the first time as of this year as a medical condition.

It's really quite amazing to see a large institution declare aging as a condition.

we hope is that it will soon change the way doctors look at aging.

we have any doctors in the audience, but where I work over at Harvard Medical School, doctors are taught, in part by me, that there are certain pathologies and diseases and if it happens to less than 50% of people, we address it aggressively.

We do medical research to stop that disease and treat it.

And just because something's common like aging, we don't really do anything about it.

But I put it to you to look around this room, what part of

this room, with maybe the exception of the wooden, no, it's a carpet.

Maybe the oxygen we're breathing is natural.

And tackling diseases and tackling aging is also natural.

We don't accept misery and frailty as natural ways of life.

We should not be doing that for any disease, and

we should not be doing it for old age either.

So I want to do a quick survey before I get into some slides here.

the audience, but you probably don't like that answer.

So there's a few people who didn't put up their hand.

between 120 and immortal that they're looking for.

We don't all want to live the same amount of years.

But what if I told you that you could be just as happy and healthy and satisfied as you are today at age 120?

How many of you would like to have a life like that?

The point is that, and in the book you'll see that the point about all of this is that we have the technologies to be able to be healthy much, much longer into later in life.

So it's not about living forever and it's not about just pushing out how long you live.

live, stopping us from getting sick, stopping cancer, heart disease, Alzheimer's, frailty, and diabetes.

And you might say, David, how is that possible?

Well, what I'm going to tell you today, if you don't already know about it, is that we have a

new understanding of what causes aging and even how to slow it down.

And early glimpses and some experiments I'll show you about actually resetting the aging clock of the body.

All right, so to really understand how to delay diseases and live longer, and it turns out, guess what?

If you're not sick, you tend to live longer.

You need to really understand how it works, why it happens in the first place.

That's not really the point for this talk.

But really, why does it happen at the nanoscale, at the molecular level?

And I think we finally have an answer to why we age.

be stopped by antioxidants, though that hasn't stopped marketers building about $150 billion industry every year.

But what's different in the book is that, and in my research, is that we've got a new idea about why we age and why we may not have to.

So we see aging so often that we take it for granted.

And we see it also so often that we don't even do anything about it.

So this person has been sunburned on 1 side of their face, as you can see.

And we know that sun damage, DNA damage, broken chromosomes make you look older and even accelerate aging.

If you have chemotherapy or radiotherapy, you will be, you won't just feel older, your body will literally be older.

And the old idea that came out of the 1950s from mostly physicists who were previously working on the Manhattan Project, their idea was that we ran out of genetic information, mutations.

of the mutation theory of aging, that we just lose our genetic information.

Because we can make mice that have a lot of mutations, and they lose a lot of their genetic information, but they don't age prematurely.

And there's a whole body of research now that has made my field essentially throw out the idea that we are aging because of

So aging, I put it to you, is simply a loss of information.

I call it the information theory of aging.

But I just told you that it's not due to the loss of genetic information.

Well, there are 2 types of information in our bodies that are essential for life.

1 is genetic, and the other is epigenetic.

And you'll probably recall from high school that epigenetic is the term for any process and structure that governs the way the genetic information is packaged and read by the cell.

So here's a cartoon of what the epigenome looks like.

We've got the DNA which is in blue, That's our genome.

And the genome, I put it to you, is a digital form of information.

This would be sort of a binary, a quaternary mode of transferring information throughout our life between cells and across the last 4.6 billion, well,

at least 4 billion years since we first emerged out

And we think that the inability to preserve genetic information is not the cause of aging.

It's important for evolution but over the lifespan of our bodies we still have a lot of that information intact.

Digital is a great way to store information as you all know.

So what else is the problem, potentially, in aging?

And that's the epigenome, which I'm showing you as these green proteins that wrap up the DNA.

Those proteins spool up the genome in the same way you might spool up a garden hose.

And when you spool them up very tightly, package that garden hose, your genes in that region of that hose or in that region of the genome will be switched off.

