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How To Stop & Reverse Aging with Dr. David Sinclair

Lace Gilger
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In this episode, we share the science of how to reprogram your body and reset your biological age. Can you permanently reverse aging? What should you do to slow down your aging process and stay young for longer.. maybe even forever.. with our guest Dr. David Sinclair. 

David A. Sinclair, Ph.D. is an entrepreneur, tenured professor at Harvard Medical School, and world leader in aging research. He has published over 160 scientific papers, is a co-inventor on over 50 patents, and has co-founded 12 biotechnology companies in the areas of aging, vaccines, diabetes, fertility, cancer, and biodefense. David is the author of the bestselling book Lifespan: Why We Age―and Why We Don't Have To. He serves as co-chief editor of the scientific journal Aging, works with national defense agencies, and works with NASA. He has received 35 honors including being one of Australia's leading scientists under 45, TIME magazine’s list of the “100 most influential people in the world” and many more. 

  • Aging doesn’t have to be that way. 

  • There are genes that control how long we live.

  • Lifespan is 80% lifestyle, 20% genetics. 

  • You can manipulate the genes that impact your lifespan both at a personal and lifestyle level, 

  • There’s a clock in your body that can be reset. Aging can be reversed. 

  • The information for your body to be young again still exists. The instructions are still in your cells. 

  • The 9 hallmarks of aging

    • Mitochondrial dysfunction

    • Genomic instability caused by DNA damage

    • Telomere attrition 

    • Epigenome alterations

    • Loss of proteostasis

    • Deregulated nutrient sensing 

    • Accumulation of senescent zombielike cells that inflame healthy cells

    • Stem cell exhaustion

    • Altered intercellular communication and the production of inflammatory molecules

  • What is the upstream cause of ALL the main impacts of aging?

  • There are unified upstream causes of aging.

  • Starting with cellular aging 

  • “Sirtuins"

    • Silent Information Regulator 

  • “The information theory of aging"

  • We are born with a perfect set of genetic information. It’s in 2 forms:

    • DNA

    • Elements that read the DNA (epigenome)

  • Information becomes lost and diluted over time. 

  • While mutations are one way, if it’s a reading error it’s another way. 

  • A genome is just a chemical - it’s words on a page. To bring it to life, you need a “reading machine” - the nucleus and the cell that supports the nucleus. 

  • “Epigenetic reprogramming” 

  • DNA damage can still be an important piece of aging. 

  • DNA Methylation - clover leaves that accumulate on your DNA

  • Your epigenetic code sits on top of your DNA and actives or turns of certain strands of DNA.

  • By reading your DNA Methylation pattern you can see what your “biological” age is. 

  • Key life interventions to extend your life by 14 years on average:

    • Eat healthily

    • Workout

    • Sleep well

    • Fasting & Caloric Restriction

  • Every cell in your body has to respond to at least one broken DNA strand per day - that’s 28 billion broken DNA strands - potential tumors or medical issues - happening in your body every day. 

  • What causes DNA damage and how can we avoid it?

    • Cancerous materials

    • Sun damage

    • Don’t microwave plastics

    • Inkjet yellow die is really toxic

    • X-rays and CT scans will break your DNA

  • How can we make our sirtuins more effective?

    • Take “sirtuin-activating molecules"

    • Eat foods that activate them. 

    • High-intensity exercise

    • Weight lifting 

    • Fasting

    • Cold Exposure

  • We’ve known for over 80 years that calorie restriction extends the lifespan of any animal from a spider to a dog. 

    • 70-80% of what it would normally eat. 

  • Cold therapy makes white fat become brown or beige fat. 

    • So this isn’t a cold shower, it’s more like cryotherapy. 

  • There are 7 sirtuin genes on our body and they are our bodies protectors. 

  • If you never experience COLD or extreme HEAT - if you’re never hungry - if you’re never under stress - your sirtuin circuit starts to relax and your epigenome degrades much more rapidly. 

  • Why external stress is a necessary component of having a healthy and active epigenome, which keeps you younger for longer. 

  • MTOR AMPK

  • How “Tet enzymes” can help a blind old mouse see like it was young again.

  • Injecting a virus into your body that reverses your age.

  • The quest for the “fountain of youth"

  • The supplements you should consider taking to slow the aging process.

    • 750-1000 mg of NMN

    • Metformin may be a powerful drug for reversing aging

    • Resveratrol

    • CoQ 10 - soluble form

  • Homework: Eat less often. You still have to eat well, and you can still eat the same amount of calories, space out the meals, and don’t snack in between. 

Thank you so much for listening!

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Episode Transcript

[00:00:04] ANNOUNCER: Welcome to the Science of Success, the number one evidence-based growth podcast on the internet, bringing the world's top experts right to you. Introducing your hosts, Matt Bodnar and Austin Fable. 

