Sauna Heart Health And Longevity Science | Vitruvian

Video·David Sinclair·9 min read·June 11, 2026

David Sinclair argues that longevity science is moving from possibility to practice, with epigenetic reprogramming, AI, and rare examples of human vitality pointing toward a longer healthspan.

The Shift From Lifespan To Longevity

Longevity begins with a clear reframing. Aging is not a passive backdrop to disease; Sinclair presents it as a root driver behind many of the conditions that shape later life. When we address aging itself, the ambition changes. The goal becomes more than adding years. It becomes preserving function, clarity, vitality, and choice.

That shift gives the new season of Lifespan its larger mission. The show returns as a bridge between closed laboratory work and public understanding, translating what is happening in research into language people can use. Sinclair describes a world where discoveries that once lived in journals and conferences are moving toward real access. The sanctuary of science is opening its doors.

The scale of the need is direct. Around 150,000 people die each day worldwide, and Sinclair states that about two-thirds of those deaths are connected to age-related diseases and conditions. This is why longevity science matters beyond curiosity. It is a public health question, a family question, and a personal protocol for how we meet the decades ahead.

The episode does not frame the field as distant speculation. It presents longevity as a near-term frontier, moving through gene therapy, AI, genomics, and better measures of biological age. The pace is deliberate and accelerating. What sounded like science fiction ten years ago now sits close enough to be tested in human trials.

For us, the promise is not immortality as spectacle. It is a longer healthspan with enough strength to move, enough cognition to decide, and enough energy to remain engaged with life. You do not simply seek more time. You seek time that still feels like yours.

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We are living through the most revolutionary period in the history of revolutionary period in the history of humanity. humanity. You could be one of the last people to You could be one of the last people to live a normal lifespan or one of the live a normal lifespan or one of the first to break the maximum limit [music] first to break the maximum limit [music] of 122. The technology is coming. OSK of 122. The technology is coming. OSK alone could reset the epigenetic clock alone could reset the epigenetic clock of human cells. One of the most exciting of human cells. One of the most exciting milestones happened recently. [music] milestones happened recently. [music] ER100 became the world's first ER100 became the world's first epigenetic reprogramming therapy to be epigenetic reprogramming therapy to be cleared for human clinical trials. It's cleared for human clinical trials. It's the same tech that cures blindness in the same tech that cures blindness in mice. People that have been treated, if mice. People that have been treated, if all goes well, will be able to see all goes well, will be able to see again. So, cross your fingers that that again. So, cross your fingers that that works. Welcome to Lifespan. A show where we discuss the cutting-edge A show where we discuss the cutting-edge science of aging and how to live science of aging and how to live healthier at any stage of life. healthier at any stage of life. I'm David Sinclair, a scientist and I'm David Sinclair, a scientist and professor working on understanding why professor working on understanding why we age and discovering new ways to slow we age and discovering new ways to slow and even reverse the aging process. On this show, I'll show an insider's look at the latest from [music] my lab,

look at the latest from [music] my lab, the field, and what's just around the 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 after the pilot episodes, which I'm so grateful went to number one. grateful went to number one. This new Lifespan show is bigger and This new Lifespan show is bigger and better now. Matt will be coming back for better now. Matt will be coming back for some shows, and I'm also going to be some shows, and I'm also going to be interviewing scientists from the interviewing scientists from the longevity field and from my lab. We'll longevity field and from my lab. We'll hear what it's like to make these hear what it's like to make these discoveries and where humanity is discoveries and where humanity is heading. These folks have more than a heading. These folks have more than a five-year view on the future because five-year view on the future because they're actually inventing it. Normally, they're actually inventing it. Normally, this would be hidden behind closed lab this would be hidden behind closed lab doors, but we're going to gain special doors, but we're going to gain special access. To join our community, visit access. To join our community, visit lifespan.com. My life's mission is to lifespan.com. My life's mission is to extend healthy lifespan for all, and extend healthy lifespan for all, and that's why I founded Lifespan, which that's why I founded Lifespan, which exists to help you and your loved ones exists to help you and your loved ones live your longest, healthiest lives. live your longest, healthiest lives. We're building the world's largest

We're building the world's largest longevity community longevity community and supporting medical research through and supporting medical research through the nonprofit lifespan foundation. Of the nonprofit lifespan foundation. Of the 150,000 people around the world that the 150,000 people around the world that die every day, approximately 2/3 of die every day, approximately 2/3 of those are due to age-related diseases those are due to age-related diseases and conditions with aging at the root and conditions with aging at the root cause of those. Hence, we can cause of those. Hence, we can dramatically improve human health by dramatically improve human health by targeting aging itself. We are in a new targeting aging itself. We are in a new era and Lifespan covers what you need to era and Lifespan covers what you need to know about the exciting world of aging know about the exciting world of aging and longevity science. In making this and longevity science. In making this episode, I used everything from tennis episode, I used everything from tennis balls to DNA models to show you how balls to DNA models to show you how cellular software might be rebooted. I cellular software might be rebooted. I recorded this over many weeks because it recorded this over many weeks because it was really hard to make. We looked at was really hard to make. We looked at thousands of papers and thousands of papers and double-and-triple-checked every fact and double-and-triple-checked every fact and even re-recorded parts for accuracy. And even re-recorded parts for accuracy. And with that, let's go. To my left here, with that, let's go. To my left here, I'm excited to introduce the Lifespan I'm excited to introduce the Lifespan smartboard. This board here I can go up, smartboard. This board here I can go up, I can touch it. We can zoom in on I can touch it. We can zoom in on figures from papers. And every show figures from papers. And every show we'll be examining the science on that

we'll be examining the science on that whiteboard and also bringing up video whiteboard and also bringing up video chats and other things. To my right chats and other things. To my right here, we have a glass cabinet as part of here, we have a glass cabinet as part of this beautiful old library that I've this beautiful old library that I've filled with objects of interest that I'm filled with objects of interest that I'm going to bring out throughout the shows going to bring out throughout the shows going forward. going forward. And they will illustrate what I'm And they will illustrate what I'm talking about from DNA molecules to the talking about from DNA molecules to the Wright brothers' plane even. Arthur C. Wright brothers' plane even. Arthur C. Clarke, the science fiction writer who Clarke, the science fiction writer who features in my book Lifespan, famously features in my book Lifespan, famously said, "Any sufficiently advanced said, "Any sufficiently advanced technology is indistinguishable from technology is indistinguishable from magic." And if you've not yet heard the magic." And if you've not yet heard the news, I'm excited to inform you the news, I'm excited to inform you the technology is coming. One of the most technology is coming. One of the most exciting milestones happened recently in exciting milestones happened recently in January 2026 January 2026 when Life Biosciences' drug candidate when Life Biosciences' drug candidate called ER100 became the world's first called ER100 became the world's first epigenetic reprogramming therapy to be epigenetic reprogramming therapy to be cleared for human clinical trials by the cleared for human clinical trials by the FDA. The tech is essentially a gene FDA. The tech is essentially a gene therapy that came straight out of my lab therapy that came straight out of my lab from my student Wang Cheng Lu. from my student Wang Cheng Lu. It's the same tech that we published on It's the same tech that we published on the cover of Nature in 2020 the cover of Nature in 2020 that we showed reverses aging and cures

that we showed reverses aging and cures blindness in mice. blindness in mice. Professor Bruce Cassandra, Sharon Professor Bruce Cassandra, Sharon Rosenblatt Glypson, and her team at Life Rosenblatt Glypson, and her team at Life Bio have since shown that this tech also Bio have since shown that this tech also works in monkeys to restore visual works in monkeys to restore visual function, and we're about to learn if it function, and we're about to learn if it works in humans to reverse vision loss. works in humans to reverse vision loss. And from there, just pick your organ of And from there, just pick your organ of interest. Ear, kidney, heart, liver, interest. Ear, kidney, heart, liver, skin, the possibilities are just too skin, the possibilities are just too numerous to list. numerous to list. I'll talk much more about all of that I'll talk much more about all of that later and give updates on how the trial later and give updates on how the trial goes in later episodes. What used to be goes in later episodes. What used to be science fiction just 10 years ago is now science fiction just 10 years ago is now coming to reality. coming to reality. And the science that used to live on the And the science that used to live on the pages of journals pages of journals and in academic conferences like the and in academic conferences like the ones I typically attend, ones I typically attend, it's now coming to the market. No it's now coming to the market. No science show would be complete these science show would be complete these days without mentioning AI. Artificial days without mentioning AI. Artificial intelligence isn't here just to solve intelligence isn't here just to solve problems faster. It's here to rethink problems faster. It's here to rethink them. them. AI systems today are helping uncover AI systems today are helping uncover previously invisible aging biomarkers, previously invisible aging biomarkers, revealing drug targets tied to revealing drug targets tied to biological aging, and even suggesting

biological aging, and even suggesting repurposed compounds that could rewind repurposed compounds that could rewind the age of cells and address multiple the age of cells and address multiple hallmarks of aging at once. hallmarks of aging at once. I know this because my lab is doing I know this because my lab is doing this, and I'm excited to bring you the this, and I'm excited to bring you the latest findings of my lab and the field, latest findings of my lab and the field, insights you can find nowhere else. insights you can find nowhere else. In the next wave, adaptive agentic AI In the next wave, adaptive agentic AI systems could partner with human biology systems could partner with human biology to optimize interventions, to optimize interventions, essentially acting like an ever-learning essentially acting like an ever-learning personal longevity scientist for you. personal longevity scientist for you. Sequencing just one genome used to be Sequencing just one genome used to be reserved for elite research labs at a reserved for elite research labs at a cost of about a billion dollars per cost of about a billion dollars per genome. In early 2026, the $100 genome genome. In early 2026, the $100 genome has been announced, which is going to has been announced, which is going to pave the way for personalized longevity pave the way for personalized longevity guidance, cancer detection and decades guidance, cancer detection and decades before it actually happens, as well as before it actually happens, as well as drug personalization and age estimation, drug personalization and age estimation, at least your epigenetic age, which we at least your epigenetic age, which we also call your biological age. also call your biological age. And this is quite different than the And this is quite different than the one-size-fits-all advice that represents one-size-fits-all advice that represents the 20th century. the 20th century. This means you have a choice.

This means you have a choice. Be a bystander or be literate in what Be a bystander or be literate in what comes next. The longevity space is comes next. The longevity space is moving really rapidly, and its progress moving really rapidly, and its progress is only accelerating. The sheer amount is only accelerating. The sheer amount of information and updates happening of information and updates happening make it extremely difficult for any make it extremely difficult for any non-expert to make any sense of what's non-expert to make any sense of what's going on. going on. It's hard to get a good grasp on what's It's hard to get a good grasp on what's real real and exciting versus speculation and and exciting versus speculation and science fiction. You've probably noticed science fiction. You've probably noticed that people who are really passionate that people who are really passionate about wellness and longevity about wellness and longevity have some very strong opinions that have some very strong opinions that often conflict with each other. often conflict with each other. It's hard to know who's right. It's hard to know who's right. Influencers are even worse, trying to Influencers are even worse, trying to gain attention by saying outrageous gain attention by saying outrageous things or hyping up a new study. I see things or hyping up a new study. I see it all the time. it all the time. Eat only meat. Seed oils will kill you. Eat only meat. Seed oils will kill you. You can't take Metformin or Berberine if You can't take Metformin or Berberine if you want to gain muscle. Detox teas will you want to gain muscle. Detox teas will cleanse you. cleanse you. Even cold plunges will melt fat away. Even cold plunges will melt fat away. What about you must eat every two to What about you must eat every two to three hours to stoke the metabolism? three hours to stoke the metabolism? A lot of these couldn't be further from A lot of these couldn't be further from the truth, and we're going to dissect the truth, and we're going to dissect the real science here on this podcast.

the real science here on this podcast. Given the opportunity, virtually Given the opportunity, virtually everyone that I talk to would like to everyone that I talk to would like to become a centenarian, someone that lives become a centenarian, someone that lives over 100, especially if they would spend over 100, especially if they would spend the vast majority of that time free of the vast majority of that time free of disease. disease. My father, for example, My father, for example, who I talk about a lot and he's in my who I talk about a lot and he's in my book, is now 86. book, is now 86. And by following the practices we will And by following the practices we will be discussing on this podcast, he be discussing on this podcast, he remains in perfect health, as energetic remains in perfect health, as energetic and as busy and even happier than he was and as busy and even happier than he was in his 30s. With everything we now know in his 30s. With everything we now know and science I know of that's coming down and science I know of that's coming down the line, this is not a crazy goal at the line, this is not a crazy goal at all and is something that's quite all and is something that's quite achievable for you and your family. achievable for you and your family. Okay, let's begin by talking about Okay, let's begin by talking about extraordinary feats of longevity and extraordinary feats of longevity and performance that are already possible performance that are already possible today. today. These are verified achievements by real These are verified achievements by real people living under current or even past people living under current or even past conditions. conditions. They establish the current outer They establish the current outer boundaries of human biological boundaries of human biological potential. potential. Each case shows what the human body and Each case shows what the human body and mind can already accomplish. mind can already accomplish. I believe that if something is

