Hi listeners — just a note that after this episode, we'll be switching to a biweekly release cadence for a while. Hope you're enjoying the show, and see you in a couple weeks! -NW
We all know that our mortality is inevitable, but the fact that people age so differently makes you wonder: is there some switch that could be flipped in our biology to let us all live to 100 with our mental faculties intact?
Most of us probably know someone who developed Alzheimer’s disease or another form of dementia as they got older.
Bu you probably also know someone who stayed sharp as a tack well into their 80s or 90s. Even if it’s a favorite TV actor, like Betty White.
We all know that our mortality is inevitable, but the fact that people age so differently makes you wonder: is there some switch that could be flipped in our biology to let us all live to 100 with our mental faculties intact? Scientists now believe we can learn something from people whose minds stay sharp — whose brains stay youthful into old age that could lead to treatments to slow down aging for the rest of us.
That brings us to today’s guest. Tony Wyss-Coray is the Director of the Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute and D.H. Chen Distinguished Professor of Neurology and Neurological Sciences at Stanford University.
Wyss-Coray's lab is renowned for experiments showing that young blood can rejuvenate old brains, at least in laboratory animals. We talked with him about this work and the prospect of achieving more youthful brains into what we now consider old age.
- Q&A: Can we rejuvenate aging brains? (Scope Blog, 2022)
- Gift from Phil and Penny Knight launches scientific endeavor to combat neurodegeneration (Stanford News, 2022)
- Young cerebrospinal fluid may hold keys to healthy brain aging (Wu Tsai Neuro, 2022) (also covered at NPR, NY Times and more)
- Blocking protein’s activity restores cognition in old mice (Stanford Medicine, 2019)
- Clinical trial finds blood-plasma infusions for Alzheimer’s safe, promising (Stanford Medicine, 2017)
- Infusion of young blood recharges brains of old mice, study finds (Stanford Medicine, 2014)
- Scientists discover blood factors that appear to cause aging in brains of mice
(Stanford Medicine, 2011)
- Young blood revives aging muscles, Stanford researchers find (Stanford Medicine, 2005)
This episode was produced by Michael Osborne, with production assistance by Morgan Honaker, and hosted by Nicholas Weiler. Cover art by Aimee Garza.
This is From our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University. On this show, we crisscross scientific disciplines to bring you to the frontiers of brain science. I'm your host, Nicholas Weiler. Here's the sound we created to introduce today's episode, brain rejuvenation.
Most of us probably know someone who developed Alzheimer's disease or another form of dementia as they got older, maybe a relative, maybe a friend, but you probably also know someone who stayed sharp as a tack well into their eighties or nineties, even if it's a favorite TV actor like Betty White. We all know that our mortality is inevitable, but the fact that people age so differently makes you wonder is there some switch that could be flipped in our biology to let us all live to a hundred with our mental faculties intact? Scientists now believe we can learn something from people whose brains stay youthful into old age that could lead to treatments to slow down aging for the rest of us. That brings us to today's guest.
Hi, I am Tony Wyss-Coray. I'm a professor of neurology at Stanford University and the director of the Knight Initiative for Brain Resilience.
I am really glad to be having this conversation because this topic is both really exciting and, I don't know, maybe a little scary. I'm not sure if scary is exactly the right word, but aging and our ultimate mortality are supposed to be this immutable part of life. So I'll just get to our main question, which is, do you think it is possible to slow or reverse the aging process?
Yeah, I mean, I have the same sentiments as you to this question, but as scary as it may sound, it is possible to slow down and to reverse the aging process in multiple different models as well as with different tools. And so while just 20 years ago, it was mostly a pipe dream maybe, it has become scientific reality that this may be possible even in humans at some point.
And are you talking about the possibility of getting rid of aging altogether or helping people live to 200? Is that what we're talking about here?
Yeah, that's a good question. I think, you go step by step. Discovery is never predictable and it can go very slow or it can jump with a major discovery that would lead you to a position where all of a sudden an organism lives twice as long. And that's where I guess the scary aspect would come in for society and how we would deal with that. But I think more realistically is that we start to understand fundamental processes that happen when a cell ages, when an organism ages, and that's where we can intervene in a very specific, targeted way.
