A

We are living through the most revolutionary period in the history of humanity. You could be one of the last people to live a normal lifespan, or one of the first to break the maximum limit of 122. The technology is coming. OSK alone could reset the epigenetic clock of human cells. One of the most exciting milestones happened recently. ER100 became the world's first epigenetic reprogramming therapy to be cleared for human clinical trials. It's the same tech that cures blindness in mice. People that have been treated, if all goes well, will be able to see again. So cross your fingers that that works. Welcome to Lifespan, a show where we discuss the cutting edge science of aging and how to live healthier at any stage of life. I'm David Sinclair, a scientist and professor working on understanding why we age and discovering new ways to slow and even reverse the aging process. On this show, I share an insider's look at the latest from my lab, the field, and what's just around the corner. Hey everyone. It's great to be back after the pilot episodes, which I'm so grateful went to number one. This new Lifespan show is bigger and better. Now. Matt will be coming back for some shows and I'm also going to be interviewing scientists from the longevity field. And from my lab, we'll hear what it's like to make these discoveries and where humanity is heading. These folks have more than a five year view on the future because they're actually inventing it. Normally this would be hidden behind closed lab doors, but we're going to gain special access. To join our community, visit lifespan.com My Life's mission is to extend healthy lifespan for all. And that's why I founded Lifespan, which exists to help you and your loved ones live your longest, healthiest lives. We're building the world's largest longevity community and supporting medical research through the nonprofit Lifespan foundation. Of the 150,000 people around the world that die every day, approximately 2/3 of those are due to age related diseases and conditions. With aging at the root cause of those. Hence, we can dramatically improve human health by targeting aging itself. We are in a new era, and Lifespan covers what you need to know about the exciting world of aging and longevity science. In making this episode, I used everything from tennis balls to DNA models to show you how cellular software might be rebooted. I recorded this over many weeks because it was really hard to make. We looked at thousands of papers and double and triple checked every fact and even rerecorded parts for accuracy. And with that, let's go to my left here, I'm excited to introduce the Lifespan smart board. This board here, I can go up, I can touch it. We can zoom in on figures from papers. And every show we'll be examining the science on that whiteboard and also bringing up video chats and other things. To my right here, we have a glass cabinet as part of this beautiful old library that I've filled with objects of interest that I'm going to bring out throughout the shows going forward. And they'll illustrate what I'm talking about from DNA molecules to the Wright brothers plane. Even Arthur C. Clarke, the science fiction writer who features in my book Lifespan, famously said any sufficiently advanced technology is indistinguishable from magic. And. And if you've not yet heard the news, I'm excited to inform you the technology is coming. One of the most exciting milestones happened recently in January 2026 when Life Biosciences drug candidate called ER100 became the world's first epigenetic reprogramming therapy to be cleared for human clinical trials by the fda. The tech is essentially a gene therapy that came straight out of my lab from my student Wan Cheng Lu. It's the same tech that we published on the COVID of nature in 2020 that we showed reverses aging and cures blindness in mice. Professor Bruce Cassander, Sharon Rosenweigson and her team at LifeBio have since shown that this tech also works in monkeys to restore visual function. And we're about to learn if it works in humans to reverse vision loss. And from there, just pick your organ of interest. Ear, kidney, heart, liver, skin. The possibilities are just too numerous to list. I'll talk much more about all of that later and give updates on how the trial goes in later episodes. What used to be science fiction just 10 years ago is now coming to reality. And the science that used to live on the pages of journals and in academic conferences like the ones I typically attend, it's now coming to the market. No science show would be complete these days without mentioning AI. Artificial intelligence isn't here just to solve problems faster. It's here to rethink them. AI systems today are helping uncover previously invisible aging biomarkers, revealing drug targets tied to biological aging and even suggesting repurposed compounds that could rewind the age of cells and address multiple hallmarks of aging at once. I know this because my lab is doing this, and I'm excited to bring you the latest findings of my lab and the field insights you can find nowhere else in the Next wave adaptive agentic AI systems could partner with human biology to optimize interventions, essentially acting like an ever learning personal longevity scientist for you. Sequencing just one genome used to be reserved for elite research labs at a cost of about a billion dollars per genome. In early 2026, the $100 genome has been announced which is going to pave the way for personalized longevity guidance, cancer detection and decades before it actually happens, as well as drug personalization and age estimation. At least your epigenetic age, which we also call your biological age. And this is quite different than the one size fits all advice that represents the 20th century. This means you have a choice, be a bystander or be literate in what comes next. The longevity space is moving really rapidly and its progress is only accelerating. The sheer amount of information and updates happening make it extremely difficult for any non expert to make any sense of what's going on. It's hard to get a good grasp on what's real and exciting versus speculation and science fiction. You've probably noticed that people who are really passionate about wellness and longevity have some very strong opinions that often conflict with each other. It's hard to know who's right. Influencers are even worse trying to gain attention by saying outrageous things or hyping up a new study. I see it all the time. Eat only meat. Seed oils will kill you. You can't take metformin or berberine if you want to gain muscle detox. Teas will cleanse you. Even cold plunges will melt fat away. What about you must eat every two to three hours to stoke the metabolism. A lot of these couldn't be further from the truth, and we're going to dissect the real science here on this podcast. Given the opportunity, virtually everyone that I talk to would like to become a centenarian, someone that lives over 100, especially if they would spend the vast majority of that time free of disease. My father, for example, who I talk about a lot and he's in my book, is now 86, and by following the practices we will be discussing on this podcast, he remains in perfect health, as energetic and as busy and even happier than he was in his 30s. With everything we now know and science I know of that's coming down the line, this is not a crazy goal at all and is something that's quite achievable for you and your family. Okay, let's begin by talking about extraordinary feats of longevity and performance that are already possible today. These are verified achievements by real people living under current or Even past conditions, they