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Why We Age – And Why We Don't Have To

Jan 07, 2022
- I must say that I am incredibly excited about the conversation that is about to take place. I want to thank the City for partnering with ISB and bringing good science. And I think this is really fabulous science. And let me say a few words about Dr. David Sinclair. He was born in Australia and transferred to MIT for a PhD and then to Harvard, where he is now a professor of genetics. David is probably the face of aging in the United States and in the world today. The book you heard about, "Lifespan: Why You Age And Why You Don't Have To," I think is really one of those life-changing books that when you read it changes the way you think about a subject.
why we age and why we don t have to
And I suspect you'll get that feeling tonight from our conversation. David has many academic honors, many beautifully published articles, but it is interesting to note that Time magazine in 2014 declared him one of the 100 most influential people in the world. And then in 2018, he declared him one of the 50 most influential people in healthcare. And I think in many ways, you'll see in the conversation tonight, that's certainly true. So with that introduction, I'd like to start our conversation and ask David the first question. And that is: You were born in Australia. David, how did you evolve from Australia to become one of the pioneers in aging and longevity? - Well, Lee, thanks for the introduction.
why we age and why we don t have to

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introduced me, but I think the introduction you just gave is probably the most important to me because I've had such respect for you even before, even before you knew who I was. And thank you for that and thank you all for the opportunity to be able to speak tonight. So yeah, I'm Australian so I


to be humble. We in Australia, if we start bragging about ourselves we won't have any friends. So I'll do my best to talk about me tonight as much as you want. Yes, I was born in Australia. I was a pretty normal kid growing up.
why we age and why we don t have to
My family had a place with, oh, a thousand acres of woods in the backyard. So I spent a lot of time studying biology, but I always had ambition. I was the kind of kid that if I was born in ancient Greece, I would go to Athens. And so I wanted to go where the action was. And as nice as Sydney is, it's not the center of the world where I like to be. I was also raised by my mother and grandmother. And particularly my grandmother gave me a very special upbringing. She was a survivor of World War II and she realized that humanity can do terrible things.
why we age and why we don t have to
She was from Hungary and she ran away to Australia with my dad. So I was brought up and told that humanity can do so much better and that David you should spend your life making humanity the best it can be and the best it can be because we know humanity can do so much better. And I remember that she told me that. And so I've spent my life really trying to leave the world a better place. Every day I wake up is another challenge. To get to the US, really what happened was I realized at the age of 17, 18 when I was entering college that we are probably the last generation of humans, at least my generation, living a human life. normal and that the technologies of the future, our children our grandchildren would greatly benefit from these understanding why we age.
My grandmother also told me that everyone eventually gets sick and dies, which for a four-year-old is pretty shocking. And we all go through it, but I couldn't get it out of my mind. So, combining all of that, Lee set my sights on the US in Boston, at MIT. I met Lenny Guarente, who became my mentor at MIT. I happened to meet him in Sydney in 1993. And I said, I want to do that. I want to study the aging of yeast cells, and to make a long story short, I was interviewed by a famous scientist, Doug Melton, for a scholarship for the Helen Hay Whitney Scholarship.
They had never given it to a foreigner before and I just argued that they should give it to me anyway. And they did. And the rest is I guess, history. - Well, great, David. One of the most interesting aspects of the book from him was at the beginning of the book, the description of the information theory of aging. And I say this because I think that absolutely fascinating hypotheses conceptually emerge from there. So can you explain simply and in layman's terms what that means? And I will say that it's also interesting because you pointed out that aging is easier to treat than cancer.
And all of this stems from the information theory of aging. - That's how it is. Yes, I have been studying aging since I was at MIT. This is now 1995. And the first set of genes that we were working on in Lenny's lab came from a random selection of any gene that would make a yeast cell more resistant to stress and longer live. And from there came the discovery that there are certain genes, which we now call sirtuins; at first they did not have that name. But what's interesting about the name is that the SIR in the name stands for Silent Information Regulator.
And at that point we really had no idea why a Silent Information Regulator, in other words something that controls the expression of other genes by turning off other genes, why would it be controlling aging? At the time, the idea was that, and for the most part, it's still that things break down and there's not much you can do about it. You could try to slow it down, but basically we'll all just fade away and be corrupted and degenerate. But that information, part of that acronym is very important. And so I've been focusing on what is it about the information that is relevant to aging?
And we did a lot of work in yeast and then in mammals in my lab at Harvard. I have always tried to think about information, and one of the breakthroughs came when I realized that I was reading about information theory, Claude Shannon, a great disciple of his, and a professor at MIT in the 1940s. mathematics of information preservation and, in fact, his mathematics led to the Internet, among other things. And his idea was that things degenerate over time, including signals like radio signals, due to introduced noise. And that really, it clicked with me. I could see that we could be the biological equivalent of a radio signal that degenerates and has introduced noise.
And it was a good fit if most of the work that was being done in my lab, if not all of it. And so I came up with the information theory of aging as I call it. And really the idea is that we are born with a relatively pristine set of information. Our DNA is a digital code, four bases, four letters instead of digital zeroes and ones, but it is digital nonetheless. But there is another type of information that is just as important for our survival. And that's called the epigenome that controls how the DNA is expressed.
