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

Welcome everybody. I'm not sure I can tell you how to live forever today, but I will tell you that we understand how to do it, so thank you Sanders, thank you for inviting me, and thank you all for coming. There are some people. here that helped make this book possible. I want to thank you all personally and also the Nick platform who made this possible and also Matt LaPlante who also helped write the book a lot and is here somewhere raise your hand Matt yeah yeah so this It has been a long journey for me. I'm going to talk for about 25 minutes and we'll leave time for a good number of questions, so yeah, write them down.

I'm a pretty open book, so ask me any questions and I'll do it. I do my best to answer honestly. Well I've been working at Harvard for nine years since 1999 so about 20 years ago 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 thing, the good thing is that now I know what I'm doing, the bad thing is that I'm much closer to reaching that limit where we all go down in physical and mental health too, and we all face 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 that we will all grow old and we will all die and that is a terrible thought, it is also terrible to think that our parents and everyone we love will also face this now dying is not the point of all this .

I mean, the goal is to try to prevent people from getting sick during the last 10 years of their lives and the hope is that our generations will be able to expect to live to be ninety and play tennis and even live to be a hundred 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 is not It's about living forever, it's about changing the way we treat people in terms of health care issues and at this time 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 do it? The medical definition of a disease is something that happens over time that causes you to lose function and become disabled. It sounds a lot like aging. The reason aging is not yet a medical condition is because it happens to more than 50%, but what? What we argue in the book is that just because something affects 51 or 50.1% of people does not mean that it is less important than a rare disease; In fact, I would say it is more important and I hope that after you have a chance to read the book you will realize that it has been folly to consider aging as something separate from a disease or disorder.

Now that the World Health Organization has declared aging for the first time as of this year as a medical condition, it is really surprising to see. A large institution declares aging as a condition and what we hope is that it will soon change the way doctors view aging. I don't know if we have doctors in the audience, but where I work, at Harvard Medical School, doctors are taught in For my part, there are certain pathologies and diseases and if it happens to less than 50% of people, it We address it aggressively, we do medical research to stop that disease and treat it, and just because it's a common thing like aging, we don't really do it.

Let's do anything about it we accept it as natural, but I propose that you look around this room what part of this room, perhaps with the exception of the wood, no, it is a carpet, it is not even a wooden floor, nothing in our lives is natural, maybe the oxygen we breathe is natural, but everything else is not unnatural, it is man-made and we change our environment and addressing disease and addressing aging is also natural, that is what we do as Humans, we do not accept misery and fragility. As a natural way of life, we shouldn't do that for any illness and we shouldn't do that for old age either, so I want to do a quick poll before we get into some slides: How many of you would like to live to be 80? but not beyond not beyond 80 is 80 enough for anyone in the audience some there are some hands 80 is enough I don't know if there is anyone 80 in the audience but you probably don't like that answer what about 220 who would? live 120 and then die, yeah what is that?

About half of you, how many of you would like to live forever? Well, there are some people who didn't raise their hand, so it's between a hundred and twenty in immortal that are looking for a pretty wide gap, maybe say 850 for that group, but that's really interesting, we don't all want to live the same amount of time. years, but what if I told you that you could be as happy, healthy and satisfied as you are today at 120 years old, how many of you would like to have a life like that? Exactly that is most of you, if not, the point is that and in the book you will see that the point of all this is that we have the The technologies to be healthy are much more isolating in life, so it is not about to live forever and it's not just about prolonging how long you live, but how well you live, keeping us from getting sick, stopping cancer, heart disease, Alzheimer's frailty and diabetes.

You might say David, how is that possible? We can't even solve cancer. How are you going to do it right? What I'm going to tell you today, if you don't already know, is that we have a new understanding of what causes aging and even how to slow it down and first looks and some experiments that I'm going to show you on how to reset the body's aging clock so that really understand how to delay illness and live longer and it turns out guess what happens if you're not sick you tend to live longer, that's what it's 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 of this talk, but why.