So what is aging? When we talk about a person, what is that process? What is age?
Yeah, that's a puzzle that nobody agrees on or a question nobody agrees on the answers yet. So I think aging has mostly been seen as passing of time, and scientists are now trying to understand is it really time or is it a specific set of molecular and cellular processes that define age. So we have different definitions of age, and we use this in everyday life. You look at somebody's face and you estimate how old they are, and then you ask them, "How old are you?" And maybe that person, you thought they must be 70, and they say, "I'm 85." And you say, "Wow, you look really young for your age." That's sort of where the difference between time and biological age come in, and that's what we're trying to capture as scientists, what keeps some people looking younger, acting like they're much younger, having more energy, or most importantly, that their brain is still functioning like a young person, or at least they don't show any signs of cognitive decline.
This is what this Knight Initiative for Brain Resilience, that's why we bring this word resilience in there. What we're trying to understand is how do some individuals achieve this healthy aging where they're 90, 95 and their brain functions just like normal. Maybe they're a little bit slower, but they can remember everything, they're funny, they can learn new things, they just interact like a young person with their peers.
And for those people who are staying sharp longer, is it just a matter of not getting brain diseases or is there some other aspect of cognitive decline that's not connected to having Alzheimer's disease but you just see different levels of cognitive decline in different people?
So sort of the spectrum from a brain functioning completely perfectly well to dementia is quite varied. And it's not the same if you have sort of age-related cognitive decline where maybe you don't find a word as quickly or you forget a few things here and there to dementia. There's not a linear path where if you have some problems or mental lapses that you're now going to get Alzheimer's disease or you're going to be demented and you cannot function anymore because you don't remember how to hold a spoon or what it's for, right? That's dementia. Or you don't know how to button your shirts. That is dementia.
So dementia is really when a person is in the final stages, unable to do very basic things, not just think or having a memory, encoding a memory. There is a spectrum there, and scientists are trying to understand what sort of the connections between these processes are and where we could potentially interfere. So healthy aging would, of course, initially prevent age-related memory lapses and things like that. But then the idea is really that you would also prevent diseases such as Alzheimer's disease, which leads to dementia in its later stages.
Well, I wanted to ask you, your lab is really well known for a particular set of experiments that show that there's something potentially in our blood that might influence how our brains and our bodies age. Could you give us sort of the high level overview of those experiments and what those findings mean?
Yeah, this is another really fascinating observation that scientists made maybe now 15 years ago, that first of all, the composition of the blood changes dramatically as we get older, as an animal gets older. If you just look what is the relative levels of different molecules in the blood, of different proteins, their levels change. Some go up, some go down. And that makes you wonder, is that just a result of aging or is it actually contributing to the aging process? So what people started to do is they basically exchanged the blood from a young mouse to an old and asked, "What if I give an old mouse young blood? Does that have a positive effect on the different tissues in the organism?" And the first data that sort of opened up this field really to understand it at a molecular level came from Tom Rando here at Sanford when he showed that the muscle could be regenerated of an old mouse with exposure to young blood.
And then we started to collaborate and show that the same can apply to the brain. So we can basically give an old mouse blood from a young mouse, and it improves the cognitive function in this old mouse. It has effects on cells and on the molecular level, we can actually measure what happens. And this has now been reproduced in multiple different labs, and it has also found its way sort of into the clinic because blood donations are something that is very well established. It's very safe, and we actually only need the liquid part of the blood, which is called plasma. And if you go to the hospital and you need blood because of a surgery or something like that, you often just get this plasma, you don't get the whole thing. So it lends itself to start clinical trials and see whether an old person with, let's say, Alzheimer's disease would benefit from plasma from young donors. And there's some signs that might indeed be the case, although these studies are still in their early stages and I think we have to be patient to learn more.
Right. Well, that's just so incredible that something as, I don't know if simple is the right word, but something as basic as a blood transfusion or blood can drastically change how aging is affecting the body and the brain. What do you think is special about the blood? Why do you think brain aging is so affected by it?
