Young Forever? How to Defy Aging. Podcast with Aubrey de Grey

Guest

Our guest for this show is Aubrey de Grey, PhD, and he refuses to accept aging as something we can not change. Aubrey is a Biomedical Gerontologist and Chief Scientific Officer of The SENS Research Foundation. I talk more about his background and the SENS Foundation in the interview. Aubrey has put forth a model for aging based on seven types of damage that occur as a product of aging. We discuss this model and the techniques to address each category of damage. This interview is longer than the others thus far but it had me gripped the entire time. So, enjoy!

If you’re as compelled as I am to support Aubrey’s work, please donate here as I did. I have no financial connection to SENS.org.

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Transcript

Aubrey de Grey - 00:00: There are many, many different types of damage and I'm just bunching them into seven categories. What's the point of that? For each category there is a corresponding generic intervention. If we access all categories reasonably well then the benefit will be far better. We're talking definitely a few decades of [inaudible 00:00:25] health in time rather than just a couple of years.

Kendall Kendrick - 00:00: HumanOS. Learn, master, achieve.

Dan Pardi - 00:00: The desire to resist or avoid aging is as old as humanity itself. We actually age from the moment we come into the world, but the science of aging do not become noticeable until later in life when our ability to repair the damage accumulated by living itself starts to exceed our ability to repair that damage. Then we start to notice signs, gray hair, wrinkles, aches and pains, less energy, and especially in some areas we have less of what we had before making aging an especially bitter pill to swallow. There have been several serious but fruitless efforts to try to delay or even improve aging. However, we are now at a point where affecting it might actually be possible. We're not quite there yet, but we have identified the best places to devote our efforts in order to make this happen. Research and labs across the world are hard at work investigating these areas now.

00:00: Today's guest is biomedical gerontologist Aubrey de Grey. He is the chief scientific officer of an organization called SENS Research Foundation dedicated to advancing the science in promising areas around aging. The organization also does its own research, but it also funds academics at other institutions doing related work and it serves as a mini incubator for certain age related businesses that spin out of the ideas that are generated there. Aubrey is also the editor in chief of the academic journal Rejuvenation Research and has authored several books, The Mitochondrial Free Radical Theory of Aging and Ending Aging.

00:00): Personally, I've been aware of Aubrey's work for quite some time. In 2003, I read the book Ageless Quest by MIT aging research Lenny Guarente which launched an interest on my part to learn more about this subject. It was only a few years after that that I started to see Aubrey's name popping up more and more. Having this opportunity to interview him have me good cause to take an even deeper dive into his work. I must admit, the more I investigated what he's doing, the more impressed I've become by his contributions. Aubrey is not just a scientist, but he's also a philosopher, a historian, a theorist around the subject. He has an obsession I'd say with getting this right and not accepting previously unbreakable limits as unsurpassable laws. At the same time, he's a pragmatist so he has a nice balance between realism and just the right amount of craziness to do what's never been done before.

00:00: This interview is longer than my other ones for personally I found it flew by, so let's get to it. Aubrey, great to have you on the show. Let's just jump right in. Obviously, the subject of today's discussion is aging, how to age better and even how to delay or avoid it altogether. Every human understands aging on some level, but from your scientific perspective, what is aging?

Aubrey de Grey - 00:00: Sure. Certainly. There are two pithy definitions of aging that I often mention which are both intended to not only explain what aging is but also to demystify it. One of them is I emphasize the relationship between aging and disease which is one of those crazy, stupid questions that people constantly ask that has no answer because it's a poorly formed question. As far as I'm concerned, it's just a question of terminology whether aging is a disease. I'd like to say that it's neither a disease nor not a disease. It's kind of an uber disease that incorporates an encompasses everything that goes wrong with physical and mental functioning later in life. Therefore, the ways in which we try to develop medicine to address the diseases of old age and the aspects of what people tend to think of as aging itself should not be nearly so desperate as they currently are.

00:00: At the moment we have this rather curious tendency to treat the things we call diseases of old age, if they were infections if they were diseases of early life which is basically never going to work because the diseases of old age have side effects of being alive. Conversely, the things that we call aging itself get so left out in the cold that most people don't even think of them as meaningful even in principle to medical intervention. I would say that aging is a kind of uber disease that encompasses all aspects of age late in your health.

00:00: The other thing I always wanted to add is that aging is not actually a phenomenon of biology if we come down to its real roots. It's a phenomenon of physics in the sense that the creation and accumulation of damage is something that all machines with moving parts, whether they're alive or not, are inevitably constrained to actually do it to themselves. It's just the second law of thermodynamics, really. If we look at the question again of what we can do in principle with medicine against aging, then we can actually get quite a lot of good pointers by looking at how we already successfully maintain the fully functioning lifespan of simple inanimate machines well beyond the point that they were designed to last. That's of course why I talk a lot about vintage cars and such like.

Dan Pardi - 00:00: I found this analogy you created very helpful in my own understanding, so if you will, please explain it further.

Aubrey de Grey - 00:00: Sure. Of course, vintage cars, cars that are over a hundred years old, they were not designed to last that long. They were designed to last maybe 10 years. The fact is, the reason why they have lasted so much longer than they were designed to is well understood. It's simply because their owners have performed comprehensive periodic preventative maintenance on them, rather than waiting until the car falls apart and getting a new one the way most of us do. There is a thing in manufacturing called planned obsolescence. Henry Ford pioneered it by finding out how to make sure that cars broke down and needed to be replaced as a reasonably predictable longevity. Of course, that whole concept of planned obsolescence only works because we are lazy. We have no particular interest in doing any more maintenance on our vehicles than the law requires. That means that the overwhelming majority of cars really do fall apart around the time that they're expected to by the manufacturer.

00:00: It's exactly the same for the human body. The human body, of course, was designed by evolution rather than by people. The other thing is that the human is vastly more complicated than any simple man made machine, but that doesn't make any difference to the fundamental fact that the human body does damage to itself, they have the consequence of its normal operation, whether it's because of breathing or because their nutrient metabolism or whatever, and that damage accumulates and the body is set up to tolerate a certain amount of that damage without significant impairment of performance but only a certain amount. Eventually that amount exceeded and we start to go downhill and eventually we don't work at all.

Dan Pardi - 00:00: Okay. Got it. This damage is an unavoidable part of life, but if we learn to do the right type of maintenance, we can delay the health impairing effects of aging and even live longer. Before we get into the details, I've heard you argue that this is the single most important issue facing humankind. Some have refuted that with arguments such as culturally we can't afford to have everybody get very old. Environmentally, we can't sustain that amount of people. Even philosophically, living forever is unnatural. Describe to as why you think this is the most important problem in the world and why we should make it a priority to try to aggressively address it.

Aubrey de Grey - 00:00: Of course whenever I'm faced with this question, my first reaction is always how is it possible that anyone could not think this, because at the end of the day, we need a problem. The problem is something that causes people dissatisfaction or pain or whatever, and it is completely incontrovertible that aging causes far more suffering worldwide than everything else put together. That's all I think I need to say to remind people of in order to justify the assertion that aging is the world's biggest problem. Of course the attitude that many people have, most people I would say even to this day, is that aging is a terrible problem, but it's not a problem that is having we ought to be thinking about because there's nothing we can ever do about it. Of course that arises from misunderstanding and oversimplification of the nature of what aging is, the idea that aging is a phenomenon of physics but that it's somehow an inevitable phenomenon that nothing can be done about rather in the same way as we can't create perpetual motion. Of course that's how we say a rather severe oversimplification.