Does it happen at the nanoscale at the molecular level? I think we finally have an answer to why we age and it's not because of free radicals and it won't be stopped by antioxidants, although that hasn't stopped marketers from creating about a 150 billion dollar industry each year. , but what's different in the book is that and in my research is that we have a new idea about why we age and why maybe we don't have to, so we see aging so often that we take it for granted. and we also see it so often that 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 sunburned on one side of their face as you can see and we know that the damage Caused by the sun on the DNA, broken chromosomes make you look older and even accelerate aging, if you receive chemotherapy or radiotherapy, not only will you feel older, your body will literally age and we have not understood why this is the case. the old idea that came up in the 1950s, mostly from physicists formerly working on the Manhattan Project, their idea was that we ran out of genetic information. mutations I'm sure you've all probably heard of the mutation theory of aging that just losing our genetic information turns out that's probably wrong because we can make mice that have a lot of mutations and lose a lot of their genetic information but don't age prematurely and There is now a whole body of research that has made my field essentially dismiss the idea that we are aging due to the loss of genetic information, so what causes aging?

So, aging, I tell 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's wrong? Well, there are two types of information in our bodies that are essential for life, one is genetic and the other is epigenetic. Okay, and you probably remember from high school that epigenetics is the term for any process and structure that governs the way the cell packages and reads genetic information, so here's a cartoon of what the epigenome looks like, we have the DNA that is in blue, that is our genome and the genome I put it to. you are a digital form of information you are a TCG base four this would be a quaternary, rather than binary, way of transferring information throughout our lifetime between cells and over the last 4.6 billion, well, at least four billion years since we first emerged.

The main thing and we believe that the inability to preserve genetic information is not the cause of aging, it is important for evolution, but throughout the life of our bodies we still have much of that information intact. Digital is a great way to store information, as everyone knows. you can copy it without error, our cells normally do it to a large extent, so what is the potential problem in aging? That's the epigenome that I'm showing you like these green proteins that wrap around the DNA, those proteins roll up the genome in the same way that you can spill a garden hose and when you roll it up very tightly packed, your genes in that region of that hose or in that region of the genome will be deactivated and those that are exposed will form a large loop. you know your garden hose is connected to your driveway, those are genes that will be activated and that is 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 us have the same genome, but what distinguishes a brain cell from a liver cell and what allows a fertilized egg to become twenty-six billion compounds of different cell types when it is born is the epigenome. and I think the epigenome is the reason we age it's 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 will lose information degrades over time scratches is a The rule is the reason we converted to digital in the late 1990s, but we are built with an analog information system.

This epigenome is useless, it is, but it has to be designed that way because the epigenome needs to respond very quickly to the environment that it has. it has millions of different values ​​instead of very discrete values ​​and you also need to be prepared for things you've never seen before. One way to think about the epigenome is that it is the software of our cells and the genome is the computer or underlying code. The interesting thing about this whole analog versus digital thing is that it gives us a new perspective on aging now, in instead of talking about a garden hose and protein wraps.

Let me show you what it really looks like again, a schematic because I don't know. I have a photo for you, we don't have a microscope that is capable of doing this, so what we are seeing on the left is a young cell and what we think is happening is that these chromosomes in these black lines are wrapped. in these loops we call them Tad, they are now called topologically associated domains and we can now map them with great precision. Only in recent years have we learned how to do this and genome-wide. I can do this for your souls. easily and what we see is that these DNA loops change as we age and what that leads to is that, as you can see in the cell on the right, over time the genes that should be deactivated are activated and vice versa and what What happens is the cells. lose its identity, which is really important, a nerve cell in an older person is no longer completely a nerve cell, it is starting to move in the so-called Waddington landscape space or epigenomic space and is becoming a different type of cell , a nerve cell in an elderly 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 forgetting things if our cells don't maintain their epigenomic information.

The question is: can we slow this down and can we reset it? Is there a system reboot? Is there a backup hard drive of this initial configuration that we can access and restore that structure that you are seeing on the left? I think it's possible that an analogy I'd like to use is this compact disc. or a DVD here for the younger audience, we used to put music and photos on these things which were very useful for a moment, but anyway they obviously store digital information, which was great but what was really bad. 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 still have the information to play the music to play the concert oh that couldbe encoded in those zeros and ones or those holes in the aluminum foil, but the reader of that compact disc cannot read the songs simply because the laser jumps and refracts, but the good thing about this analogy is that it is very simple in this situation. to reset the system you just have to polish a little, you might be able to get a rag with some toothpaste and polish those scratches and guess what is new, you can read the interpretation, oh and if we are right about the aging, will be Basically, it is possible to do the same with our body and allow our tissues and organs to play the symphony of our youthful lives again, but only if there is a backup, we don't know if that is true, but what the hell is this animal? two mice and you might want to guess which ones are older is a trick question they are twins they are genetically identical twins and when we read their genomes we find that their genomes are also identical but what we have messed up is their epigenome We have scratched their CD and you can see that what we have It's not just a mouse with gray hair and 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 Matt and I write in the book, if you can give something, you can be sure you can take it away, so that's what I'll tell you in a minute, but you can ask.