I believe that if something is biologically possible for one person, biologically possible for one person, it represents a capacity that could in it represents a capacity that could in time extend to many. First, let's talk time extend to many. First, let's talk about the longest verified human about the longest verified human lifespan on record. lifespan on record. That's Jeanne Calment of France, who That's Jeanne Calment of France, who lived to 122 years and 164 days. Andrew, lived to 122 years and 164 days. Andrew, let's call up that video of Jeanne 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 funny and said numerous jokes, one of which was, "I only have one wrinkle and which was, "I only have one wrinkle and I'm sitting on it." There's also the I'm sitting on it." There's also the story of her talking to a reporter, story of her talking to a reporter, young reporter, young reporter, and he said, "Wow, this has been great. and he said, "Wow, this has been great. I hope I see you next year." And she I hope I see you next year." And she says, "I don't see why not. You look says, "I don't see why not. You look pretty healthy to me." Jeanne was born pretty healthy to me." Jeanne was born in France in 1875 in France in 1875 and she passed away in 1997. I remember and she passed away in 1997. I remember the day clearly. the day clearly. She watched the Eiffel Tower being built She watched the Eiffel Tower being built as a teenager and lived through two as a teenager and lived through two world wars, world wars, plus the invention of airplanes, the plus the invention of airplanes, the rise of the internet, and much more. The

rise of the internet, and much more. The number 122 in Lifespan's logo recognizes number 122 in Lifespan's logo recognizes her great achievement and this her great achievement and this extraordinary milestone. Just consider extraordinary milestone. Just consider this. 122 this. 122 is over 40 years beyond age 80, is over 40 years beyond age 80, the same span of time as from age 40 to the same span of time as from age 40 to 80. 80. So, think about that. What if at 80 you So, think about that. What if at 80 you had another 40 years of healthy life had another 40 years of healthy life ahead? ahead? Calment's record stands as proof of our Calment's record stands as proof of our human biological potential. human biological potential. The question is not whether such The question is not whether such longevity can occur. It already has. longevity can occur. It already has. The question is how to make it more The question is how to make it more common common in even better health and ultimately in even better health and ultimately even longer. This human lifespan record even longer. This human lifespan record alone is powerful, alone is powerful, but what about physical performance in but what about physical performance in older age? older age? At age 22 in 2009, Usain Bolt set the At age 22 in 2009, Usain Bolt set the 100-m world record of 9.58 seconds. 100-m world record of 9.58 seconds. But in 2024, But in 2024, 80-year-old Kynton Brown ran 100 m

80-year-old Kynton Brown ran 100 m in only 14.21 seconds, setting a world in only 14.21 seconds, setting a world record for his age group. record for his age group. The times, of course, meaningfully, but The times, of course, meaningfully, but Kynton's achievement is nonetheless Kynton's achievement is nonetheless incredible. incredible. Usain Bolt, 9.58. Kynton Brown, 14.21 Usain Bolt, 9.58. Kynton Brown, 14.21 at age 80. For those watching on video, at age 80. For those watching on video, we found a video of men in their 80s we found a video of men in their 80s doing a 100-m final. Andrew, let's pull doing a 100-m final. Andrew, let's pull up that video. up that video. It's really remarkable, actually, how It's really remarkable, actually, how fast they run. It looks like it's on fast they run. It looks like it's on twice speed. twice speed. Looks like there's two Australians in Looks like there's two Australians in there at the green and gold. Go, Aussie. Oi, oi, oi, we say. Oi, oi, oi, we say. I think the red guy is going to win. I think the red guy is going to win. Yes. Yes. So, just notice the energy, the speed, So, just notice the energy, the speed, and explosive power of those guys. and explosive power of those guys. And remember, they're over 80. And And remember, they're over 80. And importantly, it's not just a single importantly, it's not just a single outlier performing this way. All seven outlier performing this way. All seven of the runners accelerate hard, maintain of the runners accelerate hard, maintain form, and drive through the finish line

form, and drive through the finish line with force. with force. At their age, they're sprinting. At their age, they're sprinting. They're also demonstrating exceptional They're also demonstrating exceptional muscle power, coordination, and muscle power, coordination, and athleticism. This is likely not athleticism. This is likely not something you've ever seen before. I something you've ever seen before. I know I haven't. And yet, it is indeed know I haven't. And yet, it is indeed what the human body can achieve even at what the human body can achieve even at 80 and beyond. Speed, of course, is just 80 and beyond. Speed, of course, is just one dimension of fitness. Endurance is one dimension of fitness. Endurance is another. In 2021, at age 80, Jose Lopez another. In 2021, at age 80, Jose Lopez ran a mile, or about 1.6 km, in 5 ran a mile, or about 1.6 km, in 5 minutes and 56 seconds. I mean, most of minutes and 56 seconds. I mean, most of us can't even approach that. He set a us can't even approach that. He set a world record for his age group. Anyone world record for his age group. Anyone who's run a mile knows that a time below who's run a mile knows that a time below 6 minutes is a difficult and remarkable 6 minutes is a difficult and remarkable accomplishment at any age, and accomplishment at any age, and especially so at 80. Jose's feat proves especially so at 80. Jose's feat proves that exceptional aerobic function and that exceptional aerobic function and cardiovascular health can be achieved cardiovascular health can be achieved even at older ages. even at older ages. Physical vitality is not limited to Physical vitality is not limited to speed or endurance. It extends to speed or endurance. It extends to fertility as well.

fertility as well. So, in 1997, it was amazing to learn So, in 1997, it was amazing to learn that Dawn Brooke naturally conceived a that Dawn Brooke naturally conceived a healthy son at age 59, making her the healthy son at age 59, making her the oldest verified mother to conceive oldest verified mother to conceive without fertility treatment. without fertility treatment. Female fertility typically declines Female fertility typically declines significantly after the mid-30s, and significantly after the mid-30s, and natural conception beyond age 50 is natural conception beyond age 50 is extremely rare. extremely rare. Yet, Dawn demonstrates that fertility Yet, Dawn demonstrates that fertility can persist far beyond typical norms. can persist far beyond typical norms. Dawn set the record, and through Dawn set the record, and through technology, my lab and others are technology, my lab and others are striving to preserve fertility for as striving to preserve fertility for as long as possible for as many women as long as possible for as many women as possible. So, let's talk about mental possible. So, let's talk about mental performance. Is a loss of memory and performance. Is a loss of memory and creativity inexorable with age? creativity inexorable with age? The Mini-Mental State Examination, or The Mini-Mental State Examination, or MMSE, partly developed by my friend MMSE, partly developed by my friend Sharon Inouye at Harvard, it's a widely Sharon Inouye at Harvard, it's a widely used screening tool for cognitive used screening tool for cognitive impairment. It assesses memory, impairment. It assesses memory, attention, language, and other skills. attention, language, and other skills. Scores range from 0 to 30, with 25 or

Scores range from 0 to 30, with 25 or above considered within the normal above considered within the normal range. In 2008, Den Dunnen and range. In 2008, Den Dunnen and colleagues in the Netherlands published colleagues in the Netherlands published a case report in the journal a case report in the journal Neurobiology of Aging, titled No Disease Neurobiology of Aging, titled No Disease in the Brain of a 115-Year-Old Woman. in the Brain of a 115-Year-Old Woman. They asked the question, are there They asked the question, are there limits to healthy life for a human limits to healthy life for a human brain? brain? In the paper, they reported a woman who In the paper, they reported a woman who had chosen to donate her body to had chosen to donate her body to science. science. And at the age of 115, the same year of And at the age of 115, the same year of her death, she scored 26 out of 30 on her death, she scored 26 out of 30 on this exam. this exam. At age 115, her performance was stated At age 115, her performance was stated to be above the typical average of to be above the typical average of healthy adults aged 60 to 75. While not healthy adults aged 60 to 75. While not a verified world record, this must be a verified world record, this must be pretty close to one. After she passed pretty close to one. After she passed away, away, scientists found almost no evidence of scientists found almost no evidence of heart disease in her body, heart disease in her body, and her brain had almost no beta-amyloid and her brain had almost no beta-amyloid plaques or vascular changes. She had plaques or vascular changes. She had around the same number of locus ceruleus around the same number of locus ceruleus neurons as those of the brains of

neurons as those of the brains of healthy 60- 80-year-olds. healthy 60- 80-year-olds. Locus ceruleus neurons are among the Locus ceruleus neurons are among the first neurons to change with age, first neurons to change with age, and one of the earliest sites of and one of the earliest sites of phospho-tau protein accumulation in phospho-tau protein accumulation in aging brains, and often accumulates aging brains, and often accumulates decades before clinical Alzheimer's decades before clinical Alzheimer's disease appears. disease appears. These findings show that the boundaries These findings show that the boundaries of human cognition can extend well of human cognition can extend well beyond what most people currently beyond what most people currently experience, experience, and that cognitive impairment need not and that cognitive impairment need not be inevitable even among be inevitable even among supercentenarians. supercentenarians. We know that a 115-year-old woman had We know that a 115-year-old woman had the same cognitive performance as the same cognitive performance as 60-year-olds, so that is possible. 60-year-olds, so that is possible. That also means it should be possible to That also means it should be possible to figure out what made her special and figure out what made her special and design medicines that could be used by design medicines that could be used by all of us to give us what she had. all of us to give us what she had. To help keep this show freely available, To help keep this show freely available, Lifespan partners with a select group of Lifespan partners with a select group of companies that I truly believe in and companies that I truly believe in and who also share our commitment to who also share our commitment to evidence-based science and supporting evidence-based science and supporting medical research. medical research. One of those partners is Ketone IQ.

One of those partners is Ketone IQ. Researchers are increasingly interested Researchers are increasingly interested in metabolic flexibility, including how in metabolic flexibility, including how the body can tap into alternative energy the body can tap into alternative energy sources like ketones, especially during sources like ketones, especially during fasting. I've been increasingly fasting. I've been increasingly interested in ketones as I go longer and interested in ketones as I go longer and longer with my fasting. longer with my fasting. Last month, for example, I managed to Last month, for example, I managed to essentially go for 3 weeks without a essentially go for 3 weeks without a full meal, full meal, and I know that sounds crazy, but I and I know that sounds crazy, but I really wanted to see what would happen. really wanted to see what would happen. During that time, my body survived on During that time, my body survived on ketones. The remarkable part is that I ketones. The remarkable part is that I felt better than ever. My strength and felt better than ever. My strength and my energy improved, and my brain was my energy improved, and my brain was really active. I even slept better. really active. I even slept better. There's a lot of great science about the There's a lot of great science about the potential benefits of fasting and of potential benefits of fasting and of ketones. But, the problem is how can you ketones. But, the problem is how can you get the benefits of fasting without get the benefits of fasting without having to reduce your food like I did? having to reduce your food like I did? You've likely heard of ketones before in You've likely heard of ketones before in the context of the ketogenic diet or in the context of the ketogenic diet or in fasting literature. fasting literature. By cutting back on carbohydrates, By cutting back on carbohydrates, especially, what you're actually doing

especially, what you're actually doing is flipping a metabolic switch that is flipping a metabolic switch that tells your body to start producing these tells your body to start producing these molecules as an alternative energy molecules as an alternative energy source besides glucose. source besides glucose. Ketone IQ is a little drink whose active Ketone IQ is a little drink whose active ingredient is a ketone precursor, and ingredient is a ketone precursor, and it's called R-1,3-Butanediol. it's called R-1,3-Butanediol. Now, you don't have to remember that, of Now, you don't have to remember that, of course. But, what's interesting is that course. But, what's interesting is that your liver converts that drink into your liver converts that drink into beta-hydroxybutyrate, beta-hydroxybutyrate, which is a main ketone fuel that your which is a main ketone fuel that your brain and your muscle can use for brain and your muscle can use for energy. There's a growing amount of energy. There's a growing amount of research into the effects of ketones on research into the effects of ketones on the body. the body. In 2012, for example, the first study of In 2012, for example, the first study of its kind showed that consuming an its kind showed that consuming an exogenous ketone raised blood exogenous ketone raised blood beta-hydroxybutyrate levels to that beta-hydroxybutyrate levels to that typically seen during a long fast like typically seen during a long fast like the one that I did. Or, if you're having the one that I did. Or, if you're having a really strict ketogenic diet. Then, in a really strict ketogenic diet. Then, in 2018, a study asked, "What fuel does the 2018, a study asked, "What fuel does the aging brain still use?" aging brain still use?" As cognition declined in their patients As cognition declined in their patients over time, the researchers found that

