28 July 2021
Over the last 150 years, our life expectancy has grown, from 40 years in 1850 to over 90 years today in some countries. This can be attributed to advances in medical science, improvements in public health, and equitable access to healthcare, especially for maternal and infant care.
What will the future hold for our world? Will we be overwhelmed by a ‘silver tsunami’ of retirees with poor health, or will we use the latest research findings to rejuvenate the elderly and extend their lifespan?
Our Longevity Futures is a show where I, Chris Curwen, speak to scientists, engineers, entrepreneurs, doctors, politicians, and community activists who are giving the world the hope that we can all live longer and better, and improve our health.
In today’s episode of Our Longevity Futures, we are delighted to host Prof. Georges Janssens. Georges is a biomedical scientist and is currently an assistant professor at the Amsterdam University Medical Centre, where the main focus of his research is on elucidating the process of biological ageing.
Georges is also the creator of ageing is beautiful. A website dedicated to the science and philosophy of ageing. Bursting with information on the basic science behind ageing, how to achieve a healthy lifespan, and how you can accurately measure your biological age.
Georges also boasts contribution on an impressive array of biomedical research papers, including one that we will be talking about today, titled “Biological Age Prediction From Wearable Device Movement Data Identifies Nutritional and Pharmacological Interventions for Healthy Aging”.
Here are some of the highlights for my conversation with George:
Chris: Firstly, could you tell me a bit more about your background, and how you got interested in looking at the science around the biology of ageing?
Georges: Yeah that’s a good question. That brings me back. Probably an answer that I hear a lot is actually the same as mine. From a young age, I saw my grandparents getting older. I saw parents getting older. I saw some doing it in a very healthy way and bursting with energy. And others really debilitated. We’ve all seen these examples. And just from a very early age, I thought this is the ultimate mystery to figure out and is because it does not only happen to people we love, but it happens to ourselves and as a lot of global significance.
So yeah, what’s going on, what’s happening. And so, it led me more towards the molecular path to understand there are a lot of ways to approach it. And so that’s how I started going into molecular biology of aging.
Chris Curwen: What is your definition of ageing?
Georges Janssens: So, that’s a very surprisingly hard question to answer. Right now we go with calendar age in a normal way. And it’s just in a way of progression over time. And with that progression, we’re more likely to get sick. We lose resilience. We lose youthfulness basically.
So, I guess the definition that I use the whole time is that just the passage of time, which makes you less likely to withstand, basically disturbances in your system. And that’s involving now more to a biological understanding which leads a bit into the work we’re doing. To say actually there are different rates of aging.
And just using a calendar age is not the best unit anymore. That’s a bit how things are shifting for me and for the field, of course.
Chris Curwen: How has your definition evolved over the time that you have been researching it?
Georges Janssens: Yeah, absolutely. So I started from really a systems perspective. And because I thought it was quite complicated. We need to measure as many things as we can and figure it out. So with that, I actually worked first with yeast. With budding yeast and replicated aging. And it’s one cell, so I figured, if you can understand it in one cell, that’s already quite good. And then I moved from there to worms and always really in genetic pathways. And lately I’ve been shifting a lot more into more therapeutics and quantifying the rate of aging with the idea that all this knowledge should actually maybe bring us something more practical.
And with that, that’s basically therapies and diagnostics. So I’ve been shifting more towards that from the more fundamental work, which I still do. But also into applying for therapies.
Chris Curwen: Your website is a treasure trove for useful information around the field of longevity.
So how important is the public dissemination of science for you. And also how important do you think it is for the field, and developing the public’s understanding of this area?
Georges Janssens: Yes, it’s fundamentally important because we are researchers funded by the public. And when it gets on the radar of the public, that’s when things can really change and especially with an aging, because there’s a bit of a taboo on the subject.
Somehow it feels uncomfortable to talk about aging. It feels like that there’s a lot of work we need to do just to bring it into the public and discuss it. And that’s why some of the work I do, is just mainly about that: trying to get more information out there, more tools, more fun things… Actually the paper you’re talking about, that just came out, is really a fun project to try to engage people more. I can say, we can track our aging, we can measure ourselves.