Well, David, how do you scratch that DVD? Of course, you're not taking sandpaper off a mouse. I hope we did and hopefully we'll post this soon. We have manuscripts under review for sale. There are a couple of manuscripts and ten years of experience. The work of my lab and that of 15 others around the world is the discovery that broken chromosomes alter the structure of those hose reels, that DNA and cells begin to lose their identity, so they don't work very well. and the end result is losing sales or identity is aging, well the really interesting thing about this mouse is that 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 life. aging and we can simply induce these DNA cuts in the genome.

As much as we want to, we can make an 80 year old mouse and we think these mice will be very useful in finding treatments for Alzheimer's disease, which I think is ridiculous, people have been using one year old male mice to study the disease Alzheimer's, which doesn't make much sense to me. The other thing we can do that's interesting with these mice that we've done is we can age just part of the animal. We have accelerated aging in the brains of these mice and we are seeing an increase. dementia, but interestingly we can wonder if other parts of the body also age faster if your brain is old.

Clearly we couldn't do it any other way. Now, one of the things that made it possible to declare that these mice are not. It's not just a disease, but they are actually biologically older. What we have given aging is that we can now measure age with great precision. This is not qualitative. This is 100% quantitative with machine learning algorithms. Well, I could do that with any of you right now. is to take a blood sample, please don't give me any blood samples before I leave, but in theory I could even take a buccal swab from your mouth and I could come back to my lab.

You could read what's called DNA methyl ohm, it's really just measuring which of the letters C of those ACTG has a methyl group a c and four H's in there and the addition of these chemicals over a lifetime is an excellent predictor of your rate of aging because we see them increase in a linear way over time and it turns out that if you extrapolate backwards even a teenager teenage girls are aging even small babies are aging even in the womb they were aging according to this clock now we used to think that this clock was just a measurement of time like a clock on the wall what we have been testing is the idea that maybe if we move the hands of the clock backwards, in this case the biological clock moves back the time, the age and the health of the animal back off and I'll tell you that in a second.

This is an example of data from the paper we hope to publish soon and with Steven Horvath, who discovered this clock, we can see that mice that are normal are in blue and are aging at a rate. 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 the exciting thing is that by all measures, these mice are 50 % older than their counterparts, but then the question arises: if you can cause aging, can you reverse it? And if you turn back the clock, will it work well?

Now I want to talk to you about one of my favorite scientists and mathematicians. Many of you may know this. person I used to work with at MIT, he also worked at Bell Labs and his name is Claude Shannon and if there is a person who gave rise to the world we live in in the Internet age it is him and what he proposed in 1948 in a a couple of fancy papers called 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 information is lost and he and his equations gave rise to the tcp/ip protocol. on the Internet that we use today and you know that if we don't receive an email correctly, if it doesn't arrive complete with all its packets, the Internet is smart enough to go back to the original backup and get the complete message that we use. to say oh, so I didn't get the message, it didn't arrive in my inbox now you can't use that excuse, it always gets there and for a while there are many people who are caught lying with that excuse anyway this is one of the diagrams most important when it comes to aging and I'm pretty sure that dr.

Shannon didn't realize that he was working on something as important as the Internet, maybe even more so, and that's how we establish the age of our bodies and what you can see here in his diagram from 1948 is that if you miss a message a signal a radio signal or let's say a Morse code signal between the sender 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 that can be use to restore the information using a corrective device, if that is true in our bodies, we could take the old epigenome and reset it to be young again, but we didn't know what the corrective device was in the transmitter cell.