[00:00:18] MB: Welcome to the Science of Success, the number one evidence-based growth podcast on the Internet with more than 5 million downloads and listeners in over 100 countries. In this episode, we share the science of how to reprogram your body and reset your biological age. Can you permanently reverse aging? What should you do to slow down your aging process and stay young for longer, or maybe even ever? With our guest, Dr. David Sinclair. 

Are you a fan of the show and have you been enjoying the content that we’ve put together for you? If you have, I would love it if you signed up for our email list. We have some amazing content on their along with a really great free course that we put a ton of time into called How to Create Time for What Matters Most in Your Life. If that sounds exciting and interesting and you want a bunch of other free goodies and giveaways along with that, just go to successpodcast.com. You can sign up right on the homepage. That successpodcast.com, or if you're on your phone right now, all you have to do is text the word SMARTER. That's S-M-A-R-T-E-R to the number 44222. 

In our previous interview, we dug into the incredible story of Blake Mycoskie, the one-for-one model. What it's like to be an entrepreneur? To be the founder of Tom's, and ultimately to find happiness. 

Now, for interview with David.

[00:01:44] MB: Dr. David A. Sinclair is an entrepreneur, tenured professor at Harvard Medical School and a world leader in aging research. He has published over 160 scientific papers. Is a co-inventor on over 50 patents and has cofounded 12 biotechnology companies in the areas of aging, vaccines, diabetes, fertility, cancer and biodefense. David is the author of the best-selling book Lifespan: Why We Age and Why We Don't Have To. He serves the co-chief editor of the Scientific Journal Aging and works with national defense agencies and NASA. He's received 35 honors, including being one of Australia's leading scientists under 45, Time Magazine's list of 100 most influential people in the world, and so much more. 

David, welcome to the Science of Success.

[00:02:29] DS: It’s great to be on. Thanks for having me. 

[00:02:31] MB: Well, we’re really excited to have you on the show today. You have an incredible background and have done so much interesting work. And I can't wait to dig into it. 

[00:02:38] DS: Let's do it. 

[00:02:39] MB: I’d love to start out with some of the key themes around aging, and specifically what you’ve talked about in your book, Lifespan. Let's start out with one of the core ideas, something that is really almost just a fundamentally accepted premise and most of today's society, which is the idea that aging is natural. Tell me what your thoughts are on that idea. 

[00:02:59] DS: Well, I agree. It is natural, but so is humans not being able to fly and people dying from cancer. We work to make our lives better. And aging is the final frontier, where it’s one of the few things in our lives and in the world that we accept. But I think, hopefully, my book is a wake-up call that it doesn't have to be that way, in the same way that we’ve overcome and continued to rile against many cancers. And we make our lives better. We have air conditioners, we have cars. We are born as species to innovate. And for some reason aging is that barrier, and I feel it's my job and my life, really, to wake the world up from that misconception. 

[00:03:41] MB: It’s such an interesting insight, because we really do almost just accept that our bodies are going to age, they’re going to break down, and we have to go through all of these negative implications as we get older. But my understanding is from really a biochemical cellular level, it doesn't necessarily have to be that way. 

[00:04:01] DS: Yeah, we didn't know that until recently. In fact, some of the work is only just about to be published, which is what's so exciting. But we've really learned over the last 20 years that there are genes that control how long we live. Some of us have good copy. Some of us don't. But most of what we do in our lives is based on how we live. Only 20% is inherited. And what we figured out in large part is that these genes that extend lifespan in everything from little worms, up to humans, is that we can manipulate them by how we live our lives, but also increasingly genetically we can manipulate them. 

But the big deal that's in the book, which is very strange because it hasn't even yet fully come out in the scientific literature, but it will soon, is that there’s a clock in our bodies that is actually resettable. You can reset the age of a cell, or a tissue, eventually, an entire animal, so that aging is not a one-way street. It's not just slowable. It’s actually reversible. 

[00:04:59] MB: That’s such an interesting piece of the research, and I want to hear a little bit more about that, because it's one thing to say, “Okay. Maybe we can slow down our aging trajectory.” But to think about actually taking someone who today would be 65-year-old and reverse aging them back to their early 30s or something like that, that's almost something that you would. I've literally read science fiction stories where that happens. 

[00:05:23] DS: Yeah. I mean, there are interesting science fiction stories, but if you go back to the 19th century, there were writing science fiction about flying and going to the moon, and the same is going to be true for aging and aging reversal. But we couldn't have done this even 20 years ago. We didn't understand what was going on during aging. We just thought things wore out and got damaged and it was impossible to fix them. That's not true. 