establish the current outer boundaries of human biological potential. Each case shows what the human body and mind can already accomplish. I believe that if something is biologically possible for one person, it represents a capacity that could, in time, extend to many. First, let's talk about the longest verified human lifespan on record. That's Jean Calment of France, who lived 222 years and 164 days. Andrew, let's call up that video of Jeanne calment on her 117th birthday. She was a great woman. She was very funny and said numerous jokes, one of which was, I only have one wrinkle and I'm sitting on it. There's also the story of her talking to a reporter, young reporter, and he said, wow, this has been great. I hope I see you next year. And she says, I don't see why not. You look pretty healthy to me. Jeanne was born in France in 1875 and she passed away in 1997. I remember the day clearly. She watched the Eiffel Tower being built as a teenager and lived through two world wars, plus the invention of airplanes, the rise of the Internet and much more. The number 122 in Lifespan's logo recognizes her great achievement and this extraordinary milestone. Just consider this. 122 is over 40 years beyond age 80, the same span of time as from age 40 to 80. So think about that. What if at 80 you had another 40 years of healthy life ahead? Calment's record stands as proof of our human biological potential. The question is not whether such longevity can occur, it already has. The question is how to make it more common in even better health and ultimately even longer. This human lifespan record alone is powerful, but what about physical performance in older age? At age 22 in 2009, Usain Bolt set the 100 meter world record of 9.58 seconds. But in 2024, 80 year old Kenton Brown ran 100 metres in only 14.21 seconds, setting a world record for his age group. The times, of course, differ meaningfully, but Kenton's achievement is nonetheless Incredible. Usain Bolt, 9.58. Kenton Brown, 14.21 at age 80. For those watching on video, we found a video of men in their eighties doing a hundred meter final. Andrew, let's pull up that video. It's really remarkable actually, how fast they run. It looks like it's on twice speed. Looks like there's two Australians in there. The green and gold. Go, Aussie. Oi, oi, oi. We say, I think the red guy is gonna win. Yes, so just notice the energy, the speed, and explosive power of those guys, and remember, they're over 80. And importantly, it's not just a single outlier performing this way. All seven of the runners accelerate hard, maintain form, and drive through the finish line with force. At their age, they're sprinting. They're also demonstrating exceptional muscle power, coordination, and athleticism. This is likely not something you've ever seen before. I know I haven't. And yet it is indeed what the human body can achieve even at 80 and beyond. Speed, of course, is just one dimension of fitness. Endurance is another. In 2021, at age 80, Jose Lopez ran a mile, or about 1.6 kilometers, in 5 minutes and 56 seconds. I mean, most of us can't even approach that. He set a world record for his age group. Anyone who's run a mile knows that a time below six minutes is a difficult and remarkable accomplishment at any age, and especially so at 80. Jose's feet proves that exceptional aerobic function and cardiovascular health can be achieved even at older ages. Physical vitality is not limited to speed or endurance. It extends to fertility as well. So in 1997, it was amazing to learn that Dawn Brooke naturally conceived a healthy son at age 59, making her the oldest verified mother to conceive without fertility treatment. Female fertility typically declines significantly after the mid-30s, and natural conception beyond age 50 is extremely rare. Yet dawn demonstrates that fertility can persist far beyond typical norms. Dawn set the record. And through technology, my lab and others are striving to preserve fertility for as long as possible for as many women as possible. So let's talk about mental performance. Is a loss of memory and creativity inexorable with age? The Mini Mental State Examination, or mmsc. Partly developed by my friend Sharon Inouye at Harvard, it's a widely used screening tool for cognitive impairment. It assesses memory, attention, language and other skills. Scores range from 0 to 30, with 25 or above considered within the normal range. In 2008, Den Dunnen and colleagues in the Netherlands published a case report in the journal Neurobiology of Aging titled no Disease in the brain of a 115-year-old woman. They asked the question, are there limits to healthy life for a human brain? In the paper, they reported a woman who had chosen to donate her body to science. And at the age of 115, the same year of her death, she scored 26 out of 30 on this exam. At age 115, her performance was stated to be above the typical average of healthy adults aged 60 to 75. While not a verified world record. This must be pretty close to one. After she passed away, scientists found almost no evidence of heart disease in her body and her brain had almost no beta amyloid plaques or vascular changes. She had around the same number of locus coeruleus neurons as those of the brains of healthy 60 to 80 year olds. Locus coeruleus neurons are among the first neurons to change with age and one of the earliest sites of phosphotal protein accumulation in aging brains, and often accumulates decades before clinical Alzheimer's disease appears. These findings show that the boundaries of human cognition can extend well beyond what most people currently experience and that cognitive impairment need not be inevitable even among supercentenarians. We know that a 115-year-old woman had the same cognitive performance as 60 year olds, so that is possible. That also means it should be possible to figure out what made her special and design medicines that could be used by all of us to give us what she had to help keep this show freely available. Lifespan partners with a select group of companies that I truly believe in and who also share our commitment to evidence based science and supporting medical research. One of those partners is ketone iq. Researchers are increasingly interested in metabolic flexibility, including how the body can tap into alternative energy sources like ketones, especially during fasting. I've been increasingly interested in ketones as I go longer and longer with my fasting. Last month, for example, I managed to essentially go for three weeks without a full meal. And I know that sounds crazy, but I really wanted to see what would happen. During that time my body survived on ketones. The remarkable part is that I felt better, better than ever. My strength and my energy improved and my brain was really active. I even slept better. There's a lot of great science about the potential benefits of fasting and of ketones, but the problem is how can you get the benefits of fasting without having to reduce your food like I did? You've likely heard of ketones before in the context of the ketogenic diet or in fasting literature. But by cutting back on carbohydrates especially, what you're actually doing is flipping a metabolic switch that tells your body to start producing these molecules as an alternative energy source besides glucose. Ketone IQ is a little drink whose active ingredient is a ketone precursor, and it's called R13ButAndiol. Now, you don't have to remember that, of course, but what's interesting is, is that your liver converts that drink into beta hydroxybutyrate, which is a main ketone fuel that your brain and your muscle can use for energy. There's a growing amount of research into the effects of ketones