Why We Age and Why We Don’t Have To | David Sinclair | Talks at Google
[MUSIC PLAYING] DAVID SINCLAIR: Welcome, everyone. 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. And so thanks, Sanders, thanks for inviting me, and thank you all for coming.
There’s a few people here that helped make this book possible. I want to thank them all personally, and also for Nick Platt for making this possible. And also, Matt LaPlante, who also helped write the book in a very big way, and he’s here somewhere.
Raise your hand, Matt. Yay. Yeah, so this has been a long journey for me. I’m going to talk for about 25 minutes and leave time for a fair number of questions. So yeah, write those down. I’m a fairly open book, so ask me any question and I’ll do my best to answer it honestly.
OK, so I’ve been working at Harvard for, well, since 1999, so about 20 years now. 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.
The bad part is that I’m a lot closer to being towards that edge where we all drop off in physical health and mental health as well, and we’re all facing that. Now, some of you are very young, and it’s easy to pretend that that’s a long way off.
But it will happen. All of us will get old, and we will all die. And it’s a terrible thought. It’s also terrible to think that our parents and everybody we love will also face this. Now, dying isn’t the point of all this.
I mean, 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? Just think about it. Why don’t we? So the medical definition of a disease is something that happens over time that causes you to lose function and become disabled.
Sounds pretty much like aging, right? 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% 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. And what we hope is that it will soon change the way doctors look at aging.
I don’t know if 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 is common like aging, we don’t really do anything about it. We accept it as natural. 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 carpet, it’s not even a wooden floor. Nothing about our lives is natural. Maybe oxygen we’re breathing is natural, but everything else is unnatural.
It’s human-made, it’s man-made, and we change our environment. And tackling diseases and tackling aging is also natural. That’s what we do as humans. 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. How many of you would like to live to 80, but not beyond, not beyond 80? Is 80 enough for anybody in the audience? A few.
There’s a few hands. 80 is enough. I don’t know if anyone’s 80 in the audience, but you probably don’t like that answer. What about to 120? Who would like to live to 120 and then die? Yeah, what, that’s about half of you.
How many of you would like to live forever? OK, so there’s a few people who didn’t put up their hands, so it’s somewhere in between 120 and immortal that they’re looking for. Rather wide gap. Maybe let’s say 150 for that group.
But that’s really interesting, right? 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? Exactly.
That’s most of you, if not all. The point is, 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. It’s about how well you live. Stopping us from getting sick, stopping cancer, heart disease, Alzheimer’s, frailty, and diabetes.
And you might say, David, how is that possible? We can’t even solve cancer. How are you going to do that? 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 in some experiments I’ll show you, they’re actually resetting the aging clock of the body. All right, so to really understand how to delay diseases and live longer– and turns out, guess what, if you’re not sick, you tend to live longer, that’s what we’re all about here– you need to really understand how it works, why it happens in the first place.
We can debate why aging has evolved. 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.
And it’s not because of free radicals, and it’s not going to be stopped by antioxidants, though that hasn’t stopped marketers building about $150 billion industry every year. But what’s different in the book and 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. We accept it as a natural way of life, but we don’t have to. So this person has been sunburned on one 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 won’t just feel older, your body will literally be older, and we haven’t understood why that is. 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– and I’m sure you’ve probably all heard of the mutation theory of aging– that we just lose our genetic information.
Turns out, that’s probably wrong 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 a loss of genetic information.
So what is it that causes aging? 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, so what is it? Well, there are two types of information in our bodies that are essential for life.
One 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. It is A, T, C, G, four bases.
This would be, instead 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 of the primordium.
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. You can copy it without error. Our cells typically do in a large way. 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.
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. It is a loss of analog information. Many of you are old enough to remember what analog information is like. If you ever had a record player or a cassette tape, it’s pathetic.
You can’t copy it very well. You lose information. It degrades over time. It scratches. It’s the reason we converted to digital in the late 1990s. But we are built with an analog system of information.