In other words, which genes are turned on and off. And it needs it because the brain has a different set of genes needed for a liver cell and a skin cell. And that's what the epigenome does. And the analogy is excuse the old fashionista, but a DVD or a compact disc has digital information, but the reader that is the head that moves and uses the laser is analog and the cell phone has two types. They have the DNA, and then they have the reader. And it seemed to me that everything we were learning was in the readers, the DNA readers and the control systems were going wrong during aging.
And that led to the conclusion that if that was true, the really interesting corollary is that there could be a backup of the original information, the genetic information, and even the epigenetic information. And we published a paper in December that we were so excited to even get the front page of that issue saying that we could actually access a backup copy of the original epigenetic information in a cell or in a tissue. In this case, we rejuvenated the eyes of the mice and allowed them to see again after suffering from glaucoma or simply getting older. So what I think is this could be a tipping point, I dare say you risk being wrong, but if I'm right then there really is the ability to not just slow aging but reset the body to a state former. age and age multiple times and reboot multiple times. - Yeah, well, I think the really important takeaway from that experience was that there are actually two aspects of aging.
It seems to me, one is, can we slow down? And the second is, can we reverse it? And it has never been shown to be reversible before. I think the job you described was one of the first. And I think a fascinating question is how far back can we reverse it? And another interrelated question that I'll leave with these two is when should we start thinking about aging and doing things that will slow down or even start to reverse the process? - Right. Well, like all of science, I mean, seriously, I'm standing on the shoulders of giants there.
From giants who discovered that you can reset the age of sematic adult cells to zero. So Jon Gordon and Shinya Yamanaka did those experiments on tadpoles and skin cells, respectively, and deservedly won the Nobel Prize for what? 2012 I think. So that was part of the reverse aging initiative. But we needed to do that. We needed to reset the age of the cells, not to zero but to 50 or 75% without the cells turning into tumors. And that was the challenge. We spent, oh, about three years testing different genetic combinations, testing genes that come in embryos, testing genes that are helpful for cancer, but don't cause cancer.
And finally I came up with a combination of three genes that resets the age of the cell by about 75%. And you might say, well, how do you know how old a cell is? Well now we have a very precise way of measuring the age of a cell or body. Some people call it Horvath's clock. It is also known as the DNA methylation clock. We can read chemicals that change over time in DNA called methyls. And that gives us a very accurate measure of age. So now we can take those mice that had restored vision and really ask if those cells are just acting young or are they literally young.
And the answer was, they are literally young again. And that was the first, I think the first discovery that in a living organism you can safely reprogram and reset the age of the body. How soon will it be available to humans? As we work to conduct our first clinical trial in the next two years, we already have two years of work under our belt. - Wow. - Yes. But what about other parts of the body? I think it will be possible to restore most of the body parts. The question is, you know, the safety issue of course, but my lab has now had some initial results restoring other parts of the body, muscle looks promising.
We have other labs doing the brain. In fact, we have some early results with Alzheimer's disease and old age, dementia, and there's another lab at Stanford. It should call out Sebastiano's lab and everything is set up. I must give credit to One Kalispell Monte for showing that you can reverse the age of cells that you take out of a mouse and put back in. And that is also beneficial. So you don't just have to reprogram cells that already exist. Ultimately, where is this going? Well, that would be like asking the Wright brothers, when will we get to Mars?
It is doable. I just don't know when, but now I can see if the information theory of aging is correct, maybe one day we can get an injection of a virus that carries these reprogramming genes and activate them with an antibiotic. In mice, we use doxycycline, it's a fairly inert drug, and we turn these genes on for four to six weeks, reversing the age of the body. And then your doctor will tell you to come back in another decade. We will do another treatment. - Yes Yes. So, in your book on "longevity genes", do you want to describe what this does and its role in this information theory of aging? - Yes, these are fascinating genes.
They arose primarily from discoveries in the 1990s and early 2000s in yeast, worms, and flies. Labs like Cynthia Kenyon, Gary Rodkin, Lenny Guarente, of course, where I've been. And these are genes that you might not suspect actually control aging, but were discovered simply by looking at the genomes of these organisms. And what we've found is that they do is that they're built to survive. They are not built for longevity, but what they do is respond when organisms perceive adversity or future adversity. For example, in yeast, we showed in a nature paper, 2003, that if you restrict the amount of calories a yeast cell receives or raise the temperature or give it too much salt or lack amino acids, it will live longer. a set of longevity genes.
These sirtuins that I alluded to and that's a defense response trying to survive. And so you can think of longevity genes that way. These are like the Pentagon that you can call and say there's an emergency, send in the troops. Even if there isn'tan emergency. And that's what our bodies are actually doing when we exercise and starve, we're calling on our body's Pentagon to send in the repair troops. And if you do it routinely, you will have a longer life. This is what has been proven time and time again. The question is, when should you start?
Well, we are starting to get old from even before we were born. This clock is ticking. So even if, even if you look in the mirror and you still don't have wrinkles, trust me, you're getting older and heading towards, you know, decrepitude. So I'm not saying, you know, have intermittent fasting if you're a teenager or a young adult, you have a lot going on for your longevity genes. But for me, by the time I hit thirty, I already felt like I needed something to help me. And that's when I started, but so there are two answers.
It's good to start early. Animal studies suggest and actually show, but I wouldn't say it's never too late either, but it's… you can start late. We can intervene in a mouse equivalent to a 70-year-old and have a life extension of 15 percent or more. So it's in that window, but it wouldn't be too old. I don't think once you're a hundred you'll be back to 20 unless our science improves. - So how do longevity genes relate to these, these now classic nine hallmarks of aging? Again, it seems that the whole process is part of this simplicity that we speak of that marks aging as a contrast to something more complicated like cancer. - Correct, so, yes, cancer has been described as a hundred different diseases.