In Dutch you say ‘meten is weten’. Measuring is knowing. Bring it out there too. It’s not just a calendar that’s going day by day. You can do a lot to keep yourself healthy and youthful.
Chris Curwen: Do you think the public perception of longevity science is changing?
Georges Janssens: Yeah, I think it’s going to take still some time. I know I’m in a bubble where I think it’s normal, but it still takes time. And if I’m out meeting new people, which is of course less now with the corona-times, but whenever I bring up the subject, I hear many theories that are just all over the place on aging and topics and views. There’s still a lot of work to do.
Actually, especially because I think in a way, because everyone ages, everyone feels the ability to be an expert on the topic and to say, ‘Yeah I read some things. I understand it. And that’s how it is’, but of course it is a whole science behind it.
Chris Curwen: Can you give us a brief overview of your recent publication?
Georges Janssens: Yes, sure. So, the idea that we started off from is there’s a lot of talk now about biological aging. Which are – I’m sure you’ve heard of them – and you can do it with epigenetic aging. You can even see associations with telomeres that there’s no clock on that. But there’s many clocks coming out and just as someone interested in it, I thought how hard is it for me to get my own epigenetic aging score basically?
Yeah, it’s really hard. And there are some companies coming up that offer it. But the idea is, that we need to make it far more accessible, I think. We have to start somewhere. And what are the things that everyone has? And that’s accelerometers. And that’s either on your phone or your watch. And then we can use that data and make a proof of principle.
And then beyond that, we can show that it’s relevant for some kinds of associations to biological age. So, that was really our end goal, not just to make the clock, but to show that we can retrospectively look at some factors that are associated to younger biological age.
And this is also something to say – biological age, everyone defines it differently. So for us, based on your movement patterns, it’s like an aging score which we’re now going to call biologic age at the moment, for this purpose. But then to see, what are those factors? We found several nutritional components, which there is evidence for that already. And we found one drug, which was underpowered in the analysis. So, we have low sample numbers to identify that.
But we still went ahead and tested it in the lab, because we do molecular work too. And saw there that drug, which is called Doxazosin, can extend the worm’s lifespan. But more interestingly, it expands its mobility. So our whole score biological aging clock is based on mobility.
And we could show that in the lab that this drug also maintains the mobility in the worms. So that was, I think the most exciting thing.
Chris Curwen: You describe developing the MoveAge model, which predicts biological age based on movement. What data was used to train this model?
Georges Janssens: Yes, so this is based on an NHANES data, which is a very large study in the United States.
And they had a few years where they asked participants to wear accelerometers. And they had them on their legs for about a week. And so this is several thousands of participants who’ve done that. So that’s the data source. So in rock accelerometry data. The model that we chose to go with is ‘Random Forest’, which is a really popular choice in the machine learning field. It’s also non-linear, so it can catch for some trends that are not necessarily linearly changing with age.
And then, what we found to be the biggest factors involved basically are, not surprisingly maybe, your maximum intensity of your accelerometer and also your variance. So that means the variety of movements that are occurring in the day or the week, for you. It’s based on a one week timeframe. The more variance you have, the more that was associated to youthful biological age.
So max intensity and variance were really the two. We calculated it throughout the day on a minute base. So we can have just a lot of data still for that. And then, that’s essentially how the model works.
Chris Curwen: How accurate is it at predicting biological age, how does it compare to other predictive models such as epigenetic clocks?
Georges Janssens: So those clocks you mentioned are extremely accurate. So they have around two or three years of error. The one we built. Depending on the data source you have. So, if you use epigenetics, you have around three years, if you use some blood markers, you can have something like 12 or 13 years.
We came out with two versions. So one was about 14 years of error. And then we included a normalization on your age, which would bring that down to about seven or eight years of error.
And when we say error, this is an interesting thing in the field of aging clocks, is we say that the error is not our model, but it’s your body. Which is, I think, a very strong thing. And so what we have to do then, is to show that the error in our model associates to mortality, which is also what we show.
So I think what’s interesting about these clocks, is it’s maybe not so interesting what the accuracy is, but it’s more interesting how the difference of your model is relative to predicting your mortality.
Chris Curwen: And what conclusions could you actually draw from the findings, that looked at the relationship between movement and aging?
