The grim news about your biological age

0:00Steve Horvath:How to live to 100, or die trying, is brought to you by Genical.

0:09We humans love the concept of longevity. It's an exciting gift, one that benefits less from our own actions and more from years of medical advances in science. But that is changing. Now that there's a legitimate shot at actually making it to 100, or reasonably close, a lot of people are looking for ways to do it with panache. To stay strong in body and mind. This goal has become a cultural norm. Eat less, get early morning sun, meditate. So, we buy books written by physicians we respect, or we listen to podcasts by men with PhDs in jacked biceps that go into the weeds on, say, 8-hour eating windows.

0:55and the deleterious impact of alcohol on the brain. And while some of this makes practical sense, like maybe best avoid alcohol-related dementia, most science on slowing aging or expanding lifespan, take your pick, is in its infancy. It's part of the great gold rush, as our next guest calls it, to be the first to find the scientific fountain of youth and trademark it. Steve Horvath is a biogerontologist, which is a scientist who studies the biological processes that cause aging and age-related diseases. Since his teenage years, he has been consumed with longevity. When he grew up and became a scientist, Stephen created an epigenetic clock, a measurement of your biological age that might even predict mortality.

1:44He named it aptly, Grimm, Age. It's like those DNA sites, but instead of identifying your ancestry, it could tell you how old your body really is. Stephen has interesting thoughts on all of this, on our desire to live longer than ever before, and the speed of these new discoveries now that artificial intelligence is a serious player. You'll have to listen to the scientists to find out your best shot at a long and healthy life. But let's just say that after all these years, our mothers were right.

2:29From the Toronto Star, this is How to Live to 100 or Die Trying. And I'm your host, Moira Welsh.

2:47So what is Grim Age and what do you do there? I developed a biomarker called Grim Age. And this biomarker measures really your age and mortality risk. people can access this biomarker and measuring their grim age by going to my non-profit foundation called Epigenetic Clock Foundation that offers this grim age test. But yeah, Grim Age is named after the Grim Reaper for a reason, because it's our best methylation-based biomarkers for predicting mortality risk. After all your years of research, what is your goal? How can epigenetic clocks be used? I use Grim Age and other epigenetic clocks. It's really the technical term.

3:45So you use epigenetic measurements of the DNA to measure your age. And I developed these biomarkers really as a research tool. It's meant to be useful for aging researchers or rejuvenation researchers. People want to develop treatments to either slow aging or reverse aging of different cells. So it's really meant as a research tool. Chronological age is based on the year, the month, or the day that we were born. Do most people understand what the biological age means? It's supposed to capture really your true state of aging, you know. And maybe the best analogy is when people go back to their high school reunion and then they look at others and they say, well, this person really didn't age much, whereas this person looks aged or stressed, you know.

4:46And so people have a sense that the biologic age may differ among people who have the same chronologic age. You know, in high school, most people of the same class have pretty much the same chronologic age. But a couple of decades later, some people have experienced many stress factors, psychological stress or metabolic stress due to obesity or smoking, lifestyle stress, hundreds of different forms of stress. And so some people are closer to death in terms of their biological state, you know, and that's what's meant by biologic age. Let's look at another definition, the epigenetic clock. In very plain language, what is that?

5:37Yeah, so the epigenetic clock is a way of measuring your age or your mortality risk based on so-called epigenetic modifications. And what are those? So epigenetic modifications are chemical changes to your DNA molecule. And there are many different types of changes. And to be more precise, many epigenetic clocks actually measure DNA methylation. So methylation is a certain type of epigenetic modification. And so you will hear the term methylation age, epigenetic age, and they both denote the same thing. Different scientists have created unique ways of measuring the epigenetic clock. Yours is based on DNA methylation.

6:35Can you explain how your measurement works? Yeah, maybe to flesh this out. So DNA methylation, if you allow me, changes with aging in multiple ways. Certain parts of the DNA gain methylation with aging, and that's bad news. Other parts of the DNA lose methylation. And so you want to track both age-related gain and age-related loss of methylation. And these methylation clocks really look at both phenomena. And they look at hundreds of locations of the DNA molecule, you know. And one metaphor is that it's similar to rust accumulating, you know, although chemically it's not rust, but it's a bit like that, you know.

7:25And yes, so these methylation clocks measure that. Now, when it comes to other ways of measuring now biological age, there's really an industry of different ways of measuring biologic age. Some people look at inflammation. We all know that as we age, inflammation increases. So some people work on that. Other groups work on immune system functioning. As we age, our immune system doesn't work properly. So people have developed biologic clocks that measure these immune changes that occur with ages. Yet another group looks at so-called proteomics, proteins. You know, when you go to your doctor's office, the doctor may order plasma proteins like C-reactive protein or hemoglobin A1C.