This epigenome is useless, 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. One way of thinking of 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, the black lines, are wrapped up in these loops.
We call these TADs now. 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.
That’s really important. 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 maybe partly a skin cell. I mean, think about that. 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, and can we reset the system? Is there a reboot? 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? I believe that it’s possible.
An analogy I like to use is this compact disc or a DVD here. For the very young in the audience, we used to put music and photos on these things that were very useful for a moment. 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. You had to be very careful with them. 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. You just get a bit of polish. It’s possible you could just get a rag with some toothpaste and polish off those scratches.
And guess what? It’s brand new. You can read the concerto. 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.
But only if there’s a backup. We don’t know if that’s true yet. Now what the heck is this animal? These are two mice, and you might want to guess which one’s older. It’s a trick question. They’re twins.
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. We’ve scratched up their CD. 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. We’ve given this mouse aging. 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, that 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.
We can make a mouse 80 years old. 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, one 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– but theoretically, I could.
I could even take a buckle 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 Cs out of those A, C, T, G, which of those have a methyl group, a C and 4 Hs 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 young infants 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. But 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 with Steven 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% 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? All right, so now I want to tell you about one of my favorite scientists and mathematicians.
Many of you may know this person. He used to work down the street at MIT. He worked at Bell Labs as well, and his name is Claude Shannon. And if there’s one 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 TCP/IP protocol in 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, it didn’t arrive in my inbox. Now you can’t use that excuse, right? It always gets there. And for a while, there were a lot of people who were caught lying with that excuse.
Anyway, this is one of the most important diagrams when it comes to aging. And I’m pretty certain that Dr. 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 is 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. We succumb to entropy. But we are biological organisms. We’re not closed systems. We’re actually open systems, 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. Yamanaka, Dr. Yamanaka– the four Yamanaka factors. These four Yamanaka factors are called O, S, K, 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.
But what he probably didn’t think of, I’m guessing, is that this is also relevant to aging. Now we don’t want to put the four Yamanaka factors into our bodies and turn us into a giant stem cell pool. That would be the world’s biggest tumor.
You’d get a teratoma. And some people have tried that, and they’ve actually killed mice within two days. So that’s not going to be a therapy anytime soon, and I wouldn’t volunteer for it if I were you.
But what we’ve discovered in my lab just recently in work that we’ve put online, which you can check out if you’d like– it’s on bioRxiv, R-X-I-V, and this is an online upload, we’re probably going to get back the reviewer’s comments from Nature any day now– this paper is something that I never thought I’d see in my lifetime that I think we’ve finally found how to tap into the observer and reset our biological edge using Yamanaka’s factors, but not all of them, just a subset.
So what did we decide to do? Well, I have to give credit to a student in the lab, Yuancheng Lu, who features in the book. We were fortunate to be writing the book as we were making these discoveries last year, and they were basically written almost in real time as they were coming out, which makes this book a very unusual kind of book.
You’re learning about science before most people have even digested it yet. So here’s the experiment that Yuancheng did. We put three of the Yamanaka factors. We left off the M, which stands for MYC. MYC is an oncogene.
You don’t want to be causing tumors. But we used the O, S, and the K, O-S-K, fit it into a virus, and we put the virus into the eye of a mouse. And these are viruses, they might sound scary, but they’re used all the time in gene therapy in patients right now.
So it’s not crazy stuff. What we did in collaboration with a lab across the street, Xi [INAUDIBLE] He’s lab, after we put the virus in the eye of a mouse, we pinched the back of its optic nerve. And what normally happens is– I’m sure you can guess– is the nerve dies.
If we’re old, even if we’re young adults, we will not grow back an optic nerve. If we break our spine, we will not grow back a spine and a spinal cord. But very young animals will, and some animals will grow new nerves.
