Everybody, I want to talk to you about mental health. If there's something that you feel like is holding you back or presenting you from achieving your goals or even just interfering with your happiness, want you to know that there is something you can do about it. So if you're suffering from depression or anxiety, as a lot of you guys know, I struggled with that for years and trying to tackle something like that by yourself, is not always the best, but a lot of people feel super nervous about therapy, or they just don't know where to start. And so I want to talk to you about better help.
Help better help makes their appear more accessible and affordable. Better help is professional counseling, done securely online using your computer, your tablet. Your mobile phone. It works through video calls, phone calls or even text messaging with licensed therapists who are certified by their states board, to provide therapy and counseling. This is not self help, it's not a crisis line. Better help is an online service available worldwide and it has a massive network of
Hours with a broad and diverse range of Specialties. So you can get a counselor with the sort of expertise that might not be available to you locally better help assesses, your needs and matches you with a licensed professional therapist within 24 hours, you can log into your account, anytime to message your counselor better. Help also has group in our sessions every week where members can learn in groups directly from license counselors on multiple topics things like relationships and ways to overcome anxiety and all kinds.
Of useful topics especially if the thought of seeking help makes you nervous. Be sure to check out over 60,000 positive reviews, posted on the better help site and just for maximum Clarity, that's better help. And help is spelled heelp better. Help is committed to making it easy for you to access the therapeutic. Help you need. Even if you have never gone to counseling before, it's free to switch therapists. It's more affordable than local therapy and they even have financial aid available.
Better help wants you to start living a happier life today, visit better help.com impact Theory again, it's better h, e, LP.com and join Over 500,000 people. Taking charge of their mental health with the help of an experienced. Professional better help cost just $65 per week and financial aid is available for those who qualify during the signup process as an
I can be listener you get 10% off your first month. So visit better help.com impact Theory and get the help you need today guys, you've got to take your mental health. Seriously, I know firsthand if you need it. Give this one a shot, take care and be legendary.
If you're looking for unique and bold men's shoes, you need to listen up right now when getting ready to look your best at all, starts with the shoes and we have a special offer just for our audience from the team at Taft. Taft is a direct-to-consumer. Men's Footwear brand specializing in unique bold designs for shoes and boots. Taff designs with boldness, in mind to ensure all of their boots and shoes are as unique and stylish as their customers. And as somebody who has more shoes than his wife, I can.
Sure that good shoes make for a red outfit. Every single detail of tafs shoes and boots are considered from the laces to the eyelets. Taff takes the extra steps to ensure the end product is perfect Taff shoes or handcrafted in Europe and they've searched the globe. Looking for the right factories and found the very best in Spain. Each shoe is handcrafted by generational shoemakers. These are artists by their own, right? And tap shoes are built to last Taff sources. The
highest quality materials in the world to make the very best shoes and boots each Taft Boot. And Taff shoe is hand-painted hand cut and stitched. This allows for only the best parts of the leather to be used. All of tafs leathers are full-grain to ensure. They are not only comfortable, but durable to tap shoes are built for longevity and added flexibility. And their souls are made from stacked, leather with rubber injections for traction, visit Taft, clothing.com.
Find yourself the perfect pair of shoes or boots and just for our audience you can save 10% off your order of any full price boot shoe or sneaker purchase with discount code. It 10. Once again go to Taft clothing.com and get 10% off your order of any full price boot shoe or sneaker purchase with discount code. I T10. All right guys, take care, get yourself a wicked pair of kicks and be legendary
flowing.
Hedging down might give us a little bit of extra life reversing aging. Even relatively uncomprehensible e well give us essentially indefinitely.
Hey everybody. Welcome to another episode of Hell Theory. I am joined by somebody who is really an incredible thinker when it comes to anti-aging. Gerontology has a very unique approach to that is name is Aubrey de grey and he is the chief science officer at the Sens Research Foundation, Aubrey, welcome to the
show. Well, thanks for having me, good. Yeah, I'm really
excited. You you have keen insights into
One of the areas that I find most interesting in the world, which is, can we live forever? So I've been telling people for years that I want to live forever and they look at me like I'm crazy and I never understood that and researching you, I realized this is something that you have come up against a lot and you call it with the pro aging trance. So I'd love to hear it one. Do you actually want to live forever?
What we liked. So I
don't really think very much. In fact, they already think at all about how long I want to live. I think it's really a pretty, it's pretty strange thing to have an opinion about to be honest. That's because it makes no sense to have any opinion about something that you can change your mind about in the meantime, you know, I compare it to having an opinion about what time you would like to go to the toilet next Sunday. You know, you may have an opinion about what trans
people.