00:00: Once one gets past that, I do say people have this rather curious tendency to fixate on problems that might be created as a consequence in solving the problem we have today, the problem of aging. Of course there's nothing wrong with raising these concerns would identify and we'd anticipate the problems, but the question is what does one do having raised those concerns, having thought of those concerns. What most people do I'm afraid is they wring their hands and change the subject, there's probably a concern they don't want to talk about the whole thing anymore because they're alleged concern is an open and shut case that we do not have any actual merit in doing anything about aging in the first place.

00:00: I find that rather frustrating for a whole bunch of reasons. First of all because the specific concerns that I raised are invariably confirmed which do have very, very good answers. For example, probably the number one most popular concern is that if people stopped getting sick when they get old then they would stop dying when they get old and that means that they would fill up the planet. We've already got a rather severe overpopulation problem, so it is an unwise thing to do because it would make matters being worse. However, this of course completely ignores the fact that the problem of overpopulation is not a problem of how many people we have on the planet but rather how much pollution those people are actually creating. Whether it's in terms of our carbon footprint or anything else.

00:00: The question is are we in a position to get best both of both worlds by increasing the carrying the capacity of the planet faster than the population is increasing as a result of new technologies that diminish the amount of fossil fuels we're burning and such like, so as to make us less polluting in the first place in order to have more people on the planet with less environmental impact. Of course the answer is absolutely extremely clear that the advances that we're seeing in renewable energy and the artificial meat and goodness knows what, will add up to a very worthy prospect in terms of increasing the carrying capacity of the planet. If you answer that [inaudible 00:10:49] go to the numbers and project well in terms of trajectory of global population resulting from the elimination of aging. It's not nearly as scary as most people instinctively predict.

00:00: I only published an ongoing paper on that about a year or two ago which was developed by a very respected forecasting group in Denver. On top of all that, the fact that we've confirmed have perfectly good answers, there is also the fact that there's a sense of proportion argument. In other words, whatever your particular concern might be, whether it's overpopulation or dictated living forever or [inaudible 00:11:25] or whatever, we have to ask ourselves even if some bizarre worst case scenario arose whereby we were unable to accept this problem and get the best of worlds, we have to ask ourselves is the problem that we would be creating actually worse than the problem we have today. To be perfectly honest, nobody chooses to be honest about that. They do not actually look at the question and say if we ended up having an overpopulation issue such that we have to make a choice between on the one hand having fewer kids than we would like or on the other hand having everyone get Alzheimer's, the question is which would we actually choose.

00:00: It wouldn't be a nice choice to have to make, but we could actually choose. I don't find many people saying that we would choose the Alzheimer's, so that's another thing. The third thing of course which is perhaps the most open and shut unclad argument in the question of freedom of choice and who's right it is to choose. The way this goes is like this, supposing we today in the position that we have in terms of the information we have about the future with or without [inaudible 00:12:27], supposing we say, "Oh dear. I don't like the sound of this overpopulation thing. Let's not go there. Let's not develop these therapies." Then what we would be doing is we would be limiting the options for humanity in the future because we will be delaying the arrival of these therapies.

00:00: That means that if we happen to be wrong, if actually humanity of the future either has succeeded in developing plenty of renewable energy and such like, or alternatively they have decided that kids are actually something that they are willing to forego in return for not having Alzheimer's disease, then they're going to look at the options available. They're going to say, "Oh dear. We do not have therapies to stop people from getting sick when they get old." We could have had them if our forefathers had got [inaudible 00:13:09] and actually develop these therapies. I would be very impressed. I do not want to be the kind of person who's involved in condemning an entire cohort of humanity of the future to an unnecessarily painful and unnecessarily early death just because I thought I knew better than they did about how the future was going to look.

Dan Pardi - 00:00: Let me summarize. For one, if you compare the risks and the benefits of achieving successful aging treatments and therefore reduce its consequences that currently affect virtually everyone. Pursuing this wins out if reduced human suffering your hallmark evaluative measurement. Second, the issue of overpopulation is really one of human ways which is addressable and third, is an ethical issue that not pursuing a solution to these problems will not only affect us but future generations. We're a making a choice for them by doing nothing and prohibiting them from having a better life.

Aubrey de Grey - 00:00: Correct, yes.

Dan Pardi - 00:00: Great. I have a several part question. I'll lay out the different parts and then we could try to address them one by one. First part is how has aging been addressed over the last 30 years. The second part is what do you think is the most advanced prescription given what we know today for better aging right now. Then what do you find exciting in terms of whether it's supplements or biotechnology and then lastly we can address related to future. Maybe we can start with what is treating aging been like up until today?

Aubrey de Grey - 00:00: Sure. I'm actually going to answer that slightly differently from how you asked within the sense that I'm going to go back longer ago than 30 years. Really there had been three full storms in the attempt by humanity to address the problem of aging. Of course the idea that aging is a problem even though it remains controversial was first discussed and raised a very long time ago indeed by Roger Bacon in the 13th century if I remember rightly. The idea has been around a long time that we really ought to develop medicine against it. Unfortunately, the ways that we have been thinking about aging have led us astray.

00:00: The first full storm can be simply described under the heading of geriatric medicine. Geriatric medicine essentially comes down to treating the specific components of age related ill health as if they were infections, in other words as if they were diseases that could be cured could be eliminated from the body. To this day billions and billions of dollars are spent trying to develop such medicines. Because the diseases of old age are side effects of being alive or else they wouldn't be diseases of old age in the first place, that's obviously not going to work. You can't eliminate something that's the side effect of being alive without eliminating being alive.

00:00: It's completely misguided and the only reason that people cling to it is because they've got nothing else. One can make very modest progress in postponing the ill health of old age in various ways by pretending that [inaudible 00:15:50] their infections and that they can be eliminated. That progress will inevitably be very modest because the processes that are driving those diseases are continuing to proceed and therefore any kind of geriatric medicine pretty much by definition is going to become progressively less effective as the person gets older. That is the first mistake that humanity made.

00:00: It's been about a hundred years since people started to realize that that was a mistake and started to think differently, where the whole field of gerontology came from. Gerontology really got going as a result of the observation that there is a great deal of variation in the natural world with regard to rate of aging. Some species clearly accumulate damage more slowly than others and live longer than others. Of course even within the species there is some variation albeit much smaller. People thought if we study this really, really, really hard and we figure out as much as we possibly can about what underlies this variation. Maybe we can exploit it medically and end up with things that will postpone the ill health of our old age by essentially cleaning up our metabolism and slowing down the rate at which damage occurs in the first place. That all sounds very splendid in principle but that too has utterly failed to deliver any kind of effective medicine to postpone the ill health of old age.

00:00: If we ask why, we can again see a very straightforward answer namely that metabolism, the way that the body actually works is fabulously astronomically complicated and fabulously astronomically clearly understood. It's really, really hard to actually describe what's really going on in the body. Sure enough, this just hasn't worked. By the 1970s and 1980s, people who were studying the biology of aging had pretty much come to that conclusion that I've just described with the result that it actually became rather unfashionable in fact or much rather verboten to even discuss the idea of doing anything about aging in any kind of important publication, like for example a grant application. It instead became, I'm thinking particularly they tend to compare gerontologist of that era to seismologists who understand that the thing that they study is bad for you but they have no aspiration whatsoever to actually do anything about it.