Of course, it's the fertilized egg and we, as young children, the recipient is our future body, let's say 80 years old, and we lose a lot of that information over time. We succumb to entropy, but we are functioning biological organisms and we are not open systems, we are not closed systems, they are actually open systems, so we can use energy to reset the system. Now the man on the left has won the Nobel Prize for learning how to take an adult cell and turn it into a stem that cleans up all the methylation from the DNA. Extract the genome by cleaning it so those cells can rebuild themselves into anything you want.

We call this the induced pluripotent stem cell induction process and we use what is named after Mr. 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 is a great discovery to be able to take a skin cell and turn it into a nerve cell that could lead to new treatments new organs that we can put back into our bodies, but I guess what you probably didn't think about is that this is also relevant to aging, now we don't want to put the four Yamanaka factors in our bodies and become a giant set of stem cells which would be the biggest tumor in the world, you would get a teratoma and some people have tried it and actually killed mice in two days so it's not going to be a therapy anytime soon and I wouldn't do it.

I wouldn't volunteer if I were you, but what we recently discovered in my lab in a paper we put online, which you can check out if you want, is in our ex ivy's biological archive and this is an online publication. upload it, we'll probably get comments from nature reviewers any day. This article is something I never thought I would see in my life and I think we finally found how to connect with the observer and reset our biological age. using Yamanaka cos factors, but not all of them are just a subset, so what do we decide to do right?

I have to give credit to a student in the lab, Cheng Liu, who appears in the book and we were lucky enough to write the book while we made these discoveries last year and they were basically written almost in real time as they were published, which makes this book a very unusual type of book in that you learn about science before most people have digested it yet, so here's the experiment that one Cheng, we put three of the Yamanaka factors that we eat. We leave aside the M, which means Mik. Mik is an oncogene that you don't want to cause tumors, but we used the OSM ek Oh SK installed in a virus and we put the virus in the eye of a mouse and these are viruses, they may sound scary, but now they are used all the time in therapy genetics in patients, so it's not crazy what we did in collaboration with a lab across the street, ji-yong. alone, after we put the virus in a mouse's eye, we pinch the back of its optic nerve and what normally happens is I'm sure you can guess the nerve dies if we roll, even if we're young adults, we will .

An optic nerve will not grow back if we break the spine a spine and spinal cord will not grow back but in very young animals it will grow and in some animals new nerves will grow an axolotl loses its limb a limb will grow back this It's not unheard of, it's just that we've lost that ability, but we think we know how to get that ability back and make the cells very young again so that they have these properties of growing back just like embryos do, so we do it. What you are seeing is a spot of the optic nerve. that has been crushed and you can see where the crush ends, that's where the orange dye goes down and stops because all those nerves have been crushed at that point and a lot of the orange dye is missing, which labels healthy nerves because the nerves have died , but look what happens if we activate this reprogramming, this age resets in the eye after we damage it, first of all, the nerves do not die and many of them somehow wake up and start growing again towards the brain if we leave this. for four weeks, that's what you see, if we leave it for 16 weeks, they grow until they reach the brain, which is unheard of in science until now.

Now that we've done this in other areas as well, you might see David with a squashed eye, it's unlikely. I'm going to have a crushed optic nerve, but what about the glaucoma pressure? Many people have pressure and it damages their retina. There is nothing that will appreciably slow down glaucoma, much less reverse that disease and restore your vision. What happens to old retinas? What happens with old age? I'm already 50 years old and I'm 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 the retina of an old mouse and do it. You look like a young mouse again, those nerves wake up, they remember your nerves, not half your skin cells, we can look at your clock, we've measured your clock, you get younger and all the genes that should be turned on When they are young they return. turned on and all the genes that should be turned off when they are young turn off it's magical now we don't fully understand how it works we know how to connect with the observer but what's behind the clock what really is that what are the gears behind In the system, we have an idea of what is happening.

I think we have found the communication device with the observer. There are at least a couple of enzymes called Tet Tet 1 and Tet. These are enzymes that remove those chemical groups from DNA as part. From that reset process, we found some gears in the wheel that turn back the aging, which is very exciting and today in the lab Matt and I were there and we had just had the final proof that if you have a mouse that doesn't have the technology The genes in your eye can't restore the growth of your optic nerve, we can't restore your 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 it lasts .

