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Dr. Jean Hébert on Brain Regeneration at EARD2021

The rest of the body is replaceable in a way that certain parts of the brain aren't.

Jean Hebert at EARD2021Jean Hebert at EARD2021
 

At Ending Age-Related Diseases 2021, Elena Milova interviewed Dr. Jean Hébert on how the human brain can be restored to youthful function.

Script

Elena: Greetings to the participants of Ending Age-Related Diseases 2021. This conference brings together thought leaders and researchers working on rejuvenation biotechnology with the goal of extending healthy human life.

The supposed irrepairability of the brain has long been a concern for longevity enthusiasts. The brain is the most important organ in our body that regulates many other functions and serves as a container for our personalities. While the brain seems to be aging slower than other organs, it still does age.

What can be done to preserve its use and prevent aging? Today, I am speaking about it with Jean Hebert, a trained molecular geneticist and neural stem cell researcher, who is now a professor of neuroscience and genetics at the Albert Einstein College of Medicine in New York. Hello, Jean, happy to have you.

Jean: Thank you. Thank you for having me.

Elena: Can you please tell our audience what happens to the brain as it’s aging? What are the most common changes?

That question, you may be asking at sort of a superficial level of what happens to the brain. At some level, we all know that cognitive function declines with time. We know 90 year olds, and as sharp as they may be for a 90 year old, they’re becoming forgetful, their cognitive abilities have declined. We know this. There’s forgetfulness; everything we think of in terms of how we use our brain declines.

I think the more important underlying question, the one that’s largely ignored, and the one that’s important if we’re going to think about reversing brain aging, is the molecular damage that accumulates over time. That is very complex damage. It occurs both inside of cells and outside of cells, that I’m not talking about cellular damage, because that definition of cellular damage is sort of a result of the molecular damage.

I think more important is the molecular damage, which occurs to proteins, to DNA, of course, and in both those cases, they’ve been shown to cause, in cells in general, not just the brain, but to cause the other hallmarks of aging. These molecular forms of damage, which again, occur to protein DNA, but also to lipids and carbohydrates, are stochastic; they’re not enzymatically driven. They’re, in many cases, irreversible, and they accumulate with time, and we ignore that, but that is essentially what brain aging is.

We have great compensatory mechanisms, the brain is very plastic, and we’ll rewire, relearn, in ways that are useful to us, but at some point, the substrate is just so degraded that it’s no longer able to compensate. Then we see the effects of cognitive decline.

Well, your research is based on the assumption that brain tissue can be replaced. Can you tell our audience a bit more about that?

That assumption is based on two established findings; one has been established for a very long time, and I just mentioned that, it’s plasticity. We know that the substrates for functions in our brain can change over time. This is well documented across mammalian species, including humans, and there’s lots of examples.

That bodes very well for replacement. If a function can move from one area of the neocortex, in particular, that’s the part of our brain that we use for our highest cognitive functions and largely defines who we are as individuals. If a function can move from one part of the neocortex to another, that means that replacement, in theory, should be possible.

I’ll give one example of that, which is the movement of language. I like that example because language is very dear to us. It’s how we think, we have connotations to words that really define a lot of our behavior, and language has been shown in humans of advanced age to be able to move from one part of the neocortex to another over time.

It takes a few years, but it occurs, and it only occurs if the original language center is slowly destroyed, which can be similar to aging or degeneration. It doesn’t occur, for example, when language is destroyed very quickly due to a stroke. Plasticity does take time, but it does occur.

The other reason why I think replacement is possible is that, not only in theory based on plasticity is it possible, but in practice, the transplants that people have been doing so far, including our lab, with young precursor cells that are normally found in the developing brain only. When they’re transplanted in the adult brain, they behave like they would if they were still in the developing brain. They don’t seem to care that they’re in an adult, mature, or old environment, they still project to the right places and make the right connections.

The two of those together, the evidence that we have so far in practice, that we can replace cells, and the plasticity, saying that functions can move to those new cells, in principle, together, I think mean that brain replacement is possible if done progressively over time.

Do you think that replacing the neocortex might be enough if we do not address the aging of other parts of the brain, such as the hippocampus? Do you have ideas on how to do that?