First of all, the blood, of course, is the tissue that sort of connects all the different parts of our body, all the different organs. The brain is extremely highly vascularized, so it has a lot and lot of blood vessels. So every tissue is exposed massively to blood. And what the blood probably contains is information and molecules from the tissues. But it can also bring them, let's say, from the liver. Something that is made in the liver, if it gets into the blood, it will go throughout the body. And this is the concept of hormones. Hormone is produced in a specific tissue and is released into the blood, and then it has an effect on a distant tissue, and it regulates all kinds of different body functions. So what we are seeing is that it actually applies potentially to thousands of different protein molecules that are produced in one specific cell or in a specific tissue. And because they change with age, whatever function they have, may then not be executed the same way as in a young organism.
So there are things in the blood that we can then start to identify that might be the culprit, essentially, in telling cells or influencing tissues?
Exactly. Yeah. This is really the hope of using the blood in this way. And we've done this in medicine for decades. If you go to the doctor, they take a blood sample and they measure a number of different things in that blood, and they always measure the concentration of something. So how much of this is in your blood? And if it's too much or too little, they give you a diagnosis of a specific disease, or they may say, "You have to take this vitamin to get back to a normal level," or, "You have to take this drug to make sure you don't get heart disease," or something like that.
And by basically expanding this concept to hundreds or thousands of different protein measurements, we get potentially much more information about the state of the organism, of different organs to a degree where we can now, at least in experimental studies that my lab is currently doing, we can tell you how old your heart is or how old your liver is compared with the number of years that you have lived. Remember we had this concept of, "You look young," or, "You look older," but you could apply this to the liver, to the heart, to the brain, because there, too, you will find people who have a younger heart and they will probably not get heart disease, and they will then another person who has a heart that is five or 10 years older than the rest of their body, and they may be at risk for heart disease, and the same may apply to the brain.
That's just remarkable, to start to take it apart piece by piece and say, "Where do we need to focus?" And this idea of blood transfusions, I think, made a lot of headlines a few years back. I think it even ended up on Silicon Valley, on HBO with wealthy people having young blood donors. So hopefully we're trying to avoid that kind of situation. So I'd love to know, I mean, what do you see as some of the big areas of focus for developing these therapies? What are some of the things that need to be done to potentially reverse some of the aging in the brain or other organs?
First of all, it's very important to say that I think the vast majority of scientists are not trying to find treatments to make people live longer, but they try to really address the aging process with this concept that if you could slow down the aging process, you would prevent age-related disease. So the goal for most people in this field of science is to achieve this hundred-year-old person who is still sharp and still has a memory that allows them to have a functional, happy life. But how do we get there? I think science is hard to predict where the breakthroughs will come from. They could come from identifying these factors in the blood. We don't think it's going to be a single one. It's going to be multiple different factors. We also know that there's an accumulation of sort of bad factors with age so one could inhibit those.
It could come from the reprogramming of cells. If you can figure out how to just get rid of some of the aging changes in the DNA, then the tissue would become younger. And this is indeed what people have been successful to show, again, in mice that you can use this approach. Or there are sort of classic metabolic interventions, metabolism changes with age, and there's a number of drugs that are currently also being tested, some even going into clinical trials that might slow down the aging process and allow you to keep your organs functioning for a longer time at a useful level.
Yeah, I mean, I think that paints just this really beautiful picture of what we really want is not necessarily to live for hundreds of years, but just to age more gracefully. On the one hand, we want to avoid devastating brain diseases and slow down cognitive aging. And on the other, maybe we need to think about what it means to be happy and sharp at 90 and if that is different from what it means at 20 or at 40.
Yeah, that's an interesting concept, is cognitive aging and it's interesting. What does it mean for your cell's identity to get older? That's an aspect that is completely cognitive. How do you feel about your age? And it's interesting, I think most people when they get older, they don't feel that their mind is necessarily older. They live in an older body, but then some people do feel older. That's another aspect that is much more societal and driven by your environment probably also to some extent of how you feel about your age. And that is a different dimension that we're not going to tackle with exchange of young blood is my guess.
Yeah. Well, thank you so much for joining us. This has been a fantastic conversation.
Yeah, thank you. It was a pleasure.
Thanks so much again to Tony Wyss-Coray. You can learn more about his research and the Knight Initiative for Brain Resilience in the show notes. This episode was produced by Michael Osborne with production assistance by Morgan Honaker. I'm Nicholas Weiler. I'll see you next time.