The effect lasts, it could last 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 it? How many times can you reset it? We do not knowyet, so until these therapies are ready for prime time and we hope to treat our first patient in two years who suffers from glaucoma, what can we do in our daily lives? I hear you ask well. In addition to reading the third part of the book, where there is a lot of talk about there being other things we can do, we have found a chemical that exists in our body and that we lose as we age and that is really important for stabilizing our epigenome and preventing the scratch is 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 and see if you can guess which old mouse in this video is drinking the nmn okay I guess I think I've seen enough Jeremy, so if you guessed the mouse on the right you'd be right.

What we found and published about a year ago in the journal Cell was that nmn activates a longevity pathway that we have been working on for many years. They are stabilizers of the epigenome and also control the survival of our cells and the defenses against aging and the interesting thing is that we have built-in longevity pathways that we can activate with these molecules like nmn, there are others that exist, one is called metformin, which is a diabetes medication that is interesting because it has been observed in tens of thousands of patients to at least apparently slow down the effects of aging and protect against disease.

There is another one that is more toxic. I wouldn't recommend it, but it's called rapamycin, but there are things. We have already found something that can actually work, but what else can you do in your life? What can you do if you don't want to go to the doctor and ask for metformin, a diabetes medication? Well, one of the things that I Probably the best thing I can tell you after having read thousands of scientific articles is to eat less frequently. That is not malnutrition, it is not hunger, but it does mean going hungry for part of the day.

What I do is skip breakfast. I eat a late lunch, sometimes I miss lunch and eat a normal dinner. What does it do that activates these longevity pathways? It increases nad levels in our body, which nmn will also do and mimic exercise and hunger. Well, hunger, of course, will imitate hunger, but ha. Any man and hunger works through these same longevity pathways and you may find that doing a little exercise like these mice, inhaling yourself a few days a week on a treadmill for just 10 minutes is enough and being hungry some days of the week. You will find that you feel noticeably better and you will be much better off for it and maybe when you are 80, 90 or even 100 years old you will be able to continue doing all the things you always wanted to do late in your life and start a new life. career if you want to start a new company leaving a legacy, we have clinical trials in progress with a molecule related to an immense this is not something from the future, this is something that is actually happening right across the street from my laboratory in the Harvard Medical School, so we know that this molecule can raise energy levels at least twofold in people, we haven't seen any negative side effects yet and we're going to do clinical trials on patients next year, but not for the aging because it is not a disease, it is let's treat 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 receive an injection of a virus and then receive a treatment with antibiotics like our mouse, so activate the reprogramming for a few weeks, you will start to look younger, your hair could change color, it could grow back, we don't know, but your organs should be improved. you should get your vision back if you've lost it and that could last a decade and after you've aged for a decade you come back for a Ries reset and all you need to do is get a prescription for antibiotics which turn on these genes again, now again , we don't know how many times you can reset, it could be three, it could 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 a thousand years but and I also don't know if it will be possible but these are the questions that we have to start thinking about because it's not a question of if now it's a question of when and ultimately I like to I like to talk about my father, who is a role model for all of us.

I think he has been taking a combination of nmn and metformin and some other things that are written in the third part of the book. I don't like to talk a lot. a lot about supplements and things like that, so that's it, it's all there and we all have a newsletter too, but let's talk about my father now, this is not a clinical trial, it's what we would call an N of one or does it include my wife and Me in NF three wasn't very well controlled, it wasn't placebo controlled, but my dad was going downhill, he didn't have much energy, he was pretty depressed, his wife had died, he was just thinking, well, I'm done, but he He noticed that his health is not declining so far and we don't know if it is because of the molecules or the exercise he has been doing or the intermittent fasting he is trying but nevertheless it is a ray of hope for all of us that we can live a better life. life as We are over 70 years old, he started a new career and travels the world and we just returned from Uganda where he went hiking with his three grandchildren up a mountain and he was the oldest person to do that and for him it was in In the blink of an eye, he is literally stronger and in better shape than I was at 50 and probably in my thirties too, so I want to end by saying thank you for coming.