on the body. In 2012, for example, the first study of its kind showed that consuming an exogenous ketone raised blood beta hydroxybutyrate levels to that typically seen during a long fast like the one that I did, or if you're having a really strict ketogenic diet. Then in 2018, a study asked, what fuel does the aging brain still use? As cognition declined in their patients over time, the researchers found that the brain became less able to use its normal fuel, glucose. And what actually happened was that the ketone uptake remained relatively preserved. That's really important and interesting because it suggests that even when the aging brain struggles to use sugar for energy, it can probably still use ketones as the alternative fuel. And finally, I briefly want to mention a study that I really love from 2022, where researchers gave soccer players some ketones and found actually that their reaction time and their cognition improved. They didn't get as much fatigue. And actually that's one of the reasons that I take ketone IQ often. Especially before I do this show, we're offering our audience a 30% off discount for your first monthly order at ketone.com lifespan or at the checkout, just use the code lifespan. Beyond general brain health, what about maintaining specific mental skills at an elite level? In older ages, chess is an extraordinarily complex game. To play at a high level, players must calculate multiple moves ahead every turn, anticipate opponents responses, recognize hundreds of board patterns and adapt in real time under pressure. Mastery demands working memory, pattern recognition, and long term planning. The title Chess Master is given to only elite players recognized by the National Chess Federation and reflects sustained competitive success. In 1984, Oscar Shapiro became the oldest person in US history to earn the title of Chess Master at the age of 74. Achieving this in his 70s demonstrates that complex skill acquisition can occur even at old age. Sure, it was years of practice, but his lifestyle or his genes might have had something to do with his success. And if so, we can mimic that too. These are rare examples, but they aren't always. Take my father Andrew, for example, a regular guy who read the science and took control of his health around the age of 50. Let's show a picture of dad. He's been doing many of the right things that longevity science says to do exercise regularly. He does a lot of walking, he takes supplements. And now at 86, he's in perfect health, stronger and fitter. Than average 30 year olds. He's certainly fitter and stronger than me. I'm super proud of dad. In later episodes, we're going to talk about what he and I do on a daily basis to maintain our youth and vigor. Wherever my dad goes, people underestimate him for his age. We climbed the Sydney Harbour Bridge and people weren't sure he could do that. And it was no problem. He'd already walked 20,000 steps before we went up there. He's climbed mountains, he's abseiled. And most recently on a big stage in Sydney. He joined me up on stage and he was a natural. Taken together, these examples show what incredible feats of longevity and performance have already been achieved by athletes and by chess champions and even my father. And that is before the benefits of the kind of technologies we're going to talk about on this show and those that will undoubtedly arrive in our lifetimes. With the exception of my father, these feats are extremely rare, but nonetheless possible and achieved. Imagine you or your loved one being 80 years old and knowing that more than 40 healthy high performance years are still lying ahead. I believe we can make these outcomes more common and hopefully one day possible for all of us. But to make that leap from rare outliers to widespread reality, we must understand what determines the true limits of human biological potential. Why do some people preserve function so far beyond the norm, while most experience steady decline? To answer that, we need a framework for what aging actually is at the biological level. And that brings us to my information theory of aging. The Information Theory of aging, or itoa, is a totally new way to view aging. From the 1950s to the 1990s, the prevailing view about aging was that it was due to DNA damage or some type of damage caused by free radicals that could be mopped up by antioxidants. And this is why you still see food and drinks in the supermarket tout the wonderful benefits of antioxidants. But we've moved on from there. What was once a minority view has moved closer to the mainstream. Increasingly, aging is no longer described as the buildup of cellular damage, but as a loss of biological information. According to the theory, the precise patterns of gene expression that maintain cellular identity gradually erode, leaving cells less able to function properly and more vulnerable to disease. ITOA proposes that aging is not fundamentally caused by mutations or some other type of damage or disrepair. It is a loss of information. So what kind of information are we talking about here? There are two types of information in all of our cells. The first is the genome A highly stable digital repository of information that's encoded in a chemical we call DNA, which can last for hundreds of thousands of years. In fact, some of my colleagues at Harvard have pulled these out of fossils, Even of Neanderthals and species older than that. The other type of information that we need to talk about here, which is so important for aging Is epigenetic information. These are the instructions that tell cells how to use the genome, the software of our cells. You could think of it. ITOA posits that what fails with age is our cells ability to read and interpret genetic information correctly. And over time, cells begin to read the wrong genes at the wrong time, and they lose their identity. Nerve cells begin to take on the properties of skin cells. Liver cells drift towards kidney cells. We start to lose our hearing, our eyesight, and our muscles shrink, Our bones weaken, and then diseases take hold. What's so important for any scientific theory and for itoa is that it's testable. And what's so exciting is that there's growing evidence that it might actually be true. For it to make any sense, you have to accept a strange premise that cells carry memories. So rather than viewing the body simply as a collection of mechanical parts that wear out over time, we can see it as a dynamic system for storing, preserving, and interpreting biological information. Aging in this framework is not just damage accumulation. It is the progressive loss of the cell's ability to maintain its identity. This eventually causes the organ or the tissue to forget how to function and stave off what we affectionately call diseases. Of course, we all started out life as a single fertilized cell. Then, during embryo development, each of our cells, which contain the same DNA, they quickly specialized by remembering which genes to turn on and off. The system that carries this out is called the epigenome. This cellular memory, maintained through epigenetic marks and folding of the genome, Is what allows a neuron to remain a neuron and a liver cell to remain a liver cell. As we get older, though, that breaks down. I have a little model here of what chromatin actually looks like. I threw this together really recently with some tennis balls and some velcro. So if you're just listening to this, you can imagine blue Velcro wrapped twice around each tennis ball in a string of bowls. So the blue velcro represents DNA. It's a little bit tangled, but that's good because the DNA naturally looks like this, and bundles of these