Geneticist Steve Horvath speaks about his pioneering invention and what he thinks might be possible for human life extension.
As a teenager in Germany, Steve Horvath dreamed of living to 1,000. He made a pact to dedicate his life to making this a reality for mankind. Horvath no longer harbors fantasies about living for hundreds of years, but he’s made good on his childhood promise to devote his career to extending healthy human life.
A geneticist and researcher of aging, Horvath in the early 2010s built the first widely used biological-age clock, a test that is designed to measure the age and function of cells, tissues, and organs. His invention, based on DNA methylation, a type of chemical modification to DNA, was a significant milestone for the field of aging research as it gave scientists a tool they could use to quantify aging. Horvath has since invented many more such clocks, including a pan-mammalian clock, which purports to measure the age of many mammal species, and a clock known as, which Horvath describes as the world’s most accurate mortality-risk predictor. “It’s named after the Grim Reaper,” he says. “It measures the probability that you will die in the next year.” A former professor at the University of California, Los Angeles, Horvath is now principal investigator of the U.K. research arm of Altos Labs, a longevity biotech company that says it is developing therapies that could reverse age-related diseases and disabilities. could make it possible for drug developers like Altos Labs to test longevity treatments in people, Horvath says: “It’s a quintessential tool to find interventions for rejuvenation.”interviewing longevity leaders and influencers, we spoke to Horvath about his pioneering invention and what he thinks might be possible for human life extension. What prompted your interest in aging research? It really goes back to my teenage years in Germany. My friends and I loved reading science- fiction novels, like the Perry Rhodan series and books by Philip K. Dick. We were especially fascinated by space travel. Then I learned about how long it would take to reach other planets—and in some cases, it was like a thousand years. So I started thinking about how we needed to work on extending our lifespan before we could even think about space travel. It’s funny, because as a teenager, I felt that our human lives were way too short. Now I'm 58 and I'm at peace with our lifespan, but at the time, it seemed to me that you could really do nothing with a lifespan of 80 or 90 years. I felt that we needed to work on rejuvenation and extending longevity. And so, I came up with a plan with my twin brother Markus, who was studying biochemistry, and another friend who was interested in computer science. It was so immature. I was like 19. We decided that we would divide up the work. I would work on the math and the gene networks, and we would each do our part and use modern science to follow the ancient dream of Gilgamesh. was one of the earliest novels of mankind and it deals with this Sumerian king who loses his friend and wants to extend lifespan, so he goes on a journey and he finds an herb that supposedly keeps us young and then the herb gets eaten by a snake. It has a bad ending, but basically, Gilgamesh goes on a quest for rejuvenation. We felt it was a cool name for our project. We called it the Gilgamesh contract and my friend actually kept it, so there’s literally handwritten notes in which we vowed to honor this agreement.The most relevant thing I worked on in those earlier years was what are known as early-detection biomarkers for cancer, and I picked up a lot of skills related to biomarkers. Then I received tenure at UCLA and I was very happy about that, and I said, OK, now I’m free. I can do anything I want, and that’s when I decided to go back to the thing that started it all. I wanted to go back to longevity research, but I thought that, because of all of my training, the easiest way for me to make a contribution to the field was to develop a biomarker for aging. People had already recognized that biomarkers of aging were important, and there had been substantial efforts from the National Institute on Aging to find biomarkers. The Institute had spent many millions of dollars on the effort, but overall, it had failed. I felt that it was important to develop clock to advance scientific inquiry in the field of longevity. I felt we needed exact measurements of aging before we could really study it and then hopefully one day find interventions that can reverse aging. I need to say, though, that I never took a single class in longevity. I came in as a complete novice. But I got so unbelievably lucky because I entered the biomarker field just when a new technology had been invented that allowed you to measure DNA methylation. Every cell in the body has the same DNA and the same four letters: A, C, T, and G , but, of course, cells turn on and turn off different sets of genes. A liver cell turns on certain genes; a brain cell turns on other genes. What determines this are all these epigenetic modifications . There are many different types of epigenetic modifications, and DNA methylation is one type. People have been interested in measuring epigenetic changes as a way to measure different kinds of stress, like pollution, obesity, and social stressors. Not right away. After I got tenure, I decided that I wanted to try to build a clock based on gene expression. But then I