Welcome and Guest Introduction

0:00

Welcome to the Healthy Brain Toolbox. I'm Dr. Ken Sharlin, neurologist, and host for this show. In each episode, I interview influential people whose work impacts how we live and how we think. My guests are leaders in the health and fitness industry, physicians, scientists. Here, you'll find conversations that expand your horizons, and give you the tools you need to protect your health and nourish your aging brain.

Dr. Ken Sharlin 0:29

Welcome to the Healthy Brain Toolbox. I'm your host, Dr. Ken Sharlin. Today, I'm delighted to welcome Dr. Aubrey de Grey, of the world's most provocative and influential voices in longevity science. Aubrey is a biomedical gerontologist, president and chief science officer at the Longevity Escape Velocity Foundation, and co-author of the groundbreaking book, "Ending Aging." He earned his PhD from the University of Cambridge and is best known for developing the concept of strategies for engineered negligible senescence, or SENS. For decades, Aubrey has challenged the conventional belief that aging is inevitable, arguing instead that cellular and molecular damage responsible for aging may eventually be repaired. His current research focuses on combining

Dr. Aubrey’s Journey into Longevity Science

Dr. Ken Sharlin 1:29

rejuvenation therapies to extend healthy lifespan, including the ambitious robust mouse rejuvenation studies. But today, we'll explore whether aging can truly be reversed, what the science tells us so far, and what the future of human longevity might look like. Aubrey de Grey, welcome to the Healthy Brain Toolbox.

Aubrey De Grey 1:55

Thank you for having me

Dr. Ken Sharlin 1:58

Dr. de Grey. Aubrey, you originally trained in computer science, not medicine or biology. Can you tell us a little bit what led you to become interested in aging and what you saw that convinced you that we were approaching the entire problem from the wrong direction?

Aubrey De Grey 2:17

I guess I should probably answer that in three parts. Firstly, how I got into computer science in the first place. That happened because when I was a kid, I came to the conclusion that I wanted to make as much difference to the world as I could. And when I was 15, I started to write software and found that I was pretty good at it. So I thought, okay, the thing that I am best equipped to contribute to is the problem of work. The fact that we have to spend so much of our time doing stuff that we would not do unless we were being paid for it. And so I went into that area. I did my undergrad degree in computer science. I worked in AI research for several years, because if we have automation, then we don't have so much work to do. And that was all very fine. But as I say, I was driven by the humanitarian motive of just helping people. The reason I did not go into the biology of aging earlier was not because I thought aging is less of a problem than work. Definitely it's much more of a problem. I certainly knew that. What I didn't know was that biologists were not thinking that way. I had completely assumed that biologists thought the same way about aging that I thought about work. It was only after I met and married a biologist while I was an AI researcher that I found out that wasn't true. We're talking about the early 1990s now. She was already a full professor at UC San Diego. She was in England on sabbatical. I met a lot of other biologists through her, of course, and I found that the same was true. And I was absolutely horrified. It was a complete bombshell. And after a couple more years of coming to terms with that, I decided I've got to switch fields even though I didn't know much biology. I knew a lot more biology by then over the dinner table through my wife, but that's all. I thought one of the reasons I thought that I should potentially be able to make a difference is that I would be coming at the problem with the mindset of an engineer, someone who had been trained in an engineering discipline. And I saw by that time that most biologists didn't think that way. And so I thought maybe I can,

SENS: Repairing the Damage of Aging

Aubrey De Grey 4:22

look at things in a different way. Certainly there's a long history of people, switching fields and making big contributions. The best example is that the whole of molecular biology was invented by a bunch of physicists back in the 1950s. So I thought I got a chance of making a difference, and so that's why I switched fields. Sure enough, it was true that five years later, after I'd spent a bit of time learning stuff and meeting people and going to meetings I had this kind of eureka moment in the year 2000 realizing what everybody was missing. Essentially, that it was gonna be a lot easier to reverse aging than to slow it down, which sounds really counterintuitive at first, but when you think about it, it makes perfect sense because if you start thinking about the body as a machine, which it is as something whose function is determined by its structure, then you can think okay, what do we already successfully do with simple man-made machines like, cars or airplanes or whatever? And of course, what we do is preventative maintenance. They accumulate self-inflicted damage in the course of their normal operation they get rust and so on. When you take your car into the shop, they don't just do something to slow down the rusting. They actually just scrape off the rust. It's the same with everything else in preventative maintenance. So once I saw that this was what everybody was missing, this seemed to make immediate sense to me. I had to flesh it out at that point into, specifically what kinds of damage do we want to eliminate from the body? How might we go about doing that? And that's what my work has been about ever since.

Dr. Ken Sharlin 5:55

I suppose they're not necessarily mutually exclusive either, slowing the aging process and repairing damage of aging?