over time, the researchers found that the brain became less able to use its the brain became less able to use its normal fuel, glucose. normal fuel, glucose. And what actually happened was that the And what actually happened was that the ketone uptake remained relatively ketone uptake remained relatively preserved. That's really important and preserved. That's really important and interesting because it suggests that interesting because it suggests that even when the aging brain struggles to even when the aging brain struggles to use sugar for energy, it can probably use sugar for energy, it can probably still use ketones as the alternative still use ketones as the alternative fuel. fuel. And finally, I briefly want to mention a And finally, I briefly want to mention a study that I really love from 2022, study that I really love from 2022, where researchers gave soccer players where researchers gave soccer players some ketones and found actually that some ketones and found actually that their reaction time and their cognition their reaction time and their cognition improved. They didn't get as much improved. They didn't get as much fatigue. fatigue. And actually, that's one of the reasons And actually, that's one of the reasons that I take KetoneIQ often, especially that I take KetoneIQ often, especially before I do this show. We're offering before I do this show. We're offering our audience a 30% off discount for your our audience a 30% off discount for your first monthly order at first monthly order at ketone.com/lifespan ketone.com/lifespan or at the checkout, just use the code or at the checkout, just use the code lifespan. lifespan. Beyond general brain health, what about Beyond general brain health, what about maintaining specific mental skills at an maintaining specific mental skills at an elite level in older ages? Chess is an elite level in older ages? Chess is an extraordinarily complex game. To play at extraordinarily complex game. To play at a high level, players must calculate

a high level, players must calculate multiple moves ahead every turn, multiple moves ahead every turn, anticipate opponents' responses, anticipate opponents' responses, recognize hundreds of board patterns, recognize hundreds of board patterns, and adapt in real time under pressure. and adapt in real time under pressure. Mastery demands working memory, pattern Mastery demands working memory, pattern recognition, and long-term planning. recognition, and long-term planning. The title chess master is given to only The title chess master is given to only elite players recognized by the National elite players recognized by the National Chess Federation and reflects sustained Chess Federation and reflects sustained competitive success. competitive success. In 1984, Oscar Shapiro became the oldest In 1984, Oscar Shapiro became the oldest person in US history to earn the title person in US history to earn the title of chess master at the age of 74. of chess master at the age of 74. Achieving this in his 70s demonstrates Achieving this in his 70s demonstrates that complex skill acquisition can occur that complex skill acquisition can occur even at old age. Sure, it was years of even at old age. Sure, it was years of practice, practice, but his lifestyle or his genes might but his lifestyle or his genes might have had something to do with his have had something to do with his success. And if so, we can mimic that, success. And if so, we can mimic that, too. too. These are rare examples, but they aren't These are rare examples, but they aren't always. Take my father, Andrew, for always. Take my father, Andrew, for example, a regular guy example, a regular guy who read the science and took control of who read the science and took control of his health around the age of 50.

his health around the age of 50. Let's show a picture of Dad. Let's show a picture of Dad. He's been doing many of the right things He's been doing many of the right things that longevity science says to do. that longevity science says to do. Exercise regularly. Exercise regularly. He does a lot of walking. He takes He does a lot of walking. He takes supplements. And now, at 86, he's in supplements. And now, at 86, he's in perfect health, stronger and fitter than perfect health, stronger and fitter than average 30-year-olds. average 30-year-olds. He's certainly fitter and stronger than He's certainly fitter and stronger than me. me. I'm super proud of Dad. In later I'm super proud of Dad. In later episodes, we're going to talk about what episodes, we're going to talk about what he and I do on a daily basis to maintain he and I do on a daily basis to maintain our youth and vigor. Wherever my dad our youth and vigor. Wherever my dad goes, people underestimate him for his goes, people underestimate him for his age. age. We climbed the Sydney Harbour Bridge, We climbed the Sydney Harbour Bridge, and people weren't sure he could do and people weren't sure he could do that, and it was no problem. He'd that, and it was no problem. He'd already walked 20,000 steps before we already walked 20,000 steps before we went up there. went up there. He's climbed mountains. He's abseiled. He's climbed mountains. He's abseiled. And most recently, on a big stage in And most recently, on a big stage in Sydney, he joined me up on stage, and he Sydney, he joined me up on stage, and he was a natural. was a natural. Taken together, these examples show what Taken together, these examples show what incredible feats of longevity and incredible feats of longevity and performance have already been achieved performance have already been achieved by athletes and by chess champions and by athletes and by chess champions and even my father. even my father. And that is before the benefits of the And that is before the benefits of the kind of technologies we're going to talk kind of technologies we're going to talk about on this show and those that will

about on this show and those that will undoubtedly arrive in our lifetimes. undoubtedly arrive in our lifetimes. With the exception of my father, these With the exception of my father, these feats are extremely rare, but feats are extremely rare, but nonetheless possible and achieved. nonetheless possible and achieved. Imagine you or your loved one being 80 Imagine you or your loved one being 80 years old and knowing that more than 40 years old and knowing that more than 40 healthy, high-performance years are healthy, high-performance years are still lying ahead. still lying ahead. I believe we can make these outcomes I believe we can make these outcomes more common and hopefully one day more common and hopefully one day possible for all of us. possible for all of us. But to make that leap from rare outliers But to make that leap from rare outliers to widespread reality, to widespread reality, we must understand what determines the we must understand what determines the true limits of human biological true limits of human biological potential. potential. Why do some people preserve function so Why do some people preserve function so far beyond the norm while most far beyond the norm while most experience steady decline? experience steady decline? To answer that, we need a framework for To answer that, we need a framework for what aging actually is at the biological what aging actually is at the biological level. level. And that brings us to my information And that brings us to my information theory of aging. The information theory theory of aging. The information theory of aging, or ITOA, of aging, or ITOA, is a totally new way to view aging. is a totally new way to view aging. From the 1950s to the 1990s, the From the 1950s to the 1990s, the prevailing view about aging was that it

prevailing view about aging was that it was due to DNA damage or some type of was due to DNA damage or some type of damage caused by free radicals that damage caused by free radicals that could be mopped up by antioxidants. And could be mopped up by antioxidants. And this is why you still see food and this is why you still see food and drinks in the supermarket tout the drinks in the supermarket tout the wonderful benefits of antioxidants. wonderful benefits of antioxidants. But we've moved on from there. What was But we've moved on from there. What was once a minority view has moved closer to once a minority view has moved closer to the mainstream. Increasingly, aging is the mainstream. Increasingly, aging is no longer described as the build-up of no longer described as the build-up of cellular damage, cellular damage, but as a loss of biological information. but as a loss of biological information. According to the theory, the precise According to the theory, the precise patterns of gene expression that patterns of gene expression that maintain cellular identity gradually maintain cellular identity gradually erode, leaving cells less able to erode, leaving cells less able to function properly and more vulnerable to function properly and more vulnerable to disease. I To proposes that aging is not disease. I To proposes that aging is not fundamentally caused by mutations or fundamentally caused by mutations or some other type of damage or disrepair. some other type of damage or disrepair. It is a loss of information. It is a loss of information. So, what kind of information are we So, what kind of information are we talking about here? There are two types talking about here? There are two types of information in all of our cells. of information in all of our cells. The first is the genome, a highly stable

The first is the genome, a highly stable digital repository of information that's digital repository of information that's encoded in a chemical we call DNA, encoded in a chemical we call DNA, which can last for hundreds of thousands which can last for hundreds of thousands of years. In fact, some of my colleagues of years. In fact, some of my colleagues at Harvard have pulled these out of at Harvard have pulled these out of fossils, even of Neanderthals and fossils, even of Neanderthals and species older than that. species older than that. The other type of information that we The other type of information that we need to talk about here, which is so need to talk about here, which is so important for aging, is epigenetic important for aging, is epigenetic information. information. These are the instructions that tell These are the instructions that tell cells how to use the genome, cells how to use the genome, the software of our cells, you could the software of our cells, you could think of it. think of it. I To posits that what fails with age is I To posits that what fails with age is our cells' ability to read and interpret our cells' ability to read and interpret genetic information correctly. genetic information correctly. And over time, cells begin to read the And over time, cells begin to read the wrong genes at the wrong time, and they wrong genes at the wrong time, and they lose their identity. Nerve cells begin lose their identity. Nerve cells begin to take on the properties of skin cells, to take on the properties of skin cells, liver cells drift towards kidney cells. liver cells drift towards kidney cells. We start to lose our hearing, our We start to lose our hearing, our eyesight, eyesight, and our muscles shrink, our bones and our muscles shrink, our bones weaken, and then diseases take hold.

weaken, and then diseases take hold. What's so important for any scientific What's so important for any scientific theory, and for I Toa, is that it's theory, and for I Toa, is that it's testable. testable. And what's so exciting is that there's And what's so exciting is that there's growing evidence that it might actually growing evidence that it might actually be true. For it to make any sense, you be true. For it to make any sense, you have to accept a strange premise have to accept a strange premise that cells carry memories. that cells carry memories. So, rather than viewing the body simply So, rather than viewing the body simply as a collection of mechanical parts that as a collection of mechanical parts that wear out over time, wear out over time, we can see it as a dynamic system for we can see it as a dynamic system for storing, preserving, and interpreting storing, preserving, and interpreting biological information. biological information. Aging, in this framework, is not just Aging, in this framework, is not just damage accumulation. It is the damage accumulation. It is the progressive loss of the cells' ability progressive loss of the cells' ability to maintain its identity. This to maintain its identity. This eventually causes the organ or the eventually causes the organ or the tissue to forget how to function and tissue to forget how to function and stave off what we affectionately call stave off what we affectionately call diseases. diseases. Of course, we all started out life as a Of course, we all started out life as a single fertilized cell. single fertilized cell. Then, during embryo development, each of Then, during embryo development, each of our cells, which contain the same DNA, our cells, which contain the same DNA, they quickly specialized by remembering they quickly specialized by remembering which genes to turn on and off.

which genes to turn on and off. The system that carries this out is The system that carries this out is called the epigenome. called the epigenome. This cellular memory, maintained through This cellular memory, maintained through epigenetic marks and folding of the epigenetic marks and folding of the genome, is what allows a neuron to genome, is what allows a neuron to remain a neuron and liver cell to remain remain a neuron and liver cell to remain a liver cell. a liver cell. As we get older, though, As we get older, though, that breaks down. that breaks down. I have a little model here of what I have a little model here of what chromatin actually looks like. I threw this together recently with some tennis balls and some Velcro. So, if tennis balls and some Velcro. So, if you're just listening to this, you can you're just listening to this, you can imagine blue Velcro wrapped twice around imagine blue Velcro wrapped twice around each tennis ball in a string of balls. each tennis ball in a string of balls. So, the blue Velcro represents DNA. So, the blue Velcro represents DNA. It's a little bit tangled, but that's It's a little bit tangled, but that's good because the DNA naturally looks good because the DNA naturally looks like this, and bundles of these proteins like this, and bundles of these proteins form chromosomes you can actually see form chromosomes you can actually see with the microscope. So, during with the microscope. So, during embryonic development, what happens is embryonic development, what happens is that these balls and DNA wrap in certain that these balls and DNA wrap in certain ways that are slightly different between ways that are slightly different between nerve cells and liver cells and skin

nerve cells and liver cells and skin cells. cells. But during aging, what we found is that But during aging, what we found is that this starts to unravel and that the DNA this starts to unravel and that the DNA becomes more open and now genes that becomes more open and now genes that should not be turned on get turned on should not be turned on get turned on and a nerve cell starts turning on genes and a nerve cell starts turning on genes that liver cells normally have on. that liver cells normally have on. That's a problem. We don't want our That's a problem. We don't want our brain expressing liver-specific genes. brain expressing liver-specific genes. Ultimately, what we see is that that Ultimately, what we see is that that causes dysfunction of all organs causes dysfunction of all organs including the brain including the brain and that leads to disease and this is and that leads to disease and this is why we think we get old. why we think we get old. Your DNA sequence is essentially the Your DNA sequence is essentially the same in a skin cell as it is in a neuron same in a skin cell as it is in a neuron in childhood and in old age. The in childhood and in old age. The difference lies not in the letters of difference lies not in the letters of the code but in how that code is read. the code but in how that code is read. By changing where chemical tags are By changing where chemical tags are added to the DNA and to the proteins added to the DNA and to the proteins that spool the DNA, you can see here that spool the DNA, you can see here that there would be little chemicals that there would be little chemicals like this bit of Velcro on the proteins like this bit of Velcro on the proteins that wrap the DNA and actually we get that wrap the DNA and actually we get chemicals like this one on the DNA