Isabel. It's so like, literally the difference between existing and not existing, you don't think that people are going to have a pretty strong sense of whether they prefer. One of the other
again, you see how you're mixing up, what people want and what people expect. So of course, one has an opinion about what time one expects to go to the toilet next Sunday because it have it, right? So but having an opinion about what time you want to go, makes no sense because you're going to have better information on the topic nearer the time that it's gonna
You're going to be able to act upon right so it's exactly the same in my view for how long you want to live? That depends on your quality of life at the time, which in turn depend on all manner of things that we don't know about, you know, like how good medicines going to be, you know, whether there's going to be a nuclear war, you know, all manner of stuff. I have absolutely no idea how long I want to live, but I do know that I want to have the Choi. I want to make sure that my choice about how long to live and how. And of course, how
Um, how high quality that life will be, is not progressively taken away from me by aging. So that's all really. It's just an investment in
having choice.
That's really interesting. And so now as you're approaching the research and looking at how we extend sort of high-functioning life, and I think that's probably important to Define. So let's get right into the idea that you have that really differentiated you from everybody. Certainly, you know, ten years ago when nobody was echoing, your sentiment. What is different about? The the approach that you have with sends versus sort of the standard approach before you present?
The
bat.
So, 10 years ago, I'd more or less won the argument and, you know, that became really apparent eight years ago in 2013, when a group of my colleagues published a paper, that's very famous. Now it's called the Hallmarks of aging and it's pretty much exactly a restatement of what I had published more than a decade earlier and it is, it is Santa Marta. Holy scripture in the field, it is the
But that everybody it's been something far more often than any other paper in the Hall of the biology of Aging in the past decade and it simply describes this kind of divide and conquer damage repair approach to aging. Same as I did. So, yeah. By Tony of the got. It was over. I had won the argument. Yeah. So when I came along 20 years ago and said, listen, we could do this damage repair thing, we could actually turn back the Aging clock and it might, it should be easier to do that than to flow.
Oh, the clock down which is what people have been trying to do before. Everybody know, first of all, nobody understood anything. I was saying I would bring a lot of biology from areas that had not historically been considered relevant to the biology of aging and that, of course, meant that the people who were throwing the biology of Aging didn't know about them. So that with a lot of, you know, getting up to speed involved in there. But yeah, I mean, just the general concept even in the abstract that
First thing aging could be easier than retarding aging to sound wrong. It sounds like reversing aging is a bigger thing and therefore it's got to be harder and so yeah the idea or had to go across really worth that when we're slowing aging down. We are interfering with the processes that drive aging. Whereas when we are reversing aging, we art what we're doing today, we're repairing the consequent of those processes. The damage that already been laid down, that's completely different.
Aunt from retracing and you know kind of running the processes in Reverse. It's not like that at all. If it were then. Yes. Absolutely reversing aging will be far harder than retarding aging. But it isn't.
It's really interesting. And so one, do you think that the early pushback on that had to do with? Just they weren't aware of some of the biology that you were bringing into the debate, or was it something where they just couldn't accept that it would one day be possible to rejuvenate
Tissues. Well, really the three part. Both of those parts were somewhat true, but they understood that I was, you know, I was basing my work on real biology. They just, you know, it takes a while to catch up. Biology is an enormous subject and nobody knows more than a small, a tiny proportion of it. So really, it was just a case of the conclusion found really surprising. Therefore, he
Probably wrong. And I was you know I benefited a lot from the fact that before I started talking about all of this in about the year 2000, I had had maybe five years in the field in which I had been having good ideas, other, good ideas that were relatively uncontroversial and were well-received. So everybody already knew that I was smart and knowledgeable and all that. So they they knew not to dismiss me too easily.
But so, you know, it was tough. But the third thing which you haven't mentioned was the really big one. The problem was that right from the beginning? I was perhaps a little bit too Fearless in the in what I said about the consequences of all of their in terms of how long people might be expected to live because that of course comes down to this thing. I've mentioned, which I guess you're going to ask me about coming up called Longevity of
Velocity that leads me to the conclusion that whereas flowing aging down might give us a little bit of extra life reversing aging. Even relatively uncomprehensible e well give us essentially indefinitely so you know that politically incendiary it sounds like I'm not a scientist and scientists really do not want to share a platform where people
Who, who sound like they are? Not scientists. However, smart they know that those
people are
Now, were you getting out over your skis from the biology perspective? At that time, I mean obviously people have come around now. So something we've discovered makes this far more plausible. Were you intuiting that this could become true or were you sort of rationalizing from first principles that? There's, there's nothing unrepairable happening at the tissue level. Like how did you come to that conclusion? Um,
yes, I was saying, well, look the body.
Machine, it's made of atoms and molecules and stuff, right? You know, it's functionally determined by its structure. Therefore, you know, restoring the structure will restore the function. Therefore, the only real question is, are there aspect of the structure that are inherently evil in principle impossible to restore to how they were in young adulthood? And it seemed to me that no, there obviously are not and no.