I would be happy to answer any questions as honestly and openly as possible and I hope you would not only start but continue this conversation because one of the most important things we can do for the planet is save on healthcare to save billions of dollars. and eventually billions that can go to other causes like global warming and species extinction and I really want to thank you for taking the time out of your day to come listen. Thanks, you mentioned that metformin and intermittent fasting can use another dose of insulin in the insulin aging process, so that's what you want to be. living longer based on everything we know in mice and humans is to be really sensitive to insulin and that means having a lot of insulin receptors, not having high blood glucose levels and in fact the best predictor of your longevity is your levels of blood glucose, which are why you want to exercise and why metformin probably works in part, so insulin is key, there is also an insulin-like growth factor molecule that is also important and when you have levels lower than it, it also extends lifespan in animals and apparently in people and what happens afterward.

One of those pathways is what is called FOXO, they are transcription factors that control our defenses against aging and disease, so we want to keep them active now if we are always satiated, if we always eat protein bars and we are never hungry and if We sat all day. Listening to pompous academics give

talks

, those transcription factors are not going to be active, in fact, they stay outside the nucleus where they do no good, so what we want to do is make sure that the insulin signaling pathway is activates and stimulate them, there is another thing that also works, 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 not active , then what sim tor as will read?

In the book I'll talk a lot about that, 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 took one If you eat a lot of steak, your mTOR pathway will always be active, always telling your cells to grow instead of fighting disease, hunger and depression, and that's why I've switched from a regular diet to a mainly plant based diet because the amount of amino acids I was getting was overloading my mTOR pathway so I'm trying to keep it low and give my body the best chance.

I'm also trying to help the planet. Very good question, thanks, good talk, the reason I got into computational biology was that I read some interesting things by Aubrey de Gray maybe 20 years ago and I thought, "Oh, interesting, but one thing I'm curious about "It's just that we have these other, more macroscopic mechanisms, I guess, around aging that we have." the rate of cell division and we have garbage accumulation inside and outside the cells, so I guess it's the management of those processes that are supposed to be downstream of the mechanisms by which you're creating the Internet.

We've stated as a field, as you said, that there are eight or nine hallmarks of aging and some of them are telomere shortening, mitochondrial dysfunction, stem cell loss, senescence cells, and it's great to say that it's Well, plant a flag in the ground, we understand aging. There are seven or eight things that cause aging, but that doesn't explain why they happen, is there an upstream cause, as you say, of all of them or are we building seven dams on seven tributaries and the information theory of aging that we propose? and it can explain how epigenetic aging, the loss of gene expression as we age, loses that information, it can also explain all of those characteristics and, in fact, if we look at those mice, even though we just altered the epigenome that they have . all of those features, from mitochondrial dysfunction to senescence cells, senescence cells are the ultimate expression of a scratched CD, but yeah, I'm excited about this theory because it can explain the last hundred years of observations.

Now all theories eventually succumb to you. 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 raises a lot of testable hypotheses, like these mice that I showed you, what are they? The chances of us having an old mouse when you cut the genome like that are one in a thousand, I said at work, so we're going to test this theory, but so far, in my opinion, it seems to explain all the observations made during the last few years. a hundred years is oxidative damage upstream or downstream or separate from what you're talking about here, both are part of the positive feedback loop, so this is what we think is that oxidative stress in the nucleus will exacerbate the genetic damage.

You will get a broken chromosome and so there are many things that cause epigenetic changes, including scratching the DVD, but the most powerful one we found is a broken chromosome and oxidative stress free radicals can cause a DNA break, but they don't. The only cause of DNA breaks happens all the time: cosmic rays, CT scans, X-rays and in fact free radicals are beneficial in biology so you don't want to flood them; It has been shown that if you take a lot of vitamin C. and even megadoses of vitamin E can mitigate the effects of a healthy diet and exercise, so I'm not saying that you're not part of this and that's why I was saying that I'm excited about these theories, it may fit all of these.

The observations in you might be asking: Why not? Why don't the oxidants enter? They work as well as we expected. One of the main reasons is that we believe that there are other causes of DNA damage besides free radicals and that more is needed. 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 antioxidant properties, those molecules are most likely not directly cleansing. free radicals, but in reality they are, we have learned that they bind to receptors and enzymes that detect the environment and activate our body's natural antioxidant defenses, such as catalase, an enzyme that is necessary to eliminate them now that we have a theory for We call it Xena or its lady Zeno, which means from other species and hormesis, which means that anything that doesn't kill you will make you stronger.