In my opinion, aging is really a relatively simple process. There are three levels. We have the environment and what we eat and how we live. So this is external and internal inputs. And I already mentioned that putting yourself in a state of adversity, walking, not eating these kinds of things does that. Second layer of longevity genes that sense that adversity and control the systems below it. So what's underneath that at the most fundamental level? Well of course there is the epigenome which I have explained is not my best theory so far to explain root causes. But along with that, perhaps influenced if not controlled by epigenetic changes are the ones you mentioned, which are the hallmarks of aging.
Many viewers will remember the loss of telomeres, the ends of chromosomes, become shorter. We have, we lose STEM cells. We have senescent cells, the zombie cells that accumulate in the body to make us age. About 10 years ago, in the matter we agreed on nine hallmarks that mainly contribute to aging. And what they do is they control the troops. It's the various divisions of the Pentagon coming out. There is the Army, the Navy, the Air Force, the Space Force. That's what these longevity genes will control. Now, what I don't know yet, but what's exciting is that maybe if we can reset the age of the cell through the epigenome, these other features of aging will disappear.
And we have some evidence that some of them actually do go away. Which means that information theory is perhaps valid. But that doesn't mean we're going to be able to tackle the epigenome. These other things need to be addressed. And so there are many researchers and companies working to find ways to address each of the individual hallmarks as well. - Yes, so you said that the environment is the upper level that initiates the entire chain of the aging process. What are the environmental manipulations that we can use to influence the characteristics of aging that ordinary people, you and I, can incorporate into the way we live? - Yeah, well, it's not that hard to live another 14 years on average, if you just do the right things, which is not to get fat, get some exercise, eat well, what are the others?
I think it's sleeping. And don't stress that, that the basic things that in themselves will give you 14 years. It's been calculated, you know, bad luck, though, but you can go beyond that. That's just, that's just the bare minimum. If I could recommend one thing for people to try, it would be to eat less often. You know, I've totally changed my life around this. So, like my father, who is 81 years old without any medical problems, we now eat one meal a day. I could have a little lunch, but not much. And the rest is just hot drinks, which I love.
Anyway, there were some really good experiments showing on many different species. And we've known this for 80 years that reducing the number of calories you eat, especially if you're restricted during certain times of the day, is beneficial. One of the best experiments I could point to is a set of experiments by Raphael de Cabo at the NIA, which is the National Institute on Aging in Bethesda. And he did a very interesting set of experiments on mice, it's true, but it was really revealing. He was trying to find out what the differences are between the diets and whether you can give mice small calories in the form of fat, protein or carbohydrates.
And he did all of those combinations, 10,000 mice, but he also did something interesting that he fed the mice throughout the night when they normally eat, called ad libitum feeding, or just during a small window during the day or overnight. , I should say. And the mice ate almost the same amount of food because you can imagine if you're a hungry mouse you're going to gobble it up very quickly within that hour of feeding. The only ones who lived longer were those with restricted feeding time. It didn't matter what they were eating. So what that tells me is more likely and there is epidemiological evidence, this is true in humans, which is not that important about what you eat.
You know, of course you can't eat a terribly horrible diet and expect to live longer, but within reason it matters more when and how often you eat. And that's what I do. I've really cut a lot. During COVID I have lost, what is it? Nine kilos? What's that? It's a lot of pounds. I'm down to the weight I was when I was 20 now. And I feel great. There are many other things you should be doing. Lift weights, especially if you're a man, an older man to maintain muscle strength, but even for women, keep your muscles toned because falling is the fastest way to die.
Actually, like someone in the US falls every 19 seconds and breaks their leg or hip, and that is ultimately fatal for most seniors. - So a really interesting question. I mean, intermittent dieting, intermittent fasting presumably stresses the body and turns on the longevity genes and kick-starts this whole anti-aging process. So my question to you, it seems to me that the most challenging aspect is how to persuade people to change their behavior and adopt activities that are actually good for them in the long run. That is, I mean, I am very interested in well-being and there the issue is exactly the same.
So I'd like to hear your thoughts on how we can make people change. - If you're right. You and I have talked about this and it is very difficult. What I find useful is the information. And even thinking about my own life, if I didn't get any feedback, positive or negative, I gave up, right? You get on the scale, but that's it. Once you start measuring things and getting feedback, I think it makes a big difference. You know, not everyone does this, but they use an Oura ring to sleep and move around. I monitor my blood work as well so I know what's going on.
So that's the future. So people don't just get an annual checkup. In fact, they will be constantly seeing when they did this or took that supplement. If things work now, that's still futuristic. We still have, you know, about 50% of the US overweight. So how do you reach those people? It is very difficult. And it's one of the reasons why I wrote my book is to reach more people and to make the people who listen or read my book realize that 80% of our longevity in our health in old age is based on how we live. And only 20% is genetic.
So you can really control how long and how healthy you are in old age. So there's the education part, there's the feedback, the positive feedback, hopefully. But other than that, Lee, I'd be interested to hear what you think about how to get people more interested in this. - Well, I would agree with you. I think, I think there are two really important aspects. One is that you have to give people a metric that shows they are succeeding or failing, and the metric can show that they can change their behavior. And I think being able to measure something like biological age, how old your body says you are compared to your birthday, I think is one of the most valuable tools we're going to have to convince people that this is a unique opportunity. .