The answer is, it’s not enough. It would be a fantastic start, because it’s the most important part of the brain, but we need to consider all parts of the brain. There’s some parts we can actually do without; people have lost certain parts of the brain. I don’t want to offend some of my colleagues who work on those parts of the brain, but the cerebellum, for example, if you completely remove the cerebellum, you’ll be uncoordinated for a while, but then you’ll compensate, you can actually live without one. Still, we should include all parts of the brain, because for optimal function, we need them all, including the cerebellum, which is different than the cerebral cortex.

All parts of the brain, we need to address and replace. The approaches will be similar for some parts of the brain. We may be able to replace them as a whole instead of progressively over time, because, again, it’s the neocortex that really defines who we are. That’s what we need to preserve in order to preserve our self-identity; for other parts of the brain, that’s less important. Their replacement may be done much more quickly.

Do you think that there is an age limit for successful brain tissue transplantation? Or maybe some disease might be a contraindication for it?

Certainly; it’s a surgical approach. As with any surgery for any part of the body, the risk increases with age. Although there are 90-year-olds that undergo brain surgery, or other types of surgery to their body, the risk is higher for them because they have less homeostasis. They’re less able to adjust to recovery, and it takes longer times.

We wouldn’t necessarily want to wait till you’re 90; in theory, there’s no limit. Of course, if you have pre-existing conditions that weaken your body, those could be mitigating factors. Eventually, we’re going to use this tissue replacement approach, initially, for indications of local damage to the brain, for example.

Initially, we’re not going to go to the clinic for aging, but hopefully, within 10, 20 years maybe, we will address senility, dementia, which is essentially aging, with this replacement. The idea is at that time, if we could start replacing, kidneys, pancreas, so that we can fix diabetes, and other things, we’ll generally be making the individual much more robust and able to sustain these surgeries, like a new heart, new lungs. At the same time, we can be implementing this progressive tissue replacement in the brain. The idea is that this will come together and will be possible even as we get older.

Yes, it seems indeed very likely. Do you think that this the same approach can work for people who have some form of physical trauma of the brain that blocks some part of the brain?

When it’s an acute form of damage, like stroke, or physical trauma, a penetrating wound to the head, to the brain, whatever tissue is damaged and lost, that function is gone, and there’s no preservation of the function at that location. What the new tissue will be able to do is provide a brain substrate that’s the equivalent of a one- or two-year-old child that can very easily really learn those functions.

For stroke, for example, that leaves people often paralyzed in half their body and unable to speak; that new tissue should allow them to regain language with the ease of a two-year-old and regain movement. That’s the idea.

For aging; we want to preserve the existing functions because that’s who we are. It has to be done more progressively. There’s a little bit more to it where you have to progressively silence the functions, the tissue that you’re going to excise in the future and then provide the new tissue close by. It’s really a replacement, not just adding tissue, because even though our brains shrink as we get older, there’s only so much new tissue we can add without eventually having to get rid of the old tissue.

Sounds really interesting. Let’s discuss a philosophical aspect of it. So many people are worried over replacing a small part of the brain, because they are afraid that with this, some part of their personality is going to be gone. Let us remember the Ship of Theseus, where every part of the ship is getting gradually replaced.

Then the question is, is the ship still the same one after everything gets replaced? How would you address those worries?

This question gets philosophical. To some extent, I think replacement is the best we can do to preserve ourselves, because again, because of this degrading substrate, all this molecular damage, if we don’t do anything, we will disappear, who we are, will disappear progressively, as we see in very old people. When we start forgetting our loved ones, it’s terrible. To counter all those forms of damage, I think replacement of tissue, not just cells, is the only way to do it.

It raises the question, at what point do we risk losing who you are by doing these replacements? It’s important to keep in mind that our brain, in particular our neocortex, the way it works, is, we’re not hardwired for who we are. It’s a very dynamic process, we learn new things every day, we forget things, new things every day that we used to know.

Things are changing all the time. The way the neocortex works is it devotes space or tissue to the functions that we need, the functions that we’re using now, things we think about and remember more regularly, so there is a risk of more quickly forgetting things that we don’t think about, which we do already, every day, “I think I know that, I can’t remember what it was.”