The idea is that plants produce these antioxidants, what we call antioxidants, but they're actually Zeno, we call them. they are helping plants survive and protect themselves through their genetic survival pathways and that by eating our plants when they are stressed we get the same benefits that we also need to protect ourselves if our food supply is going to run out, so that was you. I know five different answers. I hope I have answered your question well. In particular, I was wondering about non-nuclear oxidative damage. Well, yes, you mean themitochondria, for example, or I think collagen and even extracellular things, so we have to discover in the tissues that having a lot of collagen, whether it's fibrotic lungs or fibrotic liver, is that reversible or irreversible, that's a start, the Reprogramming is going to eliminate those problems or they will be there with us for life, hopefully not, but we will have to see, but collagen oxidation is part of aging, but what I propose is that by resetting the cell and making it behave like you were young again, you can get rid of those oxidized and damaged proteins through a process of autophagy and there are a few different types, but one of the most important is called chaperone-mediated or tofu G, which deeply cleans the cells to remove these types of proteins that have built up and the best way to activate it, in addition to the chemicals that we are working on, is not to do it.

Eat for two days and then that will eliminate even oxidized collagen, for example, so a few months ago, maybe a year, a doctor came who was a consultant to the World Health Organization and gave another talk and I read his book. and this suggested like um how to use that help and a group of doctors actually secretly give themselves these treatments because they see that it works and the data seems pretty good. Why is intermittent fasting something that really helps? I used to know it's published. studies on aging if doctors seem to pretty much agree 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 to look at these things that are a little sketchy, what?

Why isn't there something real? clinical data and backed support on these anti-aging techniques that even doctors seem to agree on, first of all, I don't recommend eating M&M's, at least not if you want to live longer, but yes, I know what you mean, there are some A One of the answers is that there are studies published and many of us are working very hard to test them, as I pointed out, but the trials cost $10,000 for each patient, so you can see how quickly it adds up, but now that we have the clock to measure . I think things will move much faster because otherwise it will be a very long essay.

There are probably 15 to 20 trials with nmn and related molecules in progress, so they will come out. There are some that have been published so far. There's one with NR that actually showed there was no improvement in blood sugar, so one was a negative trial and then there was another one that came out of an MIT-affiliated lab that showed that ALS patients They didn't do better with a combination of NR and pterostilbene, which is related to it as virtual in red wine, so yes, the bottom line is that I now see it as my role as an educator communicator and with this platform that comes with the book to being able to separate what is nonsense from reality and there is a lot of it.

It is nonsense, but there are really good studies that are published all the time and a lot of literature that no one has time to read or review and that is what I hope to do for everyone . Hi, I was a little confused by your discussion. that epigenetics is analog in nature because I thought there were both digital and analog parts, as well as chromosome folding as a topological favor, very analog but like methylation. I had already thought that it was very digital, you know, that C is methyl eyes d'O is not, so firstly, I was confused and secondly, if your research has indicated so far what parts of epigenetics are more besides the decimalization factors, other things that are the most important in the biological clock, yes, there are digital parts of the epigenome, but most of it is not digital, methyl, as you point out, is digital, but we believe that methyl is not the main component.

The epigenome is part of it, but there are other marks on the histones and others that do not occur discretely, it is more of a fog and part of the problem of measuring the epigenome is that it is not digital. that you get probabilities instead of discrete units, but I grant you that you are right that methyl is digital, but the loops move all the time. It's true that you can't say there is a loop because it doesn't exist anymore. time you measure it and then we're actually - the interesting thing is that the field right now is moving away from describing ed as something discrete - a probability which is a completely different mathematical challenge what else didn't I answer?

You had a second part of the question indicating where the biological clock is located most, on what epigenetic factors it is based. Yeah, good question, so we're looking for the deep observer. What's that. It's not just methyl. Clearly it can't be just methyl. There are proteins that probably bind. those metals let's say it's a young methyl and this one came later so let's get rid of it so we have to figure it out but there are also proteins that control the Tads so there are proteins called ctcf that you may know as a biologist that are. controlling the loops, the coiling, and we see changes in the distribution of those proteins throughout the nucleus as we age those cells in the dish, but it's still early.

I have 35 people in my lab and about half of them are now trying to figure this out. everything and a year ago only one person was working on it, so we'll get there and there are some other labs in the world working on this, but I think in a few years there will probably be between 50 and 100 terms of the levels, the way we do it I think there is a surface level which is the transcription factors that you can just by holding your breath, you can change them and they move and control the genes, but they reset, they don't if you change them, of course.