Nobody came along and said yes, there are the only real difference at the beginning was in terms of the degree of difficulty of this, their thing. And of course, even now, most people would be somewhat more pessimistic than me in terms of that. And therefore in terms of the time frames for developing this or that damage repair technology for little that type of molecular orthodontic but we're within each other's ranked, you know, you know, it's
It's not that we think we're crazy about this and even right back at the beginning. When I was first talking about all of this, you know, as I was bringing together a lot of different ideas from different areas of biology, because of course, the damage repair approach is inherently a divide-and-conquer one, you know, the people who will you better like divide and conquer oh, simply that there are lots of different types of damage. We've got to fix them all. And each of them is going to be
Fixed by a different technology and therefore you know you've got to apply the same technology, a lot of different things to the same people at the same time in order to get the result at. So let me write. So yes so well it was talking to the specialist in any given particular area. Like for example, mitochondrial mutation, I would generally not see very much pushback from those people in regard to their area. You know, I might be a little bit more optimistic than but I would be basically talking Santa they would understand that I
Where I was going with this and, you know, they wish me luck, but when you ask these people about each other their area about, which they knew very little, they were immediately threw up their hands and say, oh, this is complete, science fiction. There's no way this can work, you know? So this was the kind of consequence of the balkanization. They are siloing of expertise in biology that has happened increasingly over the years and it took a while to break break that down.
That's actually a really interesting Insight that the more somebody
Inu about the area, the more plausible, your take on things seemed but the less they knew the more than they're sort of defaulting to a base assumption that they have about longevity itself. And now is this where you see people spilling into just sort of a dogmatic approach about humans are never going to live forever. I'm not willing to let myself become optimistic about that people for thousands of years have been saying that they've cured it and people are going to live forever. Is that what you're up
against?
Yes, but in it kind of its kind of was even more than that. Because on top of the fact that this is aging, you know, and everyone's been saying this since the beginning of civilization and therefore, you know, everyone's been wrong, therefore, I'm likely to be wrong as well. On top of that, there is the general fact that within science overall expert are very reluctant to risk over.
The thing that we do every day, really, really want to go whenever they have The Misfortune to be talking to the general public, they want to say we are, we don't know, you know that in most but in most are walks of life saying, you don't know if the opposite of what you want to do. You want to pretend you do know stuff that you don't know in science. It's the other way around you pretend that you don't know stuff that you actually do. Now,
that that's actually fascinating. And there is something to that sort of level of
Bility that I like but it can obviously distort and itself become pathological. So I think now it's a good time because I want to frame we're going to get into the weeds of like what the seven types of damage are and what the sort of antagonistic thing that we apply to that to repair will be. But now I think we do need to get into what the escape Velocity is here and what you think will ultimately happen. I don't want to put words in your mouth but when I hear you speak maybe I hear what I want to hear, but I hear sort of the ultimate
I hope so, but before I put words in your mouth, what when you talk about escape velocity? What do you
mean?
Right. Yeah, okay. So let me give a nice like bit of background to it. So at the end of the day because as I mentioned earlier, the human body is a machine and therefore its function is determined by its structure. We can therefore say that the health of the body and therefore the likelihood that the body will cease to function at all, in other words that we will die anytime soon is determined by the amount of
Is that the body is carrying around?
And this damage that I went with talking about anyway, is the result of the body of normal operation. In other words, He Is self-inflicted. We Are inflicting with damage upon ourselves throughout life, even starting before were born, because this is simply consequences of things that the body needs to do and it's really intrinsic consequences than no way that we can have the body. Actually, you know, Keep Us Alive without the body also creating and inflicting this damage upon
So in that send aging of the human body or any other living organism, if no different than aging of a simple man may be seen like a car or an airplane or whatever, you know that accumulates rusted word out of the rain. What it means is that we could in principle improve the likelihood of living a bit longer, just by repairing some of the damage.
But it's better than that. The key thing that we have to take into account. And again, it is just as true for living machines, like you and me are the a thought in element machines, like cars. Is that machines are set up to tolerate a certain amount of damage without any really appreciable decline in function. So, this is why the health problems of late life are problems of late life and we do not see them at all.
Until after middle, a there is a certain threshold below which we are fine.
Even a 20 year old, or a 25 year old, has started quite a bit actually of damage in their body but you wouldn't know it. So this means that if we take someone who is, let's say 60 or 70 and they got plenty of damage in their body and they are getting sick or they're about to start declining in hell and we fixed even only half of the damage that they have in their bodies, then they will be back to the same amount of damage as they were when they were.
30 or 40 and that is fine. They will be restored to absolute function, both mental and physical what we need to do but
So supposing we try to develop therapies that repaired at and suppose we become fairly good at it so that we can indeed repair half of the damage. Let's, no, partition the damage into to category two buckets, we call them EV damage and difficult damage. The easy. Damn it is by definition. The stuff that we can repair with the first generation damage repair therapies that perhaps not very far off. Now and the difficult, one difficult language of the stuff that we cut.
Then we can race or somebody from the age of, let's say, 72 the age of, let's say 40 biologically. Of course, now what's going to happen after that? What's gonna happen is they're going to, of course, carry on being alive and damaging themselves more. And eventually they're going to get back to the amount of damage in their body that they had before they would treat it. Now, here's the tricky part that.