00:00: Yes, it wasn't very good. It was a rather miserable time to be gerontologist. Luckily I wasn't around at that time. That was phase two and again a complete forced on, people got pretty interested back in the early part of the 20th century, but it all faded away. Then a very good thing happened and now I am coming up to about 30 years ago or certainly less. A couple of labs in the US made some fantastically important discoveries about the ways in which one could alter single genes in the laboratory organisms. The result would be that the organisms would live considerably longer than normal, perhaps twice as long as normal back then. Now it's up to a considerably larger factor. Sounds fantastic, doesn't it? It also sounds very, very contradictory to everything I just told you about the reasons why the idea of looking at the way the body works and why different organisms age at different rates were so unsuccessful.

00:00: It sounds like, hang on, their metabolism is really complicated. How come some simple intervention like a single mutation could actually have a big effect? Now we shouldn't in retrospect have been so surprised because right from the beginning when the mutation started to be discovered, it's become apparent that the genes in which the mutations were occurring were genes that were intimately involved in the bodies response to something that people normally call calorie restriction which in simple terms just basically mean starvation. That response, the fact that organisms tend to live longer when you don't give them as much food as they would like, that had been discovered way back in the 1930s. It had been just ignored a bit of curiosity for a long time, but since the 1970s it had been major theme of gerontological research.

00:00: It shouldn't have really been surprise if you could do a simple dietary intervention namely reducing the quantity of calories, then a simple genetic intervention shouldn't have been much of a surprise, but it was. The result was that for a while this discovery was also ignored or at least sidelined. Eventually, people started to realize that wow, this changed everything. Somehow, there was some kind of sleeping giant in the system, in the bowels of the complexity of metabolism, that could somehow be awakened and fight aging harder than the body fights aging normally. Maybe we could actually get this going in humans as well as a medical intervention. Sounds wonderful, doesn't it? Unfortunately, that's turns out also to have been a complete forced on for reasons that again should have been obvious to everybody right at the beginning, namely that you can only turn on sleeping giants that actually exist.

00:00: In other words, if it turns out that the corresponding sleeping giant that responds to famine or to anything else in the human body is somehow less powerful than the ones that exist in short lived organisms, then to that you're just not going to be able to get the same effect by the same kind of intervention. Unfortunately, that's exactly how things are. There is a very steep inverse correlation between the natural longevity of a species and the extent to which that longevity can be increased using color restriction. The fact of that inverse correlation is in fact a bleeding obvious conclusion that one can draw from basic evolution theory, it actually arises simply from the rather well known fact that long famines happen less frequently than short famines in nature.

00:00: I'm sure not only did we have theory, we also had data. We also knew things way back that you could multiply the lifespan of a nematode worm that normally lived a few weeks by a factor of maybe five by starving it in the appropriate way, whereas the best you could get in a mouse or a rat would be about a factor of 1.5, 50%. If you try it with a dog, it was 10% or so. People will try it with monkeys and they've got a few percent if they're lucky. The data were there. Yet people were continuing to fixate on that. I have to tell you about sad news that in fact very many gerontologists, I would guess about most gerontologists, are still fixated on that for reasons that afflict the whole of science. Namely the fact that scientific career in one builds on one's first work and one tends to have difficulty abandoning one's previously adopted beliefs in favor of new ones. This is of course unmemorialized rather well in this famous quote from Max Planck for more than a century ago where he said science advances funeral by funeral.

00:00: What are we left with? Luckily, we're left with science of course. The gerontological community for some reason fails to observe until I came along about 16 years ago now. The pathway from being alive to being dead, in other words from metabolism through damage to pathology. That pathway can be interdicted not only by cleaning up the rate at which damage is created but also by repairing that damage after it has been created. You don't have to repair all of it, you don't have to repair it particularly often necessarily, you don't have to repair it well enough and often enough so that the overall amount of damage that the body is carrying around stays below the threshold that the body is equipped to tolerate, in other words stays below the point that causes pathologies.

00:00: Whether I was able to get this idea off the ground was of course not only to say, "Hang on. You seem to have missed this abstract point," but also to actually to flush it out so that it wasn't abstract at all and to say here are the types of damage that we need to fix. There's not really much dispute about this. No new type of damage has been discovered or even hypothesized for a very long time. It turns out that that's still true luckily, so this idea is standing the test of time very much. Secondly, here are other various ways in which these types of damage can be addressed, can be actually repaired by corresponding therapies, either therapies that already are existing or almost existing or at least therapies where we can see a clear step by step pathway from what we can already do to provision which is of course the pathway that SENS Research Foundation has been pursuing ever since.

Dan Pardi - 00:00: This is a good segue to bring us to the four Rs to address aging which I've borrowed and reworked slightly from one of your presentations. These four verbs, resist, replace, remove and repair, are approaches to address the seven main causative factors of the ill effects of aging. Let's discuss these causative factors.

Aubrey de Grey - 00:00: Sure. Absolutely. Yes. First of all, let us stand back for a moment and define the term damage because of course everything that I'm talking about that revolves around this thing damage. I define damage very broadly. I define it to mean any aspect of the structure and composition of the body at the molecular level or the cellular level that changes progressively throughout life as a side effect of normal metabolism of the body's normal operation. That eventually, once there is too much of it, contributes to the ill health of old age to the loss of mental or physical performance. That's a very broad definition as you can tell. Luckily, even though it's very broad, it's quite useful.

00:00: The next thing I do is I subdivide this concept of damage into this seven major categories. These categories are not abstract at all, they are very concrete things. I'll go through them in a moment. The key thing about this is number one, this classification into these seven categories seems to be really truly valid. I have been challenging people for more than a decade now to improve on it, to actually come up with types of damage that fit into my definition of damage but they do not fit into my seven categories, and it hasn't happened. I seem to be getting away with it. That's nice to know.

00:00: The other thing about this classification is of course there are many, many, many different types of damage and I'm just bunching them into seven categories. What's the point of that? You can do that in a billion different ways. The point is the interventions. For each category there is a corresponding generic intervention and approach that may differ in detail from one example within the category to another but only in detail, the basic thing is the same. With all that preamble done, I'm now ready to tell you the categories.

00:00: The first category is loss of cells. In other words, cells dying and not being automatically replaced by the division of other cells. Very simple concept. Obviously if that's going to happen over time the number of cells in the affected tissue is going to decline and eventually there won't be enough cells for the tissue to do its job. How do we fix that? Everybody knows how we fix that already. That's the best known one, the furthest developed one as well, namely stem cells. That's what stem cell therapy is. We program cells in the laboratory into a stage where we can inject them into the body and then when they get there they will divide and transmogrify into cells that will replace the ones that the body is not replacing on its own, that's all that stem cell therapy is.

00:00: For emphasis, stem cell therapy is a big, big research field and the reason it is because different stem cell therapies have different details. The reason it's a field is because all stem cell therapies also have a hell of a lot in common. It's a reasonable thing. This matters because it means that when you've got one stem cell therapy working really well for one particular tissue, then the extra step of what you need to do to get the next stem cell therapy working will be much less. You'll be able to piggyback off all that you learned in the trial and error process of developing the first one. That concept, that principle applies throughout everything I'm going to say.

00:00: What's the next type of damage? The next type of damage is having too many cells because they are dividing when they're not supposed to. Of course that is cancer, that's pretty much the definition of cancer. There are loads and loads of ideas out there to what to do about cancer and we haven't had much success over the years. Things are looking very rosy right now as compared to the past, even as little as five years ago, because of very smart and ingenious advances in a field called cancer immunotherapy where people are figuring out how to tip the balance of the arms race that exists naturally in the body between the ingenuity of the cancer and the ingenuity of the immune system. I am fairly optimistic that that will lead to pretty down to comprehensive treatment of cancer fairly soon.