Aubrey De Grey 6:05

That's absolutely right. They're definitely not mutually exclusive, but we have to take into account how much contribution each of the two things can make. So if we're taking people who are already in middle age. In other words, they're not sick yet, but they're not very far away from becoming sick. Then, slowing down the remainder of their aging is not going to benefit them very much as compared to somebody who does some age retardation thing throughout their lives. But secondly, and perhaps more importantly, it turns out that slowing aging down is very much harder to do than damage repair. as demonstrated by the fact that by the time I came along, people had been trying to slow aging down for a century, and they'd got absolutely nowhere. Essentially, the creation of these various types of molecular and cellular damage in the body is too inextricably intertwined with

Lifestyle vs. Longevity Medicine

Aubrey De Grey 6:58

the things that the body needs to do to keep us alive from one day to the next. Making it do one but not the other is just not happening.

Dr. Ken Sharlin 7:07

I'm thinking about the clinical application here and how practitioners like myself integrate both lifestyle medicine as well as principles of regenerative or anti-aging medicine. I see them as complementary. I always refer to the gentleman who actually has died. He made a movie called "Supersize Me," ate McDonald's food for a month, and nearly killed himself from the metabolic changes he inflicted on his body. And we know that from numerous studies, everything from exercise, influences aging, influences inflammation, oxidative stress, and so forth. Food, an anti-inflammatory diet, restorative sleep and the lymphatic system and other, repair aspects of sleep and so forth. So it seems to me that we can maintain the vehicle as best as possible and then repair the parts.

Aubrey De Grey 8:04

Yeah, so a couple things to say about that. First of all, I do want to clarify that when I said reversing is easier than slowing, I was talking about dramatic slowing. If we want to get people out to 150 or 200 it's gonna be far easier to do that by preventative maintenance than it is by slowing aging down, especially if we want to do it to people who are already in middle age before we start. I was not referring to what we can do today. What we can do today, the situation is very different because we do not have anything remotely approaching a comprehensive set of tools to do preventative maintenance, damage repair. That's why I have a PhD, not an MD for that reason. I'm doing research, right? And so if we look at what we can do today, then absolutely, people ought to be optimizing what they can do. However, the other thing I want to emphasize here, and you know this, but I want to really put it forward to your audience. Is that we should not be talking necessarily about comparing optimum lifestyle and diet and with a bad lifestyle and diet and so on. Everybody knows that there are plenty of easy ways to shorten your life. Whether it's smoking, whether it's only eating at McDonald's. Whether it's getting seriously overweight or having a very unbalanced diet, everyone knows that. But the comparison that we ought to be making is between the optimum diet versus just basic things, living the way your mother told you to. My claim, and it's not just my claim. Is that the difference between those is very small, that the amount that you can do by sophisticated modern methods over and above what you would already get just by living the way your mother told you to is pretty tiny. Not nothing, but pretty small. So I definitely don't disapprove of it, but I feel it's always very important to put into everyone's mind that it's not the Holy Grail, and that the only way one's gonna make a big difference to how long one can stay healthy and therefore, as a side effect, how long one lives total is by benefiting from medicines that don't yet exist.

Dr. Ken Sharlin 10:10

In the hopefully hypothetical near future

When Should Rejuvenation Begin?

Dr. Ken Sharlin 10:13

where all of this has entered our clinical toolbox.

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Dr. Ken Sharlin 12:12

Where do you see this starting? Aging arguably is something that happens in utero, right? From the time of birth, growth differentiation, childhood to adulthood. At what point should we be thinking about this in your mind?

Aubrey De Grey 12:29

Yeah, I always point this out that aging starts before we're even born. But the beauty of damage repair is that it works just as well if you start when there's a lot of damage as it does when there's hardly any damage. In fact, for a machine that accumulates damage so slowly as the human body especially in today's world where we're making rapid progress in developing better and better medicines, it actually makes sense not to take advantage of damage repair approaches once they exist until one is in middle age. Because if you're, let's say, 20, you haven't got much damage yet, you're not gonna be suffering from any kind of consequences of that damage for another 20 or 30 years at least. In that time, the treatments are gonna get better and safer and everything, so you'll be better off waiting. That applies irrespective of where we are on that trajectory of developing these things.

Dr. Ken Sharlin 13:27

Are we talking about what I'll call healthy aging? Look, the two of us, we both have a little gray hair. Mine's a bit shorter than yours is. We probably have a few extra lines on our face that reflect aging and skin damage. And I'm not even talking about my insides, but knock on wood, I don't have any chronic conditions. I don't have heart disease, I don't have diabetes, high blood pressure, et cetera. versus say I have a scenario in my clinic that's not unusual. The adult children of the patient bring mother or father in. They have pretty

What’s Working in Longevity Science Today

Dr. Ken Sharlin 14:06

advanced dementia, the patient, right? And it's like fix mom or dad. What tools are available right now, even in my clinic, where I'm an outside-of-the-box practicing clinician early intervention does make a difference.