In fact, the information in our bodies to be young again still exists. We know that. We can clone cells. Matt, I could take one of your cells if I wanted to and make a tissue out of it. I could even clone you if I had the authority to do so. Not that I would. Don’t worry. But those instructions are still in ourselves. We haven't lost them. It's similar to being able to reboot a computer and make it run like it was new again. 

[00:06:11] MB: Honestly, I wouldn't be totally opposed to having a clone of myself just to get some more stuff done. 

[00:06:16] DS: I suspect you do have one, given how much you’ve achieved and probably will achieve.

[00:06:20] MB: I could definitely say the same thing about you, and we’ll get into some of that stuff as well. But I want to really understand better the science of aging. Tell me a little bit more about both what our understanding is today of how the body ages, and what's happening when we age at a cellular level. 

[00:06:39] DS: Well, I'm excited about speaking with you today, because we have an audience, you have an audience, that is really interested in getting into the nitty-gritty. Too often, I just have to talk in analogies like the computer rebooting, but we can really get into this. So, I’m excited. And tell me if you want me to go even deeper. 

But let's start at the top and work our way in. At the high-level concept is that there are numerous causes of aging. There are eight main ones called the hallmarks of aging, which you’ll read about occasionally in the media. Mitochondrial dysfunction, telomere shortening cellular senescence, the zombie cells, protein misfolding, DNA damage. Telomere shortening, I might have already mentioned. But these things and basically a list of things that go wrong during aging. But I've never been satisfied with that. I mean, it’s a good starting point. And address one of those, and you'll be healthier and live longer. But what if you could address them all with a single treatment? That's what I'm looking for. What we call the upstream cause of all of those other things. 

[00:07:38] MB: So, tell me more about that. 

[00:07:41] DS: Right. What we’ve discovered back in the 1990s. So, I was just a kid. I was 25. I’d come from Australia. Figured I'd come to the US for a couple years, get some experience. [inaudible 00:07:52] a lab to work in. It was working on yeast aging, which sounds crazy at the time. It was crazy. Now, a whole field on it over time. And what we wanted to do, and my professor’s name was Lenny Guarente, and he was a rebellious guy. He taught me also how to be rebellious. 

We decided to figure out why the yeast cells grow old, because if we can't figure that out for our yeast cell, good luck with humans. And then we figured if we could find those genes that controlled the process. It might tell us why we age and how to control our aging process. And it's not all just a story about me today, or in my book. There was a rebellious group of about 10 labs who were doing research on the cutting edge who said, “Let's just forget what we know and use genetics to figure out if there are genes that control aging. 

In our case, in yeast, we found a group of genes called sirtuins. The sirtu part of it comes from the first gene that we were working on called Sirtu, and it’s interesting that the sir part of it, S-I-R, as in yes, sir, stands for silent information regulator, and the most important word that I've told you today is the word information, because I believe, and my theory is called the information theory of aging, is that we are born with a perfect set of information, most of us, if we’re lucky. And that information is in two forms, the DNA and the elements that read the DNA known as the epigenome. 

People have looked at the genome for many years and found that there are mutations here or there, but could never really prove or find convincing evidence that the DNA information, the genetic information was what was going wrong during aging. So we focused on epigenetic information now that we had learned that yeast use information regulators to live longer. 

And my theory basically, if you want to boil it down, is that the information in our bodies due to entropy becomes lost over time, and that’s primarily the epigenome, the readers of the genome. The reason that's really important, not only if it's true it's important, because we can potentially reverse it. But what's important conceptually is that while mutations are pretty much one way. If you're full of mutations even with the best Crispr technology, you’re not going to be able to easily reverse that. 

But if it's merely just telling the cells to read the genes the way they did when we were young, that’s doable. And in fact, it only took up my lab a couple years to achieve it. And I'll tell you more in a minute. But just to finish this thought, we’ve figured out how to reverse the age of the epigenome so that cells and tissues can read the genes like they did when the animal was very young. I'm talking about mice, of course. In two years, we hope to have tested out first patient.

[00:10:46] MB: So, just to break down and explain the concept a little bit more, basically, tell me the difference between what is the difference between the genome of the epigenome and how do they interact in the body.

[00:10:58] DS: Yeah. Well, I’ll tell you actually what it is. But think of it like a DVD. I'm sure many of us remember DVDs. These were the – We were excited we could put a movie on them. But what’s good about this analogy is that they had digital information on them, right? The pits in the aluminum. And that’s similar to the genome. These are zeros and ones on a DVD in the body. It's an A, T, C on G chemical. And string that billions of times and you've got the genome. But the genome is just a chemical. It's not life. To bring the genome to life, you need the reading machinery, and that’s nucleus, and the cell would support the nucleus. And that's really the epigenome. So what is that actually in physical space? 