Even if we continue to give them the damage repair therapy, every year every day, but they're still going to get back to the amount of damage that they had before they were there first, created because the decibel damage on its own, it's going to add up to that amount after a certain amount of time. Maybe, when they reach the age of a hundred, or I can turn even though there is a negligible amount of easy damage could, we're constantly getting rid of it.
is the critical thing that
But by that time, when they reach a hundred, you know, this is 30 years after they were first created and we the scientists will have been busy. During that time, we will have been, beavering away, improving the therapy. And that means that when someone is a hundred, they won't be getting version 1.0 of this damage repair. They will be getting therapy. That not only repair the easy damage, but they also repair some, still not all, but some
Of the difficult at me which means that the hundred-year-old will be able to be re rejuvenated so that they have the damage of a forty-year-old again or 30 year old. Even though the inherent difficulty of doing so is greater than it was when they were originally 60 or 70. So that so you got the idea now that in order to keep the level of damage in this person's body down to the level, that would naturally exist in 30 or 40 year old.
Old, all we need to do, is progressively improve how comprehensive the damage repair therapy. Arsenal, that we have is, people are getting the state of the art therapy, at any point, they can stay one. Step ahead of the problem. I've conquered long as we get closer and closer to being able to repair all the damage. And other words, the damage that still not repairable, gets less, and less, it takes longer and longer to become problematic. And therefore, we
Um, kind of even slowdown in the rate at which we continue to improve the therapy. So, this is why I believe that, once we get even the first generation therapy that give us only 20 or 30 years of additional healthy life with done, we will never fall below. This threshold of minimum rate of improvement that I've called Longevity escape velocity. So yeah, sorry that was a long answer but I felt her need to go into every step of it in order to get through to people who may not have heard it
before.
Now, I love it. I think that's really helpful, and this is what makes your book so interesting and you as sort of a leading personality. So useful, is you really give people an understanding of what's happening? And so, I actually want to go into these 7 types of damage and the intrinsic nature that to me is one of the key insights that I got from. You is look, yes, you can slow things down and you should. I've heard you talk about that before. Absolutely, eat better who don't smoke.
Exercise but recognize that, you know, we've been running whatever 200,000 year experiment and no one ever has managed to live forever doing just that. So we know that there's going to have to be more and the way that you look at how that intrinsic damage is done. I found incredibly interesting. So if you can like walk us through just like quickly what the seven types are and then we'll sort of dip into some key moments in each of them.
All right, though?
Yeah that much about so um look about damage repair. That makes it so attractive as a therapeutic modality of therapy to concept. Is that all we need to do is to identify what the damage is to characterize the nature of the damage that differences in molecular and cellular composition between older people and younger people and then figure out ways to reverse that to restore that the Young
States. Now, let me be first vegetable clarify. One thing that people do often get wrong. Okay, I am not saying that there are only seven types of damage. There are hundreds and hundreds of types of damn it. What I'm saying is that those hundreds and hundreds of types can be classified into seven categories? And that this classification is a youthful thing to do because it corresponds to therapeutic modality. So for example
One of the categories is lots of cells. So what did Locke tells me mean tell dying and not being automatically replaced by the division and differentiation of other cell, simple idea, right? And of course, this happened in various different tissue. They happen in the brain happened in the Harley happened in the thymus. And in order to fix this you would need to do different therapy of course but all those therapies come under one heading. They are all stem cell therapy of one sort or another and stuff.
Over there, please, or have a lot in common, of course, there are differences of data. Sure. But that's really important because it means that if you've got one or two stem cell therapy working for one or two tissues, then you've learned a lot about how to get stem cell therapy in general to work for getting the next one to work. In the one after that is going to be far easier and faster than the first one was, this is the general principle that underlies the whole of the approach. We're going to end up with a lot of therapy that will be applying to the same people at the same time, but the way we develop those,
Repeat will not be one therapy at a time.
I can tell you from firsthand experience. The entrepreneurial Journey can be a very rocky road. But if you never get through the inevitable challenges success is actually possible. And in today's world, the only way to be prepared for those challenges is to have a firm understanding of e-commerce. Imagine starting a business with millions of customers already on your website. That's exactly what Amazon FBA is. FBA is a program that Amazons
Started where they lend their entire fulfillment Network, to their Cellars, packing shipping returns all the hard stuff, guys, this is one of the like great e-commerce inventions but what if you're a brand new entrepreneur and need help navigating through the world of Amazon, that's where helium 10 comes in helium. 10 is an all-in-one software tool for entrepreneurs to help them start build and grow a business on Amazon helium. Tens. Cutting-edge software, makes it easier to find a winning product convert more.
Or visitors and grow your business. On Amazon helium. 10 has served over 1 million users worldwide, and they track over two billion products on Amazon helium. 10 also has over 30 tools to help you research, start and manage your business. All on Amazon, with helium 10, you can learn everything you need to know about an Amazon business, including how to find a product create a listing, grow your sales and much more enjoy webinars events, and access a community of
Sellers ready to provide knowledge and advice when you need it. The most start, your own journey and build your business on Amazon to day helium. 10 is a must-have and we have an incredible offer exclusively for our audience. Get 50% off your first month of helium 10 Platinum. When you go to helium 10.com and use code impact at checkout, don't wait to get 50% off your first month. Go to helium.