An axolotl loses its limb, it will regrow a limb. This is not unheard of. It’s just that we’ve lost that ability. But we think that we know how to regain that ability and make cells very young again so they have these properties of regrowing, just like embryos do.
And so what you’re looking at is a stain of the optic nerve that’s been crushed, and you can see where the crush ends. That’s where the orange dye is coming down and stops because all those nerves have been crushed at that point.
And a lot of the orange dye is missing, which is labeling healthy nerves because the nerves have died. But have a look what happens if we turn on this reprogramming, this age reset, in the eye after we damage it.
First of all, the nerves don’t die, and many of them somehow wake up and start growing back towards the brain. If we leave this for four weeks, that’s what you see. If we leave it for 16 weeks, they grow all the way back to the brain, which is unheard of in science so far.
Now, we’ve done this also in other areas. You might say, David, a crushed eye, it’s unlikely I’m going to have a crushed optic nerve. But what about glaucoma? Many people have pressure, and it damages their retina.
There’s nothing that will appreciably slow glaucoma, let alone reverse that disease and give you your vision back. What about old retinas? What about old age? I’m already 50 and starting to have trouble reading at night.
Can we reverse vision loss during old age? And I can tell you that, at least in mice, we absolutely can. We can reprogram a retina of a mouse, an old mouse, and make it see just like a young mouse again.
Those nerves wake up. They remember that they’re nerves, not half skin cells. We can look at their clock. We’ve measured their clock. They get younger. And all the genes that should be on when they’re young come back on, and all the genes that should be off when they’re young get shut off.
It’s magic. Now we don’t fully understand how it’s working. We know how to tap into the observer. But what’s behind the clock? What are the cogs behind the system? We have some idea what’s going on. I think we’ve found the communicating device back to the observer at least.
There are a couple of enzymes called TET, TET1 and TET2. These are enzymes that remove those chemical groups off the DNA as part of that reset process. So we found some cogs in the wheel that drives aging backwards, so that’s very exciting.
And just today in lab, Matt and I were there, and we just had final proof that if you have a mouse that doesn’t have the TET genes in its eye, you cannot restore the growth of its optic nerve. We also know you cannot restore its vision, either.
So this is super exciting. For the first time, we have the ability to reverse the age of cells. Now we don’t know how long this effect lasts. It could last for a month. We think it will probably last for years, if not decades, because we are actually getting very deep into the deep layers of aging, and the epigenome is very stable.
But could you reset? How many times can you reset? We don’t know that yet. So until these therapies are ready for prime-time– and we’re hoping to treat our first patient in about two years from now that suffers from glaucoma– what can we do in our daily lives? I hear you ask.
Well, besides reading part three of the book, where a lot of it’s talked about, there are some other things we can do. We found a chemical that exists in our body that we lose as we get older that’s really important for stabilizing our genome and preventing the scratches.
It’s called NMN. And you can see the mice on the left were drinking NMN. They recover pretty quickly. Actually, Jeremy, let’s switch to the other one. See if you can guess which old mouse in this video is drinking the NMN.
[MUSIC PLAYING] All right, I think we’ve seen enough, Jeremy. So if you guessed the mouse on the right, you would be correct. What we found and we published about a year ago in the journal “Cell” was that NMN turns on a longevity pathway that we’ve worked on for many years.
These are stabilized of the [INAUDIBLE],, and they also control our cells’ survival and defenses against aging. And what’s exciting is that we have inbuilt longevity pathways that we can activate with these molecules, like NMN.
There are others that are out there. One is called metformin, which is a diabetes drug, which is exciting because it’s been seen in tens of thousands of patients to at least seemingly slow down the effects of aging and protect against diseases.
There’s another one that’s more toxic. I wouldn’t recommend it, but it’s called rapamycin. But there are things out there that we already have run into that actually may work. But what else can you do in your life? What can you do if you don’t want to go to a doctor and ask for metformin, a diabetes drug? Well, one of the things that I do, one of probably the best thing I could tell you having read thousands of scientific papers, is eat less often.