proteins form chromosomes you can actually see with the microscope. So during embryonic development, what happens is that these balls And DNA wrap in certain ways that are slightly different between nerve cells and liver cells and skin cells. But during aging, what we found is that this starts to unravel and that the DNA becomes more open. And now genes that should not be turned on get turned on, and a nerve cell starts turning on genes that liver cells normally have on. That's a problem. We don't want our brain expressing liver specific genes. Ultimately, what we see is that that causes dysfunction of all organs, including the brain, and that leads to disease. And this is why we think we get old. Your DNA sequence is essentially the same in a skin cell as it is in a neuron in childhood. And in old age, the difference lies not in the letters of the code, but in how that code is read by changing where chemical tags are added to the DNA and to the proteins that spool the DNA. You can see here that there would be little chemicals like this bit of Velcro on the proteins that wrap the DNA. And actually we get chemicals like this one on the DNA itself. These little chemicals, one of which is called methyls, a very important one. They dictate how this is all folded. And those little tags change over time. Unlike the digital genome, which is very robust, the epigenome is mostly analog information and hence highly dynamic. In fact, if you could see these balls under the microscope in a real cell, they wouldn't be sitting here. They'd be flying around like it was a hurricane. It's actually quite a miracle that we last 80 years. That flexibility is what allows cells to adapt to the environment. So when you eat a meal, some of these balls open and you get genes for insulin, for example, switched on. But it also is our Achilles heel. It's also what makes the system fragile. Over decades, according to itoa, epigenetic patterns drift. The tags end up in the wrong places, and the instructions eventually are so badly eroded that the cell forgets how to function. So those little tags are really interesting, and those tags are what determines how cells function. I actually have a model of it down here. Those of you listening, you'll just have to imagine that got this little plastic DNA molecule. It's basically a ladder or a spiral staircase. And each of the rungs of the ladder are actually the letters of the DNA code. This might be a very small section of one gene. One strand of DNA runs down from top to bottom, and then the other strands go in the other direction, bottom up, and they form this beautiful spiral. What's important about this model is that the letter C, which are these little red Bars here on half of the rung of the ladder. Those are the letters that the cell puts those chemical tags on. And when you have lots of methyl chemicals on the Cs, that gene will shut down. That's how the cell tells a liver gene in a nerve cell to not get expressed. But over time, what we see in a very predictable manner is that those methyls get removed and even end up in other places that they don't belong. And we believe that isn't just a indicator of aging, a clock, so to speak, but actually it literally causes aging. So those little chemicals are the basis of the information theory of aging. So over time, gene expression patterns become dysregulated, cellular identity weakens, and the function declines. Now, I want to show you a diagram that illustrates what I just told you. It's metaphorical, so don't think of this exactly how cells work, but it's very useful for understanding the changes that cells go through during development and during aging. What we have on the screen here is what's called the Waddington landscape. And we've got a ball at the top of the mountain, which represents a pluripotent stem cell that could roll down into any valley in this landscape. And actually, during development, what happens is balls roll down and sometimes end up in the neuron valley, and other balls end up in the kidney valley. And that's essentially what's happening. The point is that balls that end up in the kidney valley never end up in the neuron valley, and vice versa. Cells have an identity and they stick to it. But what we see during aging is that those valleys and hills erode so that the balls can roll over into adjacent valleys, and so that neurons start to become more like kidneys, and kidney cells become more like neurons. What a TOA says is that there might be a way to push the balls back to where they came from and rebuild those hills and valleys the way they once were. When we thought of this in 2014, it was a crazy idea, but we have some really good evidence that is actually possible. The modern story of the information theory of aging began not in humans or even in mice, but in simple baker's yeast. Here's a picture of one for those of you just listening. This is a big yellow cell surrounded by little blue cells, which I stained about 20 years ago and took this photo. Old yeast cells live about 20 to 25 divisions. Takes about 10 days for them to die, and they get big, slow, ugly, and actually become sterile as well, which will be important in a minute. In the mid-1990s at the Massachusetts Institute of Technology, or MIT. In Professor Lenny Guarenti's lab, we set out to understand why baker's yeast cells age and whether that process could be slowed. At the time when I arrived in Lenny's lab, pretty much all theories of aging centered on cumulative damage, free radicals, telomere shortening, and molecular wear and tear. The idea that aging might be genetically regulated and that a simple organism could reveal its mechanisms was not widely accepted at all. In fact, down the hall, one professor scoffed at what we were doing. Let's call up that photo of us kids in 1998. There we are. It's a bit of a faded photo, as you can see. We're just a bunch of kids, a bunch of rebellious kids that most people thought were doing crazy work. Alongside Lenny were Brian Kennedy, Heidi Tissenbaum, Matt Kaeberlein, Shin Amai, and me. We all went on to become professors in the field at the time. We ended up discovering longevity genes in yeast called sirtuins that regulate the epigenome, and this was the basis of itoa. One of the first key experiments came when Brian analyzed a mutant yeast strain that had survived in the fridge for months. These plates were pretty much dried out, and most things on the plate were already dead. Using a micromanipulator, he measured the lifespan of that strain by removing and counting each daughter cell produced by a single mother cell. That's how we determine how long yeast cells live. Wild type or normal yeast produce about 24 daughters. This mutant produced roughly 30% more daughters. It was definitely living longer, and it was one of the first clear demonstrations that lifespan could be extended by defined genetic alteration. The mutation involved is called SIR4. This gene was already known to maintain gene silencing at specific loci, or regions on the genome. Its partner protein, SIR2, is actually an enzyme that removes chemical tags from those tennis balls, those histone proteins, thereby tightening up chromatin and altering gene expression and silencing down those genes. So 2 requires NAD as a cofactor to work. Without NAD, it cannot remove the chemical tags off those proteins that links cellular metabolism directly to epigenetic regulation. And it's one of the reasons that there's a whole industry for NAD boosters in the billions right now. The mammalian homologues of Sirtu became known as sirtuins, named after Sirtu. These early findings in yeast cells were completely unexpected. We were looking for proteins