Ten.com and use code impact. All right guys, take care and be legendary, listen up my friends Finding comfortable. Underwear can feel like an impossible challenge. Some are too tight summer too loose and others can feel so uncomfortable on your skin, you never want to wear them again. That's why I'm excited to tell you guys about sheath because they've found the perfect formula for men's underwear. Sheath men's. Underwear is designed to keep everything in place.
It has three individual compartments to keep everything down, their separate, cool, and comfortable traditional boxer briefs are barbaric and invented during the Neanderthal era. Sheath has a modern ergonomic design intended to prevent skin-on-skin contact for long durations, which can build up heat and sweat sheath prevents all of that. Sheath is the Holy Grail of underwear. With sheath boxers, you will chafe and readjust less because everything is in a separate compartment.
Aunt sheath boxers were invented by a US Army soldier, who came up with the idea for sheath during his second tour in Iraq. He invented. Sheath underwear to keep men. Cool, and comfortable under the hottest conditions. One of our impact Theory team members started wearing sheath underwear during his morning workouts. And he's noticed a major difference in comfort and coolness compared to any other men's underwear. He's tried. Sheath has now become his go to underwear for any workout. Sheath underwear are what you need in your life. If
You want to be a modern man and we have a special offer on sheath underwear. Exclusively for impact Theory. Listeners, go to sheathe underwear.com impact for twenty percent off your order to day that's sh ta th underwear.com impact and make sure to use promo code impact at checkout that's sheath underwear.com forward slash
For 20% off, guys, do yourself a favor and get underwear. The keeps everything down there. Separate, cool. And comfortable that's sheath underwear.com, forward slash impact for 20% off using promo code impact at checkout. All right guys, take care and be legendary.
Okay, so that's the first time that's the first category. So lat then there are two categories that they're all about having too many cells above.
I thought they were bad type of one kind or another. One of those categories is cancer. In other words, having fell for the bad in as a result of the fact that they divide uncontrollably when they're not supposed to and they take over and they got there are many different ways that people have thought about to address cancer. Cancer immunotherapy had exploded in the past 10 years which is of course much more recently than when I first started thinking about all of this
say that when I first started thinking about this, the only approach that I thought was sufficiently generic for cancer was to address telomere. Maintenance, the ends of the chromosomes which are which gets shorter with cell division and can serve circumvent that by typically by turning on a gene called to llama rate. So, I'm all about trying to stop that from happening. There are various ways to do that. There's actually been some massive progress in that area recently.
Development of a drug that essentially turned to Long Road into a suicide gene. So basically when cells are expressing a lot of te llama, Rave and you give and you give the body they've drugged those cells Jeff Keel over at once, which is much better than the version that I first put forward in 2002.
How do you selectively do
that? Oh, you don't, the point is, the selection is done by the cancer cell itself. The cancer cell has turned on too.
Gamma rays expecting it at a high level. So itself that are not expressing too long road and not affected by the drug, but the ones that are expecting to learn morees they incorporate this drug into their DNA and that caused the killer, either. It's a bread are, are
the only cells that are expressing telomerase cancer cells. I didn't think that, I thought that many cells.
It's close enough. So the stem cells of rapidly. Renewing tissues like the blood and the lining of the guts. They do Express.
I'm right. But only a really Trace level far, far lower than what counts of do. So there's plenty of therapeutic window there in terms of dose and duration to be able to kill off the cancer from well without having a bad effect, with a significant effect on those stem cell
population.
It, is that Universal to cancer, like, all cancer types expressed
alarm. Very, nearly, not a great question, not quite about. 90% of cancer of maintain. Their Taylor may have using this method. The other 10% you the method called alt, which sounds What alternative lengthening of telomeres and also install really very poorly. Understood. I'm afraid though. Actually have been massive progress over the past few years and we may be close. But yes.
Definitely to explain to address those kinds of as well. And, in fact, one of the main weaknesses of my original anti to longer a van to telomere approach works that if a cancer with expecting loads along arrive and you stopped it from doing. So, it would switch to all the great thing about this new drug is that the counter won't have time to do that the felt die so quickly.
So the other way in which you can have too many bad selves is if so are not bad by virtue of dividing too much, but they did find some other way. So they get into a state where they are, perhaps they're still doing what they're supposed to do, or maybe some of what they're supposed to do. But they're also doing bad stuff and the most well-known category of this. Got that one, sub category within this category is cells that are called senescence cell.