00:00: However, it might not. One thing that I think everybody had learned about [inaudible 00:27:52] aging over the past many years is that it's a bad idea to put all your eggs in any one basket. What we're doing is pursuing a much more ambitious and elaborate approach to combating cancer which pretty much everybody agrees would absolutely definitely really work if we can actually implement it, but the challenge is implementing it at all because it involves a good deal of gene therapy and stem cell therapies. It's pretty complicated. Nevertheless, we are pursuing it. The reason we're pursuing it is because basically nobody else is. This is generally how we prioritize our own activities in SENS Research Foundation. We do almost no stem cell therapy even though it's a very, very important part of the SENS worked earlier simply because we don't need to. Everything that needs to be done is being done perfectly well by other people that are well funded and our very limited amount of funding is best spent in focusing on the areas that are more neglected.

Dan Pardi - 00:00: Filling of gaps.

Aubrey de Grey - 00:00: It's category number three. Category number three is also as aspect of having too many cells. You must think that's very odd. Why would I split that description into two categories. The answer, it goes back to my explanation of why I have these seven categories at all namely it's all about the intervention. The other type of way in which you can have too many cells is if cells don't die when they are supposed to. First of all one might think that's actually pretty strange. Most people overlook that kind of category because they think, "I'm sure cells are never meant to die." That turns out not to be true. The immune system is a fine example of a case where it's absolutely vital that cells should die after they had done their job in order to make room for other cells. This process is impeded, it impairs in late life.

00:00: The reason why it goes in a separate category is because the elimination of cells that are around because they're refusing to die when they should is much different than the elimination of cells that we have too many of when they're dividing when they should not. Essentially, it's because cells that are hanging out and not dying when they should are not undergoing natural selection. They're not nearly so clever as cells that are dividing when they shouldn't. For that reason it's much, much easier to get rid of them. Also, we don't need to worry about any side effects like getting rid of cells that we didn't want to get rid off or at least we don't need to worry nearly so much about that as we do in the case of cancer.

00:00: We are reviewing something called suicide gene therapy which is a genetic approach that is already a routine procedure in the laboratory in [inaudible 00:30:16] we want to develop this as a clinical therapy to eliminate cells of this nature. That is something that actually had a lot of airtime over the past five years or so since a group out at the Mayo Clinic were able to make a very preliminary but nevertheless very exciting breakthrough with regard to such a thing. Since then, that group have gone private and companies have been created to identify small molecules, drugs that can preferentially kill these cells.

00:00: We think that at this point it's very unclear whether such drugs can actually be developed that will work reasonably well without too much [inaudible 00:30:53] side effect, so we are sticking to the genetic approach. Even the genetic approach actually I'm pleased to say is beginning to attract the interest of the private sector. A close colleague of ours have been able to start a company that is focused on that which is still only a very early stage startup company but nevertheless it's very important to be doing that. We're trying to do that kind of thing as much as possible so as to attract money from people who are more keen into making money than to give it away. That's number three.

Dan Pardi - 00:00: Allow me to do a recap if you will.

Aubrey de Grey - 00:00: Please, [inaudible 00:31:23].

Dan Pardi - 00:00: Thinking of things that will kill us over time as a function of life living long enough. We have cell loss and cell atrophy, that's bucket one. We want to replace these either lost or dysfunctional cells and a promising means to do this is via stem cell therapy. There's a big field of research, there's many different techniques on how to do it that are being explored, but it's well researched and it's very promising. Next big bucket we have, cells that won't stop dividing, this is cancer. You're excited about the promise of cancer immunotherapy as a means to address this. I agree, this is a very exciting area that I've been following. Then we have cells that are death resistant, but we have suicide gene therapy that get these cells to die when they should. Those are the first three big buckets that we've discussed. To go back to the four Rs, we want to replace lost cells, we want to resist cell over division and we want to remove cells that just won't die like the cyborg in Terminator 3.

Aubrey de Grey - 00:00: Correct. Correct. That was a good time to do a summary because now I can move from the three categories that are all about the number of cells we have to the categories that are more at the molecular level. There are two categories that are to do with stuff that goes on inside cells. Then after that I deal with the steps that go in the spaces between cells. Within cells, the first major category is mitochondrial mutations. Mitochondrion is this very important part of the cell that does basically the chemistry of breathing and combining of oxygen with nutrients to extract energy for our nutrients. The weird thing about mitochondrion is it has its own DNA. It's the only part of the cell that does. It doesn't have as much DNA, only 13 proteins are enclosed in it, but those 13 proteins are essential and it's rather important to make sure that those 13 proteins continue to be appropriately synthesized throughout life.

00:00: Turns out unfortunately that mitochondrial DNA accumulates mutations vastly more rapidly than the nuclear DNA which means of course that it's got a much greater chance of being bad for us. True enough, even though the details are still unclear, nevertheless most gerontologists believe that mitochondrial mutations are indeed a major contributor to eventual age related ill health. What do we do about it? The obvious thing you might think is to somehow do mitochondrial gene therapy to get a replacement or repaired mitochondrial DNA into the mitochondria so that the mutations are nullified. It turns out that that isn't going to work because of the way that mitochondria are maintained and recycled during life. It turns out that essentially we are running or losing battle against natural selection at level of the mitochondria.

00:00: Instead of that, the approach that we're pursuing which is an approach that was first put forward more than 30 years ago is to make modifications to the mitochondrial DNA so that we can put copies of this modified DNA into the nucleus, into our normal chromosome. The modifications are designed so that when the protein was synthesized, they are transported back into the mitochondrion so that it can do their job just as if they had been synthesized within the mitochondrion in the natural way. That terribly sounds fiction at first, but it turns out not to be nearly so hard as it sounds because the mitochondria is a really complicated machine that is composed of well over a thousand protein and all the others, all of those 13 proteins I've mentioned, they're already encoded in the nucleus so that the machinery for transporting proteins into the mitochondrion already exists and it's very generic. It just walks on anything that looks right. Whether that machinery works, that input machinery, it's well understood. It's been well characterized for a long time.

00:00: Of course it's not as simple as what I just described, if it were then it would have been done by now, but it isn't too bad. The way that we have to do this is to identify the right kinds of modification to make to these things so that we can put the backup copies into the nucleus. People, when they first thought of it 30 years ago, it had a bit of success and everyone got very excited. Then they hit some roadblock and everyone got very despondent and gave up and tried to do easier stuff because that was the easy way to get promoted and tenure and grant application and so on. I came along and kind of revived all of this about 15 years ago and pointed out that certainly the reasons that people had for giving up were premature.

00:00: A few other breakthroughs have been made by other people and also some minor breakthroughs by us. The result is that we are now far closer than anyone else has ever been to actually getting us working. We're still a long way away. We're already working in cell culture, but just last week or the week before we were able to publish a paper on this in a very nice prominent board review journal showing how we've been able to get two of these 13 genes working in the same cells at the same time and actually rescuing the loss of functioning mutations in the natural mitochondrial copies. That's all pretty good.

Dan Pardi - 00:00: Now, Aubrey, are these the mitochondrial transcripts like humanin and MOTS that are modifying the activity of the mitochondrion to keep them healthier longer?

Aubrey de Grey - 00:00: Okay. Great question. Not many people have heard of humanin and the other mitochondrial transcripts. This is an area that have just come to the floor over the past few years and there's still a lot that we don't know about those transcripts. No, I'm not talking about those. I'm talking about the 13 protein coding genes that have been understood and studied for many, many more years from that, from 30 or 40 years. These very small short proteins such as humanin, their function is still pretty unclear. Also, it very, very unlikely that they are going to be a part of the problem, in other words, that we would need to make up backup copies of those in the nucleus. The reason I can say that is because they tend to come from a part of the mitochondrial DNA that is not normally damaged during aging. The parts that are normally damaged are in a different part of the DNA and the ones that are going to go back to the 13 protein. We're not aware about humanin and its friends yet, but we are keeping a careful eye on that.

