From Our Neurons to Yours

The clocks in your body | Tony Wyss-Coray

• Tony Wyss-Coray, Nicholas Weiler • Season 3 • Episode 6

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Today: the clocks in your body.

We're talking again this week with Tony Wyss-Coray, the director of the Knight Initiative for Brain Resilience here at Wu Tsai Neuro. 

Last year, we spoke with Tony about the biological nature of the aging process. Scientists can now measure signs of aging in the blood, and can in some cases slow or reverse the aging process in the lab. We discussed how this biological age can be quite different from your chronological age, and why understanding why people age at different rates has become a hot topic for researchers who study aging. 

Since we last spoke, Professor Wyss-Coray and his lab have published some exciting new work that takes this idea from the level of the whole body down to the level of specific organs and tissues. We can now ask: are your brain, your heart, or your liver aging faster than the rest of you? The implications of this idea could be profound for both neuroscience and medicine more broadly.

Listen to the episode to learn more!

Further reading
Wyss-Coray lab
Phil and Penny Knight Initiative for Brain Resilience

Organ aging study in Nature:

Study coverage:

Related reading:

Episode Credits

This episode was produced by Michael Osborne at 14th Street Studios, with production assistance by Morgan Honaker. Our logo is by Aimee Garza. The show is hosted by Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute and the Knight Initiative for Brain Resilience. 

Thanks for listening! If you're enjoying our show, please take a moment to give us a review on your podcast app of choice and share this episode with your friends. That's how we grow as a show and bring the stories of the frontie

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Thanks for listening! If you're enjoying our show, please take a moment to give us a review on your podcast app of choice and share this episode with your friends. That's how we grow as a show and bring the stories of the frontiers of neuroscience to a wider audience.

Learn more about the Wu Tsai Neurosciences Institute at Stanford and follow us on Twitter, Facebook, and LinkedIn.

Nicholas Weiler:

This is From Our Neurons To Yours from the Wu Tsai Neurosciences Institute at Stanford University. Each week, we bring you to the frontiers of brain science to meet the scientists, unlocking the mysteries of the mind, and building the tools that will let us communicate better with our brains. Today, the clock's in your body.

Last season we spoke with Tony Wyss-Coray, the director of the Knight Initiative for Brain Resilience here at Wu Tsai Neuro. The gist of our conversation was we're learning that aging is something biological. We can detect it in the blood. And in some cases, we can slow it or reverse it. This biological age can be quite different from your chronological age. 

Think of it like this. You can usually guess somebody's age pretty accurately based on their skin, their hair, their posture, but sometimes looks can be deceiving. This is why we say someone looks great for their age, or someone might be old before their time. 

Scientists have been excited to discover that this phenomenon is actually measurable at the cellular, and even the molecular level. And so understanding why people age at different rates has become a hot topic. For researchers who study aging. 

Since we last spoke, Professor Wyss-Coray and his lab have published some exciting new work where they take this idea from the whole body down to the level of specific organs and tissues. We can now start to ask, are your brain, your heart, or your liver aging faster than the rest of you? The implications of this idea could be profound for both neuroscience and medicine more broadly.

Tony, I'm so glad to have you back on the show.

Tony Wyss-Coray:

It's great to be here.

Nicholas Weiler:

So today, I'd love to talk about this recent study that your lab came out with showing that we can now measure relative biological age of different organs in humans. I'd love to know, when did scientists start thinking about aging in that way?

Tony Wyss-Coray:

My guess it started when people really explored the accumulation of so-called epigenetic changes in the DNA. So this is accumulation of methylation sites and DNA that people observed. They continue to increase across the whole genome in different species, from worms to flies, to mice, to humans. And that accumulation progresses with time, with age, if you will. And again, there's a question, what is the difference between time and age? And what people found is that sometimes accumulation, it goes a bit faster than the actual age of the organism, and it's a little bit slower. And what people also found is that if they had interventions that targeted aging processes, then they could slow down this, people often call it a clock,

Nicholas Weiler:

Yeah. And I think people may have heard of things like telomeres at the level of DNA on your chromosomes. There are these epigenetic changes that seem to correspond in some way with the aging of the organism as those sort of protective caps wear down. But as the field has delved into this more over the years, it's mostly been at the level of the whole organism, right? The telomeres is a DNA level thing or a cellular level thing. And what your team has done is bring this down to looking at individual organs, right?