Little cells that get into a very characteristic state where they secrete nasty chemicals, that are bad for the cells around them. In fact, they are some of those kind of calls are conquered genic, so they can actually promote cancer in neighboring cell, but there are other ways in which these cells can be bad. So we'd like to get rid of those cell. Now again, this is an area where there's been great progress in the in the last 20 years. Originally, my view was that the only way we were going to get rid of these self-worth by essentially
a method that's also do with suicide gene. So instantly introducing a, an engineer Jean with a virus, which in therapy into the cells, that would cause them to die as a result of the other things they were doing already, and that's still a perfectly reasonable approach. It's being pursued by at least one company in this space, but the remarkable thing that we discovered less than 10 years ago. Now, if that, in fact, we may very well
Be able to do this, just with unsuitable, the maybe small molecule drugs, that can actually get in and selectively kill off the NAFTA, senescence out, and then a bunch of company, at least half a dozen companies doing that right now, so that's all good news. All right, so that's three things so far. And there's also do with cell number. There was having too few cells and there were two types of having too many cells of about time. Now, the other things are all at the molecular level and two of them are inside fell to a number outside. So the
do the inside first. First one of these is mitochondrial mutations so mitochondria are of course the machine within the cell that does the chemistry of breathing it. You know they combine oxygen with nutrients as a way of extracting energy from the nutrient
And mitochondria have their own DNA that the only part of yourself, does the chromosomes in the nucleus and you know that DNA is essential. There are only 13 proteins encoded in it, but those proteins are absolutely required. Component of the Machinery, that makes mitochondria. Do what they do. And sure enough that DNA gets mutated in fact, it gets mutated really far as compared to the DNA and nucleus because mitochondria
A bad place for DNA to be in some, you know, basically the process of extracting energy from nutrients with oxygen is chemically very hairy elaborate thing. That has by-product in particular has reactive toxic byproduct called free radical which damaged DNA. So yeah, this is the seems to be bad for us and we'd like to fix it but unfortunately fixing it easier said than done because it turns out that they even though what I mean, you think we're not very good at gene therapy, you know?
Like getting new genes into into the nuclear DNA, we have no way to do anything in the mitochondrial, DNA, the vectors that don't get there. You know, it's not going to happen not for a very long time that we noodle radical Discovery to make that possible. But we can do something out. What we can do is we can put backup copies of that mitochondrial DNA into the nucleus into the nuclear DNA with regular gene therapy.
No, you might think, well that's not going to work, is it? Because, you know, the daylight in the wrong place, the proteins are going to be in the wrong place. That's right. That's done. But actually, it might not be so dumb because the mitochondrion is a really complicated big machine. That is actually composed of, not just 13 protein, but more than thousand protein or the other are already encoded in nuclear Gene in our regular chromosome and the Machinery, obviously, therefore exists to get those proteins.
To the mitochondria after they've been synthesized in the main body of the cells are so. So the pro, the idea here is to hijack to coops that Machinery to essentially modify the DNA of the 13, right 13. So that they become sub, the proteins become substrate for this data machinery. And those proteins are imported into the mitochondrion along with all the other thousand and assembled as if they had being synthesized in the mitochondrion already.
Now, this, even though, you know, I've shown you, whether it's not nearly so implausible as you might have thought initially. Nevertheless, it's still really hard. And in fact, people thought people thought of this idea back in the 1980s and by the early 1990s, they'd given up. But I said, yeah, maybe you gave up a little too easily and so, we say having a go at this and sure enough we have made a lot of progress. We are now at a point we haven't got it working yet. I'm not okay we have but
We're far far closer to getting this working than anyone believe will ever be possible. So you know, we're fairly pleased with herself,
all right, if you're able to get that first part to happen, do you think that cell now will out-compete? That's one thing. I've never quite understood about gene therapy or editing DNA is. How do you then get that new version to win?
All right, great question. So I'm in this particular case you're not quite asking the right question.
Cuz it turns out that mutant mitochondrial DNA generally already doesn't win within the among mitochondria in cells that are dividing cells. That are dividing reasonably often seem to purify away. The mutant mitochondria as part of the mutation the right,
The ones that are problematic Arthur over the not dividing like muscle fibers, for example, further seldom, which the mitochondria still are dividing and some of them are being destroyed. Of course, and it turns out that the mutant at the thumb times from Newton, enjoy a selective Advantage. They clonally expand take over the cell. So the problem is to fix that. Now, of course, if we're putting these backup copies in the might occur in nuclear, then that
Problem of selection between mitochondria go the way because they've all got the same gene because they haven't got the damn to tour their gender, common to the door mitochondria and self the other type of damage in the that inside the cell is much easier. One to explain it just garbage waste product. So the cell is doing a million different things all the time and I've got different fell through somewhat different things, but they all do a lot of things and those processes create
Product by product has to be eliminated. Sometimes that happens by excreting, them into the circulation. And having the circulation, take them away and excrete them out of the kidney, and the liver, and sometimes the byproduct perfectly destroyed. Now, that sounds great, and it worked well for almost all of these by product. But turned out that some of these byproducts are created, only very rarely and therefore
You know, if you don't do either of those things, if you just stole them up rather than either excreting audits growing them, that's okay. It doesn't you know he doesn't kill you until all day and of course old lady what we're working on, right. But old age is something that Eeveelution doesn't care about a toy balloon. Only cares about the propagation of genetic information. And therefore, once you've had your kid, you know, you're on your are relevant to Evolution. That's why we don't have genes to keep a healthy. They can life.