Aubrey De Grey 14:21

Don't get me wrong, of course it does today. Early intervention the most popular science fiction in the post-aging arena the blockbuster movies have a huge problem. They are overwhelmingly dystopic in one way or another. They somehow try to entrench this crazy irrational concept that aging is some kind of blessing in disguise, and that we would have some terrible problem if we didn't have aging. So yeah, in that sense, science fiction is a big part of my problem

Dr. Ken Sharlin 14:50

I know you've thought a lot about how things are sequenced, and that's something that I do in the clinic as well. I have a lot of folks approach me and say, "Should I get stem cells? Should I do senolytic therapy? What do you think of peptides?" And we can talk about all of those things individually, but I think the idea that rejuvenation and repair really has to go in some sort of sequence is important, and it seems to have become very much at the core of what the work that you do.

Aubrey De Grey 15:24

I'm not really sure quite what you mean. I don't think about it as sequenced. I think each of these types of damage as something that we can address independently, even though the mechanisms by which the damage is created in the first place may be overlapping. You've got certain types of waste product like oxidized cholesterol or modified vitamin A in the eye that drives macular degeneration or you've got, the accumulation of senescent cells or the accumulation of crosslinks that reduce the elasticity of the extracellular matrix. All of these things are distinct, distinguishable types of damage, and I don't really think it matters which order we fix them in. We've just got to fix them all.

Dr. Ken Sharlin 16:06

So we talked though about preparing the soil. I certainly believe that different types of regenerative cellular therapies are very much part of the future, whether they're cells themselves secreting exosome signals, whether the exosomes or some combination. But would it make sense, for example, to start with senolytic therapy then say introduce these regenerative tissue therapies?

Aubrey De Grey 16:34

okay, now I'm seeing where you're going with this. Yes, the short answer is maybe. There will be certain cases where we can theorize that removal of one particular type of damage will potentiate the efficacy of a method for removing another type of damage. I'm all for exploring those things and optimizing things by sequencing of things. But in general, it's probably not gonna be very true,

The Debate Over Therapy Sequencing

Aubrey De Grey 17:00

let's use another example. Stem cells often when applied or exosomes for that matter, but especially stem cells, when injected, will often have only a very short-term benefit, even if they are autologous simply because they are essentially inactivated or reduced in their efficacy by the environment, by the fact that the cells around them are not doing this. This has certainly been demonstrated quite clearly in the blood, hematopoietic stem cells after bone marrow transplant. If they come from a young individual, they still don't necessarily work very well if they're put into an old individual because the stem cell niche, the other cells around the, where they engraft are essentially crippling them. Whereas conversely, stem cells taken from an old individual, if they're put into a young recipient, they start becoming more youthful in their behavior. Then we may say, "okay, maybe there's a treatment that can rejuvenate the stem cell niche first, and then we can do our stem cell therapy." But equally, one could say, "let's just put a lot of stem cells in." A lot. And then they can rejuvenate the niche themselves, by just sheer mass action. Indeed as you mentioned, exosomes there was a very high-profile report last year of a group that achieved very substantial life extension in rats using exosomes more than anyone else has been able to achieve in the past. And it was only a small study. You have to be a little bit cautious, but let's take it at face value for the moment. One thing that was particularly distinctive about that study was they used a really high dose of exosomes, like an order of magnitude more than anyone else had ever used. May be that was the key

Dr. Ken Sharlin 18:42

Can we break some of these down, some of these other strategies as well? What are your thoughts about senolytic therapy? Where are we with that? I've been interested in dasatinib with quercetin or fisetin. It's accessible, it's relatively inexpensive it appears to be safe. What are your thoughts there? Would there be more promising senolytics?

Aubrey De Grey 19:04

Yeah. So this is an area which has exploded over the past few years. And it's also an area which gave an enormous amount of boost to optimism of people like myself, even before senolytics per se were being explored. I'm now talking maybe 15 years ago when the first genetic models of senolysis were developed, in which mice had been genetically engineered so that you could kill them easily without an actual senolytic per se. It could kill the senescent cells. The health benefits to old mice that had a lot of senescent cells were much more widespread than anyone had really expected. So that was very good news. But when senolytics came along a few years later, of course, yes everyone's very interested. I would say that the senolytics that we have in this kind of first generation, such as the ones you mentioned, are promising up to a point, and they certainly seem to have a good safety profile, which is no surprise. They've been used for other purposes for a long time. But their efficacy is somewhat debatable. There's a lot of concern in the field about reproducibility in the lab, I'm not talking in the clinic. However, they're promising enough that there are clinical trials happening. The Mayo Clinic is definitely doing a trial right now on DAQ, and so that's all great. However, what my major interest is in this area is new senolytics, ones that have been developed only over the past few years and that work by different mechanisms. It's early days. we can't really make definitive statements yet. But my gut feeling, my overall impression is that there are now several ways to get rid of senescent cells that are more selective and more effective. They get rid of a higher proportion of those cells than what we had before. Therefore, senolysis is basically a solved problem at this point. That second and third generation senolytics are gonna, totally that's gonna be the end of senescent cells

Dr. Ken Sharlin 20:57

Would you consider that a preparation strategy?