Tony Wyss-Coray:

That's right. Yeah. And this is not really our discovery, but some of the first discovery were made over a decade ago in worms. When people looked at aging worms, they noticed that even at the ultrastructural level, not all organs changed at the same rate. It seemed some organs in some worms looked still younger than other organs. And when people followed up on this, they realized that there's actually molecular measures and molecular indicators, and this has really grown into looking at many different molecular modalities, whether that's proteins or RNA transcripts or lipids. If you look at anything in different organs, or even different cell types across an organism, they may not show the exact same changes at the same rate with aging. An example is you have this thymic involution where the thymus disappears at a relatively young age.

Nicholas Weiler:

What is the thymus?

Tony Wyss-Coray:

The thymus is a part of the body where the immune system matures and develops, but it's doing relatively early development. And I don't know exactly now when that time evolution happens, but it's in early adulthood where that time gets smaller and smaller because it's not necessary anymore. But it's part of almost like an aging process. That organ starts to age, and then it becomes very small, almost undetectable.

Nicholas Weiler:

So that's a clear example of where an organ has a very specific aging trajectory, right? The thymus is important when you're very young, and then it is no longer needed and it goes away.

Tony Wyss-Coray:

Exactly.

Nicholas Weiler:

Well, I want to give a shout out to our worm lab friends, just a reminder of how important things like the lowly worm are for our understanding of fundamental biology. We can start to see things like organ aging in a worm, and now we're applying these ideas to humans. What do you see as some of the opportunities here? Why is it valuable to look at the organ level rather than the organism as a whole? Does it open doors for the vision of preventing age related illnesses, or even reversing the aging process for that matter?

Tony Wyss-Coray:

Yeah, that's a great question, and I think it's all of these. If you think about it, most of the major diseases that we can cure today have a very strong aging component, but they're usually diseases of a specific tissue. Whether it's the aging heart, the aging liver, the kidney, or the brain, as they age, they become susceptible to organ specific disease. And we still don't understand exactly what the contribution of age is, and when age stops and disease kicks in, or whether they are really parallel processes, or even almost the same. And they're just the ultimate reflection of aging. So some people say if anybody lives long enough, their brain will show cognitive decline, and ultimately dementia. It will just be dysfunctional. But you could of course also say there is a much more defined difference between a disease process and aging itself. So just from that perspective, it becomes extremely important to understand aging of a given tissue.

You can imagine that aging of the brain, there could be other genes that make the brain susceptible to dysfunction than aging of the heart. So you want to understand, what are the key pathways that manifest themselves in the aging process in these tissues, and when do they occur? And when do they occur in a given individual? If you knew that, could you then intervene in the aging process of that tissue and prevent the ensuing disease?

Nicholas Weiler:

Yeah, that makes a lot of sense. It reminds me of something. I was listening to a conversation that you had with Eric Topol about this new study a couple of months ago. And I loved this term or phrase that you had. You said, we've realized that the fountain of youth is within us. It just dries out as we get older. It's a great phrase, and I think it's so interesting that it's not just one fountain of youth. It's many, right? It's all these different organs, they're all aging in their own way, and we're starting to be able to get to a place where we can see maybe one organ is aging faster than the others, and that's the organ where you're likely to run into age-related disease, as you show in the study. Well, yeah, let's dive into the study because I'd love to hear more about it.

So maybe I can give a quick overview of my understanding of what you did, and you can let me know if I've got the big picture of this basically right. So my understanding is that you started out with blood samples from thousands of research participants, and you combed through around 5,000 protein biomarkers to figure out which of these proteins were associated with particular organs or tissues. And then you were able to use machine learning to detect how those different proteins change over the individual's lifespans. And that let you see how each organ was aging relative to the person as a whole. Is that sort of the big picture of what you all found?

Tony Wyss-Coray:

Yeah, exactly. And maybe to just put it in even simpler terms, if you go to the doctor and the doctor takes us a blood sample, they measure 50 or so molecules in that blood sample in what is called clinical chemistry. And many of these molecules give an indication. Many of them are actually proteins, and they tell the doctor how well your kidney functions, for example, how well your liver functions, how well your heart functions. If they're in the normal range, all is good. But if they're too high or too low, then you would be diagnosed, or you would be followed up with additional tests, and let's say they would make a judgment that you have maybe early stage heart disease. So what we do is we expand this. Instead of just measuring a handful of proteins like clinical chemistry does now, we measure 5,000 proteins. And actually the platform we are using, it's a commercial platform. Today, I can measure 11,000 proteins.