So, we have these waste products that accumulate very slowly. But eventually by old age, they start to matter. And they cause a lot of the things that are bad for reflecting life, like, atherosclerosis and macular degeneration. So, what will I do to fix this? If we want to get the cell to be better at either breaking down or excreting, things that not be can't. It doesn't normally do and we've adopted Bertha bracket in the case of macular degeneration,
The particular waste product that needs to be eliminated, the other kind of derivative of vitamin A that accumulate in solve the back of the eye in the retina and we identified enzymes in bacteria. In fact, that are able to break these, let this stuff down the them down. Cannot exist in human, but they're doing some bacteria. So we figured out that if we could get those enzymes into human cells, then the problem would go
Go away the material would not accumulate and people wouldn't go blind and it works. We got the going working in cell culture. We were able to spend the idea out as a startup company a few years ago and with a bit of luck it'll be in clinical trials in the
aortic and the enzymes are so specific that. They only attack The Unwanted detritus, for lack of a better word.
Yeah, I mean, enzymes are usually very specific so that's not particularly
It's surprising and this molecule, you know, you don't find this molecule anywhere else. There are no other molecules in the body that look like that. That exists for good reasons, and that, look, anything like this molecule. So it's not particularly surprising that the specificity of
that. And what does the enzyme do if it were to sort of Get Loose as it were and encounter other tissue? It just sort of
dyes nothing. Well, yeah, sure. The end, oh proteins, have a half-life the enzyme just never Finds Its substrate and nothing happened. In fact, any
Immune system doesn't attack it or anything like
that. So folk with that's a very important question. Immune system would generally attack such a thing but because it is in the eye, we have a stroke of luck because they basically no immune system at all in the eye. So, there are various other early onset diseases of the eye that are being addressed with those other types of gene therapy already involving. Either actual foreign Jane, put more often human gene, but
The human being is so foreign. If someone got a congenital deficiency of that mutation in that Gene, right? Because then they're not making the project. So yeah. So and also of course there's the viral proteins itself, you know, the capsid or whatever. But yeah, you can just do gene therapy much more easily in the eye than you can in any other part of your body. Alright, then Loosely idea of excretion. So another of our spin-out company though,
Dog. Pharmaceuticals is looking at treating atherosclerosis safe by that method. Essentially they've developed a really cool molecule that they able to go in and infiltrate atherosclerosis clerks and self that are overly Laden with oxidized cholesterol which is the Target in this case and they basically just extract it. They basically kind of fully believe in if you like and bring it out into the circulation, third against excreted, through the, to the kidney,
And, of course, that's that's just as good as breaking it down, right? It means it's gone. So yeah, this is a really cool way to address this problem. We want to, we want to do other things. Other things that we want to break down and self may be more difficult. We just starting a project that breaks down proteins that accumulate in the brain, there are very capable, they are. So one of the most famous food will call neurofibroma each angle in Alzheimer's disease. These are made of mostly of a protein called Tau
Which gets misfolded and modify and we identified a way, using a clever type of antibody that can break this stuff down. If in principle, there are other side if it's very early shade with the project right now.
Um, okay, so I mentioned that I don't fight with my seven so far, and I mentioned that the other two outside this out, in the spaces between, so the, what are they? Well, the first one is actually just like the one I just talked about. It's just waste product, and again, we've got a case in the brain and Alzheimer's the thieves. Either called senile plaques. They're mostly made of a protein called amyloid beta.
You know, the thought question about exactly, which kinds of amyloid beta a bad for you, whether it's the big Aggregates that you see through the microscope or whether it's the kind of get a few of these things coming together and what that Willa kilala Gomez, that that have damaging effect on, for example, the permeability of cell membrane. But either way these are misfolded and we want to get rid of it and turns out that getting rid of stuff like this out.
It's a little easier than getting rid of stuff inside the cell. Why the idiot? The reason he's here is because the Machinery that we naturally have inside the cell for breaking things down, is really, really heavy duty. But outside the cell, the Machinery that for breaking things down, if far more primitive. So, lots of things accumulate there, which would not accumulate. If only there were inside the cell, they will be touched for all we have to do is get them inside the cell and it
Turns out that we can do that with the immune system. We vaccinations we can essentially trick the body into thinking that the material is foreign and engulf it like it would a bacterium and that takes it inside the cell and then it's tight. So that works. Now people have been able to get it working really well in affirmative Eve, there are actually well there are variations on that theme but one way or another vaccination against amyloid have been shown to really get rid of analyte doesn't have much be used.
Now that's kinda. So if been through clinical trials, all the way through phase 3, unfortunately, unfortunately if you want to get something approved for medical youth, you have to actually have a medical benefit rather than just a benefit. The time we can see down the microscope and it doesn't, or at least not to speak up. Getting rid of amyloid in the brain. The people, the people do not get better or at least not much. So you have to like what I have course, the answer.