Georges Janssens: So the conclusions were, that these two main factors come out the most. So your maximum intensity and variance. If you want to talk about the nutritional components too.
Chris Curwen: Yes, we can definitely move on to that.
Georges Janssens: We mainly built the clock to apply it, rather than to explore the underpinnings of it. Also, because all these clocks are a little bit like black boxes where you throw in data and then, there are factors involved.
And for us, because we used ‘Random Forest’, we can trace back exactly what are the key components. But we mainly want it to apply it. And we say, if we can apply it to something and something useful comes out, then we’re happy with that. And so this one involved retrospective analysis on food components. Which is really interesting because what we saw is, there’s not much association to food components in the younger ages we use.
So the twenties, for example. Food didn’t have that much association, but we saw a trend towards it having more and more importance around the sixties and seventies. Where this seems to be a bigger separation force in biological aging. And maybe either a lifelong nutritional program or a program at that moment, that these people were having, has their biological age.
Chris Curwen: And what sort of information did you have on their diets? Was it just the different things that were used or how much or…?
Georges Janssens: Yes, they give surveys to the participants. And then they break that down themselves into components, which can be calories, can be fiber, magnesium, vitamin C, vitamin E… All the components of the food, the abundance of their food.
Chris Curwen: The world of wearable health tech devices is developing at an incredible rate. The use of CPG monitors by the wider public, not just diabetics, is now becoming a mainstream debate. How do you see the future of healthcare being changed by this revolution?
Georges Janssens: I think drastically, because what we’re moving towards is… We need personalization of our recommendations. And so, what’s good for one person, won’t be good for another. And a lot in the aging space too. So you have for example, some studies in mice, which different genetic backgrounds show that calorie restriction can increase lifespan, but also really shorten lifespan. If you have the wrong, let’s say, genetic background.
So this is all personalization and we need to track the health as we’re changing our diets. As we’re trying to approach more healthier way of living, we need to track it to be sure we’re achieving what we really want rather than being detrimental. Because you can be detrimental too, if you’re not doing it right.
Chris Curwen: Are there any other health trackers that you could have involved to improve your study?
Georges Janssens: So, it’s all…. Because you asked me like dream versions of what the data I could have. But then there’s what’s accessible actually.
Chris Curwen: You answer them both separately. It’d be really interesting to hear.
Georges Janssens: So, let’s say right now, some interesting things are maybe heart rate variability. So you can check these, if you could link that into movements. Because for example, we always say let’s aim for a lower heart rate, which is healthier.
But with aging, your heart rate lowers. So you want to, of course, be sure that your heart rate is lowering from your exercise regime.
So that heart rate variability, I think on top of that, would be great.
But if you say what’s accessible, I think we can already do a lot with things like blood sugar levels, BMI, or your blood pressure. I think these can all go into a model that can actually give you a pretty good idea of your biological age too, because blood pressure changes with aging, BMI changes with aging, resting heart rate changes with aging.
So all of those things are very simple to acquire, but then you can go with the much harder data to acquire. Which should be for example, continuous blood sugar monitoring. I think, it would be fantastic to have a large data sets on this.
Chris Curwen: Could you tell me a bit more about Doxasozin, the drug that you revealed to have geroprotective effect?
Georges Janssens: It’s used clinically for a large prostate or for blood pressure. Mainly for prostate treatments. We hadn’t come across it before. It’s not such a famous thing in the aging world, to treat with Doxasozin, which made it more interesting for us.
And I guess, the mechanism is actually what we’re currently studying. So we didn’t publish any mechanism in the paper. And that’s what we’re now actively working on. To not have the paper before parts for papers, basically.
But then I was trying to figure this out. There’s an interesting study that showed actually Doxasozin users are also – so this is done in humans – are less likely to have Parkinson, which can be considered age-relating or we can go with around neurodegenerative disease. And here are the claims around glucose metabolism. If you look at the genes, it could be related to proteostasis in worms. There could be some implications for that too.
But these are all hypotheses that we’re now following up in the lab by doing the genetic epistasis. So we knock out the genes we are thinking are in the pathway, get the drug and see if the drugs effects are lost. And that’s really the traditional molecular biology ways to do it. So that’s an ongoing research now.
Chris Curwen: Could this be heralding of a new longevity drug? Or is it just far too early to tell really?