Aubrey De Grey 21:01

I guess let me say yes and no. On the one hand, no, it's not preparation. It's just removal of one type of damage, the

The Latest Progress in Senolytics

Aubrey De Grey 21:08

senescent cells, which are definitely a type of damage that was always one of my categories from the very beginning. On the other hand, one could say yes, in the sense of the crosstalk between different types of damage. If you remove one type of damage, then you are relieving the pressure on the body. The body obviously has this enormously sophisticated arsenal of mechanisms to minimize the rate of accumulation of every type of damage. That damage limitation machinery is itself impaired by the presence of damage. So if you remove one type of damage, you're gonna allow the damage limitation machinery to work a bit better on all the other types of damage, and you expect to see global benefit, kind of knock-on effects. That's really the basis for what I was mentioning about these original genetic models of senolysis from 15 years ago. So yeah, in that sense it's a preparation, but then you could say, any damage repair of one type is a preparation for all the others. Perhaps that's not the most enlightening way to put it.

Dr. Ken Sharlin 22:06

That's fair. How about our old friend rapamycin? it's been around a long time now, and it withstood the test of time? Is there still interest in rapamycin?

Aubrey De Grey 22:17

Rapamycin is a calorie restriction mimetic, and there are plenty of others. But rapamycin seems to be the best, the gold standard one that achieves the greatest amount of life extension in mice and so on. The mechanism of action is fairly well understood, especially the fact that there are two complexes, mTORC1 and mTORC2, that are both inhibited by rapamycin. One of them, seems to be the mechanism why it extends life in mice. The other seems to be something you don't want to do because it impairs the immune system. And indeed, what rapamycin was originally used for, to modulate the immune system. That has led to some fantastic research that very rapidly identified rapalogs, analogs of rapamycin that selectively inhibit mTORC1 and not mTORC2. Those are still making their way through the clinical trial process, but that's the future of that. However, when you ask me, how important is this? I have to be very careful because calorie restriction itself was discovered a century ago to extend lifespan of mice and rats. But the thing is, it's been known for decades that there is an enormous gradient of efficacy across species with calorie restriction, that you can get vastly greater proportional increase in lifespan in really short-lived species like, nematode worms, and conversely far less proportional increase in lifespan in long-lived species. If that's true for calorie restriction itself, then it's also gonna be true for any calorie restriction mimetic, because what a calorie restriction mimetic does is it simply activates the same metabolic, reprioritization, shall we say, metabolic tweaking that calorie restriction itself does. So yeah, I'm fine with rapamycin and similarly with, NAD precursors and metformin and so on these are better than nothing, but they're only a very small amount better than nothing for human beings because we already live so long. And the thing is, this is not even arguable. We've understood why this is for a long time. It's a straightforward consequence of elementary evolutionary gerontology. We just take into account the fact that long famines in the real world do not happen as often as short famines, and therefore there's less selective pressure to be able to optimize one's metabolism to respond to them. It's not a surprise. And this was rather aggressively swept under the carpet for a painfully long time by most of my colleagues. I wrote a paper on it 20 years ago when I realized how much it was being

Rapamycin, Caloric Restriction, and Their Limits

Aubrey De Grey 24:44

not said. But now, yeah, people are becoming more clean about that, and they recognize that this is really not the Holy Grail. It's better than nothing, and we can do it already, which is definitely a good thing, but it's not the Holy Grail

Dr. Ken Sharlin 24:56

Most definitely. But there's certainly been a very long history of research and demonstration across species on the effect of aging. Then, we have Longo's work with the fasting mimicking diets. We can compress that period of calorie restriction down significantly and still get remarkable results, at least clinically in human beings. In other across species. His predecessor is somebody that, whose life interested me quite a bit, Roy Walford, and I don't know if you would've crossed paths with Dr. Walford at all.

Aubrey De Grey 25:31

Yeah, very sad I never met Roy. I wish I had.

Dr. Ken Sharlin 25:34

Truly remarkable human being, and I found it somewhat ironic that he would've died of ALS.