chemicals like this one on the DNA itself. These little chemicals, one of itself. These little chemicals, one of which is called methyls, a very which is called methyls, a very important one, they dictate how this is important one, they dictate how this is all folded and those little tags change all folded and those little tags change over time. Unlike the digital genome, over time. Unlike the digital genome, which is very robust, the epigenome is which is very robust, the epigenome is mostly analog information and hence mostly analog information and hence highly dynamic. In fact, if you could highly dynamic. In fact, if you could see these balls under the microscope in see these balls under the microscope in a real cell, they wouldn't be sitting a real cell, they wouldn't be sitting here, they'd be flying around like it here, they'd be flying around like it was a hurricane. It's actually quite a was a hurricane. It's actually quite a miracle that we last 80 years. miracle that we last 80 years. That flexibility is what allows cells to That flexibility is what allows cells to adapt to the environment. So when you adapt to the environment. So when you eat a meal, some of these balls open and eat a meal, some of these balls open and you get genes for insulin, for example, you get genes for insulin, for example, switched on. switched on. But it also is our Achilles' heel. It's But it also is our Achilles' heel. It's also what makes the system fragile. also what makes the system fragile. Over decades, according to I Toa, Over decades, according to I Toa, epigenetic patterns drift. The tags end epigenetic patterns drift. The tags end up in the wrong places and the up in the wrong places and the instructions eventually are so badly instructions eventually are so badly eroded that the cell forgets how to eroded that the cell forgets how to function. So, those little tags are function. So, those little tags are really interesting and those tags are

really interesting and those tags are what determines how cells function. I what determines how cells function. I actually have a model of it down here. actually have a model of it down here. Those of you listening, you'll just have Those of you listening, you'll just have to imagine that I've got this little to imagine that I've got this little plastic DNA molecule. It's basically a plastic DNA molecule. It's basically a ladder or a spiral staircase and each of ladder or a spiral staircase and each of the rungs of the ladder are actually the the rungs of the ladder are actually the letters of the DNA code. This might be a letters of the DNA code. This might be a very small section of one gene. One very small section of one gene. One strand of DNA runs down from top to strand of DNA runs down from top to bottom and then the other strand's going bottom and then the other strand's going the other direction, bottom up, and they the other direction, bottom up, and they form this beautiful spiral. What's form this beautiful spiral. What's important about this model is that the important about this model is that the letter C, which are these little red letter C, which are these little red bars here on half of the rung of the bars here on half of the rung of the ladder, ladder, those are the letters that the cell puts those are the letters that the cell puts those chemical tags on. When you have those chemical tags on. When you have lots of methyl chemicals on the Cs, that lots of methyl chemicals on the Cs, that gene will shut down. That's how the cell gene will shut down. That's how the cell tells a liver gene in a nerve cell to tells a liver gene in a nerve cell to not get expressed. But over time, what not get expressed. But over time, what we see in a very predictable manner is

we see in a very predictable manner is that those methyls get removed and even that those methyls get removed and even end up in other places that they don't end up in other places that they don't belong and we believe that isn't just a belong and we believe that isn't just a indicator of aging, a clock, so to indicator of aging, a clock, so to speak, but actually it literally causes speak, but actually it literally causes aging. So, those little chemicals are aging. So, those little chemicals are the basis of the information theory of the basis of the information theory of aging. aging. So, over time, gene expression patterns So, over time, gene expression patterns become deregulated, cellular identity become deregulated, cellular identity weakens, and a function declines. weakens, and a function declines. Now, I want to show you a diagram that Now, I want to show you a diagram that illustrates what I just told you. It's illustrates what I just told you. It's metaphorical, so don't think of this metaphorical, so don't think of this exactly how cells work, but it's very exactly how cells work, but it's very useful for understanding the changes useful for understanding the changes that cells go through during development that cells go through during development and during aging. What we have on the and during aging. What we have on the screen here is what's called the screen here is what's called the Waddington landscape and we've got a Waddington landscape and we've got a ball at the top of the mountain which ball at the top of the mountain which represents a pluripotent stem cell that represents a pluripotent stem cell that could roll down into any valley in this could roll down into any valley in this landscape. And actually during landscape. And actually during development, what happens is development, what happens is balls roll down and sometimes end up in balls roll down and sometimes end up in the neuron valley and other balls end up

the neuron valley and other balls end up in the kidney valley. And that's in the kidney valley. And that's essentially what's happening. The point essentially what's happening. The point is that balls that end up in the kidney is that balls that end up in the kidney valley valley never end up in the neuron valley and never end up in the neuron valley and vice versa. Cells have an identity and vice versa. Cells have an identity and they stick to it. they stick to it. But what we see during aging is that But what we see during aging is that those valleys and hills erode so that those valleys and hills erode so that the balls can roll over into adjacent the balls can roll over into adjacent valleys. And so that neurons start to valleys. And so that neurons start to become more like kidneys and kidney become more like kidneys and kidney cells become more like neurons. What I cells become more like neurons. What I Toa says is that there might be a way to Toa says is that there might be a way to push the balls back to where they came push the balls back to where they came from and rebuild those hills and valleys from and rebuild those hills and valleys the way they once were. the way they once were. When we thought of this in 2014, it was When we thought of this in 2014, it was a crazy idea. But we have some really a crazy idea. But we have some really good evidence that is actually possible. good evidence that is actually possible. The modern story of the information The modern story of the information theory of aging began not in humans or theory of aging began not in humans or even in mice, but in simple baker's even in mice, but in simple baker's yeast. Here's a picture of one. For yeast. Here's a picture of one. For those of you just listening, this is a those of you just listening, this is a big yellow cell surrounded by little big yellow cell surrounded by little blue cells which I stained blue cells which I stained oh, about 20 years ago and took this oh, about 20 years ago and took this photo.

photo. Old yeast cells live about 20 to 25 Old yeast cells live about 20 to 25 divisions. It takes about 10 days for divisions. It takes about 10 days for them to die and they get big, slow, them to die and they get big, slow, ugly, and actually become sterile as ugly, and actually become sterile as well, which will be important in a well, which will be important in a minute. minute. In the mid-1990s at the Massachusetts In the mid-1990s at the Massachusetts Institute of Technology or MIT, in Institute of Technology or MIT, in Professor Lenny Guarente's lab, we set Professor Lenny Guarente's lab, we set out to understand why baker's yeast out to understand why baker's yeast cells age and whether that process could cells age and whether that process could be slowed. At the time, when I arrived be slowed. At the time, when I arrived in Lenny's lab, in Lenny's lab, pretty much all theories of aging pretty much all theories of aging centered on cumulative damage, free centered on cumulative damage, free radicals, telomere shortening, and radicals, telomere shortening, and molecular wear and tear. molecular wear and tear. The idea that aging might be genetically The idea that aging might be genetically regulated and that a simple organism regulated and that a simple organism could reveal its mechanisms was not could reveal its mechanisms was not widely accepted at all. In fact, down widely accepted at all. In fact, down the hall, one professor scoffed at what the hall, one professor scoffed at what we were doing. Let's call up that photo we were doing. Let's call up that photo of us kids in 1998. of us kids in 1998. There we are. It's a bit of a faded There we are. It's a bit of a faded photo. As you can see, we're just a photo. As you can see, we're just a bunch of kids, bunch of rebellious kids bunch of kids, bunch of rebellious kids that most people thought were doing

that most people thought were doing crazy work. crazy work. Alongside Lenny, Alongside Lenny, were Brian Kennedy, Heidi Tissenbaum, were Brian Kennedy, Heidi Tissenbaum, Matt Kaeberlein, Shin-I and me. Matt Kaeberlein, Shin-I and me. We all went on to become professors in We all went on to become professors in the field. the field. At the time, At the time, we ended up discovering longevity genes we ended up discovering longevity genes in yeast called sirtuins that regulate in yeast called sirtuins that regulate the epigenome. the epigenome. And this was the basis of I TOWER. And this was the basis of I TOWER. One of the first key experiments came One of the first key experiments came when Brian analyzed a mutant yeast when Brian analyzed a mutant yeast strain that had survived in the fridge strain that had survived in the fridge for months. for months. These plates were pretty much dried out, These plates were pretty much dried out, and most things on the plate were and most things on the plate were already dead. already dead. Using a micromanipulator, he measured Using a micromanipulator, he measured the lifespan of that strain by removing the lifespan of that strain by removing and counting each daughter cell produced and counting each daughter cell produced by a single mother cell. That's how we by a single mother cell. That's how we determine how long yeast cells live. determine how long yeast cells live. Wild-type or normal yeast produce about Wild-type or normal yeast produce about 24 daughters. 24 daughters. This mutant produced roughly 30% more This mutant produced roughly 30% more daughters. It was definitely living daughters. It was definitely living longer. longer. And it was one of the first clear And it was one of the first clear demonstrations that lifespan could be

demonstrations that lifespan could be extended by a defined genetic extended by a defined genetic alteration. alteration. The mutation involved is called SIR4. The mutation involved is called SIR4. This gene was already known to maintain This gene was already known to maintain gene silencing at specific loci or gene silencing at specific loci or regions on the genome. regions on the genome. Its partner protein, Sir2, is actually Its partner protein, Sir2, is actually an enzyme that removes chemical tags an enzyme that removes chemical tags from those tennis balls, those histone from those tennis balls, those histone proteins, proteins, thereby tightening up chromatin and thereby tightening up chromatin and altering gene expression and silencing altering gene expression and silencing down those genes. Sir2 requires NAD as a down those genes. Sir2 requires NAD as a cofactor to work. Without NAD, it cannot cofactor to work. Without NAD, it cannot remove the chemical tags off those remove the chemical tags off those proteins. proteins. That links cellular metabolism directly That links cellular metabolism directly to epigenetic regulation and it's one of to epigenetic regulation and it's one of the reasons that there's a whole the reasons that there's a whole industry for NAD boosters in the industry for NAD boosters in the billions right now. billions right now. The mammalian homologs of Sir2 became The mammalian homologs of Sir2 became known as sirtuins, named after Sir2. known as sirtuins, named after Sir2. These early findings in yeast cells were These early findings in yeast cells were completely unexpected. We were looking completely unexpected. We were looking for proteins that regulated telomeres or

for proteins that regulated telomeres or repaired DNA. Instead, we found repaired DNA. Instead, we found epigenetic regulators, gene silencing epigenetic regulators, gene silencing proteins, proteins, which suggested to us that aging, at which suggested to us that aging, at least in yeast, was not solely the least in yeast, was not solely the accumulation of random damage, accumulation of random damage, but involved in changes in chromatin but involved in changes in chromatin structure and how genes are regulated. structure and how genes are regulated. What we proposed was that in yeast, at What we proposed was that in yeast, at least, the redistribution, the movement least, the redistribution, the movement of Sir proteins during aging led to the of Sir proteins during aging led to the loss of silencing at some genes and loss of silencing at some genes and inappropriate gene expression at others. inappropriate gene expression at others. This pointed to a breakdown in the This pointed to a breakdown in the maintenance of epigenetic information. maintenance of epigenetic information. Here are my notes from October 1996. Here are my notes from October 1996. This is the first documentation of iTOA. This is the first documentation of iTOA. I love this. What happened was I woke up I love this. What happened was I woke up in the middle of the night and in the middle of the night and I just couldn't stop writing. I spent I just couldn't stop writing. I spent about 3 hours writing down pages and about 3 hours writing down pages and pages of notes. It just came to me. As pages of notes. It just came to me. As we talked about in this episode, most of we talked about in this episode, most of us won't die from infections or us won't die from infections or accidents. What we're going to die from accidents. What we're going to die from are diseases caused by aging. So, that's

are diseases caused by aging. So, that's why it's really important that we all why it's really important that we all track our own health closely over time. track our own health closely over time. And that's how we can know if we're And that's how we can know if we're progressing and what we're actually progressing and what we're actually doing is working. doing is working. Wearables make that super easy. But, you Wearables make that super easy. But, you don't need to watch these numbers all don't need to watch these numbers all the time. You can look at them once a the time. You can look at them once a week or even once a month. But, it's week or even once a month. But, it's really important that you check how really important that you check how you're doing, which brings me to a you're doing, which brings me to a wearable that I'm particularly fond of, wearable that I'm particularly fond of, partly because of its scientific partly because of its scientific foundation at Harvard, where I work, foundation at Harvard, where I work, and also the founder's own research and and also the founder's own research and scientific rigor. scientific rigor. The company's only a couple of blocks up The company's only a couple of blocks up the street here from the studio, and I the street here from the studio, and I visit them occasionally and and see what visit them occasionally and and see what an active, caring company they are. an active, caring company they are. I'm talking about the Whoop band. This I'm talking about the Whoop band. This wearable is a health and fitness coach wearable is a health and fitness coach that gives me insights into my sleep, my that gives me insights into my sleep, my recovery, and my body strain. recovery, and my body strain. The researchers have studied how The researchers have studied how accurate these devices are, and in the accurate these devices are, and in the 2022 study, they compared six wearable 2022 study, they compared six wearable devices, including Whoop, against devices, including Whoop, against clinical-grade ECG and sleep recording

clinical-grade ECG and sleep recording devices. devices. Whoop showed strong accuracy for heart Whoop showed strong accuracy for heart rate and heart rate variability rate and heart rate variability measurements during sleep, especially. measurements during sleep, especially. Using the Whoop band, I can see how my Using the Whoop band, I can see how my daily behaviors are impacting my health. daily behaviors are impacting my health. Wearing the Whoop over the last 2 Wearing the Whoop over the last 2 months, I've seen dramatic improvements months, I've seen dramatic improvements in my personal biomarkers, indicating in my personal biomarkers, indicating that the changes that I'm making to my that the changes that I'm making to my lifestyle, including a much healthier lifestyle, including a much healthier diet and more exercise, is definitely diet and more exercise, is definitely having a positive effect on my body. having a positive effect on my body. For example, my resting heart rate has For example, my resting heart rate has gone down to 45, which is great, and my gone down to 45, which is great, and my heart rate variability, which you want heart rate variability, which you want to be higher, that number has shot up to to be higher, that number has shot up to 90, putting me in the top few percent or 90, putting me in the top few percent or so for my age. so for my age. It's not only interesting and useful, It's not only interesting and useful, but it's also important to build up a but it's also important to build up a record about your body that you can aim record about your body that you can aim for when you're older. When you're 90, for when you're older. When you're 90, you can go back and aim to be what you you can go back and aim to be what you were in your 40s or 50s. If you're a were in your 40s or 50s. If you're a regular listener to this show, you'll regular listener to this show, you'll know that we only partner with companies know that we only partner with companies like Whoop, who we really believe in.