Nicholas Weiler:

Wow.

Tony Wyss-Coray:

So we measure these thousands of proteins, and we ask where do they come from? Which cell in the body produces each of these proteins? And a majority of them are produced by many different cells, or even by all cells because they're essential building blocks, let's say that provide the scaffold of the cell. So every cell needs that protein. So we cannot get a lot of information from that protein.

Nicholas Weiler:

That'll give you something about the organism as a whole, presumably.

Tony Wyss-Coray:

At the organism as a whole, exactly. But there may be a protein that is only produced in neurons in your brain. And if we detect this protein in the blood, and indeed we can with this platform about 200 proteins, we know are most likely coming from the brain. So if they change now with age, it gives us an indication of what's happening in the brain, right? And as an extension, because we know as you get older and as these proteins get out of whack, they are associated with brain disease, with cognitive aging, and ultimately potential with Alzheimer's or other neurodegenerative diseases. They allow us to predict whether somebody will get Alzheimer's disease in the future.

Nicholas Weiler:

And is the power of this, in part from the number of proteins you're able to look at, that you're able to pull out these patterns that would be hard to have predicted in advance?

Tony Wyss-Coray:

Absolutely. Yeah. It's a combination of advances in technology and just doing the obvious. If you look at it from the perspective of what have we done in clinical chemistry in diagnosing diseases, what if you take that to a new level and you just use the same principle idea? A protein comes from the heart, so it tells me something about the heart. We basically use all these organ specific proteins, and we built these models of biological aging, or people often call them clocks. So we could build a clock with heart proteins for the heart with liver proteins for the liver, with brain proteins for the brain.

Nicholas Weiler:

And do you see this as something that could expand those clinical chemistry tests in the near future? Do you see people getting a body wide, organ wide aging profile?

Tony Wyss-Coray:

I think this is totally realistic. We still have a lot of questions. It's super exciting, right? One of the key questions is, how stable is such a signature? So if we look in a given person and we find the proteins that track heart function that change with age, if I tell you your heart is five years older today, is it tomorrow, still five years older? Is what we're reading really reflecting the age of the heart, or is it just some biological variation that happens? We think it has predictive power because we have actually, in the meantime, now looked at 50,000 individuals from the UK Biobank. This is a large healthcare study, and we can predict with very, very high probability whether somebody who has these heart proteins out of normal range, whether they will develop a heart attack in the future. And the same for brain proteins predicting dementia now in 50,000 people, and in fact, with a different platform even. It's not the same protein platform that we use in the current study.

So we think there is some predictive power that these signatures are stable to some extent, but we have to prove that by following people longitudinally. So over a long time and see how their profiles develop. But then also more practically, when do you have to do something about this, right? If let's say your heart is older at age 30, but you will get a heart attack at age 80, what's the value in knowing that 50 years in advance? Is there any clinical intervention one should do, or is this not of concern? Because it only becomes a concern when you are 70 and your heart is five years older. So there's a lot of more clinically relevant questions that have to be tested in more defined clinical settings where you say, okay, you identify now a group of proteins that track brain function and brain health or brain age. Let's now use these in a more clinically defined setting and see, do they bring value to clinical interventions or prediction of cognitive decline?

Nicholas Weiler:

Right. It seems like you might also... There's a potential to also have a biomarker here where you could see, okay, let's say your heart is now 10 years older than the rest of your body. Well, we're going to have you cut out salt or take this medication. And then you could see, maybe you can bring that number down. Maybe you can bring that age gap down to where your heart is no longer acting like it's 10 years older.

Tony Wyss-Coray:

Exactly. Yeah. Thanks for bringing this up. That's really the beauty, in a way, compared to a gene screen, a 23 and Me where you know your genome. Here, the proteins are malleable in a way. So as you said, if you found your brain is older and you get clinical advice that you could do this intervention maybe to take, oh my God, three fatty acids, vitamins, and then your brain becomes younger again or more in line with your age, that could have tremendous benefits. And again, coming back to my earlier comment, what we really need to do now is we need to look at some of these studies that have already been done. I'm talking to an investigator who did a study with 3000 older individuals in Europe where they use some of these supplements, and they have collection of blood samples, and they have functional benefits in some individuals. So you can now look at these clinical studies and say, okay, the people who benefited. They actually had an older brain at the beginning and it became younger as part of the intervention, right?