that regulated telomeres or repaired DNA. Instead, we found epigenetic regulators, gene silencing proteins, which suggested to us that aging, at least in yeast, was not solely the accumulation of random damage, but involved in changes in chromatin structure and how genes are regulated. What we proposed was that in yeast at least, the redistribution, the movement of SIR proteins during aging, led to the loss of silencing at some genes and inappropriate gene expression at others. This pointed to a breakdown in the maintenance of epigenetic information. Here are my notes from October 1996. This is the first documentation of Aetower. I love this. What happened was I woke up in the middle of the night and I just couldn't stop writing. I spent about three hours writing down pages and pages of notes. It just came to me. As we talked about in this episode, most of us won't die from infections or accidents. What we're going to die from are diseases caused by aging. So that's why it's really important that we all track our own health closely over time, and that's how we can know if we're progressing and what we're actually doing is working. Wearables make that super easy. You don't need to watch these numbers all the time. You can look at them once a week or even once a month, but it's really important that you check how you're doing. Which brings me to a wearable that I'm particularly fond of, partly because of its scientific foundation at Harvard, where I work, and also the founder's own research and scientific rigor. The company's only a couple of blocks up the street here from the studio, and I visit them occasionally and see what an active, caring company they are. I'm talking about the WHOOP band. This wearable is a health and fitness coach that gives me insights into my sleep, my recovery, and my body strain. The researchers have studied how accurate these devices are, and in a 2022 study, they compared six wearable devices, including Whoop, against clinical grade ECG and sleep recording devices. WHOOP showed strong accuracy for heart rate and heart rate variability measurements during sleep. Especially using the WHOOP band, I can see how my daily behaviors are are impacting my health. Wearing the whoop over the last two months, I've seen dramatic improvements in my personal biomarkers, indicating that the changes that I'm making to my lifestyle, including a much healthier diet and more exercise, is definitely having a positive effect on my body. For example, my resting heart rate has gone down to 45, which is great. And my heart rate variability, which you want to be higher, that number has shot up to 90, putting me in the top few percent or so for my age. It's not only interesting and useful, but it's also important to build up a record about your body that you can aim for when you're older. When you're 90, you can go back and aim to be what you were in your 40s or 50s. If you're a regular listener to this show, you'll know that we only partner with companies like whoop, who we really believe in. These are products that I use daily, the team uses daily, and these companies align with our values, our mission of supporting medical research and supporting young scientists. If you want to try it and get a free Whoop 5.0 smart band and a month off membership, go to join.whoop.com lifespan or use the code lifespan what we see here is a picture of a yeast cell and we see that the sirtuins are going to DNA and relocalizing and changing gene expression. It's called a theory on replicative senescence in yeast and other organisms. So that was the beginning. In 1996, Andrew here was what, about eight months old? Marisa and Rajeev, you weren't even born yet. But we had the initial idea that aging may be due to information loss, not just damage. Many years after, this idea remained peripheral to the dominant damage based models of aging. Then over the next two decades, evidence accumulated in worms, flies, and even in mice. Sirtuins were shown to regulate stress, resistance, metabolism, DNA repair, and many other cellular functions. And again, the levels of that molecule NAD were critical. Those chemical tags on the letter C, those patterns were found to change in highly predictable ways that correlated with biological age. And in fact, those chemicals are now the basis of biological clocks. And we found that double stranded breaks that snap chromosomes and that happen every day in every one of our cells, these can accelerate the movement of SER proteins and these epigenetic alterations actually accelerating the aging process, suggesting that the response to DNA damage, not the damage itself or the mutations, may be the major driver of aging itself. Together, these observations support a framework in which aging is due to the progressive loss of biological information, particularly epigenetic information. And what began as a study of gene silencing in yeast evolved into a broader model of aging, one that raises the possibility that if biological information is degraded over time, it may actually be possible to restore it. To test whether such shifts in epigenetic information could cause aging, rather than just simply accompany it, we created what we called the isemouse model, which stands for inducible changes to the epigenome. In these mice, we were able to introduce targeted, easy to repair DNA breaks. And we could turn them on and off at will. At about five months of age, we induced these double stranded DNA breaks for about three weeks in total. And this was about three times the overall number of changes that would normally happen in a mouse. The reason we created those DNA breaks is that we'd already shown in yeast and then in human cells that the movement of sirtuins to repair the DNA breaks is one of the reasons that gene expression changes with aging. So we asked the question, if we create those breaks, does aging accelerate? And the result in those mice was really striking. Andrew, let's call up the video of those mice. So the ice mouse is on the left. And if you can't see this, it looks a lot older than its sibling born on the same day. These mice are about 18 months old. The one that was untreated has black fur, normal skin, and the ice mouse looks and literally is a lot older, Even though it was born on the same day. The animals had an advanced epigenetic age of about 50% and functional signs of aging much earlier than expected. Pretty much every tissue we looked at, their skin, their kidneys, their livers, their brains, they looked a lot older. They had loss of cognition and frailty. Their underlying DNA sequence, though, remained essentially intact. I've actually got a copy of the paper here that we published in 2023 in the journal Cell, and I'm very proud of this paper and my colleagues that put it out. There were 46 scientists involved, and it took us 13 years. In fact, three of our team died along the way. What we showed in this paper for the first time was, and I quote from the paper, a loss of epigenetic information as a cause of mammalian aging. It was the first clear evidence that disrupting epigenetic information could drive aging in an animal. And what we like to say in my lab is, if you can give something, maybe you can take it away. So that brings me to age resetting. Around 2013, I began to think about information preservation. Of course, if we could preserve biological information, the prediction of ITOA is that we would live longer and much healthier. And I was fortunate to come across one of the most important papers that I've ever read. It was transformational to my thinking. It was a paper written in 1948 by a professor at MIT named Claude Shannon. Many people know about Claude Shannon