Did you want to talk a bit about that? - I'd love to. Yeah, we've been working behind the scenes in my lab to try to democratize that test. Now that proof, if you haven't heard of it, I mentioned it earlier, is the Horvath watch as it's usually called. What we can measure are chemical changes in the DNA itself in the blood or in a buccal swab. And that will pretty accurately tell you your actual age, not your birthday candles. I like to joke that, I mean, who cares how many times the earth has gone around the sun?
That is not what determines your health. It's really more about your true biological age. And so, in my lab, we've been able to develop new technologies to be able to read that test. And, you know, I'll say publicly for the first time that we plan to make this commercially available to the public, because I think it's very important that everyone who wants this test has an inexpensive way to do it. And I totally agree. Change your mindset when you can actually measure how well you're doing and also see if you can improve on it. - I'll tell you the second thing, David, I think that education from level K to 12 is really important.
So, for example, ISB is putting together a health program where we have 20 units that are based on this vision of health, which is predictive and preventive, personalized and participatory. And one of those units is going to be on aging. And wouldn't it be wonderful if every high school senior came out of a school with an understanding of the things we're talking about right now, and it's easy for young people to trade for a lot of the things older people do? The easiest way to get them to change is to make them die and let their children change.
Anyway, I think education and metrics are, but you know, there's a really interesting third chance. I would love for you to talk about that, because you know that Americans really like the idea. I mean, his big new idea is that age, aging is really a disease and we know how we can deal with disease. And the way Americans like to deal with disease is with pills. So you want to talk about pills and aging and where is that going in the future? - Yes, it is a very hot area at the moment. Going back to when I started my first company, 19-No, 2004, it was crazy to think that you could develop a drug that would address the root causes of aging or slow it down.
And people didn't even understand how to think about it, let alone build companies out of it. I think we showed that it was possible. And now we're in a world where longevity research and longevity drug development, longevity drug development, is one of the hottest areas of biotechnology. You know, I sit in the center of a tornado of activity and see that it has really gone almost vertical on an investor interest chart. In fact, I'm part of a group that recently said we were going to invest in a longevity-related company. We haven't picked which company yet and there was a billion dollar interest.
So this is, you know, it's a zeitgeist. In other words, I think science has reached a point where Wall Street and Main Street have increasingly realized that science has come of age and that we can actually develop drugs that use this knowledge. Not just to treat aging, but to treat the effects of aging, and in fact, 85% of all suffering on the planet, including most major diseases, is due to aging. We deny that aging is not important, but it is actually much more important for lung cancer than smoking, by at least an order of magnitude. So this is a major problem, but I'm optimistic now that we've apparently taken a similar turn to use the Wright brothers as a good example.
You know, we're talking, we're now in the 1920s, where people have seen Wright's plane work and there's a lot of interest in building, you know, eventually a Boeing 747. - You know, I think one of the ideas The most exciting things I took away from his book was the idea that aging is theleading cause of virtually all chronic diseases. Let's just say you can control aging. Then we can start thinking about controlling all these diseases. So the argument is why don't we spend the 6 pr 7 billion on cancer and the 11 billion on something else? Why don't we spend them figuring out how to control aging?
Wouldn't that be more efficient than taking diseases one at a time? It is, as I would say, a system, a very powerful and inclusive global approach that you are defending. - Very well, what I wrote in my book, I still believe is that I am not going to try to steal from Peter to pay Paul. I think all medical research is important and there is not enough funding. However, the amount of money that we spend on aging research, if you just look at the biology of aging and if you don't include Alzheimer's and other things, which are sometimes unfairly included, I think it's really just a few fighter jets in the US spent on this.
So I would say that as a country, the US can afford to invest more money in understanding the biology of aging, even without stealing, without stealing, but taking from other places. But I definitely agree with you that the impact of this could be much greater than tackling one disease at a time. One of the problems with the approach that we have now is that we have been effective in treating some areas of aging, such as heart disease. We have statins for cholesterol. We have very good medications to lower blood pressure. And we usually live longer because of it, but the brain still ages.
And now there's a rise in dementia and that's the wrong way to approach medicine. I would rather try to keep all parts of the body younger and healthier for longer and have an extension of our health period rather than just our lifespan. - Yeah, well, look, this discussion really brings up a fascinating point that you and I have discussed before. And that is our determination to advance the vision that we have, your vision for aging and so on. So my question is, where do we go beyond government funding to get the resources to power What is the science that is really going to transform aging? - Well, I've seen a lot more interest from philanthropists and non-profit organizations.
So I think that's an area where people can make a big difference. - Yeah. - George Church and I talked a lot about this just over a couple of million dollars. It can have a big impact in a lab. You can basically develop a drug that is almost ready to go into humans. If you are very efficient with capital. And often people who have the wealth to fund this sort of thing are surprised that such a relatively small amount can make such a big difference, but in the early stages discoveries can only be made by graduate students who stay behind. awake at night dreaming. .
And this is what changes the planet, not the billions of dollars of investment in the latest stage of technology. - Yes, well, I think another approach that you and I share is this idea. We can take useful knowledge and transfer it to companies that can generate enormous resources for the maturation of ideas and that greatly amplifies the type of things that can be done. And he's certainly been very successful in taking that approach as well. - Oh thanks. You know, I have a few idols, and you're one of them. Lee, I'm not kidding. It was very difficult as a young scientist in my thirties at Harvard starting companies in the 1990s, especially in the 1990s and even in the 2000s, it just wasn't something assistant professors did.