Now that’s not malnutrition, it’s not starvation, but it does mean going hungry for part of the day. What I do is I skip breakfast. I eat a late lunch, sometimes I miss lunch, and eat a normal dinner.
What does that do? That turns on these longevity pathways. It raises the NAD levels in our body, which NMN will do also, and it will mimic exercise and hunger. Well, hunger will, of course, mimic hunger, but NMN and hunger work through these same longevity pathways.
And you might find that by exercising a bit like these mice, getting yourself puffed a few days a week on a treadmill just for 10 minutes is enough and being hungry for a few days out of the week, you’ll find you feel remarkably better, and you’ll be a lot fitter because of it.
And perhaps when you’re 80, 90, and even 100, you’ll be able to continue doing all the things you always have wanted to do late in life. Start a new career, if you want, start a new company, leaving a legacy.
We have clinical trials in progress with a molecule-related NMN. So this isn’t future stuff, this is stuff that’s actually going on just across the street from my lab at Harvard Medical School. So we know that this molecule can raise NAD levels at least two-fold in people.
We haven’t seen any negative side effects yet. And we’re going to be doing clinical trials in patients next year, but not for aging because it’s not a disease. We’re going to be treating a rare disorder, most likely– at least the plan if all goes well– is to treat a rare condition called Friedreich’s ataxia, which is considered a mitochondrial disorder, a lack of energy.
But imagine a future where you can have an injection of a virus and then have a course of antibiotics, like our mice are given, and turn on reprogramming for a few weeks. You’ll start to look younger.
Your hair might change color. It might regrow, we don’t know. But your organs should be improved. You should get your vision back if you’ve lost it. And that might last for a decade. And after you’ve aged for a decade, you come back for a reset.
And all you need to do is to get a prescription for antibiotics that turn on these genes again. Now again, we don’t know how many times you can reset. It might be three, it might be 3,000. And if you can reset your body 3,000 times, then things get really interesting.
And I don’t know if any of you want to live for 1,000 years, and I also don’t know if it’s going to be possible, but these other questions we have to start thinking about because it’s not a question of if, it’s now a question of when.
And finally, I’d like to talk about my father, who’s a role model for all of us, I think. So he’s been on a combination of NMN and metformin and some other things that are written down in part 3 of the book.
I don’t like to talk a lot about supplements and things, so it’s all in there, and I have a newsletter as well. But let’s talk about my father. Now, this is not a clinical trial. It’s what we’d call an N-of-1, or if you include my wife and I, an N-of-3.
Not very well controlled. It’s not placebo controlled. But my father was heading downhill. He was not very energetic. He was pretty depressed. His wife had died. He was just thinking, OK, I’m done for.
But he’s realized that his health isn’t declining so far, and we don’t know if it’s because the molecules or because of the exercise he’s been doing or the intermittent fasting that he’s trying. But nevertheless, he’s a beacon of hope for all of us that we can live a life like his, where, in his late 70s, he’s started a new career and he travels the world.
And we just got back from Uganda, where he went hiking with his three grandkids up a mountain and was the oldest person to ever do that And for him, it was a breeze. He’s literally stronger and fitter than I am at age 50 and probably when I was 30 as well.
So I want to end by saying thanks for coming. I’m happy to answer any questions as honestly and as openly as I can. And I hope that you not just begin, but continue this conversation because it’s one of the most important things we can do for the planet to save on health care, to save billions of dollars, eventually trillions, that can be put to other causes, such as global warming and species extinction.
And I want to really thank you for taking time out of your day for coming to listen. Thanks. [APPLAUSE] AUDIENCE: So you’ve mentioned metformin and intermittent fasting. Can you talk about the role of insulin in the aging process? DAVID SINCLAIR: Of insulin? AUDIENCE: Yes.
