David Sinclair: "Lifespan: Why We Age and Why We Don't Have To" | Talks at Google
Welcome. Everyone I'm not sure I'm gonna tell you how to live forever today but I'm gonna 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 help make this book possible I want to thank, them all personally. And also so, Nick, platform. 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. Gonna talk for about 25, minutes and we leave time for a fair number of questions, so. Yeah write. Those down I'm I'm a fairly, open book so ask me any question, and I'll do my best to answer it honestly. Okay, so I've, been working. At Harvard for nine. 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 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. That's, a it's a terrible, thought it's also terrible, to think that our, parents and everybody we we, love will also face this, now dying, isn't 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 ninety and play tennis and even make it to a hundred and still have. A career a second, third or fourth career. Second. Third or fourth partner. If you want. But. The, the important, point here is that this. Isn't about living forever it's about changing, the way we treat people. Terms. Of healthcare matters, and 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, it. 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 it's 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 a carpet it's not even a wooden floor nothing. About our lives is natural, maybe. The oxygen we're breathing is natural but everything else is not unnatural. It's. 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 220. Who would like to live 120, and then die. Yeah. What that's about half of you how, many of you would like to live forever. Okay. So that there's, a few people who didn't put up their hand so it's somewhere in between hundred and twenty in immortal that, they're looking for. Rather. Wide gap. Maybe. Let's, say 850, for that 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 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 insulator. 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 you're 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 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 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 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 nano, scale 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, a about, 150. Billion dollar industry every. Year, but. What's different in 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 we, we don't even do anything about it we accept it as a natural way of life 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, damaged 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. We haven't understood why that is and the. Old idea that came out of the 1950's from. Mostly. Physicists, who were previously. Working on the Manhattan Project their. Idea was that we. Ran out of genetic, information. Mutations. 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 the 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 they're essential, for life. One, is genetic, and the. Other is epigenetic. Okay. 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 TCG. Four bases, this would be a 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 four billion years since, we first emerged, out of the primordial 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 spill up a garden hose, and. When you spool them up very tightly packaged, 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, you know, your, garden, hose is looped out of the driveway, those are genes that will be switched on and that's. An 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 ourselves have the same genome, but. What distinguishes a. Brain. Cell from a liver cell and what, allows a fertilized. Egg to become, a twenty six billion, come, 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 had a record player or, a cassette tape it's, pathetic. You. Can't copy it very. Well you'll lose information it. Degrades, over time it, scratches it's a rule, 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, it's. It 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 that 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 wrap top 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 a capable, of doing us so. What we're seeing on the left is a young cell and what, we think is going on is that these chromosomes, in these the, black lines are, wrapped. Up in these, loops we call these Tad's 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 can do this for your souls pretty, easily and what we see is that these loops of DNA change, as we get older, and. What that leads to is 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. Let, me 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'd 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 they 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 have 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 concert oh that might be encoded in those zeros and ones or those pits in the aluminum. Foil but. This the reader of that compact. Disk 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. Construed oh 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. Ones 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, epigenome.
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 it 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 sell there's. A couple of manuscripts, and ten 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, sale or identity, is, aging. Okay. 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. Male 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 old 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. Well 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 buccal swab of your mouth and I could go back to my lab I could read what's called the DNA, methyl. Ohm 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 four 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 turns. Out if you extrapolate backwards, even. A teenage person, teenage girls are aging, even.
Young Infants, are aging, even in the womb were 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. 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 the 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. Alright, 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. Or. 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 so I didn't get 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 are a lot of people who are 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 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. Do we set the. Age of our bodies and what, you can see here in his diagram, from 1948, is that, the. 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 there is 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 body's in the future let's. Say an 80 year old and. We lose a lot of that information over time we. Are we, succumb to entropy, but. We are biological, organisms work and we're not open we're not closed systems 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. 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 induce. Induced. Pluripotent stem cells and we. Use what are called named. After mister Yamanaka dr. Yamanaka, the. Four Yamanaka, factors these. Four Yamanaka factors are, called, OS. K and M for short now. Yamanaka won his Nobel Prize because it's 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 any time 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 bio archive, our ex ivy, and, this. Is an online up upload, it's we're probably going to get back the reviewers, comments from nature any day now this. Paper is. Something that I never thought I'd see in my lifetime that. I think we finally found how, to tap into the observer and reset, our biological age, using. Yamanaka. Cos 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 one, Cheng Liu who. Features in the book and, 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 one Cheng did, we. Put three, of the Yamanaka, factors we eat we left off the M which. Is stands for Mik Mik is an oncogene you don't want to be causing tumors but. We use the OSM ek Oh SK. Fitted, 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 ji-yong. He's alone 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. Rolled even. If we're young adults you will we will not grow back an optic nerve if, we break our spine will not grow back a spine and a spinal. Cord but. Very young animals will and some, animals will grow new nerves an axolotl, it loses its limb 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 that 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 see David a crushed, eye it's. Unlikely, I'm gonna have a crushed optic nerve but, what about glaucoma. Pressure. From. 