And those that are exposed in a big loop, so your garden hose is looped out over the driveway, those are genes that will be switched on.

And that's also an essential type of information because it tells each cell what type of cell it should be.

All of our cells, essentially all of our cells, have the same genome.

But what distinguishes a brain cell from a liver cell and what allows a fertilized egg to become a 26 billion composite of different cell types when it's born is the epigenome.

And the epigenome, I believe, is the reason that we age.

Many of you are old enough to remember what analog information is like.

If you've ever had a record player or a cassette tape, it's pathetic.

It's the reason we converted to digital in the late 1990s.

But we are built with an analog system of information.

But it has to be engineered that way, because the epigenome needs to respond very quickly to the environment.

It has to have millions of different values rather than very discrete ones.

And it also needs to be ready for things that it hasn't ever seen before.

the epigenome is it's the software of our cells, and the genome is the computer or the underlying code.

The interesting thing about this whole analog versus digital is it gives us a new perspective on aging.

Now, instead of talking about a garden hose and wrapped up proteins, let me show you what it really looks like.

Again, a schematic, because I don't have a photo for you.

We don't have a microscope that's capable of doing this.

So what we're seeing on the left is a young cell.

And what we think is going on is that these chromosomes in the black lines are wrapped up in these loops.

These are called topologically associated domains.

And we can now map these with great accuracy.

Just in the last few years, we've learned how to do this.

And right across the genome, I could do this for your cells pretty easily.

And what we see is that these loops of DNA change as we get older.

And what that leads to, as you can see on the cell on the right, is that over time, genes that should be off come on and vice versa.

And what happens is cells lose their identity.

A nerve cell in an older person is no longer fully a nerve cell.

It's starting to move around in so-called Waddington landscape space or epigenomic space and it's becoming a different type of cell.

A nerve cell in an old person may be partly a skin cell.

No wonder we start to lose the function of our retina.

No wonder we start to forget things if our cells don't maintain their epigenomic information.

Question is, though, can we slow this down?

Is there a backup hard drive of this early setup that we can access and restore that structure that you're looking at on the left?

An analogy I like to use is this compact disc or DVD here.

For the very young in the audience, we used to put music and photos on these things.

But anyway, so obviously, they store digital information, which was what was great about them.

But what was really sucky about them was that they would get scratched.

And you can see this is a great analogy for aging, because the cells on the right, by this analogy, they still have the information to play the music, to play the concerto that might be encoded in those zeros and ones or those pits in the aluminum foil.

But the reader of that compact disc cannot read the songs merely because the laser is skipping and being refracted.

But what is great about this analogy is it's very simple in this situation to reset the system.

It's possible you could just get a rag with some toothpaste and polish off those scratches.

And if we're right about aging, it will be possible to essentially do the same to our body and allow our tissues and our organs to play the symphony of our youthful lives once again.

These are 2 mice and you might want to guess which one's older.

They're genetically identical twins and when we read their genomes we find that their genomes are identical as well.

But what we've messed up is their epigenomes.

And you can see what we get is not just a mouse with gray hair, wrinkled skin, and if you could look inside, organs that look old.

We haven't just given it diabetes or osteoporosis or dementia.

And as we wrote in the book, Matt and I, if you can give something, you can be sure that you can take it away.

So that's what I'll tell you about in a minute.

But you might ask, well, David, how do you scratch up that DVD?

Of course, you're not taking sandpaper to a mouse, I hope.

What we did, and we are going to publish this, hopefully, shortly, we have manuscripts under review at Cell.

There's a couple of manuscripts and 10 years of work out of my lab and 15 others from around the world, is the discovery that broken chromosomes disrupt the structure of those hose reels, the DNA, and cells start to lose their identity so they don't function very well.

And the ultimate outcome of losing cellular identity is aging.

Now what's really interesting about this mouse is now that we can accelerate aging, we can do a couple of things.

We can create a mouse that has the equivalent of 80 years of aging.

And we can just induce these DNA cuts in the genome as much as we want.