How could you? Let alone go into the media and speak directly to the public. That was totally frowned upon. I look to people like you for inspiration and to give me the courage to do it. And I'm so glad I did. And luckily, we now live in a world where it's quite acceptable- - It's quite common. - For us to do that, but it wasn't always like that and you were doing it before me and you had the courage to do it. And I'm assuming it's because you didn't want to just post articles. You wanted to change the world. - And that's where we both are, I think.
So one of the absolutely necessary things to change the world is to convince CEOs at all levels, healthcare, industry, high level people in government of the validity of the vision. And you have ideas on how to do it because that's one of the most challenging. If you can reach leaders, you can change organizations. But reaching out to leaders and changing their thinking is a huge challenge. However, there are approaches one can use, obviously. - Yes, so there are leaders in the industry. There are leaders in government, leaders in regulatory authorities, like the FDA. And I think we have to talk to all of them and you and I have been doing that, actually, in my opinion, I haven't been that good at it.
It's been hard enough turning the world upside down. In fact, I'm having more success from the bottom up. But I think we have to take both approaches to be- - Both approaches, yes. - And the FDA surprisingly a few years ago said they were open to calling aging a treatable disorder. If only we could show that this was the case and that those experiments are ongoing with a drug called metformin that many of you may have heard of. It is a first-line diabetes medicine - type 2 diabetes medicine for the elderly and people with high blood sugar.
And that drug appears to be based on at least tens of thousands of patients who have taken that drug who had protection not only against high blood sugar, but also against cancer and heart disease, and even Alzheimer's, frailty with security. And so this could already be a longevity drug that is available. It's very cheap. It's probably a few cents a pill. Unfortunately, it's available over the counter in many countries, not here in the US. But if the FDA allowed doctors to prescribe metformin before you had type 2 diabetes, that would be revolutionary. This would be the equivalent of taking statins for heart disease or blood pressure medications.
This would be a massive change, but right now, doctors, most doctors are either ignorant or reluctant to prescribe such a drug that would prevent multiple diseases. - How would you classify rapamycin in that sense? Another drug that manipulates one of the main of these central systems to establish the defense that leads to a reducing agent. - Yeah, well, what you said really resonated before, which is that you and I believe, well, I certainly believe that I believe that aging is simpler and easier to treat than cancer, which is a bunch of different diseases. . When it comes down to it, aging isn't that complicated.
Yes, the after effects and all the various things you see in older people are complicated, but at the core of what controls all of that there are really only three major systems that we've figured out. There may be a few more, but we know of three. One is the sirtuins I work on. Another is called AMPK or MP kinase that metformin works on. And now, Lee, you mentioned the third leg of the stool, which is a protein complex that detects amino acid intake called mTOR. And so mTOR, which is lowercase m TOR. If you eat a steak full of leucine, isoleucine valine.
And this protein complex will sense it and say, oh, times are good. We just killed a mammoth. Let's build more, more skin. Let's do more. - Let's play. - Yes, exactly we will reproduce. But there's a trade-off: The trade-off is that the body turns off its defenses, like recycling proteins called autophagy, a very important hallmark of aging that diminishes over time. And so taking this drug, rapamycin, which has been shown to definitely, or has been shown to selectively target mTOR, which is actually used to modulate the immune system, is in low doses, it looks really promising as a longevity molecule. .
In rodents, it is probably the most successful molecule in prolonging lifespan even late in life. The problem with rapamycin, it turns out that if you take high doses, I think more than 10 milligrams, for a long time, it can damage the kidneys and among other things. So it's not a perfectly safe drug that you'd want as something you'd use for longevity. That being said, rapamycin taken once a week or in low doses of three milligrams are things that people talk about. And I'm aware of people who are trying, you might say, well, why would you try something if it's not proven to work?
Well, if we wait until it's all proven to work, you know a lot of people hearing this and watching this are going to die. So there's a risk-reward calculation going on in people's minds. And that it's all done under the supervision of a doctor because it's a prescription drug, but we're actually at that tipping point, I think in human history where we can say there's a very high probability that some drugs that are already approved could affect the aging process positively. - Right, well, you know, one thing that we promised to have a conversation with each other in the future is my idea if we can measure in patients, huge amounts of data that I say all major systems and everything in clinical trials. , as if we are talking to aging, we can reduce the number of patients that give you compelling results.
And two, we can see results a lot faster because we're looking at a lot more features for subtle changes, etc. And I think this is going to be a really key part of accelerating acceptance of some of the types of things that we've talked about here. So my last question, because we have to address the audience now, is if you were to prioritize for the audience, the things that they could do now, what would be your list of priorities for them to live in a healthy way as they age? - Okay, well, I mentioned eating less frequently.
I think three meals a day plus snacks is wrong and I'm happy to debate with nutritionists about that. Other things you can do is make sure you maintain your muscle mass. We lose a percentage or so each year as older men and women as well, and women also have to watch their bone loss especially. So exercise if -- -- So is exercise primarily to maintain muscle mass or does it do other things as well? - Oh, it does a lot of good things. Some of which I won't even mention, but testosterone will increase if you build the big muscles in your body.