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 it 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 their 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's really, that 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 Tet. 1 and Tet - 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 had just had, final proof that. If you have, a mouse that doesn't have the tech genes, in its eye you, cannot restore. The. Growth of its optic nerve we, also you cannot restore it to 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'll probably last for years, if not decades because. We're 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 are these, therapies, are ready for primetime 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've, found a chemical that. Exists in our body that we lose as we get older that's really, important for stabilizing our, epigenome, and preventing. The scratches, it's called nmn, and you. Can see the mice on the left or drinking animun. 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. All right I think 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 stabilizers, of the epigenome 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 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 the 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. Ha. Any man, 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 better 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, to an immense 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 energy 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 not a disease it's we're, going to be treating a rare disorder most, likely at. Least the plan if all goes well, it's. 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 mouse are my so 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 Ries 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 three thousand and if. You can reset, your body three thousand times then things get really interesting, and, I. Don't know if any, of you want to live for a thousand years but and. I also don't know if it's going to be possible but. These are the 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 like to I. 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 three of the book I. Don't. Like to talk a lot about supplements. And things so it's all it's all in there and we all 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 one or if you include my wife and I in NF three 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 okay I'm 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 we're, in his late 70s he 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 thirty 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'd be 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. So. You've mentioned metformin and, intermittent, fasting can use another roll, of insulin in the, aging process of. Insulin. Right. So. There's. 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 the of those pathways. Are. What's. Called FOXO are, 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 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 isn't active so what sim tor as you'll, read in the book I'll talk a lot about it the. MTOR. Senses 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 hunger and 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 give my body, the best chance I'm also trying. To help the planet as well very. Good question. Thank. You good talk I 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 but 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 rate, of cellular division and we have accumulation, of junk inside. Both inside and outside of cells so I suppose is the management, of those those. Processes, assumed to be downstream. Of the, mechanisms, where you're making your internet they are they, are so we 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 senescence. Cells and, these. It's. Great to say okay plant, a flag in the ground we understand aging you've got seven or eight things that cause aging but, that doesn't explain why, they happen is there a 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 our. Proposes, and can, explain, how. Epigenetic. Aging that the loss of gene expression as, we get older lost, that information, is, can, explain all of those hallmarks, as well and in, fact if we look at those mice. Even. Though we've just just just disrupted. The epigenome they. Have. All of those hallmarks from. Mitochondrial, dysfunction through, to senescence cells senescence. Cells being the the, ultimate, expression, of a scratched CD. But. Yeah it I'm, excited about this theory because it can explain, the last hundred years, of observations. Now all, theories eventually, succumb, to you, know 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 all, right what are the chances we'd get an old mouse when you cut the genome like that one. In a thousand I'd saying at work so we we're to, test this theory but.
So, Far it seems to explain in, my view all the observations over, the last hundred years. Is. Oxidative. Damage upstream, or downstream or. Separate. From what you're talking about here. Is. Both it's part of the positive feedback loop which, so this is what what, we think is that. Oxidative. Stress in the nucleus will. Exacerbate. The genetic, damage so you'll get a broken chromosome, and. That's 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 can. Cause a DNA break but. It's. Not the only cause of DNA breaks they're happening all the time cosmic. Rays take. CT, scans x-rays. And. Actually. Free radicals are beneficial, in biology so you don't want to swamp 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 you're not part of it and that's why, I was saying, I'm excited about this theories it, can fit all of these observations, in you. Might be asking well why don't why. Don't. Enter. Oxidants, work as well as we hoped well. One of the main, reasons is that we. Think that there are other 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 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 they actually are we've. Learned that they 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 called it Xena or her missus Zeno. Meaning from other species and hormesis 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 Zeno, her meetin's we call them. 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, we also need to hunker down if our food supply is going to run out so. That was you. Know five different answers hopefully answered, your, question well I I, was in, particular, wondering about non-nuclear, oxidative, damage all right yeah. Well, you mean a mitochondria, for example or I think, collagen, and even, just extracellular, things. 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 is a, part of aging but what I'm. Proposing. Is that. By, resetting the cell and making it behaviors. Oh 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, or tofu G 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 then, that'll and that's, thought, to clear out even oxidized. Collagen. For example. So. A. Few. Months maybe a year ago doctor. From the who was a consultant, from the World Health Organization, came and gave another talk and. I read his book and this suggested. Like mmm. As. Using. That help. And a bunch of doctors are actually like, secretly, giving, themselves these, treatments. Because, they see it works and, the, data. Seems fairly good why. Is an. Intermittent. Fasting as, something, that really helps well, I used to know like published, studies about, aging, if 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 like real, clinical, data and backed, up, support. On these anti-aging. Techniques that even doctors seem to agree, on. All, right first of all I don't recommend eating M&Ms. At. Least not if you want to live longer but. Yeah I know what you mean. 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 patients $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, gonna 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 MIT that showed ALS, patients didn't, do did do better with a. Combination, of, NR. And pterostilbene. Which is related, to her as virtual in red wine so. Yeah that 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. Hi. I I, was, a little bit confused, by your discussion, of epigenetics. Being analog, in nature because I thought, there was both digital, and analog parts.