You're not going to permanently go back ten years. A different layer is the epigenetic modifications on the histones and they are quite stable, but they are still quite transient, they won't last very long, but those DNA methyl marks are the very deep third 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 penetrate that deep layer, but how does the cell get to that deep layer and then know what parts of it. reprogram, reset and reorganize, that's the challenge, so I was wondering about the experiment with twin mice, so in addition to showing all these symptoms of aging, the mouse with this genome-shattered visit actually ended up living a shorter life or still Keep the same light trap so they live shorter, but we didn't have enough mice to be able to tell you statistically that for sure, in a small group, I think we had 10 and 10, the ice mice died younger on average, but it was not so.

It's just a significant CLE because you normally need 40-50 per group, but yeah, it looks like they died from normal mouse diseases, they're not riddled with cancer any more than a normal mouse would be, so it's a Good question, they should do it. They live less and we can also measure their fragility and for that we have used machine learning to be able to use measures of fragility to predict longevity and, based on those measurements, it is also consistent with those mice aging and dying younger, so you have promising technology five. Within a few years you will find the treatment that works five to ten years later, the FDA approves it and now it is going through the insurance system.

Clearly, this is like a blockbuster drug of our time. Do you have any ideas on how it will be handled? when all of a sudden you can say go to your doctor, go back 10 years, yeah that's what we have to talk about what happens when this happens now, I don't know if it'll be five or ten years, I mean nmn. Things are already here, you can follow that, but the initial reprogramming is that we don't think it is dangerous in mice, at least we put it in mice for more than a year, there they are healthy, they are not a giant. tumor, but yeah, let's talk about what's going to happen when this comes, hopefully within our lifetimes, what the world is 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 Yes, I Do. and possess full disclosure so that it can treat glaucoma cases, glaucoma patients are all doing well and will regain their vision in a few weeks, but the world will know that this is a reset. What can prevent a doctor in Costa Rica from giving this intravenous line to his patients? Nothing nothing. that's where it will start to spread a little bit if it works, hopefully those people won't get sick from this, but then project another 20 years, people will be knocking on their doctors' doors saying give it to me or else they'll probably what will really happen is that there are doctors who are more willing than others to prescribe things and the same in the case of metformin, you can find doctors who have read the literature and agree with that, but yes, I think it will be a world away. interesting. where at 30 you can say: I don't want to get old, yes, many ethical things.

One of the things Matt and I put in the book was for all those people who say, "This is too much, I'm not doing it." We don't want this, we write, we also don't want you to live longer than you want, so we are not forcing this on anyone, but if you have a choice, that's great, we also say that we both believe it, you should have done it. the option to die whenever you want too so it's important to balance it thanks good question one amendment for n R okay so n n R is Nikitina my driver side which is similar to any man without a phosphate group on a man and in our NR it is cheaper than that of 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 me why I should accept it. and in a man and my father is partially available, we have a stash that we have tried, but that doesn't help you. What I think would help you is to go to the website I have about the book. Honestly, I'm not promoting it. I have written everything I can say about NM n and n R. I can also tell you that an amine is more shelf stable and if n R gets a little wet or runs out too.

Over a long time it will degrade to nicotinamide and I would not take high doses of nicotinamide, it may have the opposite effect but that is the main reason now in mice, both showed notable effects in protecting the body of those animals and clinical trials are being carried out With both. molecules, so at this point I couldn't really say that one is better than the other. What does the M factor mean that you are not using? Sorry, stem cells and transformation and the factor you're not using. Oh Mick C m' yes, then Simek is a gene that controls cell proliferation and if you activate it in normal cells, they will be part of the path to a tumor, hence its name as oncogene and it is very useful if you want to reset the age of a skin cell. to zero, but it is not so useful if you want to partially reset the retina towards youth.

Thanks, we were lucky to work without Mick, but that's, you know, you have to fight for the fences if I can give you some racing advice now. I have to take some risks, not everything will work out when they fail, just keep going, you will get there eventually if you focus on a dream and my dream has been to find out why we age and see if we can live 10 more healthy years. of life more questions I think that's all Janice thank you