So I exercise my quadriceps. So my leg muscles, my back muscles are the main ones. You know, the rest is probably just for vanity, but big muscles are really important in men and women. If you have strong hips and there is a piriformis muscle, which basically holds your hips together, the problem with today's lifestyle is that sitting all the time causes those muscles to degenerate. And it's very easy to be weak there. And most people don't realize that they are weak. One of the things. I'll get back to the Lee question in a second, but there's an easy way to find out about how old you are, it's called the sitting and standing test, and it will test these muscles.
You sit cross-legged and if you can get up without touching the ground with your hands and stand up, you're young, a middle-aged person like me might need to use one hand to get up. And an older person will have to kneel down to get up. And that's really just testing your muscle strength. I think doing 20 push-ups is also considered very good at my age, but that's not very accurate compared to the other things we've talked about. But you are right that strengthening your muscles has multiple benefits. It is an increase in testosterone for men and, to a lesser extent, women, the muscles release hormones that are beneficial.
That's what you know, Lee, they're called myokines that we think circulate throughout the body and also lead to better health. We don't know all of them, but we do know some. The other thing that muscle strength and aerobic exercise in particular will do is make sure that blood glucose levels don't spike in your body. And when you eat a meal, blood sugar levels don't rise, and high blood glucose is one of the quick ways to suffering and death. Anyone who has had type 2 diabetes the bad way will tell you that, including poor circulation, heart disease, et cetera, and dementia. - Yes. - So that there are all those benefits besides feeling good and being able to walk in old age and making sure that if you fall, you'll recover. - Yes Yes.
Okay, with that, I'll start reading some chat box questions that the audience has asked. So the first is when do you plan to have the Horvath watch trial available to consumers? - Oh, that's hilarious. Just because that's one of the questions someone was asking me before I got on. Alright, this is public information. So let me think what I can say. We areright in the process of making that happen, the test will drop a lot in price. And I mean, hopefully I can conservatively have something available before the end of this year. Yeah, that's probably all I need to say at this point, but it's coming close and will be, backed by my science and reputation, and also providing feedback and suggestions on how to improve your score. - Well, you know, I'll make a comment about a competitor now called Longevity that has a biological age test that uses blood analytes. - Yes. - And again, it's already available.
Then you can look up Longevity and read about it. But I think both possibilities are absolutely fascinating. Second question. What is the ideal window to eat with intermittent fasting? You eat only one meal, does that mean the window is only one to two hours of eating per day? - Not even that. I'm like everyone else, I'm a normal person. I like to eat cheesecake, you know, but I've noticed that I feel a lot better. I am more alert, I am excited. I am I have a better perspective, I am optimistic. If I don't eat constantly, I've never really liked breakfast.
So that's just my physiology. Some people need to eat breakfast, I don't. But then I started skipping lunch and having hot tea instead, I could have a piece of fruit, but that's about it. And then at dinner time, you know, I'll find a dinner. If I'm dining out socially, I'll eat normally, that's fine. I will not reduce my joy in life. But most dinners are small. They look more like what a rabbit would eat than a lion. As fish. I try not to eat large steaks, but overall I have cut down on portion sizes a lot.
And you know, I've never felt better. I, you know, probably bragged too much about getting my 20-year-old body back, but I really do. And it's exhilarating to be like this. And it wasn't that hard. I really started in earnest in February and you know, now we're in April. It was not that difficult. Hope everyone can consider it. If they aren't already doing it, I encourage you to do it for at least two weeks before giving up because it takes two weeks to get used to. You know, we all have habits. We go to the fridge and eat sandwiches.
And once you get over that psychological thing, just have hot drinks, hot water, tea, whatever you feel like, then it's easy. I'm definitely not hungry. In fact, I feel much better without all these foods. One question I get, however, is should I fast longer than 18 hours, which is what I tend to do. And you can do that. I'm not that good at it actually. I don't have much willpower to be honest. Many people are better than me. So some people go for three days maybe every few weeks if you go for three days you get a real deep clean by this process called autophagy the body will start recycling more protein than it normally would using a system called autophagy mediated chaperones, or CMA.
I would love to try three days. I just haven't been able to do that yet. And then there is the extreme version that is a colleague of ours. Peter, Dr. Peter Attia, who has become very well known for this. He fasts for a week on water only. And he does that, I think every few months. And apparently that's extremely good for you by his estimations, but it's hard to do. I would say at least try not to eat three meals a day. That is a good start. - And then if you can come up with one, that's even better. - Yes, you really start to appreciate food, that's for sure.
But it does not dominate your life. I lived through a childhood where my mother used every meal to discuss what was for the next meal. And I'm quite happy not to live like this anymore. - Great, so in your book you write about Resveratrol, NMN and other supplements. What does the latest research say about this? Would you give any advice to people who are… what advice would you give to people interested in adopting them? - Very good, so the technology in my laboratory has been constantly improving. Resveratrol was a very early discovery in the early 2000s.
What we were trying to understand was, can you activate these longevity pathway mechanisms with a safe molecule? And at the time we didn't know that, now it seems obvious, of course everyone talks about it, but we didn't know. So what we and my co-authors discovered was that plant polyphenols are a variety of molecules that plants make when they're also under adversity. And one of which is resveratrol, which is found in grapevines and red wine, was quite effective in activating one of the sirtuin enzymes that my lab and others have shown to be beneficial to mammalian and even animal health. humans.