Nicholas Weiler:

Right. It gives you something quantitative.

Tony Wyss-Coray:

Exactly. Yeah.

Nicholas Weiler:

I'm sure listeners will be curious to know if they might have organs that are aging faster than the rest of their body. I'm sure it's hard to generalize, but how common is that in your data, to see that someone has one organ that shows a really large age gap compared to the rest?

Tony Wyss-Coray:

Yeah, so we made sort of a random cutoff and said if you are two standard deviations above what you should be, what your actual ages, then we call this an extreme nature for a given tissue. And we find, very curiously, roughly one to one and a half percent across the people we've analyzed to have one organ older or not. And overall, about a quarter of all the people we studied had one organ older. It was also interesting that we didn't find that many people who have two or three organs older. It tended to be just one.

Nicholas Weiler:

Did you say 1% of participants had one super aging organ, but you also said a quarter of participants, so I didn't catch the distinction there.

Tony Wyss-Coray:

Sorry. So a quarter of the participants had one or more organs significantly older, or extreme organ ages. But if you look at the whole, we find 1% are kidney agers, or one and a half percent are kidney agers, 1% are brain agers, 1% are lung agers. It's fairly distributed across all organs. And again, we need probably more data to get this firmed up.

Nicholas Weiler:

Very interesting.

Tony Wyss-Coray:

Maybe that's still part of our relatively small participant number. Even though we have 5,000 people, they were mostly from studies that focus on Alzheimer's disease and dementia and the healthy controls from these studies. So there could be a bias there. I think, again, that we want to look at large longitudinal health cohorts and gather more information to get better numbers for you.

Nicholas Weiler:

Interesting. Well, I love the idea of using this kind of data that we can now acquire. There are so many recommendations out there for what to do to improve your aging process. I think the same ones come up over and over again. They're probably right. Eat well, sleep well, exercise, stay active mentally and physically. Do you think that there's anything that we will soon be able to offer or can already offer to be able to give more rigorous data-based guidance about how people can slow the aging process or age more gracefully?

Tony Wyss-Coray:

Great question. I believe it will take some more time, but now we start to have tools, and there's other research labs that are thinking along similar lines and try to make organ specific clocks. But where we can then look in studies that used interventions, how did that benefit the organ age? Let's say somebody exercises and you have them in a study before and after they start exercising, and you see the lung is benefiting, but the heart doesn't. Then you could use this information in the future to guide somebody with an older lung to do exercise because we know now that this has an effect. But it could also go beyond that, that you get much more personalized information because you will get this feedback, right?

You could test the age of your organs. You start with an intervention, and you see, does it work for you within two, three months? If it doesn't work, you could try something else because now you have a readout. And it's well possible, and we actually noticed from animal studies, that one mouse benefits from exercising, but another one doesn't. And so if you could find what really benefits the individual, then you really have personalized medicine.

Nicholas Weiler:

Absolutely. That's so interesting. That'll be a exciting future though. As you say, we may also get some bad news. "You're aging really fast. Sorry, we don't have anything for you yet."

Tony Wyss-Coray:

Yeah.

Nicholas Weiler:

Well, thank you again, Tony, so much for coming on the show. This has been fascinating.

Tony Wyss-Coray:

Thank you. Yeah, it was a pleasure,

Nicholas Weiler:

And we'll have to have you back again soon. There's always something exciting to talk about.

Tony Wyss-Coray:

Wonderful.

Nicholas Weiler:

Thanks again to our guest, Tony Wyss-Coray. 

If you enjoyed this conversation, I encourage you to listen to the episode we did last year on the biology of aging. Tony and I had a great conversation about the molecular fountain of youth that his lab has detected in the blood. We'll link to that episode and more info about his latest work in the show notes. 

If you're enjoying the show, please subscribe and share with your friends. It helps us grow as a show and bring more listeners to the Frontiers of Neuroscience. We'd also love to hear from you. Leave us comments or give us a shout out on social media. We're @StanfordBrain and @BrainResilience. 

From Our Neurons To Yours is produced by Michael Osborne at 14th Street Studios with production assistance from Morgan Honaker. Our logo is by Aimee Garza. This episode was supported by the Knight Initiative for Brain Resilience. I'm Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute. See you next time.