like Whoop, who we really believe in. These are products that I use daily, the These are products that I use daily, the team uses daily, and these companies team uses daily, and these companies align with our values, our mission of align with our values, our mission of supporting medical research and supporting medical research and supporting young scientists. supporting young scientists. If you want to try it and get a free If you want to try it and get a free Whoop 5.0 smart band and a month of Whoop 5.0 smart band and a month of membership, go to membership, go to join.whoop.com/lifespan or use the code lifespan. What we see here is a picture of a yeast What we see here is a picture of a yeast cell and we see that the sirtuins are cell and we see that the sirtuins are going to DNA going to DNA and relocalizing and changing gene and relocalizing and changing gene expression. expression. It's called a theory on replicative It's called a theory on replicative senescence in yeast and other organisms. senescence in yeast and other organisms. So, that was the beginning in 1996. So, that was the beginning in 1996. Andrew here was what, about 8 months Andrew here was what, about 8 months old. old. Marissa and Rajiv, you weren't even born Marissa and Rajiv, you weren't even born yet. yet. But, we had the initial idea that aging But, we had the initial idea that aging may be due to information loss, not just may be due to information loss, not just damage. damage. Many years after, this idea remained Many years after, this idea remained peripheral to the dominant damage-based

peripheral to the dominant damage-based models of aging. Then, over the next two models of aging. Then, over the next two decades, evidence accumulated in worms, decades, evidence accumulated in worms, flies, and even in mice. Sirtuins were flies, and even in mice. Sirtuins were shown to regulate stress resistance, shown to regulate stress resistance, metabolism, DNA repair, and many other metabolism, DNA repair, and many other cellular functions. cellular functions. And again, the levels of that molecule And again, the levels of that molecule NAD were critical. Those chemical tags NAD were critical. Those chemical tags on the letter C, those patterns were on the letter C, those patterns were found to change in highly predictable found to change in highly predictable that correlated with biological age. And that correlated with biological age. And in fact, those chemicals are now the in fact, those chemicals are now the basis basis of biological clocks. And we found that of biological clocks. And we found that double-stranded breaks that snap double-stranded breaks that snap chromosomes and that happen every day in chromosomes and that happen every day in every one of our cells, every one of our cells, these can accelerate the movement of sir these can accelerate the movement of sir proteins and these epigenetic proteins and these epigenetic alterations actually accelerating the alterations actually accelerating the aging process, aging process, suggesting that the response to DNA suggesting that the response to DNA damage, not the damage itself or the damage, not the damage itself or the mutations, may be the major driver of mutations, may be the major driver of aging itself. aging itself. Together, these observations support a Together, these observations support a framework in which aging is due to the

framework in which aging is due to the progressive loss of biological progressive loss of biological information, particularly epigenetic information, particularly epigenetic information. information. And what began as a study of gene And what began as a study of gene silencing in yeast silencing in yeast evolved into a broader model of aging, evolved into a broader model of aging, one that raises the possibility that if one that raises the possibility that if biological information is degraded over biological information is degraded over time, time, it may actually be possible to restore it may actually be possible to restore it. it. To test whether such shifts in To test whether such shifts in epigenetic information could cause aging epigenetic information could cause aging rather than just simply accompany it, we rather than just simply accompany it, we created what we called the ice mouse created what we called the ice mouse model, model, which stands for inducible changes to which stands for inducible changes to the epigenome. In these mice, we were the epigenome. In these mice, we were able to introduce targeted, able to introduce targeted, easy-to-repair DNA breaks. easy-to-repair DNA breaks. And we could turn them on and off at And we could turn them on and off at will. At about 5 months of age, we will. At about 5 months of age, we induced these double-stranded DNA breaks induced these double-stranded DNA breaks for about 3 weeks in total. And this was for about 3 weeks in total. And this was about three times the overall number of about three times the overall number of changes that would normally happen in a changes that would normally happen in a mouse. The reason we created those DNA mouse. The reason we created those DNA breaks is that we'd already shown in

breaks is that we'd already shown in yeast and then in human cells that the yeast and then in human cells that the movement of sirtuins to repair the DNA movement of sirtuins to repair the DNA breaks is one of the reasons that gene breaks is one of the reasons that gene expression changes with aging. So, we expression changes with aging. So, we asked the question, if we create those asked the question, if we create those breaks, does aging accelerate? breaks, does aging accelerate? And the result in those mice was really And the result in those mice was really striking. And really, let's call up the striking. And really, let's call up the video of those mice. video of those mice. So, the ice mouse is on the left, and if So, the ice mouse is on the left, and if you can't see this, it looks a lot older you can't see this, it looks a lot older than its sibling born on the same day. than its sibling born on the same day. These mice are about 18 months old. These mice are about 18 months old. The one that was untreated has black The one that was untreated has black fur, normal skin, and the ice mouse fur, normal skin, and the ice mouse looks and literally is a lot older even looks and literally is a lot older even though it was born on the same day. The though it was born on the same day. The animals had an advanced epigenetic age animals had an advanced epigenetic age of about 50%. of about 50%. And functional signs of aging much And functional signs of aging much earlier than expected. earlier than expected. Pretty much every tissue we looked at, Pretty much every tissue we looked at, their skin, their kidneys, their livers, their skin, their kidneys, their livers, their brains, they looked a lot older. their brains, they looked a lot older. They had loss of cognition and frailty.

They had loss of cognition and frailty. Their underlying DNA sequence, though, Their underlying DNA sequence, though, remained essentially intact. I've remained essentially intact. I've actually got a copy of the paper here actually got a copy of the paper here that we published in 2023 in the journal that we published in 2023 in the journal Cell. Cell. And I'm very proud of this paper and my And I'm very proud of this paper and my colleagues that put it out. There were colleagues that put it out. There were 46 scientists involved, and it took us 46 scientists involved, and it took us 13 years. In fact, three of our team 13 years. In fact, three of our team died along the way. died along the way. What we showed in this paper for the What we showed in this paper for the first time first time was, and I quote from the paper, was, and I quote from the paper, a loss of epigenetic information a loss of epigenetic information as a cause of mammalian aging. It was as a cause of mammalian aging. It was the first clear evidence the first clear evidence that disrupting epigenetic information that disrupting epigenetic information could drive aging in an animal. could drive aging in an animal. And what we like to say in my lab is, And what we like to say in my lab is, if you can give something, maybe you can if you can give something, maybe you can take it away. take it away. So, that brings me So, that brings me to age resetting. to age resetting. Around 2013, I began to think about Around 2013, I began to think about information preservation. Of course, if information preservation. Of course, if we could preserve biological we could preserve biological information, the prediction of I Toa is information, the prediction of I Toa is that we would live longer and much that we would live longer and much healthier. healthier. And I was fortunate to come across one

And I was fortunate to come across one of the most important papers that I've of the most important papers that I've ever read. It was transformational to my ever read. It was transformational to my thinking. thinking. It was a paper written in 1948 It was a paper written in 1948 by professor at MIT named Claude by professor at MIT named Claude Shannon. Shannon. Many people know about Claude Shannon Many people know about Claude Shannon from his work on communication and from his work on communication and information systems. His paper from 1948 information systems. His paper from 1948 is titled A Mathematical Theory of is titled A Mathematical Theory of Communication. Communication. And let's call that up. And let's call that up. I've probably read this 50 times now. I've probably read this 50 times now. I don't understand all of it. There's a I don't understand all of it. There's a lot of heavy math, lot of heavy math, but Professor Claude Shannon was working but Professor Claude Shannon was working on the problem of information on the problem of information transmission, having survived World War transmission, having survived World War II and seen what happened when a radio II and seen what happened when a radio signal is misinterpreted. He showed that signal is misinterpreted. He showed that by building redundancy into the message by building redundancy into the message and comparing what comes in against a and comparing what comes in against a clean reference, the receiver can clean reference, the receiver can reconstruct the original signal. reconstruct the original signal. He called this backup copy of the signal He called this backup copy of the signal the observer. the observer. Now, we call it the backup copy or the Now, we call it the backup copy or the TCP/IP protocol of the internet.

TCP/IP protocol of the internet. Let's scroll down to see the figure of Let's scroll down to see the figure of the observer. It's a classic diagram I the observer. It's a classic diagram I actually put in my book. actually put in my book. Where is the page 21? Here There Let's Where is the page 21? Here There Let's blow that up. And if you're just blow that up. And if you're just listening, listening, it's a bunch of boxes, but what it shows it's a bunch of boxes, but what it shows actually is that the observer sits above actually is that the observer sits above the boxes. the boxes. Along the bottom, the boxes represent Along the bottom, the boxes represent the transmitter of the signal and the the transmitter of the signal and the receiver. receiver. And the observer sits above, and if the And the observer sits above, and if the receiver doesn't get the signal, it receiver doesn't get the signal, it actually can go and correct actually can go and correct the original signal. the original signal. It's all a lot of math, and it might It's all a lot of math, and it might sound a bit confusing, but basically, sound a bit confusing, but basically, here he's saying is that if you shout at here he's saying is that if you shout at someone or send a message or even send someone or send a message or even send out an email, out an email, the reason that it's not corrupted the reason that it's not corrupted anymore is that there's a backup copy anymore is that there's a backup copy up here that can be used to correct the up here that can be used to correct the original signal. original signal. Now, what occurred to me when I was Now, what occurred to me when I was looking at this was this could represent looking at this was this could represent biology. biology. This could be the original embryo at the This could be the original embryo at the beginning,

beginning, and that's the signal, and the receiver and that's the signal, and the receiver is us in the future, our future bodies, is us in the future, our future bodies, and that's aging because what's and that's aging because what's introduced in the middle introduced in the middle is is informational noise. informational noise. So, that really what happens to us in So, that really what happens to us in the future is that the signal the future is that the signal is not received fully. is not received fully. But, what if there's a backup? What if But, what if there's a backup? What if there's an observer in biology that is there's an observer in biology that is able to correct able to correct the epigenetic information and restore the epigenetic information and restore our youth, so that even in the future we our youth, so that even in the future we are still young. are still young. And that's what gave me the idea. I'd And that's what gave me the idea. I'd love to show you some of the original love to show you some of the original diagrams that I was drawing in Fiji. diagrams that I was drawing in Fiji. Well, I really should be should have Well, I really should be should have been out on the beach with my kids. been out on the beach with my kids. Andrew, you have you got those? It'd be Andrew, you have you got those? It'd be fun to show those as well. Let's just fun to show those as well. Let's just quickly scroll through some of these quickly scroll through some of these ideas. You can see I was ideas. You can see I was inventing new words, epigenetic drift. inventing new words, epigenetic drift. This was one of the first figures that I This was one of the first figures that I drew drew uh during my time in Fiji. I really like uh during my time in Fiji. I really like this diagram. This was to represent this diagram. This was to represent young cells that express all the genes young cells that express all the genes correctly, and due to epigenetic drift,

correctly, and due to epigenetic drift, now they start expressing the wrong now they start expressing the wrong genes. genes. I did a little bit of math here, but I did a little bit of math here, but let's scroll down, Andrew. There might let's scroll down, Andrew. There might be something interesting to see. be something interesting to see. Yeah, this represents the sirtuin Yeah, this represents the sirtuin proteins jumping around in response to proteins jumping around in response to DNA breaks, which we discussed earlier. DNA breaks, which we discussed earlier. Keep going. Keep going. Oh, I really like this one. This was Oh, I really like this one. This was comparing comparing the the analog and digital system that we were analog and digital system that we were talking about before talking about before where the epigenome is analog and the where the epigenome is analog and the DNA is digital. DNA is digital. And I represented that by a compact And I represented that by a compact disc, which is digital information. And disc, which is digital information. And then there were scratches that led to then there were scratches that led to noise, and the music started to jump noise, and the music started to jump around, and I around, and I was starting to think that could was starting to think that could actually be aging. There's another one actually be aging. There's another one where I was using a record player where I was using a record player instead of a CD. instead of a CD. But you get the idea. Actually, I never But you get the idea. Actually, I never published this, but it was important for published this, but it was important for not just writing my book, but eventually not just writing my book, but eventually coming up with the fully fledged coming up with the fully fledged information theory of aging. information theory of aging. So, if aging truly reflects corrupted