Dan Pardi - 00:00: Got it.

Aubrey de Grey - 00:00: All right. What is the other type of damage inside cells? This one's much easier to explain than the previous one because all it is is waste products, molecular garbage that the cell create in the course of its normal operation and then for whatever reason, it does not have a system for breaking the garbage down or for excreting it. Whenever any type of garbage is created rapidly, evolution does create a system for either excreting as they're breaking it down because if it doesn't, then we wouldn't get to be old enough to reproduce which would be not be [inaudible 00:37:40]. Some types of garbage it turns out are created really, really slowly which means that the only accumulate to a level that's problematic for the cell and for the body by the time that people have ceased caring about us because we have already reproduced.

00:00: That turns out to be vital as the driver of some of the most important and prevalent diseases of old age, not least atherosclerosis which is the number one killer in the western world because it's the cause of heart attacks and strokes, and also macular degeneration which is number one cause of blindness in the elderly. What are we going to do about that? The reason why this garbage accumulates is because we don't naturally have machinery to break it down. What we're trying to do at SENS Research Foundation is to create exactly that machinery to essentially augment the machinery that we do have to break other things down and would like to have broader arsenal, broader portfolio or target. Rather than about that, it's by identifying other species that can break down with target subjects of interest.

00:00: It turns out that it's quite easy to find bacteria that can break down more or less whatever you want as long as it's organic and that there's energy in it. We are getting quite successful. Maybe with much as eight years ago or so we found bacteria that could break down oxidized cholesterol which is the main driver of atherosclerosis. We started publishing on that way back then. Of course just finding the bacteria is just the first step. Then you've got to figure out what genes they have, the bacteria, that allows them to break down the target substance. It turns out that also is not very hard. Some of the genomic techniques can address that pretty quickly. We were able to do enough to find out what genes are involved, so that's easy. First step is the really hard one.

Dan Pardi - 00:00: Let me ask real quick. Are these autophagy resistant targets that we're after? On that note, can you tell us what autophagy is? Then if you can tell if this new technology is addressing what autophagy cannot?

Aubrey de Grey - 00:00: First of all, no. Actually this is not about autophagy. Autophagy is actually rather misunderstood because everyone talks about it as something that's really vital for the maintenance of cells and the elimination of garbage. It is absolutely important for the elimination of garbage, but it does not eliminate garbage on its own. What autophagy does actually it's simply a transport device, a transport machinery that moves stuff from wherever in the cell into this place called the lysosome which is the place where the garbage disposal really happens.

00:00: That means that actually what happens in atherosclerosis or in macular degeneration or whatever is not an impairment of autophagy. Autophagy itself is basically working fine. It's just that they end up being, if you like, a traffic jam whereby the autophagy machinery doesn't have anywhere to dump its cargo because the lysosomes are being impaired in their function because they're failing to break down stuff because they've been poisoned by stuff that they don't know how to break down. Autophagy itself is not the problem. The problem is that at the end, the thing that autophagy delivers to, the lysosome.

00:00: Now in the lysosome there are loads and loads of enzymes, that would be 60 enzymes that breaks stuff down. That's why the lysosome is so good at breaking down such a wide variety of stuff. But, as they say, that portfolio stuff that the lysosome does break down is not universal. There are some things that do not get broken down, oxidized cholesterol is one of them and it turns out that other oxidized cholesterol poisons the lysosome, in fact poisons some of the important proteins of in the lysosomal membrane and the result is that the lysosome species to be able to break down stuff that it normally would be able to and everything [inaudible 00:41:06] rather rapidly.

00:00: What do we do? We find these bacteria that can break down stuff. When we find the genes that they have, then we throw the enzymes that allow them to break down stuff. Then it's part three which is the hard part namely identifying where to modify those enzymes so that we can put the genes for them in human cell and they will still work. Human cells and bacterial cells are very different in their internal structure, so there's a lot of tinkering to do. That took us years. A couple years ago we were able to publish that we had achieved this and that we could only insert culture initially of course, but still we were able to show that cells could be protected against certain toxic concentrates into the major type of oxidized cholesterol that accumulates in atherosclerosis. They could tolerate, they could grow and survive in higher concentration to that stuff than if they didn't have our engineered gene. That was very wonderful. That too have been [inaudible 00:41:58] now.

00:00: What we did won back, taken on board by one of our major donors an internet entrepreneur from Phoenix and from the company, hired one of our people and they are proceeding with that. Actually, I mentioned already that macular degeneration, the number one source of blindness, is the same kind of aging problem. Even though we ourselves have not been able to get quite so far on that project than we had on atherosclerosis project, nevertheless again a company, in this case in upstate New York, has taken that on pursuing it and getting nice funding that we couldn't get. That's very good. All right. Now I've dealt with the three categories of damage inside the cell. The other two categories involve damage outside the cell.

Dan Pardi - 00:00: Let me ask you a question about that last part. Do you see the insertion of bacterial genes that are effective at doing this clean up process into human DNA as a potential use for the gene editing technology CRISPR?

Aubrey de Grey - 00:00: This is a bit parenthetical. CRISPR is a fantastic technique and it's getting more fantastic all the time for modifying the genome in various ways. In particular it's great for making small modifications, for example in activating a gene. What it can't do is insert genes. They can't insert large amounts of DNA like a couple of kilobase. In order to improve ability to do that, which is one thing that we'd certainly be required in order to introduce the bacterial genes or for that matter to introduce the mitochondrial gene that I was mentioning earlier, one thing that we have to do is to somehow combine CRISPR with something else that would also very, very safe and effective but would have the complimentary capability, mainly to actually insert large amounts of DNA. We are working on that too. We have developed some mice which are great proofs of concept of this using a system that's actually originate with bacterial viruses. It would take me a [inaudible 00:43:46] out of this, but [inaudible 00:43:48] of it, we're on that case.

Dan Pardi - 00:00: Great.

Aubrey de Grey - 00:00: What about damage outside the cell? Most categories damage outside the cell is waste products just like the last category. Again, the reason why I call that category different category is because the way to address it is different. It turns out that conceptually the way to address molecular garbage outside the cell is probably the simplest of all the seven categories because all we need to do is vaccinate against it. If you can persuade the body, the body's immune system, that this molecular garbage outside the cell is foreign, then the very cell of the immune system will simply engulf it and get it inside the cell.

00:00: Now you may think that won't do, will it? Because you still got the problems of having bacterial genes or whatever. It turns out that actually that's not the case. The machinery inside the cell, in the lysosome, is really, really powerful already. The machinery outside the cell for breaking stuff down is really primitive. It's very, very poor in its [inaudible 00:44:45], which means that by and large the stuff would accumulate up outside the cell is stuff that the body already has the gene and enzymes to break down just as long as the stuff can get to a different place namely the lysosome. That's exactly what happens when you vaccinate against it. The result is that in the case of the best known type of molecular garbage outside the cell, amyloid , the senile plaques, that are accumulating in Alzheimer's disease. This has already been done. People have developed vaccines that can not only in mice and mouse models but actually in humans can cause the immune system to get rid of the stuff and it works. They actually do get rid of the amyloid.