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Dr. Ken Sharlin 27:43

But on the other hand, in studying his biography, which I did, he lived about, about 11 or 12 years with the disease, certainly more than, a little more than 10 which of course is possible with ALS, but it's very much the exception, and then doing some writing about Walford, I even raised the question of whether or not perhaps his experimentation on himself may have extended his life in the face of that disease

Aubrey De Grey 28:13

I think that's the general consensus, in fact. You're quite right about his history coming down with ALS not long after his experience in Biosphere 2 possibly causal. And the fact that he did survive for unusually long with the disease. I think most people would say cryotherapy probably helped him in that. However, that's not what we're really talking about when we ask, is that the way to go in for the general population? Are we going to postpone health, extend health span and lifespan in the way that we do with short-lived species? I think there the answer is pretty clearly no. But again, as I say, we may get a little bit, and we may get more health span than lifespan, which again, it mustn't be sneezed at

Dr. Ken Sharlin 29:00

Not at all. One of the terms that comes up a lot in the world which I move is neuroplasticity. It's a broad term. It can be specific, depending on context, of course. More recently, I spent time reading about the pharmacology of psychedelics and their ability to changes at the cellular level within a matter of hours, really dendritic spine growth, and came to the conclusion that as remarkable and hopeful as this emerging class of Psychoplastogens, neuroplastogens are, they are still agnostic with respect to neuroplasticity in the sense that we can trigger this growth, but we have to tell the growth what to do, where to go, how to act, how to be. In other words you can make

Neuroplasticity and Brain Aging

Dr. Ken Sharlin 29:56

new cells, but if you're a newborn baby, you're not ready for a Cambridge University, right? You had to probably wait a few years. So my question ultimately is, how does neuroplasticity play into the model that you're promoting?

Aubrey De Grey 30:09

Yeah. It's a huge question. We know that neuroplasticity diminishes even during adolescence relative to early childhood, right? So we know that it's not exactly aging. There's also plenty of reasons to believe that loss of neuroplasticity is something that's a necessary component of maturation of the brain and achieving full function in young adulthood. that's not to say that we shouldn't restore it once we get sufficient control over how and when to restore it. And then, of course, there is the aspect that does relate to aging. The fact that loss of synaptic connectivity is definitely, the main thing that goes on during cognitive decline well before any actual cell death neuronal death. So again, it would be quite nice to be able to fix that. So then we have to ask, first of all, what's really going on there? Is the loss of synaptic connectivity a result of things that we already know we want to fix, like getting rid of plaques and tangles in Alzheimer's or getting rid of waste products inside neurons, inside lysosomes of neurons that cause them to be just less healthy? These are things that we currently can't-- the questions that we currently can't really ask, even in the lab, let alone the clinic because we don't have sufficiently powerful technologies to get rid of these things. In Alzheimer's specifically, there are plenty of mouse models of Alzheimer's disease, and you ask anyone who works on Alzheimer's research, and they will freely admit that these models are absolute crap. They have very little resemblance to real Alzheimer's disease. Even though, superficially under the microscope, there might be some similarities. What's really going on at the molecular level is nothing like Alzheimer's. So yeah, there's a huge set of unanswered questions and unanswerable questions there that will be answered only when we develop treatments to eliminate these various types of damage and see, the extent to which the brain recovers. Now, I don't want to be too downbeat about that because there are some parts of brain aging that we should be able to reverse pretty soon, and we will be able to obviously look at the consequences of that for function. One really important one that's quite high profile these days is senescent glia. So glial cells, of course, constitute 90% of the cells in the brain, and they definitely senesce. They definitely start to exhibit the same kind of gene expression changes that senescent fibroblasts or whatever exhibit in the rest of the body. And, as analytics work just as well on senescent astrocytes as they do on senescent fibroblasts. So we're probably fairly close to being able to get some answers to these questions about synaptic plasticity. But what I will say is this, synaptic connectivity is something that is genetically programmed. It's something that the cells know how to do. Therefore, to the extent that they are ending up doing it less well later in life, we may say if we give them a more friendly environment to be in, then that's probably all we need to do. We don't have to give them the instructions for how to form synap-synapses. They've already got that. Same with oligodendrocytes. Obviously myelination is a big thing in brain aging, loss of remyelination capacity. And there again, there's been great progress. It's probably 10 years ago now that, maybe more, that a group in Cambridge, Robin Franklin's group, collaborated with Irina Konoval's group in Berkeley and showed that heterochronic parabiosis causes a recovery of remyelination capacity. Of course these days we wouldn't do it. Emphasis of that kind of research angle has moved on to plasma exchange and neutral blood exchange and so on. And as of now, I'm not aware of any attempt to repeat those studies from back then with these new techniques, but that's something that I would place high value on, and I would be optimistic that it would work.