Of It so like the. Folding. Of the chromosome, as, a topological favor very analog, but like methylation. I'd already thought of as being very digital you know you that, C is either methyl, eyes d'Or it isn't yeah and so, first I was, confused and second whether, your research has indicated, so far. Which parts, of the, epigenetics, whether it's more than decimalisation factors other things that are the most important, in the biological clock 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 is not the main component, of the epigenome it's a it's, part of it but there, are other marks, on. Histones, and others that don't. Occur in discreet. Ways. That. It's more of a it's a, 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 is digital. But. The loops the, loops are moving. All the time right. That you can't say there's a loop because. It's gone by the time you measure it and. So. We're actually - what's interesting is the field is right now moving away from, describing. At ed as a discrete thing - a probability, which is a. Whole, different mathematical, challenge. What. Else didn't. I answer you had a second part of the question. Indicates. Where the biological clock is more which. Epigenetic. Factors it's based on yeah good question so I we're. Searching, for the deep observer. What that is it's not just methyl, it's clearly cannot be just. Methyl there, are proteins that probably bind to those metals - say that's, a youthful methyl and this, other one has come later so get rid of it so we need to find out but, also there, are proteins that control the Tad's 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 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. Terms. Of the levels the way I think about it is that there's a superficial level which is transcription. Factors which you can just. By holding your breath you can change them and they move around and they control genes but. They reset. They don't if, you change those of course you're not going to. Permanently. Go back ten years a, different. Layer are the, epigenetic, modifications. On histones and, those are fairly, stable. But but still quite transient, they won't last for a long time but those DNA, methyl marks are the third very, deep layer that, lasts. 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 you. The. Cell gets, to that deep layer and then knows, which parts of it to reprogram and reset. And reorganize, that's. The challenge. So. I was wondering about the experiment, with twin, mice. So. Aside. From. Having. Showing. All these symptoms of aging does. The mouse. With, this. Crushed-up genome visit actually end up living a shorter life or. Did they still keep the same light, snare. So. They live shorter but we didn't have enough mice to, be. Able to statistically, tell you that with, certainty they. In. A small group I think we had 10, and 10 the. Ice mice died younger, on average, but, it wasn't just it's just a CLE significant, because you typically need about 40 to 50 per group but.
Yeah It looks like they died from regular, Mouse, diseases, they're not riddled with cancer, more than a normal Mouse would be. So. That's it's a good question they should live shorter and they are we, can also measure their frailty and that's. 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 so. You, have promising, technology, five years from now you find the, treatment, that works five, to ten years later the FDA approves it and now. You're going through the insurance system clearly. This, is like a blockbuster drug of 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. Yeah. That's the thing that's, the thing we need to talk about what happens when. This happens now I don't know if it's gonna be five or ten years the. The, I mean, the nmn stuff is is here already you, can go by that but the, reprogramming. Early-day, is we. Don't think it's dangerous in mice at least we put it into the mice for over, a year in there 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. Is the world look like up. So. First of all it'll let's say it's for glaucoma this is where the first trials will be done we, have a company called I do and own full disclosure so. You. Can treat glaucoma case, glaucoma, patients of 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'll begin a little. 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, in. The same with the case of with with metformin you can find doctors that have read the literature and they were okay with it but. Yeah I think it's gonna be interesting 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 wow this is way too much I don't want this we. Write we don't want you to live any 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 it you you should have the choice to die when you want to as well so. It's important, to, balance it out, thanks. Good question. An. Amendment for n R. Okay. So n n R is Nikitina my driver-side, which. Is similar, to any man without a phosphate, group. In. A man and in our NR is cheaper than, any man. 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 in and in a man and wide my father, partly. Its availability, we have a stash of it that, we've tested, but. That doesn't help help, you what 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 NM n and n R I can. Also tell you that, an. Amine, is more stable, on the shelf and if n R gets a little bit wet or is, out for too long it'll, degrade into nicotinamide, and. I wouldn't take high doses from nicotinamide, it may have the opposite effect, but. That's the main reason now, in mice they. 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. What. Does the M factor that you're not using do. Sorry. The. The stem cell and transformation, and the factor that. You're not using Oh Mick C m'q yes, yeah, so Simek is a gene, that controls cell, proliferation and. If. You turn it on in normal. Cells they will be. Part way 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 part, way back towards youth.
Thanks. We, were just lucky that work without Mick but, that's uh you know you gotta swing for the fences, if. I can give you an advice about careers, now, you gotta take some risks not everything will work when. They fail just keep going, you'll. Eventually get there if you focus on an 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. Janice. Thank you. You.