8:23So many protein measurements. And so other researchers develop proteomics, clocks, you know. And then to briefly digress, some people are all about image analysis. So the face, you know. You can go to your phone, you download an app, and it estimates your age based on a picture of yourself. So many researchers are trying to capture this elusive concept of biologic age by looking at proteomics, images. In my particular case, I'm quite enamored with epigenetic changes and methylation. And I'll explain to you why. But before I do that, I want to say every readout has a purpose, you know. But why have I spent the last 13 years of my life studying methylation?

9:16First of all, there's something really beautiful about having a clock that applies to every cell of the body. What do I mean by that? So really, actually, most cell types contain DNA. And the DNA determines, of course, everything about our body. And it carries the genetic information. But the new insights from epigenetic clocks is that the same DNA molecule is actually one gigantic clock. So we can measure age pretty much in every cell and every tissue of the body. That's a very beautiful scientific insight. The second reason why we like DNA methylation is we can actually build clocks that apply to every mammalian species.

10:11In other words, you could send me blood from your dog or from your cat and from yourself, and I can use the same clock to measure ages of all these different species. That's very appealing from a scientific point of view because we can measure conserved aspects of aging. Most people know, of course, that all mammals age. And there's something very nice to measure it in a uniform way. Whereas when we come back to this idea of measuring your age through a photograph, the face of a human is quite different from that of a dog. So it's very different to come up with a clock that works in both species.

10:54We'll be right back.

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11:34Let's discuss the way people age. Are there, say, fast-agers and medium-agers? So when we have a particular clock, such as grim age or any other epigenetic clocks, we can definitely define fast-agers, average-agers, and slow-agers. We have a reference population, and we can tell somebody, you are in the 50th percentile, you're pretty much average, or you're in the 10 % category of fastest agers. What might be the difference between a fast ager and a slow ager? Can anyone actually say? Yes, we can. So let's say if your grim age is eight years older than that of the average person, meaning average determined by both your sex and your chronologic age.

12:33So in other words, you're a 50-year-old man, but your grim age is 58. Then your what we call hazard of instantaneous death would be more than twice that of the average. So this is a technical term, hazard ratio. But in certain ways, it's a relative risk. What is the likelihood that you will drop dead in the next year compared to the average? In terms of our biological age, how heavily weighted is our DNA over our lifestyle? So lifestyle has a surprisingly strong effect on grim age. In particular, smoking has a huge effect, but also something as obvious as vegetable intake. So interestingly, people who really eat a lot of vegetables have a much reduced grim age.

13:33You know, exercise also has an effect, you know, possibly a weaker effect. But honestly, everything related to lifestyle has the expected effect on grim age. So vegetables, can you get your vegetables through powder or supplements for people who don't actually like to eat them? Or does it have the same impact? Do you actually have to eat them? Yes. So we had data from the Women's Health Initiative. That's a famous study of postmenopausal women. And the researchers evaluated vegetable intake through so-called food questionnaires. And then, so people have to remember how many servings of broccoli do they eat.

14:19And when we looked at these food questionnaires, our results were somewhat disappointing, you know. And I mention it because people have bad memory, really. But then we used the blood-based markers of vegetable intake. So you can literally measure the amount of carotene in the blood, you know. So there are blood-based measures of how many vegetables you consume. When we used the blood-based biomarkers of vegetable intake, people really couldn't cheat. And then we saw very strong correlations between vegetable intake and grimmage. and meaning the more vegetables you eat the longer you're going to live that's correct that's correct yeah so after learning about that i really changed my lifestyle i need to tell you you know so i increased my consumption of vegetables by a lot with a simple trick i eat vegetables for breakfast you know because i can control my breakfast very well as opposed to lunch where I'm at work, you know.

15:26But yeah, I consume a lot of frozen vegetables. If one was to benefit from a steady diet of vegetables, would we have to have started by the age of five, say? Or if someone wants to start eating vegetables now after listening to you, would that help? Yeah, that's a very good question. I don't have a completely rigorous response because I haven't carried out such an interventional study. However, other people are starting to publish these types of interventional studies. So I've seen a couple where people reported a beneficial effect, you know. So with all due caution, I would say there will be a benefit.