Dr. Ken Sharlin 34:12

I absolutely understand what you're talking about, but I wonder just for our audience to make sure that they understand what you're making reference to. The parabiosis studies were fascinating and there was some attempt to clinical application of that, at least outside of the United States. I think one actually was in Great Britain. There was a clinic and maybe one in Canada where you could at least receive infusions of young blood. I don't know that's really reproducing necessarily having circulatory systems sewn together, so to speak.

Aubrey De Grey 34:47

Yeah, let's talk about that a bit because I've been quite heavily involved in this work. So the original work that happened at Stanford about 20 years ago, now on literally surgically joining together the circulatory systems of a young rat and an old rat was a kind of revival of similar work that had been done in the Soviet Union decades earlier and had been basically forgotten. And it worked really well. As I say, that's how this remyelination work was done. But then after people got really excited about this, the next step was to move on to blood exchange, as you say. In fact, my foundation funded the pioneering work in that area. We

Young Blood and Plasma Exchange

Aubrey De Grey 35:27

had a fantastic guy, Justin Ribo, who worked as a postdoc with our funding in the Conboy lab and perfected the microsurgical techniques that were required to do plasma exchange.

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Aubrey De Grey 37:20

Now, specifically plasma, in other words, not the cells, right? Now, that's quite important because you're asking a very, important scientific question there as well as an important clinical question. You're asking, what is it in young blood that's good for old animals and/or what is it in old blood that's bad for old animals that you're diluting out, so to speak? This is still a very open question in which there is quite sharp polarization among experts in the field. Nevertheless, the point is it was done only with the plasma. Something else that was done much more recently was to do it with only the cells. You basically take old mice, and you give them a bone marrow transplant with stem cells taken from the bone marrow of young mice. And you do it in such a way that there's some engraftment that happens in the recipient so that the cellular component of the old mice is made younger. And sure enough, that works too. You get that extension. So there's a huge amount that we still don't know about all of this. But what we can be very happy about is that unlike surgically joining a young individual to an old individual, we do have ethically acceptable approaches to this in the form of plasma exchange and neutral blood exchange. In other words, you take old plasma out of somebody but rather than putting young plasma in, you just put water in. Not quite water. You're putting water with a bit of salt in it and one protein, albumin 'cause you need a lot of that. but basically nothing else. And that has pretty damn good effects as well. Arguably, according to at least anecdotal reports from people the effects are not as beneficial as they are with young plasma per se, and I guess that's no surprise. But nevertheless, this is really going gangbusters now. There are clinics around the world providing this intelligent, well-informed people are, early adopters. Nevertheless, they are going and paying money to get this treatment, and they are reporting the results. That's one area which is moving fast now

Dr. Ken Sharlin 39:19

It's rather exciting. I have a colleague in Nashville who's been doing that for quite a while. I understand it's not yet definitive, but certainly promising and anecdotally I've heard some great results. I wonder if it's practical in the long run. There's been a lot of interest in using this in the context of Alzheimer's disease, and as you probably know, in the US alone, 7.4 million or so currently affected, currently symptomatic. Who knows how many millions are asymptomatic developing the disease? Do therapeutic plasma exchange on all these people? How would we bear the costs and things like that? But it may be more rational than targeting the amyloid

Alzheimer’s: Rethinking the Amyloid Theory

Dr. Ken Sharlin 40:02

protein as our sole sort of monotherapy. I wonder if you could talk a little bit about that. Our patients sometimes wonder, "Why isn't my memory getting better?"