So, if aging truly reflects corrupted epigenetic instructions, then nudging epigenetic instructions, then nudging those instructions back towards youth those instructions back towards youth might help damaged tissue recover might help damaged tissue recover and even establish youthful organs that and even establish youthful organs that are even diseased. are even diseased. This way of thinking and the information This way of thinking and the information theory of aging led to a really theory of aging led to a really important question whether we could important question whether we could safely access and restore epigenetic safely access and restore epigenetic information in cells or even in living information in cells or even in living tissues. That is where age reversal via tissues. That is where age reversal via epigenetic reprogramming enters this epigenetic reprogramming enters this story. story. First in the lab and now being tested in First in the lab and now being tested in human trials for the first time. We human trials for the first time. We don't yet know much about this backup don't yet know much about this backup copy or what we also affectionately call copy or what we also affectionately call the observer the observer or even what it's made of. And some say or even what it's made of. And some say it doesn't even exist. Resetting the it doesn't even exist. Resetting the epigenome is complicated, involving epigenome is complicated, involving thousands of genes and 3D rearrangements thousands of genes and 3D rearrangements of the DNA. of the DNA. Still, the fact that embryos can reset Still, the fact that embryos can reset their age and reprogramming can push their age and reprogramming can push adult cells towards youth suggests adult cells towards youth suggests strongly that biology already knows how

strongly that biology already knows how to recover that information. to recover that information. The challenge for us is to understand The challenge for us is to understand how do embryos do it? how do embryos do it? And how do other animals like fish and And how do other animals like fish and lizards regrow limbs and tails, lizards regrow limbs and tails, apparently using the same method? If apparently using the same method? If cells really carry a backup of their cells really carry a backup of their youthful state, the obvious next youthful state, the obvious next question is whether we can access it and question is whether we can access it and do so in a safe way. The first clue that do so in a safe way. The first clue that cells can be reprogrammed was shown by cells can be reprogrammed was shown by John Gurdon in the UK. John Gurdon in the UK. And in the 1950s, he and his team And in the 1950s, he and his team took nuclei out of tadpole cells, adult took nuclei out of tadpole cells, adult tadpoles, and replaced the DNA for an tadpoles, and replaced the DNA for an egg with that DNA, and they got a young egg with that DNA, and they got a young tadpole, showing for the first time that tadpole, showing for the first time that old DNA could make a new organism. The old DNA could make a new organism. The next big clue that cells could be next big clue that cells could be reprogrammed came from Shinya Yamanaka, reprogrammed came from Shinya Yamanaka, a Japanese professor who showed in 2006 a Japanese professor who showed in 2006 in a beautiful cell paper. in a beautiful cell paper. The paper showed that turning on four The paper showed that turning on four genes, Oct4, Sox2, Klf4, and c-Myc, genes, Oct4, Sox2, Klf4, and c-Myc, OSKM, now called the Yamanaka factors,

OSKM, now called the Yamanaka factors, could turn mature cells like skin cells could turn mature cells like skin cells back to an induced pluripotent stem back to an induced pluripotent stem cell, or iPSC. cell, or iPSC. In 2012, that discovery and John In 2012, that discovery and John Gurdon's for his work deservedly won the Gurdon's for his work deservedly won the Nobel Prize, but it also came with a Nobel Prize, but it also came with a problem. problem. Fully reprogrammed cells forget what Fully reprogrammed cells forget what they once were. they once were. In fact, they have no identity. They can In fact, they have no identity. They can become anything. become anything. In animals, turning on these four genes In animals, turning on these four genes actually drives lethal tumors, and can actually drives lethal tumors, and can even kill mice within 2 days. even kill mice within 2 days. That's not going to be a therapy anytime That's not going to be a therapy anytime soon. soon. If you've listened to this show before, If you've listened to this show before, you've probably heard me say that you you've probably heard me say that you cannot optimize what you don't measure. cannot optimize what you don't measure. That's what we do as scientists, and That's what we do as scientists, and it's true also when it comes to body it's true also when it comes to body metrics. metrics. Many people only measure their total Many people only measure their total body weight, if anything, but this only body weight, if anything, but this only tells a small part of the story. tells a small part of the story. So, how can you measure these other So, how can you measure these other aspects? aspects? Withings, one of Lifespan's partners Withings, one of Lifespan's partners supporting medical research, make some supporting medical research, make some of the coolest devices that you can

of the coolest devices that you can measure yourself with. measure yourself with. They have watches, a sleep monitor pad, They have watches, a sleep monitor pad, and advanced bathroom scales, one of and advanced bathroom scales, one of which I use every morning. which I use every morning. I've actually been using Withings I've actually been using Withings devices for over 13 years, since they devices for over 13 years, since they first came out with their first scale. first came out with their first scale. And today the Withings Vision clocked me And today the Withings Vision clocked me at 59 beats per minute heart rate, which at 59 beats per minute heart rate, which I'm very happy with. It's actually I'm very happy with. It's actually pretty healthy, and at night it drops pretty healthy, and at night it drops down to about 49 as I previously down to about 49 as I previously mentioned. mentioned. Another metric that impacts lifespan is Another metric that impacts lifespan is body composition, and it's impossible to body composition, and it's impossible to know this unless you measure it. know this unless you measure it. We've already talked about visceral fat, We've already talked about visceral fat, the evil fat that sits around your the evil fat that sits around your organs, and it's associated with risk of organs, and it's associated with risk of cardiovascular disease, diabetes, and cardiovascular disease, diabetes, and even death. even death. So getting rid of visceral fat, or at So getting rid of visceral fat, or at least minimizing it, can have a strong least minimizing it, can have a strong impact on your long-term health and impact on your long-term health and longevity. longevity. I've got all the valuable data on my I've got all the valuable data on my scale in my bathroom here, and also on scale in my bathroom here, and also on my phone. my phone. The Withings Body Scan scale can help The Withings Body Scan scale can help estimate your muscle mass, your fat

estimate your muscle mass, your fat mass, and importantly your visceral fat mass, and importantly your visceral fat percentage, among other things. percentage, among other things. I stand on this scale almost every I stand on this scale almost every morning. Here's the digital twin on my morning. Here's the digital twin on my phone spinning around. phone spinning around. So the numbers speak for themselves. So the numbers speak for themselves. I've got 11.3% I've got 11.3% fat on my arms, fat on my arms, 14% torso, and visceral fat, which we 14% torso, and visceral fat, which we mentioned is the evil fat, at 2.7. All mentioned is the evil fat, at 2.7. All of these numbers I'm very happy with. of these numbers I'm very happy with. And you can also look at muscle and And you can also look at muscle and other different things here. other different things here. And in the past couple of months, by And in the past couple of months, by changing my diet and improving my changing my diet and improving my exercise regimens, I've lost over 12 lb exercise regimens, I've lost over 12 lb for spring. And importantly, I was able for spring. And importantly, I was able to ensure that I didn't lose any of my to ensure that I didn't lose any of my muscle mass. muscle mass. This is a common problem when you're This is a common problem when you're eating less. eating less. And especially if you take a GLP-1 And especially if you take a GLP-1 receptor agonist, like Ozempic, a receptor agonist, like Ozempic, a Withings scale can really help ensure Withings scale can really help ensure that you you only the fat, not muscle. that you you only the fat, not muscle. It's the only smart scale that also It's the only smart scale that also comes with an FDA-cleared ECG that can comes with an FDA-cleared ECG that can analyze your heart rhythm and even analyze your heart rhythm and even detect atrial fibrillation, which is a

detect atrial fibrillation, which is a heart condition that can cause strokes heart condition that can cause strokes and even heart failure. We here at and even heart failure. We here at Lifespan are partnering with Withings Lifespan are partnering with Withings because we share a common commitment to because we share a common commitment to preventative health, and also we want to preventative health, and also we want to support medical research and young support medical research and young students. As a Lifespan listener, we students. As a Lifespan listener, we invite you to join us. invite you to join us. You can learn more about Withings or get You can learn more about Withings or get a scale or just one of their other a scale or just one of their other really cool smart devices at really cool smart devices at withings.com/lifespan. Or for a 10% off discount, use the code lifespan. In a now classic paper in lifespan. In a now classic paper in 2016, 2016, Aleixo Ocampo, a postdoc, and his Aleixo Ocampo, a postdoc, and his supervisor Juan Carlos Belmonte, decided supervisor Juan Carlos Belmonte, decided to turn on OKSM to turn on OKSM in prematurely aged mice to see what in prematurely aged mice to see what would happen. What they found was that would happen. What they found was that the mice actually were much healthier the mice actually were much healthier and lived about 30% longer. and lived about 30% longer. They published that, and it was a They published that, and it was a striking discovery. striking discovery. A lot of people just couldn't believe A lot of people just couldn't believe it. it. Here were these factors that seemed to Here were these factors that seemed to promote health, promote health, but it wasn't clear if this was actually

but it wasn't clear if this was actually age reversal or just simply stressing age reversal or just simply stressing the heck out of these mice. the heck out of these mice. And if reprogramming meant erasing the And if reprogramming meant erasing the cell identity, cell identity, causing cancer or killing mice, how causing cancer or killing mice, how could this ever be used on patients? In could this ever be used on patients? In 2009, my lab set out to find a way to 2009, my lab set out to find a way to reset the epigenome. And by 2014, reset the epigenome. And by 2014, the current version of I Tua was really the current version of I Tua was really taking shape. And this was the same year taking shape. And this was the same year I put Wang Cheng Lu, I put Wang Cheng Lu, one of my star PhD students, on the one of my star PhD students, on the problem. problem. The goal of his was to safely reset the The goal of his was to safely reset the epigenome like embryos do. In old human epigenome like embryos do. In old human cells, he tried dozens of different gene cells, he tried dozens of different gene combinations and culture conditions to combinations and culture conditions to see if age could be safely reset without see if age could be safely reset without turning them into cancer cells. turning them into cancer cells. He put in developmental genes, OSKM, a He put in developmental genes, OSKM, a gene called Nanog, grew them in low gene called Nanog, grew them in low oxygen, high oxygen, no nutrients, low oxygen, high oxygen, no nutrients, low nutrients, high nutrients. After 3 years nutrients, high nutrients. After 3 years of failure, Wang Cheng was on the verge of failure, Wang Cheng was on the verge of quitting, and he almost did until I

of quitting, and he almost did until I convinced him to try one more convinced him to try one more experiment. Use only a few of the experiment. Use only a few of the Yamanaka factors. Yamanaka factors. No one thought it would work, of course. No one thought it would work, of course. The dogma was that you need all four of The dogma was that you need all four of the Yamanaka factors for anything to the Yamanaka factors for anything to happen, and even then, you'll just get happen, and even then, you'll just get cancer. Even Shinya Yamanaka told me cancer. Even Shinya Yamanaka told me that he never tried OSK and M in animals that he never tried OSK and M in animals because it would clearly cause cancer, because it would clearly cause cancer, as he showed in his 2006 paper. as he showed in his 2006 paper. And leaving out a factor was not on the And leaving out a factor was not on the cards because he told me that wouldn't cards because he told me that wouldn't work anyway. work anyway. But in 2017, But in 2017, the experiment did work. the experiment did work. Wang Cheng discovered that leaving out Wang Cheng discovered that leaving out the Myc gene, the M, the Myc gene, the M, OSK alone could reset the epigenetic OSK alone could reset the epigenetic clock of human cells without causing clock of human cells without causing them to become cancerous. them to become cancerous. Using just OS and K could rewind the Using just OS and K could rewind the epigenetic age in human cells by up to epigenetic age in human cells by up to 75% and then stop. 75% and then stop. That's important. We never see cells That's important. We never see cells becoming cancerous.