And we think that these mice will be very useful for finding treatments for Alzheimer's disease, which I think ludicrously people have been using one-year-old mice to study Alzheimer's disease, which to me doesn't make much sense.

The other thing we can do that's interesting about these mice and that we've done is we can age only part of the animal.

We've accelerated aging in the brain of these mice, and we're seeing increased dementia.

But interestingly, we can ask the question, do other parts of the body age faster as well if your brain is old?

Clearly, we couldn't do that any other way.

Now, 1 of the things that made this all possible to declare that these mice aren't just sick, but they're actually biologically older, that we've given them aging, is that we can now measure age with great accuracy.

This is not qualitative, this is 100% quantitative with machine learning algorithms.

What I could do to any of you right now is take a blood sample.

Please don't give me any blood samples before I leave.

I could even take a buccal swab of your mouth, and I could go back to my lab.

I could read what's called the DNA methylome.

It's really just measuring which of the letter C's out of those ACTG, which of those have a methyl group, a C and 4 H's on there.

And the addition of these chemicals over a lifetime is a really great predictor of your aging rate, because we see them go up in a linear fashion with time.

And it turns out if you extrapolate backwards, even a teenage person, teenage girls, are aging.

Even in the womb, we're aging according to this clock.

Now, we used to think that this clock was just a measure of time, like a clock on the wall.

What we've been testing is the idea that perhaps if we move the hands of the clock backwards, in this case, the clock, the biological clock, does time go backwards?

Does the age and the health of the animal go backwards?

And I'll tell you about that in a second.

This is an example of data from the paper that we are hopefully publishing soon.

And with Stephen Horvath, who discovered this clock, we can see that the mice that are normal are in blue, and they're aging at a certain rate according to these DNA methyl marks on the DNA.

But if we scratch the genome and cause epigenomic changes, we can age the mouse 50 percent faster.

And what's exciting is that pretty much by all measures of these mice, they're 50% older than their counterparts.

But then the question arises, if you can cause aging, can you reverse it?

And if you do take the clock back, does it do anything?

So now I want to tell you about 1 of my favorite scientists and mathematicians.

And if there's 1 person that gave rise to the world we live in, the Internet age, it's him.

And what he proposed in 1948 in a couple of elegant papers called the Mathematical Theory of Communication are a set of diagrams and equations that explain how to preserve information between a sender and a receiver and what to do if there's lost information.

And he and his equations gave rise to the TCPIP protocol and the Internet we use today.

And you know that if we don't get an email correctly, if it doesn't arrive fully with all its packets, the Internet is smart enough to go back to the original backup copy and get the full message.

We used to say, oh, sorry, I didn't get your message.

And for a while, there were a lot of people

the most important diagrams when it comes to aging.

Shannon here didn't realize that he was working on something just as important as the Internet, perhaps even more so, and that's how to reset the age of our bodies.

And what you can see here in his diagram from 1948 is that if you lose a message, a signal, a radio signal, or, say, a Morse code signal between the sender, which he calls the transmitter, and the receiver, if you lose some of that information, don't worry, because there's what he called an observer, the backup copy of that original information, which you can use to restore the information using a correcting device.

If that's true in our bodies, we could take the old epigenome and reset it to be young again.

But we didn't know what the correcting device was in the cell.

The transmitter, of course, is the fertilized egg and us as a young child.

The receiver is our bodies in the future, let's say an 80-year-old.

And we lose a lot of that information over time.

So we can use energy to reset the system.

Now, the man on the left won the Nobel Prize for learning how to take an adult cell and make it a stem cell, wiping all of the DNA methylation off the genome, wiping it clean so that those cells could be rebuilt into anything you want.

We call this the process of induced pluripotent stem cells.

And we use what are called, named after Mr.

These 4 Yamanaka factors are called 0SK, and M for short.

Now, Yamanaka won his Nobel Prize because it's a great discovery to be able to take a skin cell and turn it into a nerve cell.

It could give rise to new treatments, new organs that we can put back in our bodies.

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David Sinclair | Why We Age and Why We Don't Have To | Talks at Google