Aubrey De Grey 40:13

Yeah. So the whole amyloid debacle has been a one of the biggest embarrassments of the whole medical industry for God knows how long. And when I say the medical industry, I include research here, because essentially the fixation on the idea that removing amyloid plaques would be the number one route to curing Alzheimer's disease was driven by extraordinarily over-dogmatic beliefs of a very small number of strong personalities who happen to have a lot of power in the research community. At the expense of research that could have been done but couldn't be funded because of the influence of these people in alternative approaches. Now The result was that billions of dollars were spent by big pharma developing immunological approaches to remove amyloid, and the effects were distinctly underwhelming as you mentioned. However, what's even worse is the backlash that now, there's been an almost universal tendency to say okay, this means that amyloid doesn't matter at all." Which is complete nonsense for two reasons. First of all, it's nonsense because amyloid plaques don't appear out of thin air. They appear as a result of a sequential process of A beta monomers aggregating together into oligomers and then eventually into fibrils and plaques. And there's plenty of good evidence, which is now widely accepted but not as widely publicized, that the oligomers are the real problem, that they basically distort. They make cell membranes more permeable in bad ways, things like that. And so getting rid of the oligomers with the same kind of approach, an antibody-based approach, could be perfectly fine. It could actually genuinely be a good way to go. The other thing is that we don't yet even know that plaques are harmless, because it could be very easily that Alzheimer's being this obviously rather multifaceted disease, which was defined as having these two types of aggregate plaques and tangles just we need to do multiple things. And doing a subset of, doing only one of those things is not going to have appreciable benefits because the other ones are doing just as much damage and causing just as much functional decline on schedule, so to speak. So I think the fact that we have methods to remove amyloid plaques in our back pocket is a piece of progress that needs to be revised as and when we get similar ways to remove other types of damage in the Alzheimer's brain. On top of that, the very extensive work that was done to remove amyloid plaques can be repurposed with only minor modifications. To remove other types of amyloid that occur elsewhere in the body. For example, a lot of people don't know that in the later stages of type 2 diabetes, you get a type of amyloid in the pancreas, which is really important in the death of beta cells. It's called islet amyloid. It's been known for a long time, and it's been almost entirely ignored. There's been like two research groups working on getting rid of this stuff. but the approach that had worked so well, though not clinically well, in terms of amyloid in the brain, can totally work elsewhere. We funded a group a decade ago working on another type of amyloid, which is in the heart and is formed by the protein transthyretin, whose physiological function is to transport thyroid hormone around the body. It aggregates also everywhere, in fact, but especially in the heart. Seems to be a very major cause of death in the extreme elderly people who get to 110 years old. We funded it. There's some work that developed antibodies that can crunch it up

Dr. Ken Sharlin 44:01

Yeah. A lot of people may not realize the two currently FDA-approved drugs for Alzheimer's, the anti-amyloid therapies, actually have slightly different targets, right? Donanemab targets those mature amyloid plaques, whereas lecanemab in fact does target the protofibrils, the perhaps more toxic of the two. It is interesting that clinically the outcomes of the main clinical trials were more similar than different. I have used both. I was on the trailblazer to ALZ, which is the phase three trial actually despite its title. And my site was a large enrolling site, so I have a fair amount of experience on top of what I do in the clinic. But I have whether rationally or not, decided that when my patient might come to me with more advanced, but I certainly still mean within that sort of early stage Alzheimer's disease, but lower scores on cognitive testing, a little higher burden, whether it's of amyloid plaque or the p-tau 217 as an, as a indirect measure, if you will, of that. If and if they're older, I might say use donanemab. If they're on the younger side, relatively speaking. 60s with Alzheimer's disease, for example, their plaque burden is a little bit lower. Their cognitive function's a little bit better. I will tend to use lecanemab. I look at it as the long game with them and hope that we can also layer in other therapies such as, I have personal interest in what we're gonna see with phosphodiesterase inhibitors but I'm anxiously awaiting the results of a completed clinical trial from a South Korean company called Erybio. But I think it's gonna be confirmatory. And again, what I've seen in the clinic on a just a case series basis has been just stunningly remarkable.

Aubrey De Grey 46:06

Yeah. I applaud all of this. I think people like you who are at the cutting edge of the administration of existing treatments are going to be providing invaluable information that will hasten the development

AI and the Evidence from Case Reports

Aubrey De Grey 46:22

of treatments that work better. I always say that one thing the medical profession doesn't do nearly well enough is case reports, essentially, is getting and aggregating information on what they're doing and what's working. And this is becoming even more of a problem or of a priority in the world of AI. Because what we have with AI is the ability to discern really subtle patterns in large quantities of data, right? That's basically what AI does. And that's exactly what we have here. At the moment, there is still this dogma within the medical profession that really nothing matters except for randomized controlled clinical trials with, all the exclusion criteria and uniformity of patient population and so on. That is no longer justifiable at all, I believe. I think that the ability to take n of one studies, whether it's patients from credentialed people like you, or whether it's people who just self-administer something or other. You can take those studies if they've been done in a manner that gives good information having good baseline measurements of this or that. And just aggregating all that data. It doesn't even have to be in any kind of uniform format, aI doesn't care about that. truly good, valuable information and suggestions about what might be the next direction to go in can come out of that. And the, deprecation of that kind of data that exists within the medical establishment is hugely counterproductive, I believe.