So resveratrol got a lot of hype, it was actually kind of unavoidable. A couple of things were going on. The red wine industry loved it. Red wine sales increased more than 30 percent and have held up. And then there was the business entity. So I started a company called Sirtris which, you know, had a professional team of people who talked to the media. So all of that, you know, 60 minute interview with Barbara Walters, all of that was pretty funny. But what really emerged was the realization that a safe, small molecule could be used to mimic the benefits of fasting.
So we fed resveratrol to mice that were on a high-fat Western diet, and they lived as long and were just as healthy as lean mice. So that in itself was, I think, a radical departure from what people were thinking. Why do I take resveratrol? Well, I still take resveratrol. I take a teaspoon full every morning. I take it with some yogurt just because it needs to dissolve. It's like brick dust. Otherwise it does not dissolve. And I've been doing that since my thirties and I'm still alive. So, we don't know if it'll make me live longer, but- - You're the good test subject, yes. - Well, I'm Australian.
As you know, there is a tradition of Australian scientists experimenting on themselves. Just like Barry Marshall discovered that stomach ulcers are caused by bacteria. In fact, he drank the bacteria and went himself and then he was cured. - But he won a Nobel Prize, so sometimes it works. - Yeah, well, instead of waiting 30 years for the clinical evidence, but you know I'm not doing this to try to live forever. I don't really worry about it, but I am very curious and like to learn things quickly. My father has been taking resveratrol for the same amount of time.
And as I mentioned, he is 81 years old and as fit or more fit than me, but no, I do not recommend supplements. I'm not a doctor and we don't know if these are going to work, but there is a lot of evidence I would say in animal studies that resveratrol is relatively benign and may also be beneficial for your metabolism and protecting organs. So I continued to take it until I saw evidence that it might be dangerous. And I haven't seen anything like it in 20 years. I take another molecule that's pretty prominent in the media, which is called a NAD enhancer.
You can buy them, they are called NR or NMN. I certainly don't sell anything at all. I don't promote anything, but I find a lot of people are interested in it. So I bring it up tonight. NAD enhancers are... they came from research in my lab, as well as Lenny Guarente. We discovered that the sirtuin enzymes are controlled by the level of NAD. This is a molecule that our bodies produce for metabolic reactions but also controls the activity of sirtuins. And when you're hungry, whether you're a yeast cell or a human, your NAD levels will rise.
And, but as you get older, it decreases. So what we were trying to do is artificially increase NAD levels in the body. And that's why I take the molecule called NMN which is a precursor to NAD. Interestingly, and what is rarely acknowledged is that one of the companies that I founded, co-founded called Metro Biotech, has been doing clinical trials in people for over two years with a NAD-enhancing molecule that is related to NMN and found really excellent. so far. I'm not yet free to say what they are, but I'm still taking NMN, having seen all the data.
But I don't want anyone to get the impression that I'm a cowboy just experimenting on himself. It's not that, you know, I just take very calculated risks, you know, barely, but also, at the same time, I do clinical trials with these molecules to try to quickly find out A, are they safe? And B, are they effective? - Okay, I love this question. Is it totally good to get younger? Wouldn't that populate the world with a lot of new young people? - Well, then I don't think the world is a cake that has only a certain number of slices.
I think we can continue to grow the pie. Now the world has limited resources of course we can't keep burning oil and we can't keep overpopulating and populating a growing population. But as I explained in the last part of my book when you actually do the math and I, we're actually going to publish a mathematical model in Nature Aging soon on this. What happens is that no... if you stop aging or slow it down, certainly if you slow it down it doesn't contribute appreciably to world population. Despite what you may think, not so many people die from old age, actually the problem is birth.
Unfortunately, fertility rates, or at least the reproductive number in families, are steadily declining all over the planet and are even negative for most developing or developed countries. America would go negative if it had no immigration. So don't worry. I don't think you need to worry about population. Well, resources, yes, we need to solve that, but I am very encouraged by, for example, the energy transition to renewable resources. I drive a Tesla for a good reason, and I believe that humans are capable of designing themselves and innovating to solve any problem. It is only a matter of will and investment and we can solve any problem. - I think the other point is that being younger means that you are vital, energetic, curious, creative.
I mean, it's hard to believe that practically no one would like those, those traits. - Another question, if someone was interested in a career switching to an aging field from a business related field, where would you recommend starting? - Yeah, what, let me start. If you're in high school, have a strong interest in science. You want math, you want a little physics, chemistry. You want biology. When you get to college, I'd do some basic biology. I would do some philosophy. I would do a bit of history if you're interested, get a broad education that will help you a lot in the rest of your life.
And when you get to my age, it's very hard to do that kind of broad thinking and learning. So do that, but then start focusing on maybe your second third year in genetics, which now covers molecular biology and even nanotechnology, things that Lee has developed in his career. Now we are in a revolution, both in our ability to read and write the genome and to read and write the epigenome and to do millions of experiments a day, as one person, something that took me a whole PhD which was to discover three genes to read the code can now be done.
Well, it wouldn't even be done. It would be, the whole genome can be done in an hour by a graduate student from a yeast cell. So we're at a point where it's a good time to bring together molecular biology, genetics and general science, because we have these tools that people like Lee have created for us and now we can do a million experiments a day. So that's a long way of saying also get some experience in bioinformatics because being able to analyze all that data is invaluable. And I can't find enough good bioinformaticians right now. - Yes absolutely.