Georges Janssens: Well, that would be great if it worked, although a lot more research is needed.
So it’s definitely not something to run out and take at all. So we need a lot more research on that. But it could be, and I think that’s interesting why there are other studies that show its associations to lower risks of age-related disease. And I think more and more will come out.
And that’s what’s interesting is, it has not too severe side effects. You could imagine it could make its way, but a lot more work is needed.
Chris Curwen: What are two or three things that you believe are inevitable over the next 5/10 years in the field of longevity?
Georges Janssens: That’s a good question. So inevitable things in the field of aging or death. But I guess you mean more on what breakthroughs will happen?
Chris Curwen: Yeah. And over the next 5 or 10 years, is there some aspects where you think, this is really going to click off? Or things that you feel like that definitely can happen?
Georges Janssens: So I think, a big field I think that is going to emerge is combinatorial drugs. So right now, everyone looks at one drug and tries to do something with that. But the problem with one drug, is you usually need a bit of a higher dose and then it’s accompanied by side effects. And what we’re just at the infancy of looking at, is combining drugs that are targeting different elements of the same path.
To achieve lower doses, lower side effects, risks, and more likeliness to be applied in humans. So, combinatorial drugs is one more that is more on the applied side.
And I think on the research side, we’re just, unfortunately, starting to look at health span. We’re still looking at lifespan nonstop, in many papers. But yeah, we can’t keep doing that. So we need to look at how is the health span of the animal affected. So this, I think, will be a big shift in the coming year.
Chris Curwen: One of our recent talks we had with Dr. Greg Fahy from the US who had recently, or I think in 2019, published that the TRIM-trial that looked at a combinatorial drug combination of Metformin, DHEA and growth hormone.
Which effectively, according to the Horvath epigenetic clock, actually reversed the biological aging that it showed.
Georges Janssens: Yeah, exactly. Those are some that might act in different pathways, which is also interesting. So I think those are the two elements of either different pathways to synergize around all the hallmarks of aging let’s say, or focusing on one pathway and say maybe lower dose of Rapamycin, but with another drug, but then also inhibits or boost autophagy or inhibit translation, or these things. So that’s focusing more on one lower side effects.
Chris Curwen: What are the obstacles that we will need to overcome to realise these things?
Georges Janssens: The big issue is, in the research we do we’re publicly funded. So we all struggled to get grants. In the grant world, it more leans towards mechanistic studies and less towards drug studies. While drug is a bit left to pharma.
And so, it’s a bit I think a challenge to say, I’m going to study this drug rather than I’m going to study this gene. And so I think that’s something that if that shifts, we can get a lot more research on how to use these drugs. What doses, what timing, what things, which are expensive studies to run. So that’s what I think is a big hurdle actually to get over.
Chris Curwen: What are you working on next?
Georges Janssens: Yeah. So Doxazosin is one branch we’re following. We’re also following a few other accessible age predictors, we say. So ways that the public can use them. Maybe moving more towards not just theoretically showing it, but having an app or having something like that.
And then one branch we always keep working on is FOXO3 activators. So FOXO3 is probably one of the sole genes associated to human longevity, which makes a strong case for finding components that activate that. So those are all a lot more diagnostics and therapeutics.
Then our work is on the underlying mechanisms still to figure out what genes and discover new pathways either in mitochondrial biology and different metabolism for transcription factor. Those are the main ones at the moment.
Chris: Is there anything else you’d like to share with us?
Georges Janssens: Yeah, I guess what’s nice to see is initiatives like you have to try to bring it out to the public. And I think one element that can come from that, is more publicly supported or based as studies where, you know, if you look at the amount of data that ‘23 and me’ has, for example, it’s nothing academic in there. No research like that, but they can move mountains with the data they have.
And I think the public can reach something like that too. If we make an infrastructure through apps, software, platforms to share data anonymously a lot can be done there. So I’m always open to talking about those in your efforts like this to spread awareness, I think is great to see.
We really appreciate Georges for taking the time out of their day to come and talk to us. A massive thank you from Chris and everyone on the Gowing life team. You can keep up-to-date with everything that Georges is doing here.
Please join us for future episodes and tell your friends and family about us!