00:00: The clinical benefit is very variable. Usually in fact in a lot of [inaudible 00:45:30] people anyway there is basically the benefit simply because the amyloid is not the main problem that their Alzheimer's has. Some people that have a lot of amyloid and not much in the way of other types of damage that's happening outside this disease. Sure enough they will do benefit somewhat, but really this is a great example of why aging is complicated and the treatment of aging is just going to be pretty complicated too. It could divide and conquer a [inaudible 00:45:53] that we need. We're just developing more therapies to address the other aspects of Alzheimer's and when we put them all together then we can expect a very big result. All right. That's number six.

00:00: The final category of my seven point plan is again outside the cell. However, in this case it's not molecular garbage, it's cross linking. There is this lattice of proteins that we have it's called the extracellular matrix. It's all over the body. It's a bunch of proteins that are linked together in a very regular array that's why I call it a lattice. That regularity gives our tissues their biophysical property, in particular their elasticity. Some of our tissues it's very important that they should be elastic in order to do their job.

00:00: One example is the lens of the eye which of course has to be deformed by the muscle around the eye in order for us to see things close up. There's actually one type of tissue in the body where the loss of elasticity happens during aging just like in the lens of the eye where the consequence is very life threatening and that is the major arteries. In the major arteries, the stiffening that goes on is the main cause of our increase in blood pressure during life. Of course increased blood pressure causes all manner of problems like kidney failure and such like we've really got to fix it.

00:00: We don't want to get rid of the extracellular matrix and make the immune system think that it's foreign or absent. We want simply to restore its elasticity. The natural way that one might think of to do that is to recycle it. To have it broken down and rebuilt periodically or incrementally or whatever. It turns out that that's hard. It turns out that it already has developed ways in which to build the extracellular matrix that most of the time do not actually incorporate recycling it just builds one and it sits there. That of course is why it accumulates molecular changes that would use its elasticity. If it were being constantly recycled that wouldn't happen.

00:00: What we have to do is somehow work with what we have. The ideal situation is to identify drugs that can simply react chemically with the chemical bonds that cause the stiffening. Those chemical bonds are actually well understood now. We have been studying this for a long time. It's more than 30 years since the whole concept of stiffening from the bonds was first thought of and there's now a great deal on the chemical reactions that create these bonds and what their chemical structure is. The really good news is that the chemical structure of these cross links as they're often called is very, very different from the chemical structure of anything that the body lays down on purpose. Which means that a small molecule might very easily be developed to react with these cross links and break them without having significant side effect on molecules that we want to leave alone. Of course as with everything else, if it were that easy it would have been done by now. Sure enough, it turns out that these cross links are actually quite hard to break, but we're getting closer.

00:00: Actually, another big breakthrough that we were able to publish just less than a year ago now from the group that we funded at Yale University is a way to synthesize large amounts of the main culprit. The pubic enemy number one in cross linking, then the testing, [inaudible 00:48:53]. That's vital because now that we can make grounds of the stuff whenever we like, we're in a position to do a bunch of experiments that were completely impossible before. Things like raising antibodies against it, growing bacteria to see if they can break it down, that kind of stuff. Those experiments are all happening now and going pretty well actually. Though they're not at the level where we can talk about them yet, but they couldn't be done before. We essentially were able to unblock a scientific research log jam that had existed for at least 20 years. We're very happy and proud that we were able to do that.

Dan Pardi - 00:00: Okay. We've reviewed the seven things that cause the ill effects of aging. The first three related to cells, replace lost cells and cells that are atrophied. Next, resist cell over division. Third, remove cells that just won't die. Then we talked about mitochondrial mutation technologies and how that it might just help our mitochondria remain functional for longer. Then we discussed how clean up of the inter cellular junk with the insertion of bacterial genes can in fact do a better job than our own at cleaning up this junk and how the accumulation of it ultimately leads to things like macular degeneration, the leading cause of blindness in humans, and can also, by addressing this, prevent things like oxidized LDL which causes some major forms of heart disease.

00:00: Then we moved to discussing the remover of extracellular junk and we can use our immune system and vaccination technologies to do this. Lastly, we discussed the extracellular matrix. This seems very challenging, this matrix doesn't recycle, but we now understand the chemical links that make it that much better than before. We might just be getting closer to reducing a stiffening that happens over the course of the aging process. Decent summary?

Aubrey de Grey - 00:00: Very good indeed.

Dan Pardi - 00:00: Okay, good. Do you think we can get incremental benefit by addressing these factors individually, or do we need to address all these areas simultaneously in order to get any benefit at all, or is this a situation where once we can address each area adequately then we see real synergism that allows us to extend lifespan beyond what is currently possible and in really profound ways.

Aubrey de Grey - 00:00: It's pretty much like that. Each one of these things, it would be exception with mitochondrial mutations, has been very clearly identified as the number one driver of one or another major disease of stability of old age. For example, molecular garbage inside the cell as I mentioned is the driver of atherosclerosis. That means that for each one of these things that we develop, we can expect that that subset of people who turn out to accumulate that type of damage faster than the others because everybody has slightly different rates of accumulation of different types of damage.

00:00: The people who do that are for example the people who tend to die of heart disease before they die of cancer. A lot of people will benefit, but because these variations in the rate of accumulation of damage and variations in the amount of damage that could be tolerated before [inaudible 00:51:41]. Because those variations are relatively small, it means that the benefit will we relatively small. That we'll be able to stop people from getting heart attacks and strokes but they will die of cancer anyway only a few years later on average.

00:00: Yes, there will be incremental benefit but I really mean incremental. Whereas when we fix absolutely everything, even if we fix absolutely everything reasonably clearly just fairly well, not completely perfectly. If we access all categories reasonably well, then the benefit will be far better. We're talking definitely a few decades of [inaudible 00:52:14] rather than just a couple of years.

Dan Pardi - 00:00: Extending lifespan and compressing morbidity where we live to let's say 130 or 140 years old and importantly most of that time is with excellent health.

Aubrey de Grey - 00:00: All right. I want to jump on you a little bit there because compression of morbidity is one my least favorite phrases. The problem here is that compression of morbidity is defined as postponing the ill health of old age by X and that we're slowing death by X. Postponing death by less than X, if at all, such that the difference between the two is reduced, is compressed. I have never really been much a proponent of this. It seems to me that absolutely we want to postpone the ill health of old age by as much as we can, but having done so, the goal is simply to postpone that ill health more. The longevity of effects are just a side effect but the fact is when you are healthy and you probably don't want to get sick and die really quickly even if you happen to have been born a long time ago.

00:00: I don't know I really believe either in the feasibility or the desirability of compressing morbidity. I think we should think entirely in terms of postponing morbidity. The really good news is that this is realistic with these rejuvenation therapies that we're talking about, these damage repair therapies, because the effect of getting, let's say 30 years additional life, from therapies that I've been discussing and enumerating in this interview is that we will buy time. We will have the opportunity to use those 30 years to improve the therapy. Not only in terms of their convenience and cost control but also in terms of their comprehensiveness.

00:00: In other words, the aspect of damage that we couldn't really quite hit very well with the first therapy. Then we got away with it, we got our 30 years, but in those 30 years we develop we have to get rid of some of types of damage too. The same people, let's say he's 90, will be able to come in having been treated, let's say 30 years previously, to get rid of most of their damage, they're back to being biologically 60 because they've accumulated a lot of the difficult damage that the therapy couldn't work on. Some of that difficult damage can now be repaired with [inaudible 00:54:19] shall we call it, so they end up not having to come back for their third re-rejuvenation until they're chronologically 150 or something.