Presumably he currently does his own sequencing for his methylation age calculations. Is this the kind of thing someone could do for themselves today on a regular basis with their own DNA sequencer? - Who has their own DNA sequencer for crying out loud? If you had a DNA sequencer, that's fine. - With Olink you can have a small DNA sequencer that costs nothing. I mean, with England's single cell sequencing technology, yes. - Yes MNI you mean, or is this something else? - Yes, MNI that's right. - Correct, a small sequence the size of a chocolate bar. So you can safely do that.
If I think you can do your own test at home, you would need a bench and you would need a core fusion. You'll need a pipette and a kit. You probably don't want to make your own reagents, but... - And it will probably cost you a thousand times more than getting it from someone who is a professional. - I would, I would. So, you know, come to Lee or come to me, we'll do it routinely and we can help you interpret the results as well. But I think it's an interesting point that science has reached, genetics has reached a point where you can edit the genome and read the genome even in your garage or in your kitchen, if you want to. - Absolutely.
You can bring a DNA sequencer to field tests and observe the organisms in the field. So it's amazing. What is the most accurate way tomeasure NAD levels after consumption of precursors? What is your perspective on IV NAD+ for longevity similar to what we have done for addiction detox? - Well, for IV NAD, I haven't seen any solid data yet. I am aware that it is offered. I went to one of the hotels in Hollywood and they offered it to me at the front desk, which was fun, but it also seems to be helpful, at least anecdotally, in helping with addiction at their clinics across the country, particularly in Florida.
But I can't say as a scientist that I've seen convincing, you know, placebo-controlled experiments that would tell you whether that's working or not, and I'm open to it. I certainly think it's possible. And if anyone has data they'd like to share with me, please go ahead and send it to me. And I will judge it as I would any other study. - Well, I think we have to close with the last question. I'll ask you David. I know from our conversation that you're writing another book, and I'll offer you the opportunity to comment on it or decline it at this point, whichever you choose. - Right, well, it's late at night here on the east coast.
So, you know, maybe I'm in the mood to talk, but yeah, I'm excited that the first book, "Lifespan," was a New York Times bestseller. It was very exciting. I enjoyed the process, the feedback I received from you, Lee and many others, but particularly your voice was very meaningful to me and made me want to do it again, right? You get enjoyment, you find satisfaction, you do it again. So I'm writing another book with my co-author, Matt LaPlante, who is a genius at putting together a bunch of crazy disparate stuff in my mind. And I know Lee, you've worked with Matt, so you know what I'm talking about.
My new book, we're not revealing exactly what it's about yet, but I can tell you that I'm very excited about it. It's going to be as interesting and revolutionary as the first book. We like to take what seems obvious to the world and look at it from behind the mirror and really see what's going on. And it's going to be a journey of understanding where we've come to in the last few million years as humans. Why do we exist with, with crazy hands like this? Why do we look like this? Why are we a lollipop, physicist?
That's pathetic. You put us in a cage with a chimpanzee and one punch and we're dead. We are pathetic as a species. Why did we genetically evolve to be so pathetic? And then what happened to the world we've made around us? Obviously, we have technology to try to make our lives easier to cope with all the faculties that we have lost over time since we went out into the wild, but we built a world that is not perfect for our physiology. And I'm looking here at the lights. I'm not going to sleep well tonight. You know, we suffer from social media.
We have a lot of depression and anxiety in our young children. We have other problems. We sit all day, you know, time and time again our technology solves one problem and causes another. And I call this the treadmill we're on. And really since humans have taken a stone and used it to hit an animal on the head, or maybe one of their enemies on the head, we've been on this treadmill. And the question is, can we ever date? And what does the future hold? And that's what I'm writing. - Yes, well, David, I want to thank you for an absolutely stimulating and wonderful conversation.
I thought you did a great job bringing the world of aging closer to everyone. And I'm just saying, if you will, the lessons I took home with me when I read your book were something we haven't talked about is that this aging process that David and others have discovered is preserved even in the simplest of single-celled organisms. And I think there are two interests with respect to that conservation. One is that it underscores the idea of ​​simplicity and elegance and something that all creatures share. And number two was the idea that we can use model organisms like mice and yeast to discover fundamental things that apply very directly to humans.
And that's really an exciting idea. I think number two, the idea that aging is a disease and that we really have powerful tools to cure and delay and even potentially reverse that disease. And I think number three, if we can do that, we can start to think about a very powerful way to attack the broad set of chronic diseases whose main predisposing factor is actually aging itself. And I think that eventually, with all the revolutionary changes that David has discovered in the next 10 years, we're going to see remarkable opportunities coming our way for each of us to fundamentally change our lives.
And presumably it takes us back to the 1980s and 1990s physically capable, mentally alert, enthusiastic about life. Now, that raises some other really interesting questions about where we're going to get enough money to do all the fun things we like. As we can? We're going to have multiple jobs, all kinds of exciting things. Anyway, I want to thank the City for allowing us to do these wonderful and exciting programs. I think to the audience, please, we will have other exciting programs in the future that combine ISB and Town Hall. And if you're interested in keeping up with all of this, check out our website at ISB, which is
So thank you, and especially you David, have a great night. We truly appreciate your contributions and your expression of them. - Well, thanks, Lee. And thanks to everyone, to the people at the city hall and everyone who tuned in tonight, I thought it was a wonderful discussion. And Lee, thank you also for all you've done for science and technology. - Of course.

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