Dr. Ken Sharlin 47:56

Dr. Duray, I know we're about to wrap up. We're running out of time. I want to look a little into the future and an area I'm perhaps wondering if you're using or you're beginning to put the pieces into place. It certainly excites me tremendously, is this idea of the digital twin

Digital Twins and the Future of Medicine

Dr. Ken Sharlin 48:16

and how we can use that type of technology to really advance things quickly and to provide, truly individualized predictive care to patients

Aubrey De Grey 48:26

I have hopes for this, but the thing that I really have... I feel unable to form a strong opinion on right now is the timeframe for when that kind of approach is gonna become truly useful. The whole concept of a digital twin is really. First of all, different people mean different things by what they, by that term, right? So essentially, if we define it using the language of medicine in general, then I would say it's really the next level of personalized medicine. It's the next level of identifying what works for one person and not for another. So then the question is what's different than, someone, a human being like you diagnosing things and, making the appropriate measurements to decide what drug to diagnose or to prescribe. The real difference is that simulations, computer simulations can potentially be more informative, can have better granularity, if you like, in terms of identifying things. But then what is required for them to actually have better granularity and not just, do more harm than good by a lot of false negatives and so on? And that's where I haven't yet been able to form an opinion, because honestly, we just don't know how accurately, how precisely we need to be able to instruct a digital twin, to create one. How much, what granularity of data we need, what kinds of data we need, so a digital twin does actually behave in a manner that is predictive of how the actual person's gonna behave. I think my gut feeling is there's still a few years to go before we can start using digital twins as a fundamental major tool in medicine, but I would love to be wrong, and certainly I know plenty of people who are trying to prove me wrong,

Dr. Ken Sharlin 50:17

We're trying to figure it out here. I don't have the skillset to be in the lab. I always said you should be glad that I'm not a carpenter, because if you hand me a hammer, I'll probably be more likely to break something. But my strength is in the clinic and willingness to explore within reasonably evidence-based parameters meaning I don't necessarily have to wait for the completed phase free trial, but first do no harm, of course.

Aubrey De Grey 50:44

Since we're wrapping up, let me say something that you may find more provocative than anything else I've said so far. I think that the whole concept of first do no harm is doing enormous harm. That it was absolutely the right way for the medical profession to be thinking in the time of Hippocrates, but it's not the way that medics should be thinking these days. If you think it means, what is the concept of harm in medicine? Harm means essentially giving somebody a disease when they didn't have it before.

Rethinking “First, Do No Harm”

Aubrey De Grey 51:17

And, the opposite is getting rid of, curing someone with a disease that they did have before, right? Now, the point then is that if somebody doesn't have any diseases, if they're healthy, then you can't do good by the medical definition of good. You can only do harm. So even if the probability of doing harm is really small, it's not zero, and the probability of doing good is exactly zero. So essentially, the dictum first do no harm is synonymous with preventative medicine is a bad thing, right? That's a problem because every medical student gets taught first do no harm in their first day of medical school. I believe that this is not just semantics. This is a genuine practical significance in making it harder for the medical profession to embrace preventative medicine, even though they know in their heart of hearts that it's a good thing.

Dr. Ken Sharlin 52:11

Yeah. I believe we're on the same page there. I can certainly cite, and I'm sure you could, many examples of situations where unfortunately false conclusions in regard to studies have led to changes in practice that have probably created greater harm than what was happening before the conclusion was drawn. I always use an example in my world of the withholding of hormone replacement therapy to women post-menopause and the impact, you know, i often say I'm a neurologist and I prescribe estradiol, progesterone, and testosterone to women. That shouldn't be surprising because if we just look at the brain alone, not the heart, not the muscles and bone density and metabolic parameters and all the other things that these hormones do for us, just the brain, I find it unethical, truly unethical, that this practice is only now coming back into.

Aubrey De Grey 53:17

I don't think we should really overgeneralize from that because let's face it, that was a one-off, totally catastrophic misinterpretation of one clinical study. A very big clinical study, of course, but nevertheless, it was a one-off. So I would hesitate to overgeneralize from that. Nevertheless, still I stand by everything I said a moment ago.

Dr. Ken Sharlin 53:37

Thank you so much, Dr. Aubrey De Grey, for joining us on the "Healthy Brain Toolbox" podcast. It's really been an honor to have you join us today. Thank you so much

Aubrey De Grey 53:50

Thank you so much for having me. I've definitely enjoyed it myself.

COMMERCIAL BREAK 53:52

Hi everyone. Dr. Ken Sharlin here with the Healthy Brain Toolbox. I'd love to hear from you. If you have general questions about brain health, neurology, or the science of keeping your brain sharp. Send them to questions@healthybraintoolbox.com. I'll be reading your questions on the upcoming episodes. Please remember, these need to be general questions, can't answer personal medical questions, or provide individual medical advice. So if you've ever wondered about brain health strategies, lifestyle

Closing Thoughts and Thanks

COMMERCIAL BREAK 54:28

tips, new research, or the future of neuroscience, send those questions in. I look forward to hearing from you and who knows? You might even hear your question featured on the show. Thank you for tuning into the Healthy Brain Toolbox podcast. I hope today's conversation gave you new insights to protect and nourish your brain. Be sure to subscribe, leave a review and share this episode with anyone looking to take control of their health. Until next time, stay sharp and keep learning.