16:11And anecdotally, I can tell you that there may have been an effect on my personal grim age because I remember following a poor diet for most of my life. And when I turned 50 or so, I really changed things around, you know, and I increased my vegetable intake and my grim age went down by a couple of years. To build on this piece of our conversation, if someone wants to lower their biological age, what are the evidence-based interventions that would help with this, other than vegetables. People talk about exercise as being the most powerful tool you can use. But from your knowledge, what is the answer?

16:53Yeah, so exercise definitely has an effect, but there is a sex effect. So it turns out that women benefit more from exercise than men. I don't know why, but it's a well-known finding. And exercise sounds very daunting, but what we're talking about is walk your dog if you have a dog. So walking already has a tremendous benefit, you know, just move, you know. The more the better, but there's a big difference between no exercise and some exercise, you know. I like the 20-80 rule. 20 % of the effort gives you 80 % of the benefit. There was a surprise recently where an investigator evaluated an anti-diabetic drug known as metformin.

17:47It's actually a well-known drug in the longevity field. Many people talk about it. There's a famous researcher, Nia Baselai, who has advocated its use for many years. What I can say is there's evidence that metformin slows epigenetic aging. But it brings me to a larger point. Drugs prescribed by the doctor seem to have a much stronger effect than lifestyle factors. Disappointingly, you know, so it would have been nice if you eat your vegetables and then you get the same effect as you get from a drug, you know, but there it is. And there's quite some literature that various drugs that are used against diabetes or obesity or what they call metabolic syndrome, things that disrupt your metabolism, that these drugs could have a benefit on epigenetic age, but also on many other readouts.

18:48You know, readouts meaning your heart functioning and many other, your blood pressure and so on. Now, I hasten to add, don't self-prescribe, of course, get a doctor, because not everybody should take metformin. If we could stick with metformin, which again is a very popular topic among longevity researchers, but metformin has certain side effects. So it could negate your muscle growth as you exercise. Maintaining muscle function is absolutely critical for healthy aging. You want to be strong as you age. And you can see how you don't want to impair this muscle generation that takes place during exercise.

19:34And there have been papers that suggest that metformin and similar drugs impair that muscle regeneration. So be very careful how you go about slowing your aging. I've listened to a lot of podcasts on longevity and exercise, and I wonder if the idea of a biological clock can be somewhat anxiety-inducing. You get caught up in this idea, but you might actually be creating stress that you would not otherwise have experienced. I agree with that. But for the life of it, I don't understand why people measure their biologic clock. I really don't understand it. Because let's say I take such a test and these tests are expensive.

20:18They can cost you a couple of hundred dollars. Okay, so then you learn your age is a particular number, 50. What do you do with this information? So for most people, the age estimate will be pretty much the chronologic age. They learn nothing. Other people will learn they are younger than expected. And here's the one use of that measure. You can brag to your friends. You can say, look, I'm five years younger than I should be. It all paid off, you know. And so bragging rights, all good. However, does it mean that you should now stop your healthy lifestyle? Absolutely not. You know, you continue.

21:01Conversely, the people who learn that they are older than expected And hopefully they get motivated to lose a bit of weight, to avoid sweets, exercise. However, do you really need such a molecular test for that? Because my point is, of course, you should be following a healthy lifestyle. Of course, stop smoking, reduce sugar intake. I personally rarely measure my biologic age. I do it because I'm curious, but I just don't do it because I follow a healthy lifestyle no matter what, you know. Now, other people have said, well, you can use this test to inspire people to change their lifestyle. If so, that's good.

21:45But conversely, just how about you measure your weight? There are cheaper ways to motivate yourself. We'll be right back.

22:00Do you recognize this new obsession that people have with longevity? In general, I think it's a wonderful obsession to care about your health and to care about the health of your loved ones. I also think it's a healthy hobby to have. If you care about your health, you will get benefits from it. I would say that epigenetic clocks and all of these other biomarkers I mentioned, they've all actually elevated the field. Because when you think about it, 20 years ago, we also had longevity companies, but they could just make up anything. There was no way to evaluate their treatments whatsoever. Nowadays, in theory, a consumer can test things and say, well, I tried this supplement and for me, it did have an effect or it didn't have an effect.

22:55So at least they have a measurement. And because of that, I am glad that these biologic clocks are not being regulated. Because you could take the opposite view. You could say, well, there is a danger that people misinterpret these readouts and get very obsessed with death and depressed. And therefore, one should regulate them and even forbid them. Let me give you an anecdote. So a year ago, somebody emailed me and said, I measured my methylation age and it was 100 years, which is unbelievable. So then I said, by email, I said, well, measure it again. And they said, well, I did. I measured it three times.