DAVID SINCLAIR: Right. What you want to be to live longer, based on everything we know in mice and humans, is to be really insulin sensitive, and that means having a lot of insulin receptor, not having your blood glucose levels go high.
And actually, the best predictor of your longevity is your blood glucose levels, which is why you want to be exercising and why metformin probably is, in part, working. So insulin is key. There’s also an insulin-like growth factor molecule that’s also important.
And when you have lower levels of that, it also extends lifespan in animals and seemingly in people. And what’s downstream of those pathways are what’s called FOXO, our transcription factors which control our defenses against aging and disease.
And so we want to keep those active. Now, if we’re always satiated, if we’re always eating protein bars and never hungry and if we sit around all day listening to pompous academics give talks, those transcription factors are not going to be active.
In fact, they stay out of the nucleus where they don’t do any good. And so what we want to do is make sure the insulin signaling pathway is active and that they stimulate those. There’s another thing that also goes, which is the TOR pathway.
So TOR is also controlled by the insulin-signaling growth factor pathway, and you want to have less of that signal. And then mTOR is an active. So what’s mTOR? As you’ll read in the book– I talk a lot about it– the mTOR censors how many amino acids you’re eating, and you don’t want a lot of mTOR activity.
And the more protein you eat, think about those protein bars– I just had one– if you eat a lot of steak, your mTOR pathway will be always active, always telling your cells to grow rather than fighting disease and hunkering down.
And so that’s why I have actually switched from a regular diet to a mostly plant-based diet because the amount of amino acids that I was getting was overloading my mTOR pathway. And so I’m trying to keep that down as well and give my body the best chance, and I’m also trying to help the planet as well.
But very good question. AUDIENCE: Thank you. Good talk. The reason I got into computational biology was that I read some exciting things out of Aubrey de Grey maybe 20 years ago, and I was like, oh, interesting.
So one thing that I’m curious about is we have these other more macroscopic, I suppose, mechanisms around aging. We have the rate of cellular division, and we have accumulation of junk both inside and outside of cells.
So is the management of those processes assumed to be downstream of the mechanisms where you’re making your intervention. DAVID SINCLAIR: They are. They are. So we’ve declared as a field, as you said, that there are eight or nine hallmarks of aging, and some of them are telomere shortening, mitochondrial dysfunction, loss of stem cells, senescent cells.
And so it’s great to say, OK, plant a flag in the ground, we understand aging, we’ve got seven or eight things that cause aging, but that doesn’t explain why they happen. Is there an upstream, as you say, cause of all of those? Or are we building seven dams on seven tributaries? And the information theory of aging proposes and can explain how epigenetic aging, the loss of gene expression as we get older, loss of that information can explain all of those hallmarks as well.
And in fact, if we look at those mice, even though we’ve just disrupted the epigenome, they have all of those hallmarks, from mitochondrial dysfunction through to senescent cells, senescent cells being the ultimate expression of a scratched CD.
But yeah, I’m excited about this theory because it can explain the last 100 years of observations. Now, all theories eventually succumb to a paradigm shift. And I’m not saying this is the be all and end all, but I think it’s a great way to think about aging, and it brings up a lot of testable hypotheses, such as these mice I showed you.
What are the chances we get an old mouse when you cut the genome like that? One in 1,000, I’d say, and it worked. So we’ll continue to test this theory, but so far, it seems to explain, in my view, all the observations over the last 100 years.
AUDIENCE: Is oxidative damage upstream or downstream or separate from what you’re talking about here? DAVID SINCLAIR: It’s both. It’s part of the positive feedback loop. So this is what we think is that oxidative stress in the nucleus will exacerbate the genetic damage, so you’ll get a broken chromosome.
So there are a lot of things that cause epigenetic change, including to scratch the DVD, but the most potent one that we found is a broken chromosome. And oxidative stress, free radicals, can cause a DNA break, but it’s not the only cause of DNA breaks.