burned through two years analyzing so-called gene-expression data and found nothing. At around that time, Eric Vilain was doing epigenetic research on sexual orientation, and he asked me if my twin brother Markus and I would take part in his study. Markus is gay and I’m straight, so we’re what is known as discordant twins. Given that we have identical DNA, the question was, is there something different in our epigenome? I was the statistician for that study, which looked at DNA methylation patterns, but we didn’t find any signal for homosexuality. But then I thought, maybe I should look at this data for aging. And because I had just done all this work on analyzing gene-expression data in a hundred different ways, I had all the software scripts. So it was literally a five-minute analysis—and I'm telling you, I fell off the chair. I thought there was a coding error. It couldn’t be right because the signal was so strong. I immediately knew that methylation was the future. It was a real eureka moment.It was a chronological-age clock based on saliva, and it could estimate the age of individuals within approximately five years. So let’s say a 50-year-old gave me their saliva: the clock would tell you their age plus or minus five years. I was blown away. After that first clock, I started building more clocks based on blood and skin and different organs. I was like a kid in a candy shop. New important data kept coming in, and eventually, I worked my way towards what is now known as the pan-tissue clock . People call it the Horvath clock, but I don’t call it that. Epigenetic clocks were very controversial for many years, but now, I would say most leading labs in the aging field use methylation clocks or have used them. The No. 1 criticism of these clocks has been that they are blackbox measurements, and we don't know what they actually measure. Are they just measuring noise? But leading labs of the world have looked at these clocks in 100 different ways and used them to test pretty much any stress that you can think of—everything from metabolic stress, obesity, viral stress, and many diseases—and I think we really understand a lot by now. I don't think I'm allowed to say that. What I can tell you is we're using clocks, and in 2023, we published what I think is an important paper that details awe built that can apply to all mammalian species. It’s very accurate, and this pan-mammalian clock has since been used in phenomenal studies to understand the nature of aging. A recentBroadly speaking, my research at Altos focuses on rejuvenation. I'm excited about anything and everything rejuvenation—so finding both gene-therapy approaches, but also small molecules to accomplish rejuvenation. so they might one day be used in clinical trials and by medical doctors. Do you think any of these clocks are ready for primetime? Yes, I would say so. The field is developing and all over the world, there are amazing efforts to build better clocks. Sometimes you need to see the forest for the trees, and I see the forest. It doesn't mean we can't do better and we need to have some standardization, but sometimes one needs to recognize that certain milestones have been reached, and I feel like in this case, they have been. When it comes to consumer versions of these clocks, though, I don’t think people should be using them overall. Clocks differ. So if you take a GrimAge measurement, it gives you one readout. If you take my pan-tissue clock, it's another readout. As a scientist, I know these are actually very different clocks. So if one readout says you're 50 and the other says you're 40, I have no problem with that, because I understand different biology. However, a naive consumer might say,"My methylation age is that." Company A might be measuring certain parts of the DNA, and company B is measuring other parts of the DNA. There naturally could be inconsistencies, so that's why it would be very desirable to have some standardization.In my late 30s, I met up with that friend who had kept the agreement, and he said, “Do you remember the Gilgamesh contract?” He gave it to me to read, and it blew my mind. My work had basically followed the trajectory that these immature teenagers had written down so many years ago. I had promised to work on gene networks. At the time, I barely even knew what they were. But then, I ended up writing a wholethat suggests that your dreams as a teenager really determine your life, and I have to say that for me, this is 100% correct. My brother, Markus, initially got totally derailed. He was the first one to violate the contract because he became a psychiatrist. But this all has a happy ending, because he now works at Altos on longevity research. Can you believe it? In the end, he finally joined the Gilgamesh project. As a teenager, you hoped humans could live for a thousand years so they could go to another planet. Are we any closer today to that fantasy? We're not close at all. It's totally science fiction. But my mathematical answer is, I do think at some point there will be drastic extensions of lifespan. Imagine we have 100 more years of biomedical innovations—what will that do for health? Of course, we would expect major breakthroughs. So in an abstract sense, if we don't wipe each other out in a nuclear holocaust and if we can avoid wars and pandemics, I think our species at some point will find ways to extend lifespan drastically.
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