from his work on communication and information systems. His paper from 1948 is titled A Mathematical Theory of Communication. Andrew, let's call that up. I've probably read this 50 times now. I don't understand all of it. There's a lot of heavy math. But Professor Claude Shannon was working on the problem of information transmission, Having survived World War II and seen what happen when a radio signal is misinterpreted. He showed that by building redundancy into the message and comparing what comes in against a clean reference, the receiver can reconstruct the original signal. He called this backup copy of the signal the observer. Now we call it the backup copy or the TCPIP protocol of the Internet. Let's scroll down to see the figure of the observer. It's a classic diagram I actually put in my book. Or is it page 21? Here it is. Let's blow that up. And if you're just listening, it's a bunch of boxes. But what it shows, actually, is that the observer sits above the boxes along the bottom. The boxes represent the transmitter of the signal and the receiver. And the observer sits above. And if the receiver doesn't get the signal, it actually can go and correct the original signal. It's all a lot of math, and it might sound a bit confusing, but basically here he's saying is that if you shout at someone or send a message or even send now an email, the reason that it's not corrupted anymore is that there's a backup copy up here that can be used to correct the original signal. Now, what occurred to me when I was looking at this was this could represent biology. This could be the original embryo at the beginning. And that's the signal. And the receiver is us in the future, our future bodies, and that's aging. Because what's introduced in the middle is informational noise. So that really what happens to us in the future is that the signal is not received fully. But what if there's a backup? What if there's an observer in biology that is able to correct the epigenetic information and restore our youth so that even in the future, we are still young? And that's what gave me the idea. I'd love to show you some of the original diagrams that I was drawing in Fiji. Well, I really should be. Should have been out on the beach with my kids. Andrew, you've got those. It'd be fun to show those as well. Let's just quickly scroll through some of these ideas. You can see I was inventing new words. Epigenetic drift. This was one of the first figures that I drew during my time in Fiji. I really like this diagram. This was to represent young cells that express all the Genes correctly, and due to epigenetic drift, now they start expressing the wrong genes. I did a little bit of math here, but let's scroll down, Andrew. There might be something interesting to see. Yeah, this represents the sirtuin proteins jumping around in response to DNA breaks, which we discussed earlier. Keep going. I really like this one. This was comparing the analog and digital system that we were talking about before, where the epigenome is analog and the DNA is digital. I represented that by a compact disc, which is digital information. And then there were scratches that led to noise, and the music started to jump around, and I was starting to think that could actually be aging. This is another one where I was using a record player instead of a cd, but you get the idea. Actually, I never published this, but it was important for not just writing my book, but eventually coming up with the fully fledged information theory of aging. So if aging truly reflects corrupted epigenetic instructions, then nudging those instructions back towards youth might help damage tissue, recover, and even establish youthful organs that are even diseased. This way of thinking and the information theory of aging led to a really important question, whether we could safely access and restore epigenetic information in cells or even in living tissues. That is where age reversal via epigenetic reprogramming enters this story. First in the lab and now being tested in human trials for the first time. We don't yet know much about this backup copy, or what we also affectionately call the observer, or even what it's made of. And some say it doesn't even exist. Resetting the epigenome is complicated, involving thousands of genes and 3D rearrangements of the DNA. Still, the fact that embryos can reset their age and and reprogramming can push adult cells towards youth suggest strongly that biology already knows how to recover that information. The challenge for us is to understand how do embryos do it? And how do other animals, like fish and lizards, regrow limbs and tails, apparently using the same method? If cells really carry a backup of their youthful state, the obvious next question is whether we can access it and do so in a safe way. The first clue that cells can be reprogrammed was shown by John gurdon in the UK and in the 1950s, he and his team took nuclei out of tadpole cells, adult tadpoles, and replaced the DNA for an egg with that DNA. And they got a young tadpole showing for the first time that old DNA could make a new organism. The next big clue that cells could be reprogrammed came from Shinya Yamanaka, a Japanese professor who showed in 2006 in a beautiful Cell paper. The paper showed that turning on four genes October4, Sox2, KLF4 and CMIC, now called the Yamanaka factors, could turn mature cells like skin cells back to an induced pluripotent STEM cell, or IPSC. In 2012, that discovery and John Godin's for his work, deservedly won the Nobel Prize. But it also came with a problem. Fully reprogrammed cells forget what they once were. In fact, they have no identity. They can become anything. In animals, turning on these four genes actually drives lethal tumors and can even kill mice within two days. That's not going to be a therapy anytime soon. If you've listened to this show before, you've probably heard me say that you cannot optimize what you don't measure. That's what we do as scientists, and it's true. Also, when it comes to body metrics, many people only measure their total body weight, if anything. But this only tells a small part of the story. So how can you measure these other aspects? Withings, one of Lifespan's partners supporting medical research, makes some of the coolest devices that you can measure yourself with. They have watches, a sleep monitor pad, and advanced bathroom scales, one of which I use every morning. I've actually been using within Withings devices for over 13 years, since they first came out with their first scale. And today the Withings vision clocked me at 59 beats per minute heart rate, which I'm very happy with. It's actually pretty healthy. And at night it drops down to about 49. As I previously mentioned, another metric that impacts lifespan is body composition, and it's impossible to know this unless you measure it. We've already talked about visceral fat, the evil fat that sits around your organs and it's associated with risk of cardiovascular disease, diabetes, and even death. So getting rid of visceral fat, or at least minimizing it, can have a strong impact on your long term health and longevity. I've got all the valuable data on my scale in my bathroom here and also on my phone. The Withings body Scan scale can help estimate your muscle mass, your fat mass, and importantly your visceral fat percentage, among other things. I stand on this scale almost every morning. Here's the digital twin on my phone spinning around so the numbers speak for themselves. I've got 11.3% fat on my arms, 14% torso and visceral fat, which we mentioned is the evil fat at 2.7. All of these numbers I'm very happy with. And you can also look at muscle and