That might increase a little bit. The things that are important to us, the people that are important to us, the memories that are important to us, as long as we keep thinking about those, they will get transferred to the new substrate.

Again, because this is a very plastic substrate, to us, it won’t make a difference. The people who have relocated their language over time, they never noticed any difference to themselves. The people closest to them never noticed any difference in their personality, who they were.

As long as we keep using these functions, our brains will encode them. That’s really the important point to remember. It’s not like part of our brain is hardwired and we’re like a recording device and if we lose that, we lose the memory. That’s not how the brain works. It’s more fluid and plastic.

Yeah, that’s an interesting idea that we may care more about the environment and the circumstances of our lives if we want to remain the same. Then, basically what is required is for the circumstances not to change. If we move elsewhere, meet new people, learn a new language, or learn how to play a new musical instrument, it’s unavoidable that we’re going to change internally, even though we cannot really notice this. Interesting. I haven’t thought about it this way.

With this replacement strategy, because you map every part of the brain before doing any subtraction or addition of tissue, you know what’s encoded there. Brain surgeons do this all the time now, because brain surgery is done in the awake state for that reason, so that they know what they’re dealing with.

The plan is to identify beforehand, what part are you going to subtract when you progressively it silence over time, so that you can purposely be focusing on that,  for the next year, just think about it every so often to make sure that that memory gets transferred. In this way, I think there’s a better chance that you will maintain yourself and your memories that are important to you, than if you were left without doing this replacement strategy.

Thank you. That’s interesting. There has been a lot of research on regenerating neurons, but your graphs contain several types of cells, such as vascular cells and scaffold.

What’s the difference between those approaches, when you are only replacing the neurons or using this mix of cells?

I think it’s really important to think about tissue replacement as opposed to just cell replacement, because much of who we are, much of our tissue, is extracellular. We know that putting young cells in an old environment has limited benefits, because the young cells adopt an old behavior very quickly. One of the reasons why things like epigenetics, or mitochondrial replacements, or a lot of these other approaches that are focused on the cells themselves, we know that that will have limited benefits, because even if we change the epigenome of cells in an old environment, they’re still going to realize that they’re in an old environment. Just like transplanting young cells that have a young epigenome, young mitochondria, young everything, putting them in an old environment, they still behave like old cells.

I think these other approaches may have some utilities, but they’re not gonna reverse brain aging because they’re only focused on cells and what’s inside cells and not their environment, the extracellular matrix. That’s why replacing tissues is the way to go, I think that’s going to have very clear benefits.

What might be the possible problems with this therapy? For instance, can there be any potential damage to the brain? How do we avoid adverse effects from the surrounding old tissue, because whatever you do, you will still deal with the environment that is older probably than the transplant that you’re making.

That’s a good point, is the effect of the old environment on the young tissue. Again, because we’re not just putting in cells, we’re putting in the whole tissue, those cells are surrounded by the young tissue. There, they should be happy, as far as we know, and behave like young cells. That should mitigate, in part, that issue.

We know from Parkinson’s patient transplants that were started in the 80s, that even if you don’t transplant full tissues and just transplant dissociated cells, not single cells, but maybe a hundred thousand to a million cells without surrounding tissue, they can still do quite well in the human brain for decades. In postmortem tissue for some of these Parkinson’s patients, these cells still looked and were functioning well, after 16 years in one patient. At 24 years, they were starting to show pathology; that’s still over two decades, where they were still showing some benefits but now acquiring the environmental pathology of degeneration.

That was with single cells without even the tissue around them. By doing it the way we propose with the whole tissue, and not just the cells, I think we’ll be much better off. Much more than 24 years, they’ll be behaving as a young tissue. The other issues with this approach, we’ve touched upon before, like surgery. It is a surgery, and doing that in very old individuals, especially if they have pre-existing conditions, there’s a much higher risk there that we have to be aware of and plan for, either with treating these other conditions first to reverse organ aging or at least doing it in a way that gives them the greatest chance to survive and recover from the surgery.

Community members often reflect on how exactly we can beat aging, and one of the thoughts that has been discussed quite regularly is that we must probably think about replacing all of our organs one by one in order to gain some form of rejuvenation.