becoming cancerous. That day in 2017, I'll never forget. It That day in 2017, I'll never forget. It was a momentous one. The retina was an was a momentous one. The retina was an ideal testing ground for the gene ideal testing ground for the gene therapy. It's an enclosed space, and therapy. It's an enclosed space, and it's much safer than delivering it it's much safer than delivering it throughout the body. throughout the body. So, we started there. So, we started there. Also, retinal nerve cells connect the Also, retinal nerve cells connect the eye to the brain via the optic nerve, eye to the brain via the optic nerve, and once damaged, they don't naturally and once damaged, they don't naturally regenerate, certainly not in adults. But regenerate, certainly not in adults. But in young mice, they do. So, we thought in young mice, they do. So, we thought that we would test that. that we would test that. Injury to the optic nerve, like Injury to the optic nerve, like glaucoma, leads to irreversible vision glaucoma, leads to irreversible vision loss and even blindness. We hypothesized loss and even blindness. We hypothesized that if aging could be reversed at the that if aging could be reversed at the cellular level, perhaps regenerative cellular level, perhaps regenerative ability could be restored as well as ability could be restored as well as vision. On Thursday, June 28th, 2018, at vision. On Thursday, June 28th, 2018, at around 10:00 p.m., Wenchang, my student, around 10:00 p.m., Wenchang, my student, sent me a series of texts that led to sent me a series of texts that led to the cover article of Nature in 2020. the cover article of Nature in 2020. I'd love to show you some of those texts I'd love to show you some of those texts now. now. Here's a picture of Wenchang at the Here's a picture of Wenchang at the machine that was cutting the tissue to

machine that was cutting the tissue to look at look at before he put them under the microscope before he put them under the microscope to show me. to show me. He's got his watch there. It says 10:06. Next text was, he says, "I know my hands are shaking. are shaking. Let's prepare for the worst and hope for Let's prepare for the worst and hope for the best." And I wrote back, as a good the best." And I wrote back, as a good mentor should, mentor should, "Any result is the best." "Any result is the best." Then a few minutes later, he wrote, Then a few minutes later, he wrote, well, actually, he sent me a picture of well, actually, he sent me a picture of optic nerves that were regenerating. I optic nerves that were regenerating. I asked the question, "Is this an AAV asked the question, "Is this an AAV infection? Is the viral infection? Is infection? Is the viral infection? Is this an optic nerve? What is it? Tell this an optic nerve? What is it? Tell me." Smiley face. me." Smiley face. And then I looked up, I scrolled up, and And then I looked up, I scrolled up, and I wrote, "Oh, I wrote, "Oh, I didn't scroll up." Four exclamation I didn't scroll up." Four exclamation marks. "Holy crap." marks. "Holy crap." Wenchang writes, Wenchang writes, "I sent you three pictures. "I sent you three pictures. These nerves are so long that they reach These nerves are so long that they reach out of the vision." And I write, "Wow." out of the vision." And I write, "Wow." This time, five exclamation marks. This time, five exclamation marks. "Let's frame that photo." "Let's frame that photo." He writes, "They are 12 months old. He writes, "They are 12 months old. Jesus, I still can't believe it. Here

Jesus, I still can't believe it. Here are some other samples that have good are some other samples that have good regeneration, too." regeneration, too." And I write, "The best result in the lab And I write, "The best result in the lab in years." in years." What made that result so remarkable was What made that result so remarkable was what those long nerves actually meant. what those long nerves actually meant. In an adult animal, including ourselves, In an adult animal, including ourselves, once the optic nerve is damaged, those once the optic nerve is damaged, those fibers usually don't grow back very far, fibers usually don't grow back very far, if at all. if at all. So, when Wenchang saw how long they So, when Wenchang saw how long they were, it suggested that these damaged were, it suggested that these damaged nerves were actually regaining a nerves were actually regaining a youthful capacity to regenerate, which youthful capacity to regenerate, which is something we almost never see in the is something we almost never see in the adult central nervous system. It was adult central nervous system. It was certainly an exciting moment, and and I certainly an exciting moment, and and I recorded it in my book, Lifespan. recorded it in my book, Lifespan. And another few years later we published And another few years later we published that on the cover of Nature magazine. that on the cover of Nature magazine. So in aged mice experiencing natural So in aged mice experiencing natural decline in visual acuity, OSK treatment decline in visual acuity, OSK treatment we also found restored visual function we also found restored visual function as measured by eye and head tracking as measured by eye and head tracking movements and electrophysiological movements and electrophysiological tests. tests. In mice with glaucoma, pressure in the In mice with glaucoma, pressure in the eye characterized by

eye characterized by failing of the retinal nerve cells in failing of the retinal nerve cells in the back of the eye, OSK not only the back of the eye, OSK not only promoted survival of those nerves, but promoted survival of those nerves, but also improved visual performance. also improved visual performance. They literally got their vision back. They literally got their vision back. For the first time ever, a gene therapy For the first time ever, a gene therapy had reversed aging and vision loss had reversed aging and vision loss associated with both disease and aging. associated with both disease and aging. In later experiments, Wang Cheng showed In later experiments, Wang Cheng showed that the OSK gene therapy also reversed that the OSK gene therapy also reversed age-related molecular signatures age-related molecular signatures in other tissues such as muscle and in other tissues such as muscle and kidney kidney including in the ice mice whose including in the ice mice whose epigenome had been artificially aged by epigenome had been artificially aged by repeated DNA breaks. repeated DNA breaks. And without the enzymes that remove the And without the enzymes that remove the methyl chemical tags from the DNA, methyl chemical tags from the DNA, the treatment no longer cured blindness. the treatment no longer cured blindness. Taken together, these experiments Taken together, these experiments suggested that Waddington's landscape suggested that Waddington's landscape that's been eroded over time can be at that's been eroded over time can be at least partially rebuilt by temporarily least partially rebuilt by temporarily re-engaging the cells own youthful re-engaging the cells own youthful program using only three genes, OSK.

program using only three genes, OSK. A central mechanistic question then was A central mechanistic question then was how this rejuvenation occurred. how this rejuvenation occurred. One analysis focused on the epigenome, One analysis focused on the epigenome, specifically DNA methylation patterns, specifically DNA methylation patterns, which change predictably with age and which change predictably with age and serve as biomarkers of biological aging. serve as biomarkers of biological aging. We also checked those methyl marks on We also checked those methyl marks on the DNA that we talked about earlier and the DNA that we talked about earlier and they were more youthful after OSK they were more youthful after OSK treatment as well. treatment as well. So that showed that not only was vision So that showed that not only was vision improved, but the actual biological improved, but the actual biological clock could be reset. clock could be reset. Critically, Critically, this reversal did not involve the loss this reversal did not involve the loss of cell or identity. The study also of cell or identity. The study also suggested that mammalian cells retain a suggested that mammalian cells retain a backup copy of youthful epigenetic backup copy of youthful epigenetic information. information. Reprogramming appears to access and Reprogramming appears to access and restore that stored information, restore that stored information, re-establishing youthful patterns of re-establishing youthful patterns of gene expression. gene expression. These findings provided experimental These findings provided experimental evidence for iTOwa in a living mammal. evidence for iTOwa in a living mammal. Safety, of course, was critical. Safety, of course, was critical. Full reprogramming is known to cause Full reprogramming is known to cause tumors and other problems. In our

tumors and other problems. In our experiments, OSK expression was experiments, OSK expression was carefully induced, and we saw no tumor carefully induced, and we saw no tumor formation, no loss of retinal structure, formation, no loss of retinal structure, and no evidence of uncontrolled cell and no evidence of uncontrolled cell proliferation. proliferation. This demonstrated for the first time This demonstrated for the first time that age reversal and oncogenesis are that age reversal and oncogenesis are separable processes separable processes when reprogramming is done in a when reprogramming is done in a controlled way. controlled way. The broader significance of all of this The broader significance of all of this extends way beyond vision. extends way beyond vision. The retina is part of the central The retina is part of the central nervous system, or CNS. nervous system, or CNS. Demonstrating regeneration and Demonstrating regeneration and functional recovery in the CNS suggests functional recovery in the CNS suggests that potential applications could that potential applications could include neurological conditions, even include neurological conditions, even Alzheimer's disease. Alzheimer's disease. It could also include hearing loss and It could also include hearing loss and spinal injuries. And the principle that spinal injuries. And the principle that aged tissues can be epigenetically aged tissues can be epigenetically rejuvenated also probably applies to rejuvenated also probably applies to muscles, heart, liver, skin, and other muscles, heart, liver, skin, and other tissues. tissues. The eye served as a proof of concept for The eye served as a proof of concept for many other possibilities. many other possibilities. These results and subsequent studies in These results and subsequent studies in non-human primates set the stage for

non-human primates set the stage for Life Biosciences development of the drug Life Biosciences development of the drug candidate called ER100, which stands for candidate called ER100, which stands for epigenetic reprogramming 100. epigenetic reprogramming 100. ER100 is a gene therapy that contains ER100 is a gene therapy that contains the OSK genes designed for human use, the OSK genes designed for human use, and I'm proud to share that in January and I'm proud to share that in January 2026, it became the world's first 2026, it became the world's first epigenetic reprogramming therapy to epigenetic reprogramming therapy to receive clearance from the FDA to begin receive clearance from the FDA to begin human clinical trials. This was a real human clinical trials. This was a real milestone for the field. For the first milestone for the field. For the first time, a therapy specifically designed to time, a therapy specifically designed to reset epigenetic age was authorized for reset epigenetic age was authorized for testing in patients. I thought I'd show testing in patients. I thought I'd show you how ER-100 is being delivered to the you how ER-100 is being delivered to the patients. patients. I've got a model of the eye here, about I've got a model of the eye here, about the size of a small melon. the size of a small melon. ER-100 is an injection of a gene therapy ER-100 is an injection of a gene therapy that's delivered through the front of that's delivered through the front of the eye, a very quick, painless the eye, a very quick, painless injection, and the genes move through injection, and the genes move through the eye through the liquid the eye through the liquid and find their way to the nerves at the and find their way to the nerves at the back in the retina, the part that we use

back in the retina, the part that we use to see. Of course, the retinal nerves to see. Of course, the retinal nerves form the optic nerve that goes to the form the optic nerve that goes to the brain. That's how we get the electrical brain. That's how we get the electrical signals. In glaucoma, because of a lot signals. In glaucoma, because of a lot of pressure in the eye, those optic of pressure in the eye, those optic nerves have aged rapidly and they're nerves have aged rapidly and they're actually defective. They're not dead, actually defective. They're not dead, they're just defective and old. they're just defective and old. So, the gene therapy, if it works, So, the gene therapy, if it works, what's going to happen is that these what's going to happen is that these nerves will get younger over about 6 nerves will get younger over about 6 weeks and start to function again. And weeks and start to function again. And people that have been treated, if all people that have been treated, if all goes well, will be able to see again. goes well, will be able to see again. So, cross your fingers that that works. So, cross your fingers that that works. This first clinical trial, This first clinical trial, run out of three sites across the United run out of three sites across the United States, States, is designed primarily to test safety. is designed primarily to test safety. Dr. Joe Rizzo, my colleague at Harvard, Dr. Joe Rizzo, my colleague at Harvard, is running one of these sites here in is running one of these sites here in Boston. The phase one trials will test Boston. The phase one trials will test ER-100's effects on patients with ER-100's effects on patients with glaucoma, the pressure in the eye that glaucoma, the pressure in the eye that we tested on mice. we tested on mice. Glaucoma in humans is the largest cause Glaucoma in humans is the largest cause of blindness across the planet. of blindness across the planet. And another disease will be tested And another disease will be tested called NAION, which is non-arteritic called NAION, which is non-arteritic anterior ischemic optic neuropathy,

anterior ischemic optic neuropathy, which is essentially a stroke in the which is essentially a stroke in the eye. eye. We now know that the prevalence of NAION We now know that the prevalence of NAION in patients on weight loss injections in patients on weight loss injections has increased as these drugs have become has increased as these drugs have become even more widely used. You can look up even more widely used. You can look up the trial if you want at the trial if you want at clinicaltrials.gov. clinicaltrials.gov. Current treatments for glaucoma mainly Current treatments for glaucoma mainly aim to slow progression of the disease aim to slow progression of the disease by either lowering the eye pressure or by either lowering the eye pressure or managing other disease risk factors like managing other disease risk factors like obesity. obesity. However, they do not restore vision that However, they do not restore vision that has already been lost. In contrast, has already been lost. In contrast, ER100 seeks to rejuvenate damaged ER100 seeks to rejuvenate damaged retinal nerve cells so they can function retinal nerve cells so they can function more like they did when they were more like they did when they were younger. younger. Early stage trials typically enroll a Early stage trials typically enroll a small number of patients and use a small number of patients and use a gradual dose escalation approach. In gradual dose escalation approach. In this case, 18 patients will be tested. this case, 18 patients will be tested. Doctors will closely monitor patients Doctors will closely monitor patients for any side effects, of course. for any side effects, of course. Although is the main focus at this Although is the main focus at this stage, doctors will also look for signs stage, doctors will also look for signs that vision has improved. If ER100 that vision has improved. If ER100 proves to be safe and shows some

proves to be safe and shows some benefit, benefit, it will advance, of course, into larger it will advance, of course, into larger trials. Because there is no alternate trials. Because there is no alternate medicine that can fix blindness, medicine that can fix blindness, there is the potential it will be there is the potential it will be advanced more rapidly by the FDA so they advanced more rapidly by the FDA so they can reach patients sooner. can reach patients sooner. The broader significance extends beyond The broader significance extends beyond the eye. the eye. If restoring youthful epigenetic If restoring youthful epigenetic information can repair damaged nerve information can repair damaged nerve cells in optic nerves, cells in optic nerves, similar strategies could work in other similar strategies could work in other tissues. Over the coming months, doctors tissues. Over the coming months, doctors will learn how safe and effective the will learn how safe and effective the approach may be. approach may be. But regardless, a path from a laboratory But regardless, a path from a laboratory science to patients and clinics has now science to patients and clinics has now been established. For the first time, been established. For the first time, epigenetic reprogramming is no longer epigenetic reprogramming is no longer confined to the lab. It's being confined to the lab. It's being evaluated as a potential therapy in evaluated as a potential therapy in people, people, representing a new chapter in the effort representing a new chapter in the effort to treat age-related disease at its to treat age-related disease at its root, aging. In this episode, we've taken a glimpse into what I believe is a turning point into what I believe is a turning point in the history of medicine.