00:00: I really do not think that it's appropriate to make all this fuss about compression and morbidity. I think, to be honest, the reason that many of my colleagues are so fond of talking about it is just because people aren't really paying attention to the real science and the real prospect find it an intuitively attractive idea and they will write big checks rather than because it makes any kind of logical sense.

Dan Pardi - 00:00: I guess I say it because maybe there are unknowns that are having an effect that would be affecting our health independent of the mechanisms that you've laid out. Although, as I've heard you say before, it's becoming increasingly improbable that finding an 8th factor out of the ones listed is actually even possible. I guess it's saving room for the unknown.

Aubrey de Grey - 00:00: You go ahead, but I want to make sure that you understand we're bound to find new things that are growing wrong in the body. The thing I'm willing to say is that the overwhelming likelihood is that those new things will fit into the existing seven point classification. They will be simply new examples within the existing category which means of course by the reason I gave earlier for why the classification is useful, it means that the therapies to address those newly found examples aspects of aging will be relatively easier to develop as minor adaptations of the therapies that we've already developed with other things we did know about. Again, it may very well be that there isn't a category out there that we haven't found. I'm not absolutely betting against it.

00:00: Here's the really good news. First of all, if there really is one out there, then it's hiding very well. Maybe the only way we can actually discover it is by going in and repairing all the ones we do know about and thereby unmasking it. Certainly of course, we have the opportunity to look at shorter lived species, preferably ones that are closely related to us and apply these therapies to them too. Perhaps get a bit a bit of an advanced warning so that we see these eight categories appearing in those other animals in time before they start appearing in us so that we can start the serious business of developing therapies for them.

Aubrey de Grey - 00:00: In order to answer this properly, I have to introduce a concept that I like to call the penumbra effect. The simple direct answer to your question is nothing at all. There is nothing that we can do to postpone even by a small amount the accumulation of the various types of damage I'm talking about. As I say, that's only a simple answer. Let me tell you what the penumbra effect is. The various mechanisms that have been discovered for the accumulation of these various of damage are not just simple bang, one off phenomena, they tend to be multi set systems.

00:00: For example, cancer. Cancer obviously is caused by mutations in our DNA. Those mutations accumulate by a multi step process whereby typically for example a base is chemically modified, oxidized for example, then most of the time it's repaired. Occasionally the repair doesn't happen in time and the DNA gets replicated and the oxidized base is replaced by an unoxidized based but the wrong one. That of course is more of a problem. Even that can be repaired because the oxidized base will not be the appropriate match into the base on the other strand. Again, that can be repaired. Again, very occasionally it doesn't get repaired, the DNA gets replicated the second time and after that there is no repair mechanism for fixing it and so you're screwed.

00:00: The thing is that the probability that this multi step process actually proceeding through each of the steps is all a kind of race between the processes of repair and the other processes that the cell has to do like DNA replication. I'm just using DNA replication because we use one to explain, but the same applies to everything else I was talking about. That means that if we can manipulate things a bit, so it'll slightly speed up the repair process or slightly slow down the process that repair needs to outrun, then we will end up with less of the damage at the end of the day, in particular where we'll end up with less of the intermediates.

00:00: The intermediates turn out to matter because they themselves get in the way. In the case of previous [inaudible 00:58:56] lesions as they're often called in the DNA, that is not too much of a problem. There are other cases where it certainly is. Fatty deposits and atherosclerosis for example. It's possible by [inaudible 00:59:07] to somewhat modify the kinetics of base, the under base that I'm talking about, between repair and other stuff. The result is that it sometimes looks as though you're getting bonafide rejuvenation from these simple interventions, but you're not really getting it. You're not getting rid of any of the things that do get all the way to end of the pipeline. That means that you're not really slowing aging down. This kind of explains why we do see a certain amount of what looks like compression of morbidity in consequence of something like calorie restriction.

00:00: We do seem to see an extension of health even though we look slightly greater than the extension of life. We're doing very well and I know definitely I'm not knocking it. The critical thing to understand is the actual numbers involved, the n amount that we get. Even these interventions they may prevent certain of the more overt diseases of old age bu they don't really that much postpone the over physiological decline any more than they postpone longevity. As I say calorie restriction for example seems to extend longevity by only a very small amount if anything in humans. Sure enough people who do calorie restriction or in monkeys that have been put on calorie restriction, they look healthier for a while but ultimately if you measure things that actually accounted performance, mental acuity and so on, they don't actually have much of a [inaudible 01:00:25].

Dan Pardi - 00:00: Okay. Are we talking about the average effects of groups or populations versus the potential effects for a given individual? We certainly know that there are things that we can do that make us age faster by acquiring chronic disease and therefore there are things that we can do to help us age more slowly by avoiding those things. We can age better, we just can't necessarily, by doing the right things, age significantly longer because it's going to catch up with us in one way or another. The real excitement for better aging which is being much younger much later is yet to come.

Aubrey de Grey - 00:00: Correct, yes. Let me perhaps elaborate a little bit. I'm talking about the individual and about populations, but I am specifically talking about the difference between a reasonably well behaved lifestyle, the kind of living the way your mother taught you to, versus something particularly exotic that might be very unusual and most people might not do that might be hunched to do better. What I'm saying is the difference between those is always very small, certainly in terms of life span and really also in terms of health span. Whereas, I think what you are leading to a moment ago, is the opposite difference, the difference between behaving the way your mother told you to and behaving the way most Americans do for example, being overweight and smoking and such like. Yes, absolutely. The things that have been known for many decades to be bad or are indeed bad for you and can substantially shorten your health span and your life span. I wasn't referring to those.

Dan Pardi - 00:00: Right. I'm always very interest to explore, if you're trying to be healthy, what does that mean? Fasting has becoming certainly more popular and the different techniques that are being used to implement that into a person's life seem practical for many. Some of the benefits for calorie restriction appear to transfer from occasional fast into real health [inaudible 01:01:58] whether it's looking at biomarkers in humans and in animals into actual longevity.

Aubrey de Grey - 00:00: There's another thing I ought to point out about this actually in respect specifically in human intervention of this kind which is that we never have the control information. People virtually never have any kind of baseline, what kind of state they were in before they started calorie restriction for example. Also we have to look at the question of who does this, it's a self collected group. Sure enough, it turns out that the people who find calorie restriction easier to actually do are people who didn't eat very much in the first place. Sure enough, the people that would have the least likelihood of benefit from all of this. It's a little bit difficult to interpret.

Dan Pardi - 00:00: Yeah. That makes sense. That makes sense. I guess it's good news for me because I like [inaudible 01:02:45], so maybe I could stay on the benefit. All right. The second part of that question, is there anything that is on the horizon that you feel is pretty exciting?

Aubrey de Grey - 00:00: Yes, I do. Of course it comes back to the seven point plan, the divide and conquer strategy. A number of the things that really matter, does it really going to make the difference are indeed on the horizon. I already mentioned how the elimination of senile plaques in Alzheimer's disease is basically done. It's been all the way through it's phase three clinical trials. Even though you read the headlines first clinical trials we're unsuccessful, that's only because the clinical trial end points were defining terms of actual cognitive performance with overall effect on Alzheimer's rather than on the actual target, namely the elimination of amyloid. Similarly stem cells, stem cell therapy are moving into the clinic and clinical trials all over the place.