Do you think that this is the future of rejuvenation therapies, that rather than repairing, we must be replacing?

I do. We can do it organ by organ, but there’s alternatives as well. We’re getting to the point where tissue-engineered organs, or lab-grown organs, are getting better and better; some have already been transplanted and successfully in humans, but there’s many more that would need to be developed and are being developed for reversing aging. I’m hopeful that that will be here soon enough for us. But I think it will, progress is being made every day.

There’s also alternatives that are more shocking to people. For instance, the whole body is potentially replaceable with synthetic replacements. There’s a group at Yale that developed this system of circulating blood in the brain of a fairly big animal, a cow in this case, and keeping it alive or even reviving it after it was supposedly dead, all synthetically.

It had a filtration system that replaced kidneys, it had a heart-lung system that pulsed oxygenated, synthetic blood through the brain and then removed the the CO2 that came out of the brain through this synthetic blood. That was pretty amazing.

It’s possible, this might be scary to a lot of people, that for most of our bodies, we can replace that synthetically, certainly for limbs, right? The prosthetic limbs right now are going to very soon surpass the ability, if they haven’t already, of our biological ones. Other than biological tissue replacement, there’s also that side of things.

Even from biology itself, I know this is gonna scare even more people, but we can fairly easily imagine how if we ever wanted to go down that road, that we could replace the whole body at once. We kind of know already in animals how to grow bodies that don’t have heads, that don’t have brains, but this is a very scary topic to people and very science fictiony, but it is in the realm of possibility.

It’s actually something we can do if we wanted to, very soon, as a possibility, but I’m not too worried about the rest of the body. It’s really the brain that that is the biggest challenge.

To me, it doesn’t really sound so scary; quite honestly, I’m most scared by the fact that we will still have to wait until all of those marvels are going to be available in the clinic, because right now, we’re only speaking about a laboratory environment for such things, sadly.

Then again, if you think about it as a person that doesn’t have any other choice, when there is a fatal disease, something that is really aggressive that happens with the body and that technically, your days are counted, would it still be scary to be like living in a synthetic body with your natural biological brain? If this way, you can still live? It’s an open question. It’s just a matter of time when our society will adjust to the possibilities of innovative technologies. Most of those things that we are currently discussing as experimental treatments are going to be perceived as normal and available probably in the clinic nearby.

What’s most scary to me, just to wrap it up, is aging. I’ve had to care, a little bit, not as much as some people have, for loved ones who are old and falling apart. It’s horrible. They’re good people, and they’re suffering for years, falling apart. They really don’t deserve that. To me, aging is worse than these other alternatives that may sound scary to some people, but aging is the scariest.

I completely agree with you, sadly, same experience as everyone, I guess, had some friend, or relative, or parents, that would succumb to aging and eventually go away. All right, let us try to be more optimistic and discuss what’s going on now.

What are your plans, your goals, your area of research right now? What’s the timeline for all those things that we are currently discussing to actually become tested and then available to people?

We’re focusing first on the neocortex replacement. Again, what we develop initially will be used, in the first clinical indication, will likely be stroke, because it’s the most common form of brain damage and neocortical damage in humans.

We’re still early stage, we have some nice, early proof of concept that this should work, but we’re missing a lot of components to make that tissue functional. There’s a lot of testing that we need to do to show that this tissue can support normal behavior for the individual.

This is a very big project; there’s a lot of technologies, a lot of expertise that’s needed to ensure that the tissue functions well enough to be transplanted into a human. We’re still in the early stage. What will make a big difference, obviously, is funding so we can build bigger teams working on the different aspects of this project.

If that happens, we have an outline of what we need to do. We just don’t have the personnel yet. If we have that personnel tomorrow, then, I think, ambitiously, but not impossible, in five years, we talk to the FDA, we have our tissue, and we talk to the FDA about treating stroke. Then, it’ll take a couple of years, probably, for it to get approval for clinical trials, and then maybe another year or two after that to start seeing benefits.

As soon as we start seeing benefits from this tissue, we can expand the indications to, for example, frontotemporal dementia, which is sort of like aging, but not everywhere. It’s still the neocortex, and it’s a little more restricted. That is devastating. There’s, again, no treatment to these conditions.