in the history of medicine. For decades, aging has been seen as For decades, aging has been seen as inevitable, something to slow, maybe inevitable, something to slow, maybe manage, but never truly change. manage, but never truly change. That view is now beginning to shift. We That view is now beginning to shift. We have explored the remarkable examples of have explored the remarkable examples of what the human body is already capable what the human body is already capable of. of. Jeanne Calment living to 122. Jeanne Calment living to 122. 80-year-olds sprinting. 80-year-olds sprinting. People maintaining cognitive function People maintaining cognitive function well over 100. These are not anomalies well over 100. These are not anomalies to ignore. They are clues to what the to ignore. They are clues to what the future might look like. And we also future might look like. And we also talked about the information theory of talked about the information theory of aging. The idea that aging is driven by aging. The idea that aging is driven by a loss of biological information, not a loss of biological information, not just accumulated damage and wear and just accumulated damage and wear and tear. That led us to epigenetic tear. That led us to epigenetic reprogramming, a way to restore the reprogramming, a way to restore the instructions that cells need to be young instructions that cells need to be young again. All of this is no longer again. All of this is no longer theoretical. It's happening now. theoretical. It's happening now. FDA-cleared clinical trials are in FDA-cleared clinical trials are in progress. And there are many more trials progress. And there are many more trials coming, not just from Life Biosciences, coming, not just from Life Biosciences, but from companies associated with but from companies associated with people like Jeff Bezos and Sam Altman. people like Jeff Bezos and Sam Altman. Humanity is moving beyond just slowing

Humanity is moving beyond just slowing [music] aging. We're learning how to [music] aging. We're learning how to reverse it. It's been great to have you reverse it. It's been great to have you with us. This is a show where science with us. This is a show where science and evidence come first. The team works and evidence come first. The team works hundreds of hours to bring you only the hundreds of hours to bring you only the facts. To learn more and to join our facts. To learn more and to join our community, visit lifespan.com. And community, visit lifespan.com. And you'll get early access to future you'll get early access to future episodes, to the Lifespan magazine, and episodes, to the Lifespan magazine, and to detailed episode show notes. You also to detailed episode show notes. You also get transcripts and links to the papers get transcripts and links to the papers that we talked about today. As a member, that we talked about today. As a member, you'll actually be helping us support you'll actually be helping us support medical research to extend all of our medical research to extend all of our healthy lives. If you found this episode healthy lives. If you found this episode valuable, do consider subscribing. And valuable, do consider subscribing. And also turn on your notifications so you also turn on your notifications so you don't miss new episodes. It'll also help don't miss new episodes. It'll also help us make a better show for you. And feel us make a better show for you. And feel free to share this episode with any free to share this episode with any family or friends who you think might family or friends who you think might enjoy it and learn from it. Finally, for enjoy it and learn from it. Finally, for the latest discoveries in longevity the latest discoveries in longevity science, consider following us on science, consider following us on Instagram at lifespan and on X at

Instagram at lifespan and on X at joinlifespan. joinlifespan. From all of us at Lifespan, thank you From all of us at Lifespan, thank you for being part of this growing for being part of this growing community. And remember, life's short, community. And remember, life's short, so let's change that together. Lifespan so let's change that together. Lifespan is produced by Andrew the wonderman is produced by Andrew the wonderman Ying, Rajiv Geek Me Out Ramesh, Marissa Ying, Rajiv Geek Me Out Ramesh, Marissa Who's on First Volgamore, Kathleen Till Who's on First Volgamore, Kathleen Till DR Fitzgerald, DR Fitzgerald, >> [music] >> [music] >> and our researchers Shivani Just One >> and our researchers Shivani Just One More Thing Sethi, and Adeeve Meet Me in More Thing Sethi, and Adeeve Meet Me in the Year 3000 Johnson. the Year 3000 Johnson. Also, I want to mention our new recruit Also, I want to mention our new recruit Daniel Rocket Man Salazar, who's our new Daniel Rocket Man Salazar, who's our new producer. And of course, Serena my honey producer. And of course, Serena my honey poon. poon. I also want to thank Inspiro Studio and I also want to thank Inspiro Studio and Create Ape for making this show Create Ape for making this show possible. And finally, thanks to our possible. And finally, thanks to our partners for helping us support partners for helping us support longevity research. We'll see you next longevity research. We'll see you next time. This show is for informational purposes only and is not medical advice. Please

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Reprogramming The Aging Cell

The most consequential update in the episode is ER100. In January 2026, Sinclair says Life Biosciences' drug candidate became the world's first epigenetic reprogramming therapy cleared by the FDA for human clinical trials. That clearance matters because it moves cellular reprogramming from concept toward clinical evaluation. A new chapter begins when an idea can meet people.

What used to be science fiction just 10 years ago is now coming to reality.

The therapy traces back to work from Sinclair's lab, including research by Wang Cheng Lu and the use of OSK factors. In the source, Sinclair describes OSK as technology that can reset the epigenetic clock of human cells; the outcome he emphasizes is restored function, first through vision. The science is intricate, but the human meaning is simple. A cell may retain more renewal capacity than we once believed.

The eye is the first doorway because vision gives researchers a clear and measurable function to follow. The same technology was published in Nature in 2020 in work Sinclair says reversed aging and cured blindness in mice. Since then, he notes that Life Biosciences teams have shown restored visual function in monkeys. Human vision trials are the next test.

This sequence matters because it respects the pace of real science. Mice are not humans, and early promise still needs proof. Yet the progression from laboratory model to monkey data to human trials gives the field a concrete path. It turns enthusiasm into a protocol for verification.

Sinclair presents eye health as the beginning, not the full destination. If reprogramming can restore function in one tissue, the question naturally expands to others: ear, kidney, heart, liver, skin. He does not claim those applications are solved. He points to a broader regenerative medicine frontier, where preserving the body's instructions may help preserve performance.

The larger insight is that aging may include recoverable information. When cellular identity becomes less precise, function declines; when that information is restored, function may return. That is the elegant possibility beneath ER100. Longevity becomes not only defense against decline, but a disciplined search for renewal.

AI, Genomics, And The End Of One-Size-Fits-All Advice

The next frontier is interpretation. Sinclair describes AI systems that can find aging biomarkers, reveal drug targets tied to biological aging, and suggest repurposed compounds that may act across multiple hallmarks of aging. The value is not speed alone. It is the ability to see patterns in biology that remain invisible to ordinary analysis.

This matters because longevity is too complex for generic advice. Sleep, nutrition, movement, medicines, supplements, biomarkers, and family history all interact over time. A future agentic AI system could become a personal longevity scientist, reading your biology as it changes and helping refine your protocol. The outcome is not more noise. It is clearer decision-making.

Genomics brings the same movement toward precision. Sinclair notes that sequencing one genome once cost about a billion dollars and belonged to elite research labs. In early 2026, he says the 100-dollar genome was announced. That shift points toward wider access to personalized longevity guidance, cancer detection long before disease appears, drug personalization, and age estimation through biological age.

The contrast with the twentieth century is sharp. One-size-fits-all guidance treats people as averages, while modern longevity science increasingly treats biology as individual, dynamic, and measurable. You can track what changes. You can adapt with intention. A refined protocol begins when the signal becomes visible.

Sinclair also draws a boundary between evidence-based literacy and wellness spectacle. He names the confusion directly: strong opinions, conflicting claims, and attention-driven interpretations of new studies. The field is moving quickly, and that speed creates opportunity and distortion at the same time. Discernment becomes part of the practice.

This is where agency enters. You can stand outside the conversation and let headlines, influencers, and fragments of advice shape your choices. Or you can become literate in what comes next. Longevity requires more than access to tools; it requires the calm capacity to separate signal from performance.

What Human Potential Already Shows Us

The future of longevity is easier to imagine when we look at what humans have already done. Jeanne Calment lived to 122 years and 164 days, the longest verified human lifespan on record. Her life stretched from the construction of the Eiffel Tower through two world wars, airplanes, and the rise of the internet. The ceiling is not theoretical. It has a name, a date, and a human story.

That record changes the question. The issue is not whether exceptional longevity can occur, because it already has. The issue is how to make longer life more common, in better health, with more function preserved. Forty years after 80 is not a small extension. It is a second horizon.

Performance in older age reveals another boundary. Sinclair points to Kynton Brown running 100 meters in 14.21 seconds at age 80, setting an age-group world record in 2024. He also highlights men in their 80s sprinting with acceleration, form, and force. Speed at that age is more than spectacle. It shows power, coordination, and trained resilience.

This means you have a choice. Be a bystander or be literate in what comes next.

Endurance offers the same lesson in a different register. In 2021, Jose Lopez ran a mile in 5 minutes and 56 seconds at age 80, setting a world record for his age group. A sub-six-minute mile demands cardiovascular capacity at any age. At 80, it becomes a quiet refusal of the assumption that decline must define the body.

The examples extend beyond athletics. Dawn Brooke naturally conceived a healthy son at age 59, a rare case that challenges conventional expectations around fertility. Sinclair also describes a 115-year-old woman who scored 26 out of 30 on the MMSE, a cognitive screening exam, in the year of her death. Her preserved memory and attention point toward clarity that can endure.

Her brain and body added weight to the observation. The report described almost no evidence of heart disease, almost no beta-amyloid plaques or vascular changes, and locus ceruleus neuron counts similar to healthy people aged 60 to 80. These details matter because they connect structure with lived outcome. Preserved biology can mean preserved cognition, presence, and independence.

Skill can also remain alive. Oscar Shapiro became the oldest person in United States history to earn the title of chess master at age 74, after years of practice and sustained competitive play. Chess asks for memory, pattern recognition, planning, and adaptation under pressure. His achievement shows that mastery does not belong only to youth.

Sinclair then brings the lesson closer through his father, who took control of his health around age 50 and remains active at 86. He describes regular exercise, extensive walking, supplements, travel, climbing, and an ease with physical challenges that surprises people who judge by age first. This is not a laboratory result. It is daily practice made visible.

Taken together, these stories do not prove that every person will reach 122, sprint at 80, or preserve elite cognition past 100. They do something more useful. They establish that the human range is wider than our assumptions. To understand why some people preserve function so far beyond the norm, we need a framework for aging itself. That is where the information theory of aging begins.

The question is not whether such longevity can occur. It already has.

Wim's Wise Words

A second take, from someone who's lived it.

If you take one thing from this, make it practical: longevity is not something you wait for science to deliver. It is something you rehearse in small, deliberate ways before the future arrives.

I like the ambition in this conversation, but I would be careful with the excitement. The more advanced the science becomes, the more tempting it is to outsource responsibility to the next test, the next compound, the next machine. That is the wrong order. Your foundation still comes first: sleep, strength, nutrition, walking, heat, cold, and enough stillness to notice what your body is telling you.

Where I Would Start

Begin with a protocol you can repeat for years. Not the most elaborate one. The one that makes you steadier.

For most readers, that means two or three sauna sessions a week, followed by a calm cooldown and no rush back into noise. Heat gives you a clean stressor. Your heart works, circulation rises, and the body learns to return to equilibrium. Pair that with simple strength work and daily movement, and you have a longevity practice with texture, not just theory. For a deeper view of thermal stress, read Thermal Stress, Cellular Longevity next.

Cold has its place too, but I would not make it a badge of discipline. Use it when it improves clarity, mood, or recovery. Stop when it becomes performance for its own sake. A short cold exposure after heat can sharpen focus and build resilience through hormesis, but more is not automatically better. Precision beats intensity.

The point is not to chase discomfort. The point is to become adaptable. You apply stress, then you recover. You repeat the cycle until your system learns a wider range.

I also pay attention to how a protocol changes the next day. Did you sleep deeper. Did your resting state feel calmer. Did training feel cleaner. Did you wake with more focus. These signals matter because longevity is lived in feedback, not in headlines.

None of this replaces proper medical guidance, and none of it makes you immune to age. Be especially measured if you have heart concerns, blood pressure issues, pregnancy, or a condition affected by heat or cold. The strongest practice is the one that respects your actual body.

The future may bring remarkable tools. I hope it does. But the reader who benefits most from that future will be the one who arrives with a body already trained in recovery, adaptation, and restraint. That is where healthspan becomes real: not in the promise of more years, but in the quality you build into this one.