They’re happening all the time– cosmic rays, CT scans, X-rays. And actually, free radicals are beneficial in biology, so you don’t want to swap those out. It’s been shown if you take a lot of vitamin C and even mega doses of vitamin E, you can blunt the effects of a healthy diet and exercise.
So I’m not saying they’re not part of it, and that’s why I was saying I’m excited about this theory is it can fit all of these observations in. You might be asking, well, why don’t antioxidants work as well as we hoped? Well, one of the main reasons is that we think that there are other causes of DNA damage besides free radicals and that you need more than that.
But the other thing that’s interesting to think about is that we’ve discovered that the molecules that you ingest when you drink one of those drinks that have the antioxidant properties, what’s more than likely happening is that those molecules aren’t directly mopping up free radicals, but we’ve learned that they bind to receptors and enzymes that sense the environment and they turn on our body’s natural antioxidant defenses, such as catalase, an enzyme that’s necessary for mopping those up.
Now we have a theory for that. We call it xenohomesis– xeno meaning “from other species” and homesis meaning “anything that doesn’t kill you will make you stronger.” The idea is that plants make these antioxidants, what we call antioxidants, but they’re actually [INAUDIBLE],, we call them, that are helping the plants survive and hunker down through their genetic survival pathways, and that by ingesting our plants when they’re stressed out, we get the same benefits.
We also need to hunker down if our food supply is going to run out. So that was five different answers hopefully answered your question. AUDIENCE: Well, I was in particular wondering about non-nuclear oxidative damage.
DAVID SINCLAIR: All right. Yeah. Well, you mean in mitochondria, for example? AUDIENCE: Or I think collagen and even just extracellular things. DAVID SINCLAIR: Right. Well, so we need to figure out in tissues that have a lot of collagen, whether it’s fibrotic lungs or fibrotic liver, is that reversible or irreversible.
That’s a start. Is reprogramming going to get rid of those problems, or are they there with us for life? Hopefully not, but we’ll have to see. But the oxidation of collagen is a part of aging. But what I’m proposing is that by resetting the cell and making it behave as though it’s young again, it can rid itself of those oxidized and damaged proteins through a process of autophagy.
And there are a few different types, but one of the most important one is called chaperone-mediated autophagy that is really deep cleaning the cell of getting rid of these kind of proteins that have accumulated.
And the best way to turn that on besides chemicals we’re working on is actually to not eat for two days, and that’s thought to clear out even oxidized collagen, for example. AUDIENCE: So a few months, maybe a year ago, a doctor who was a [INAUDIBLE] from the World Health Organization came and gave another talk.
And I read his book, and it suggested like M&M as using that help, and a bunch of doctors are actually secretly giving themselves these treatments because they see it works and the data seems fairly good.
Why is intermittent fasting something that really helps? Why is there no published studies about aging? If doctors seem fairly agreed that this looks good, it’s useful, there should be more trials. And I don’t like going to random websites on the web to try and see these things.
That’s just kind of sketchy. Why is there no real clinical data and backed up support all on these anti-aging techniques that even doctors seem to agree on? DAVID SINCLAIR: All right, first of all, I don’t recommend eating M&M’s.
I know you misspoke. At least not if you want to live longer. But yeah, I know what you mean, NMN. There’s a few answers in there. One is that there are published studies, and many of us are working very hard to try these, as I pointed out.
But trials are expensive. Each patient’s $10,000, so you can see how quickly it adds up. But now that we have the clock to measure, I think things will move much quicker. Because otherwise, it’s going to be a very long trial.
There are probably 15 to 20 trials with NMN and related molecules in progress, so they will come out. There are some so far that have been published. There’s one with NR that actually showed there was no improvement in blood sugar, so that one was a negative trial.
Then there was one also that came out from affiliated with a lab at in MIT that showed ALS patients did do better with a combination of NR and pterostilbene, which is related to resveratol and [INAUDIBLE].