00:00: If we look at specifically aspects of stem cell therapy that are relevant to aging, a great example I'd like to mention is Parkinson's disease which is a disease much more easy to define and describe than Alzheimer's. It's caused by the loss of cells in just one particular part of the brain, particular type of cell, and even 20 years ago, there were some sporadic success in treating it with stem cells. They were sporadic but really sporadic is basically because we didn't know very much about how to manipulate and pre program these stem cells in the lab before injecting them. Now it's crosses a great deal of more information and expertise in that area. Sure enough, they've looked pretty optimistic and new clinical trials are underway right now. I'm certain they're very optimistic, but we could be talking about finding finally a cure of Parkinson's disease fairly soon.

Dan Pardi - 00:00: That's very exciting. Also, younger blood transfusion. I read an article recently about how Peter Thiel who's a supporter of SENS is optimistic about this. Do you think that that is a near term target that we can be excited for and do you think also that the type of blood that would be transfused needs to be matched to the individual?

Aubrey de Grey - 00:00: Yes, it's very exciting. It would very much be a stop gap, but it's exciting. The matching is not a big issue. It's a little bit of an issue maybe, but it's not a big issue because the idea is not to actually infuse the whole blood from other individuals, younger individuals. The idea is to get rid of all the cells and only put in plasma. That does not mean to get rid of most of the stuff that is specific to the individual and likely to accompany the attention of the recipients of the input. The idea here is that there is stuff in the blood that is problematic in older people. Therefore, if we can replace some or all of it, some of it anyway, with younger plasma then that'll be great.

00:00: The question of course then arises why is older blood more messed up, more lower quality and the answer [inaudible 01:05:17] must be because either cells in an older individual are pumping bad stuff into the old blood or cells in the older individual are failing to extract bad stuff from the blood or putting less good stuff into the blog. These are obviously not mutually exclusive. I have lot of work going on now to try to figure out what those actual active ingredients really are. There is still a lot of dispute about that actually because it's a hard experiment to do, lots of controversy exist in the field, but it's a very large field. A very, very active one.

00:00: As you say, a lot of people are coming to a conclusion that they don't want to wait for that research to actually come its logical conclusion and identify factors, they want to just [inaudible 01:05:58] that and use plasma whatever it may or or may not contain and see what happens. That's great. I think that even though these things are in many cases no by a means all the way through regulatory approval, of course things are being done in clinical trials, things are also being done offshore. This is all going to be data that people are, of their own volition, to think to obtain on themselves and with a bit of luck, that data will accelerate the path towards identifying the right factors so that the whole thing could be done much more cheaply and conveniently and indeed more effectively in the future.

Dan Pardi - 00:00: Do you have a potential dialysis like situation? What is the time interval that's currently being researched in how often you need to get these sorts of transfusions?

Aubrey de Grey - 00:00: Wide range as far as I understand it. Sometimes people are just looking at single one off transfusions. Of course it's not just the time range, the frequency, it's also the amount that you put it. Some people are looking at quite small amounts of the own person's plasma, some people like no amount at all.

Dan Pardi - 00:00: Let's finish by discussing your organization. The SENS, S-E-N-, Research Foundation, and how people can get involved to support your work. Aging research is woefully underfunded. What can someone do who wants to participate and get involved?

Aubrey de Grey - 00:00: SENS Research Foundation is the organization that's been created around my work that is spearheading the development of these therapies. We are a public charity 50123 based in Silicon Valley, California. Most of what we do is by medical research. We also have an education initiative. We organize internships both in our own facility and elsewhere, but that's a relatively minor component of what we do. Mostly, we have a 3,000 square feet amount of space where we do a couple of our major projects, and we also fund research projects in the university laboratories mostly in the US to different [inaudible 01:07:46]. I mentioned earlier that we tend to prioritize work that had not been done by other people because it's difficult to other parts with that cell criteria. Really, we essentially cover all the bases of science.

00:00: Yes, we are far too small, budgeted only about $12 million per year. If we had even one more zero on the end of that, I believe that we could go at least three times faster. We can be appreciating in the science much in a manner that is only limited by how difficult the science is rather than by how many dollars we can spend and we're talking about perhaps as much as a decade of delay that's currently being risked in terms of the eventual arrival of these therapies which if you do the arithmetic comes out to something in the region of half a billion lives that would be unnecessarily lost. We're a bit upset about that. We're doing our very best to get as much money in the door as we can. If you go to our website sens.org, that's sens without the E on the end, S for sherbet, E for elephant, N for November, S for sugar, dot O-R-G. That is where to go if you want to give us more amounts of money. There's a nice big friendly donate button.

00:00: Also, of course we are ultimately in need of live donations and anyone who happens to be interested in doing that would be very welcome if they would get in touch. Of course anyone who knows anyone who they think might be able to get interested in doing that, the same applies. Anyone who does a podcast should do exactly what you're doing right now [inaudible 01:09:06]. The ultimate thing here is that as this is moving forward, we are increasingly being able to transition project after project into the private sector into startup companies which of course in many ways is much easier to attract funding for because funding can come from people who want to invest but who are just generally disinclined to [inaudible 01:09:28].

00:00: However, it's absolutely essential to emphasize that we're still at the point where a number of the projects we absolutely believe are vital to the eventual success of SENS are too early stage for that to be a viable approach. Therefore the status of SENS Research foundation has, if you like, the engine room of the creation of the rejuvenation biotechnology industry. That status is unchanged and we absolutely vitally need more money. I can say that this whole line of thinking has somewhat borne fruit recently in the sense that a wealthy IT professional from Germany named Michael Grieve, is inclined enter us and commit $10 million to our mission. He totally understands this juxtaposition between the non profit and full profit aspects of it. What's he's done is he's provided us with a commitment for $5 million of those dollars to the foundation itself at 1 million a year over the next five years and the other 5 million to go into startup companies that are taking these projects forward.

00:00: One thing I should also empathize however is that Michael very sensibly is interested and encouraging and incentivizing other people to do the same as he has done whether on a larger scale or a smaller scale or any scale. Therefore he has stipulated that the $5 million dollars that should be spent on with the foundation should be spent at matching money, in other words, every dollar is only released to the extent that another dollar comes in from somebody else. We are very actively looking for those additional dollars from other people.

Dan Pardi - 00:00: SENS is an organization that addresses the gaps in aging research. It serves as an incubator for promising but underadressed ideas. It does research and even supports research at other institutions and even spends off promising businesses that are developing therapies for the marketplace. If you're a wealthy individual or organization who cares about the stuff we discussed today, the single most important issue facing humanity and interested in making a serious impact here, this is the time and this is the place to go.

Aubrey de Grey - 00:00: I just want to add one thing down there which is of course the whole thing is predicated on the new philosophy like this fourth wave of gerontology that exceeds all the three full storms I mentioned earlier on. The idea that the real way to fix aging is to develop rejuvenation biotechnologies, damage repair strategies. This is an idea that I put forward maybe 15, 16 years ago now, but that's not a very long time in the acceptance of scientific paradigm shifts. The fact is it's still very, very early days in terms of getting this out there to the extent that it will be pursued in the mainstream, as such every dollar makes a huge difference.

Dan Pardi - 00:00: Incredible. There are a few places where the money you donate can have such a massive impact dollar for dollar. I am not involved with SENS. Aubrey has not asked me to help fundraise in any way, but to the listeners out there, share this episode with your friends and family and consider finding the donate button on their website which I'll link to in the show notes. Aubrey, thank you for coming onto the show. Thank you for your work. It's so exciting to think we're on the precipice of a world changing innovation and betterment. You're a critical piece to the whole of making it happen.

Aubrey de Grey - 00:00: Thank you very much for having me on the show. It's been a pleasure.

Kendall Kendrick - 00:00: Thanks for listening and come visit us soon at humanos.me.