other different things here. And in the past couple of months, by changing my diet and improving my exercise regimens, I've lost over £12 for spring and importantly, I was able to ensure that I didn't lose any of my muscle mass. This is a common problem when you're eating less and especially if you take a GLP1 receptor agonist like Ozempic, a Withing scale can really help ensure that you lose only the fat, not muscle. It's the only smart scale that also comes with an FDA cleared ECG that can analyze your heart rhythm and even detect atrial fibrillation, which is a heart condition that can cause strokes and even heart failure. We here at Lifespan are partnering with Withings because we share a common commitment to preventative health and also we want to support medical research and young students. As a Lifespan listener, we invite you to join us. You can learn more about Withings or get a scale or just one of their other really cool smart devices@withings.com lifespan or for a 10% off discount, use the code Lifespan In a now classic paper in 2016, Alex Ocampo, a postdoc, and his supervisor Juan Carlos Belmonte, decided to turn on OKSM in prematurely aged mice to see what would happen. What they found was that the mice actually were much healthier and lived about 30% longer. They published that and it was a striking discovery. A lot of people just couldn't believe it. Here were these factors that seemed to promote health, but it wasn't clear if this was actually age reversal or just simply stressing the heck out of these mice. And if reprogramming meant erasing the cell identity, causing cancer, or killing mice, how could this ever be used on patients? In 2009, my lab set out to find a way to reset the epigenome, and by 2014, the current version of ITOA was really taking shape. And this was the same year I put Wan Cheng Lu, one of my star PhD students, on the problem. The goal of his was to safely reset the epigenome like embryos do in old human cells. He tried dozens of different gene combinations and culture conditions to see if age could be safely reset without turning them into cancer cells. He put in developmental genes oskm, a gene called nanog grew them in low oxygen, high oxygen, no nutrients, low nutrients, high nutrients. After three years of failure, Yuanchang was on the verge of quitting. And he almost did, until I convinced him to try one more experiment. Use only a Few of the Yamanaka factors, no one thought it would work. Of course, the dogma was that you need all four of the Yamanaka factors for anything to happen, and even then, you'll just get cancer. Even Shinya Yamanaka told me that he never tried OSK&M in animals because it would clearly cause cancer, as he showed in his 2006 paper. And leaving out a factor was not on the cards because he told me that wouldn't work anyway. But in 2017, the experiment did work. One Cheng discovered that leaving out the myc gene, the M O SK alone could reset the epigenetic clock of human cells without causing them to become cancerous. Using just O, SNK could rewind the epigenetic age in human cells by up to 75% and then stop. That's important. We never see cells becoming cancerous. That day in 2017, I'll never forget. It was a momentous one. The retina was an ideal testing ground for the gene therapy. It's an enclosed space, and it's much safer than delivering it throughout the body. So we started there. Also, retinal nerve cells connect the eye to the brain via the optic nerve. And once damaged, they don't naturally regenerate, certainly not in adults, but in young mice they do. So we thought that we would test that injury to the optic nerve, like glaucoma, leads to irreversible vision loss and even blindness. We hypothesized that if aging could be reversed at the cellular level, perhaps regenerative ability could be restored as well as vision. On Thursday, June 28, 2018, at around 10pm, one Chiang Mai student sent me a series of texts that led to the COVID article of nature in 2020. I'd love to show you some of those texts. Now, here's a picture of one Cheng at the machine that was cutting the tissue to look at before he put them under the microscope to show me. He's got his watch there. It says 10:06. Next text was, he says, I know my hands are shaking. Let's prepare for the worst and hope for the best. And I wrote back as a good mentor should any result is the best. Then a few minutes later, he wrote, or actually he sent me a picture of optic nerves that were regenerating. I asked the question, is this an AAV infection? Is the viral infection? Is this an optic nerve? What is it? Tell me. Smiley face. And then I looked up, I scrolled up and I wrote, oh, I didn't scroll up for exclamation. Marks. Holy crap. One Cheng writes, I sent you three pictures. These nerves are so long that they reach out of the vision. And I write, wow. This time five exclamation marks. Let's frame that photo. He writes, they are 12 months old. Jesus, I still can't believe it. Here are some other samples that have good regeneration too. And I write the best result in the lab in years. What made that result so remarkable was what those long nerves actually meant in an adult animal, including ourselves. Once the optic nerve is damaged, those fibers usually don't grow back very far, if at all. So when Wancheng saw how long they were, it suggested that these damaged nerves were actually regaining a youthful capacity to regenerate, which is something we almost never see in the adult central nervous system. It was certainly an exciting moment and I recorded it in my book Lifespan. And another few years later we published that on the COVID of Nature magazine. So in aged mice experiencing natural decline in visual acuity, OSK treatment We also found restored visual function as measured by eye and head tracking movements and electrophysiological tests. In mice with glaucoma pressure in the eye characterized by failing of the retinal nerve cells in the back of the eye, OSK not only promoted survival of those nerves, but but also improved visual performance. They literally got their vision back. For the first time ever, a gene therapy had reversed aging and vision loss associated with both disease and aging. In later experiments, Wan Cheng showed that the OSK gene therapy also reversed age related molecular signatures in other tissues such as muscle and kidney, including in the ICE mice whose epigenome had being artificially aged by repeated DNA breaks. And without the enzymes that remove the methyl chemical tags from the DNA, the treatment no longer cured blindness. Taken together, these experiments suggested that Waddington's landscape that's been eroded over time can be at least partially rebuilt by temporarily re engaging the cell's own youthful program. Using only three genes, osk. A central mechanistic question then was how this rejuvenation occurred. One analysis focused on the epigenome, specifically DNA methylation patterns, which change predictably with age and serve as biomarkers of biological aging. We also checked those methyl marks on the DNA that we talked about earlier, and they were more youthful after OSK treatment as well. So that showed that not only was vision improved, but the actual biological clock could be reset. Critically, this reversal did not involve the loss of cellular identity. The study also suggested that mammalian cells retain a backup copy of youthful epigenetic information. Reprogramming appears to access and restore that stored information re establishing youthful patterns of gene expression. These findings provided experimental evidence for ITOA in a living mammal. Safety, of course, was critical. Full reprogramming is known to cause tumors and other