So yeah, bottom line is, I see it as my role as an educator, communicator now, and with this platform that’s come with the book, to be able to sort out which is BS from reality, and there’s a lot of BS out there.
But there are really good studies that are coming out all the time and a body of literature that nobody has time to read or to sort through, and that’s what I hope to do for everybody. AUDIENCE: Hi. DAVID SINCLAIR: Hi.
AUDIENCE: I was a little bit confused by your discussion of epigenetics being analog in nature because I always thought there was both digital and analog parts of it. So like the folding of the chromosomes as a topological [INAUDIBLE] were very analog, but methylation I’d always thought of as being very digital.
That C is either a methalyzed or it isn’t. And so first of all, I was just wondering if I was confused. And then second, whether your research has indicated so far which parts of the epigenetics, where there’s more the methylation factors or other things that are the most important in the biological clock.
DAVID SINCLAIR: Yeah. So there are digital parts of the epigenome, but most of it is not digital. The methyl, as you point out, is digital. But we think that the methyl is not the main component of the epigenome.
It’s part of it, but there are other marks on histones and others that don’t occur in discrete ways, but it’s a haze. And part of the problem of measuring the epigenome is that it’s not digital, that you get probabilities rather than discrete units.
But I’ll grant you that. You’re right that the methyl is digital. But the loops, the loops are moving all the time, that you can’t say there’s a loop because it’s gone by the time you measure it. And so what’s interesting is the field is right now moving away from describing a TED as a discrete thing to a probability, which is a whole different mathematical challenge.
What else didn’t I answer? You had a second part to the question. AUDIENCE: Just whether any of your research indicates which epigenetic factors it’s based on. DAVID SINCLAIR: Yeah, good question. So we’re searching for the deep observer, what that is.
It’s not just methyl. It clearly cannot be just methyl. There are proteins that probably bind to those methyls to say that’s a youthful methyl and this other one has come later, so get rid of it. So we need to find that.
But also, there are proteins that control the TADs. So there’s proteins called CTCF. You might know as a biologist then that they are controlling the loops, the spooling, and we see changes in the distribution of those proteins throughout the nucleus as we age those cells in the dish.
But it’s early days. I’ve got 35 people in my lab, and about half of them are now trying to figure this all out. And a year ago, only one person was working on it. So we’ll get there. And there’s a few other labs in the world working on this, but I think in a few years, they’ll be probably 50 to 100.
In terms of the levels, the way I think about it is that there’s a superficial level which is transcription factors, which just by holding your breath, you can change them and they move around and they control genes.
But they reset. If you change those, of course, you’re not going to permanently go back 10 years. A different layer are the epigenetic modifications on histones, and those are fairly stable, but still quite transient.
They won’t last for a long time. But those DNA methyl marks are the third very deep layer that last for years, even decades, and that’s the very deep layer. And that’s why I’m excited about what we’re working on because we finally penetrated that deep layer.
But how the cell gets to that deep layer and then knows which parts of it to reprogram and reset and reorganize, that’s the challenge. AUDIENCE: So I was wondering about the experiment with the twin mice.
So aside from showing all these symptoms of aging, does the mouse with the scrunched-up genome, does it actually end up living a shorter life? Or do they still keep the same life span? DAVID SINCLAIR: So they live shorter, but we didn’t have enough mice to be able to statistically tell you that with certainty.
In a small group, I think we had 10 and 10. The ice mice died younger on average, but it wasn’t statistically significant because you typically need about 40 to 50 per group. But yeah, it looks like they die from regular mouse diseases.
They’re not riddled with cancer more than a normal mouse would be. So it’s a good question. They should live shorter, and they are. We can also measure their frailty, and we’ve used machine learning to be able to use frailty measures to predict longevity.
And based on those measures, it’s also consistent with those mice aging and dying younger. AUDIENCE: So you have a promising technology . Five years from now, you find that the treatment that works. 5 to 10 years later, the FDA approves it, and now you’re going through the insurance system.