One on the conveyor amyloid doesn't matter. I think that's a dumb answer. I think that the right answer is that animal is not the only thing that mattered and that the other thing we're not fixing with those therapies. Like, the tangles that I mentioned earlier, the synaptic density. And so on these things also matter a lot. And and if you fix them as well, you're not going to see a benefit. But the my bet is still that. If you fix all the other things, you didn't fix amyloid. You'd fill.
Also have only a mullet benefit therefore it for fantastic than that. We have this therapy in our back pocket to to be combined in the future with therapy that are still being developed
man. I'm really interested in what happens is you begin to attack their amyloid. So when you know I think about Alzheimer's is sort of blood sugar disease, you know, Diabetes Type 3 or diabetes of the brain and you think of the amyloid is sort of going in and grabbing on to
Goals that would otherwise be problematic and sort of encapsulating them. If you're taking that out, I mean, that seems like it would really prolong the sort of Health span even though you still have the underlying condition or whatever. That's kicking off the things that have to be grabbed. Ahold of our. Were you surprised by how little efficacy that has
no Arena? I mean, a way of looking at it really is that Alzheimer's is Aging in my
oh Cosmo. There are lots of different types of damage accumulating and the crosstalk between the processes that create different type of damage, but they're still semi-independent process. So, yeah, I mean, it's just like, you know, if you fix five of the seven different type of damage that I'm listing for you at the moment, then again, you will not expect to see all that much benefit, you've got to fix them or you haven't got to fix any of them perfectly but you've got to fix them all pretty well.
Incredibly interesting.
So, as we look into the future, the, the model sounds, it sounds really useful because right now, I feel like we're still a long way away from really understanding all of the biology even just have something like metabolism. Which in your book, you talk a lot about how a mass amount of the damage that happens happens at the level of metabolism. But what's our timeline look like? Are we 20 years away from escape velocity? Are we a hundred years away?
Way.
So, we are far enough away that I can't give you a number. In other words, you know if I mean, because clearly pioneering technology, right? Even even five years away, pretty much a toss-up, but I think we've got a 50-50 chance of getting there within 15 years. I think, you know, at least a 10% chance that we won't get there for a hundred years. But who cares, you know, if it's a percent chance is quite enough to be worth fighting, for right now, of course, how we get there.
You have to break that down into, you know what steps need to happen. The big thing that happened in the past 15 years. We've basically the acceptance that this is a promising. Way to go and the consequent arrival of a lot of money, especially in the past five years from the private sector, which is definitely speeding. Things up a lot, but there's a long way to go. And so I've already mentioned that there's going to be a period where we take the therapies that work.
Individually in small more patient population, and combine them. That's good. That's bound to throw up a few. I anticipated interactions that we have to address one way or another, but even before then we've got to get all the bits working. Some of them are already working, fairly well, at least, in some examples. So, if themselves the Parkinson's disease, for example, or and I mentioned already small molecule, the dressing senescent cells and quite a few of the other things are going to be in clinical trials.
Next year or two, but the wall gotta get their mitochondrial mutations. For example, I can see that still being maybe five years away from clinical
trial. And so looking at some of the like, really promising winds that have got you excited what are some? Like I know there's been some big wins in Parkinson's or at least certain types of Parkinson's. What are the things that you find most exciting?
Well remember I don't work at the level of clinical
Call trial, I'm focused on the early stage stuff. When something is even within a couple of years of going to the clinic, we've already spun it out into a startup company. So what excites me is, typically, the Breakthrough is that would take me half an hour of background to describe why it's even important. Hey, but honestly, I'm excited about everything. I think that really the difference between the answer, I will get to this question. Now, the versus five years ago is that five years ago
If I was being honest, I would have to have said that there were a couple of strands in which progress was still imperceptible. We were really not making very much Headway on mitochondrial, mutations. We're also making pretty much no Headway on the one that I never got to yet, which is the stiffening of the Exeter Matrix. Mmm, lot of electricity, but real five years ago, in both of those cases. We cracked it. We got. We've made a really important, you know, Log Jam,
Breaking breakthrough that essentially released the bats and we got we started moving much faster on both of those. So now there is nothing where we're really stuck.
Aubrey is your world is is so exciting and vast. I mean, it's crazy. I cannot believe that we've already been going for an hour and we've like, gotten through chapter one of your book, it's really breathtaking man. Where can people connect with you to learn more about what you're doing?
Well, of course, throughout that you guys are websites since the hook after September e for elephant ends, November s, the September Dot o--.
R-- g--.
Amazing man. Will this conversation has been so much fun? I actually, at one point that I may have missed remembered what time we started, because it went so fast. Your book is phenomenal. All the talks you've given her wonderful guys. I highly encourage you to engage with him, man. You talk about hitting escape velocity, and where this is going and somebody, whose voice, you know, the more that we can get it out there. I think the faster things will progress. So thank you, Aubrey for being here and speaking of a pre-emptive, thanks.
You haven't already. I'll thank you now for subscribing. And until next time, my friend's be legendary, take care.
Thank you guys so much for watching and being a part of this community. If you haven't already, be sure to subscribe. You're gonna get weekly videos on building a growth mindset, cultivating, grit and unlocking your full potential.