problems. In our experiments, OSK expression was carefully induced and we saw no tumor formation, no loss of retinal structure and no evidence of uncontrolled cell proliferation. This demonstrated for the first time that age reversal and oncogenesis are separable processes when reprogramming is done in a controlled way. The broader significance of all of this extends way beyond vision. The retina is part of the central nervous system, or cns. Demonstrating regeneration and functional recovery in the CNS suggests that potential applications could include neurological conditions, even Alzheimer's disease. It could also include hearing loss and spinal injuries. And the principle that aged tissues can be epigenetically rejuvenated also probably applies to muscles, heart, liver, skin and other tissues. The eye served as a proof of concept for many other possibilities. These results and subsequent studies in non human primates set the stage for life biosciences development of the drug candidate called ER100, which stands for Epigenetic Reprogramming 100. ER100 is a gene therapy that contains the OSK genes designed for human use. And I'm proud to share that. In January 2026, it became the world's first epigenetic reprogramming therapy to receive clearance from the FDA to begin human clinical trials. This was a real milestone for the field. For the first time, a therapy specifically designed to reset epigenetic age was authorized for testing in patients. I thought I'd show you how ER100 is being delivered to the patients. I've got a model of the eye here, about the size of a small melon. ER100 is an injection of a gene therapy that's delivered through the front of the eye. A very quick, painless injection. And the genes move through the eye, through the liquid and find their way to the nerves at the back. In the retina, the part that we use to see, of course, the retinal nerves form the optic nerve that goes to the brain. That's how we get the electrical signals in glaucoma. Because of a lot of pressure in the eye, those optic nerves have aged rapidly and they're actually defective. They're not dead, they're just defective and old. So the gene therapy, if it works, what's going to happen is that these nerves will get younger over about six weeks and start to function again. And people that have been treated, if all Goes well, will be able to see again. So cross your fingers that that works. This first clinical trial, run out of three sites across the United States, is designed primarily to test safety. Dr. Joe Rizzo, my colleague at Harvard, is running one of these sites here in Boston. The phase one trials will test ER100's effects on patients with glaucoma, the pressure in the eye that we tested on mice. Glaucoma in humans is the largest cause of blindness across the planet. And another disease will be tested called nyon, which is non arteritic anterior ischemic optic neuropathy, which is essentially a stroke in the eye. We now know that the prevalence of NYON in patients on weight loss injections has increased as these drugs have become even more widely used. You can look up the trial if you want@clinicaltrials.gov Current treatments for glaucoma mainly aim to slow progression of the disease by either lowering the eye pressure or managing other disease risk factors like obesity. However, they do not restore vision that has already been lost. In contrast, ER100 seeks to rejuvenate damaged retinal nerve cells so they can function more like they did when they were younger. Early stage trials typically enroll a small number of patients and use a gradual dose escalation approach. In this case, 18 patients will be tested. Doctors will closely monitor patients for any side effects. Of course, although safety is the main focus at this stage, doctors will also look for signs that vision has improved. If ER100 proves to be safe and shows some benefit, it will advance, of course, into larger trials. Because there is no alternate medicine that can fix blindness, there is the potential it will be advanced more rapidly by the FDA so they can reach patients sooner. The broader significance extends beyond the eye. If restoring useful epigenetic information can repair damaged nerve cells in optic nerves, similar strategies could work in other tissues. Over the coming months, doctors will learn how safe and effective the approach may be. But regardless, a path from a laboratory science to patients and clinics has now been established. For the first time, epigenetic reprogramming is no longer confined to the lab. It's being evaluated as a potential therapy in people representing a new chapter in the effort to treat age related disease at its aging. In this episode, we've taken a glimpse into what I believe is a turning point in the history of medicine. For decades, aging has been seen as inevitable. Something to slow, maybe manage, but never truly change. That view is now beginning to shift. We have explored the remarkable examples of what the human body is already capable of. Jean calment living to 12280 year olds sprinting people maintaining cognitive function well over 100. These are not anomalies to ignore. They are clues to what the future might look like. And we also talked about the information theory of aging, the idea that aging is driven by a loss of biological information, not just accumulated damage and wear and tear. That led us to epigenetic reprogramming, a way to restore the instructions that cells need to be young again. All of this is no longer theoretical. It's happening now. FDA cleared clinical trials are in progress and there are many more trials coming, not just from Life Biosciences, but from companies associated with people like Jeff Bezos and Sam Altman. Humanity is moving beyond just slowing aging. We're learning how to reverse it. It's been great to have you with with us. This is a show where science and evidence come first. The team works hundreds of hours to bring you only the facts. To learn more and to join our community, visit lifespan.com and you'll get early access to future episodes, to the Lifespan magazine, and to detailed episode show notes. You also get transcripts and links to the papers that we talked about today. As a member, you'll actually be helping us support members medical research to extend all of our healthy lives. If you found this episode valuable, do consider subscribing and also turn on your notifications so you don't miss new episodes. It'll also help us make a better show for you. And feel free to share this episode with any family or friends who you think might enjoy it and learn from it. Finally, for the latest discoveries in longevity science, consider following us on Instagram Instagram at Lifespan and on xoinlifespan. From all of us at Lifespan, thank you for being part of this growing community. And remember, life's short, so let's change that together. Lifespan is produced by Andrew the Wonder Man Ying Rajiv Geek me out Ramesh Marissa who's on first, Volgamore, Kathleen Tldr Fitzgerald and our researchers Shivani. Just one more thing, Sethi and a Dive Meet me in the year 3000 Johnson. Also, I want to mention our new recruit, Daniel Rocketman Salazar, who's our new producer and of course Serena my honeypoon. I also want to thank Inspiro Studio and Create Ape for making this show possible. And finally, thanks to our partners for helping us support longevity research. We'll see you next time. This show is for informational purposes only and is not medical advice. Please consult a qualified healthcare provider as individual results may vary. Views expressed are my own and not those of Harvard University or Harvard Medical School. Full disclaimer is in the show. Notes.