Clearly, this is like a blockbuster drug of our time. Do you have any thoughts on how that will be handled when suddenly you can, say, go to your doctor, go back 10 years? DAVID SINCLAIR: Yeah, that’s the thing.
That’s the thing we need to talk about, what happens when this happens. And I don’t know if it’s going to be five or 10 years. I mean, the NMN stuff is here already. You can go buy that. But the reprogramming early days, we don’t think it’s dangerous, in mice at least.
We put it into the mice for over a year, and they’re healthy. They’re not a giant tumor. But yeah, let’s talk about what happens when this comes, hopefully within our lifetimes. What does the world look like? So first of all, let’s say it’s for glaucoma.
This is where the first trials will be done. We have a company called [INAUDIBLE],, full disclosure. So you can treat glaucoma, OK? Glaucoma patients, if all goes well, get their vision back within a few weeks.
But the world will know that this is a reset. What’s to stop a doctor in Costa Rica giving this IV to their patients? Nothing. Nothing. That’s where it will begin, how it’ll spread if it works. Hopefully, those people will not be sick from it.
But then project another 20 years, will people be banging down the doors of their doctors saying, give it to me or else? Probably what will actually happen is that there are doctors that are more willing than others to prescribe things.
And with the case with metformin, you can find doctors that have read the literature and they’re OK with it. But yeah, I think it’s going to be an interesting world where you can at age 30 say, I don’t want to get any older.
Yeah. A lot of ethical things. One of the things that Matt and I put in the book was, for all those people who say, whoa, this is way too much, I don’t want this, we write, we don’t want you to live any time longer than you want to, either.
So we’re not forcing this on anyone. But if you have a choice, that’s great. We also say we both believe that you should have the choice to die when you want to as well. So it’s important to balance it out.
Thanks. Good question. AUDIENCE: NMN versus NR. DAVID SINCLAIR: OK, so NR is nicotinamide riboside, which is similar to NMN without a phosphate group. NMN and NR, NR is cheaper than any NMN. As a professor at Harvard Medical School, I don’t recommend anything and I certainly don’t talk about supplements and I don’t work with any supplement companies.
That’s my disclaimer. If you ask why would I take NMN and why did my father, partly it’s availability. We have a stash of it that we’ve tested, but that doesn’t help you. What I think would help you is go to the website that I’ve got on the book.
Honestly, I’m not promoting it. I’ve written down everything that I can say about NMN and NR. I can also tell you that NMN is more stable on the shelf. And if NR gets a little bit wet or is out for too long, it’ll degrade into nicotinamide.
And I wouldn’t take high doses of nicotinamide. It may have the opposite effect. But that’s the main reason. Now in mice, they’ve both shown remarkable effects to protect the body of those animals, and clinical trials are ongoing with both molecules.
So at this point, I really couldn’t say one is better than the other. AUDIENCE: What does the M factor that you’re not using do? DAVID SINCLAIR: Sorry? AUDIENCE: The stem cell M transmission factor that you’re not using.
DAVID SINCLAIR: Oh, MYC, c-MYC. AUDIENCE: Yes. DAVID SINCLAIR: Yeah, so c-MYC is a gene that controls cell proliferation. And if you turn it on in normal cells, they will be partway towards a tumor, hence its name as an oncogene.
And it’s very useful if you want to reset the age of a skin cell to zero, but it’s not so helpful if you want to reset the retina partway back towards youth. Thanks. We were just lucky that worked without MYC, but you got to swing for the fences.
If I can give you any advice about careers, you got to take some risks. Not everything will work. When they fail, just keep going. You’ll eventually get there if you focus on a dream. And my dream has been to figure out why we age and see if we can live an extra 10 healthy years of life.
Any more questions? I think that’s it. Sanders, thank you. [APPLAUSE]