23:43Every time it was 100 years. What does it mean? And to me as a scientist, utterly interesting. As I said, it would happen once in 10 ,000. I'm surprised it happened at all. But you could see how people in theory could get alarmed and depressed. And I want to emphasize that here comes the greatest error that people make with these methylation tests. They translate the age to lifespan, you know. So imagine you are this man and your methylation age is 100. You would say, oh my God, I will drop dead tomorrow. Very high mortality risk, you know. But that's not at all the case because the methylation age does not translate to lifespan one year to one year.

24:29Globally, centenarians are one of the fastest growing demographics. Have you been able to examine their epigenetic clocks? And do you know if the children of centenarians are also likely to live that long? So if my parents died at 90, are the odds that I will likely die at 92 unless I don't first get hit by a truck or something? I did evaluate the offspring of centenarians and compared them to the offspring of non-centenarians. So in other words, I had blood samples from a 70-year-old whose parent made it to 100 plus and a 70-year-old whose parents died early. And interestingly, there was a difference in epigenetic age.

25:17There clearly was a benefit for children of centenarians. their epigenetic age was a couple of years younger. And that highlights one of the points of epigenetic age, which is there is a genetic component, no question about it. I want to throw out a number, maybe 20 % is under genetic control. So yes, people who have long-lived parents have a slight benefit. The other finding was that centenarians have a younger epigenetic age in general. So if I take a regular epigenetic clock and evaluate a 110-year-old person, their methylation age could be 95, or substantially lower. And some of my colleagues like that findings.

26:07They say, well, it makes sense because the biologic age of centenarians should be younger. But I now want to tell you an anecdote. The most famous long-lived person was a French lady called Jeanne Calment, who famously reached the age of 122. So the French are very proud of her. But recently, there was a large controversy surrounding her where people said she actually was her daughter. At the time, in the 1930s, the French inheritance taxes were exorbitant. So this family owned a business, and the thinking was that the daughter impersonated her mother so that they avoided inheritance taxes. So then I took it as a challenge, and we developed what we call centenarian clocks.

27:03So these are now methylation clocks where we can verify the age claims of centenarians. But you often hear these stories where people are in a remote village. There's a famous case of a man in Indonesia who claimed that he reached the age of 147. He even had a driver's license. People make these claims. They're exceptionally old. But now we have methylation clocks for checking these claims. In a 2020 interview, you said that a number of labs are trying to come up with interventions to slow aging. calling it a gold rush to see who would come up with the first of those interventions. That was five years ago.

27:46Do you still believe that a gold rush is underway? No, the gold rush is alive and amplifying. So there are many biotech companies that aim to slow, call it biologic age, but most of them also use methylation age. Methylation age is really the benchmark molecular marker. It's not the only marker, but most labs use it. And of course, we're all desperate to find interventions to reverse epigenetic age. There's now a competition for the longevity X prize where the winner will gain over$100 million if they come up with a credible intervention. This intervention will be judged by different functional measures, organ rejuvenation.

28:36but hopefully also by methylation clocks. I'm very happy that this has become an interest in the biotech industry, which just shows that the science has advanced. In the past, the biotech industry was focused on, I call it, traditional diseases, cancer, and hundreds of other FDA-approved diseases. But now there's an interest in longevity interventions. A geriatrician who was on this podcast said a lot of people are caught up in collecting data on their bodies. And he said when they bring it to him, most of it is absolutely meaningless, but they're compiling a lot of it. At the Gerontological Society of America conference, there was a leading advocate from a very large organization who said that the science on many of these advances is too young to be worthy of our money.

29:29How do you respond to these critiques? I think these are fair critiques. So most data that people collect are useless, you know, and I would say they would probably agree with that statement. You know, the issue is you never know what you should have collected. So again, it's the best way to frame it as it's a hobby. So some people have that hobby of measuring a lot about themselves. And if you take it like that, then it's a nice hobby. For a clinician, it's also true most of the measurements at this point are not valuable in any way because they may not be linked to any disease. And more importantly, we don't have a drug for them.

30:17Which brings me to the greatest criticism of the Grimmage clock and methylation clocks. I want to emphasize it. We don't have a validated treatment for methylation age. And so this is the main reason why a doctor will not measure it for you, because doctors measure things that are actionable, where they can give you a pill or an intervention. And with the methylation clocks, we are not quite there yet. In your lifetime, for these concepts, what do you see as the value of their benefit for humanity? Yeah, so the good news is we're in the middle of this AI, artificial intelligence revolution, which will change everything, including methylation measurements and clinical practice.