I think that would be the next step. Then, it’s a natural progression from there to senility, which is essentially brain aging. At the same time, though, as we mentioned earlier, we’re going to start building tissue for the other parts of the brain. Because eventually what we want is to really be able to reverse aging.

That sounds like a great plan, but it seems like we still have to wait. Let us discuss what can we do now to preserve our cognitive function, the health of our brain, in order to live long enough to be able to benefit from those technologies.

In one of your papers, you found that an enriched environment and exercise can increase neurogenesis in certain parts of the brain. Would you recommend this as an actionable strategy to delay brain aging?

Yeah, so I would definitely recommend it because it has benefits. Exercise, enriched environment, they do wonderful things to the brain in terms of maintaining function and cognition.

I don’t know if, at all, they slow down brain aging, though. They might keep you going much better until you’re 90, 100.

At that point, your brain has still aged, and you’re still going to lose function, cognitive function. You’ll be able to, instead of the decline occurring progressively, it’ll be more asymptotic. So you’ll be high-performing for longer.

These are good things, but the important thing to point out about neurogenesis. We love hippocampal neurogenesis just as much as anybody else, but it’s a very small part of the brain it only affects. There’s no neurogenesis in the neocortex. That’s what we’ve been talking about, most important part of the brain.

The hippocampus is very important as well, but it’s small. It’s important in forming new memories. It regulates mood as well. It could potentially be replaced as a whole organ without us losing who we are. It has neurogenesis, but it’s a small part of the brain. Within it, there’s like three or four different structures. One of them is called the dentate gyrus, so it’s a smaller part of a small part of the brain.

Within the dentate gyrus, there’s a thin layer of cells that actually are stem cells that may be producing even in humans, new neurons as we go. Those cells play an important role, probably, in learning new things. Yes, environment might increase their function for, again, longer periods of time as we age, environment, exercise.

That would be a good thing, but overall, it’s not gonna impact brain aging very much. It might make us function better for longer. For that reason alone, it’s worth it. It’s worth continuing to exercise and challenge ourselves, learn new things. That’s a good thing, but it’s not the solution.

We’re not discussing this as a form of solution, rather the possibility to extend healthy life as much as possible.

We hear a lot about these endogenous stem cells. Why can’t we just, have them do more of what they do? The thing is, they give rise to a very specialized type of neuron and a very small part of the brain, and that’s all they do. We can’t really get them to fix the rest of the brain. I think it’s worth pointing that out.

Can I ask you a personal question? What do you use yourself for extending your healthy life?

I think the best thing I do for myself is exercise. I try to remain very active. I play street hockey every week with people half my age. That’s the main thing. I take antioxidants. I think that’s more of a placebo effect. I don’t think there’s very good evidence that they do much, but they make me feel better, so I take that.

Every so often, I try to fast. The health benefits of that are undeniable. In terms of extending maximal lifespan, or actually slowing the molecular process of aging, there’s no evidence for that. In fact, in mammals, it doesn’t look like it does, but the health benefits are still clear. Anything to stay healthier, while we figure out how to beat aging, I’m on board with that.

All right, anything else?

I don’t take any supplements like metformin or rapamycin or anything, which, again, I think can have benefits, depending. Certainly, if you have like, predispositions to diabetes, things like that, then it probably makes sense for people to take that. I’m lucky enough that my family history is relatively free of that, and so I’m not too worried about that.

Jean, we’re getting close to the end of our conversation, do you have a take-home message for our audience?

Stay healthy and educate yourself about what we know of what aging is. If you’re interested in longevity, in that space, whether you’re an enthusiast, or an investor, or a scientist, look at all the great work that biochemists have done for decades showing this accumulation of damage, because most people ignore that even scientists in the longevity field now.

You’ll come to realize that aging is very messy, that the damage that occurs is horribly messy and not likely to be addressed with simple pills or drugs. I think I would leave that as my main takeaway message, that we should really study what’s known about aging and include it in our approaches. Is our approach going to reverse these aspects of aging?

All right, thank you. Thank you very much for finding the time to join us at the conference. I hope you enjoy the rest of the conference, and good luck with your work.

Thank you, Elena. Thank you very much.

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