Well, we know the genome is a chemical, right? What's an incorrect double helix? But the epigenome is a lot more complicated, and that's the reason why we don't know as much about it as we do DNA. But think of the epigenome as if you’re spooling up a hose on your driveway, how about that thing that winds up your hose. That kind of thing. There were systems that are in place to bundle up the DNA when we don't need those genes or to release them as a big loop of DNA so the cell can read those genes. And that combination of loops and bundles, loops and bundles, tens of thousands in a row across a chromosome is what tells the cell how to live, how to survive, and what type of cell it should be. And all of that gets established during embryo development until we are born and eventually we become teenagers. But, essentially, once you've locked in that you are nerve cell, or a skin cell, or a liver cell, you’re not going to change. And thank goodness, otherwise we'd all be the world's biggest humor. 

A nerve cell has to say a nerve cell, and it's the epigenome loops that I’ve described that allow that to be maintained. Of course, anyone who’s saying and thinking will realize that aging is the destruction of those loops and bundles, in my view.

[00:12:55] MB: That totally makes sense. And so the DNA is essentially just a set of instructions or almost like a set of computer code. And the cells, the nuclei and so forth are almost many machines that are reading that code. And over time, they start to develop small errors in the way that they read it, but the code itself is essentially unchanged. And so you can just tweak the machinery, get it to read the code perfectly and things will revert back to – I don’t know, the term the DAs or the less-aged version. Is that I correct characterization?

[00:13:27] DS: Yes, it is way. We call it epigenetic reprogramming. But you’re right. Now, I just want to make sure that my colleagues don't get upset with me. I'm not saying that mutations aren’t important. There are certainly mutations in cells that are exposed to the air, to our food, to the light. Anyone who's lived in Australia has gotten wrinkles in their 40s knows this to be true. But, really, what I'm saying is that they're not the main driver but DNA damage is still important, because what we've discovered in my lab over the last decade is that the damage to the DNA is one of the main – Possibly the main reasons those loops and bundles get disrupted in the first place. 

[00:14:08] MB: So, I want to bring us back to something you said earlier and start times into how we understand it more effectively. So you mentioned previously that genetics is about 20% of age-related. I guess, genetics controls about 20% of your lifespan. And the other 80% is essentially the broad category of epigenetics. Is that a correct understanding?

[00:14:29] DS: Generally. There’s always finer detail. 

[00:14:31] MB: Right. Yeah, sure. 

[00:14:32] DS: The word I have to use as a scientist is heritable. And you can inherit more than your DNA. You inherit some of your epigenome, right? From your parents. In fact, if your parents eat a lot of food and are hugely obese, because of epigenetic, you’ll be more predisposed to obesity and diabetes yourself. But yeah, what you don't get from your parents, it’s the other 80%, which is how you live your life, and that is I think really one of the most important messages we could ever have in our lifetimes that our genes are not our destiny in the long run. 

[00:15:05] MB: So, give me a sense of at an epigenetic level within cells and the cellular structures inside of our bodies. How does that epigenetic reprogramming actually starts to take place?

[00:15:18] DS: Well, I could talk all day about this, because it's the most exciting thing I've ever worked on. Let's start from a little bit of background here. Those loops and bundles are controlled by proteins mainly, a little bit of RNA. But, essentially these are proteins that either bind to the DNA or bind to those proteins that bind the DNA and assemble these structures in three dimensions. And we’re finally developing these technologies. In fact, I was on a scientific advisory board meeting today for a few hours of a company that's on the cutting edge of being able to read the genome in its three-dimensional state, which is blowing the field wide open. 

Besides those proteins that bundle and spool, including these SIRT1s that I work on, the silent information regulators, they shut down the genes and bundle them up. There’s something else that we haven't mentioned that’s really important for this process to be understood and to reprogram it. It's called DNA methylation. And DNA methylation is a very simple process. Metals are carbon with three hydrogens on it. Think of a clover leaf. And those get decorated on our DNA. 

Initially, it's done during development so that the cells remember what type of cells they are. And it's a very important and permanent mark, one semi-permanent mark on DNA. And there are enzymes that add those chemicals, stick them on there, they’ll stay there up to 100 and something years. In the case of a whale, few hundred. And then there are enzymes that take them off, they’re called TETs. I think I’ll bring up TETs later. 

But think of this as a code on top of the genetic code called the epigenetic code, and it's a read/write system, but it also allows the cell to say permanently, “Okay. That's a group of genes that should never come on. That's a liver group of genes, and we’re supposed to be neurons. So shut them off.” 

In fact, DNA methylation is really important for telling the body where the head is and the tail is as you're developing. And what we’re finding is during aging, is that those genes, they’re called hox genes, H-O-X, they come on during aging. But getting back to this clock, these DNA methyl groups can be read by a machine in the lab. We have sequencing machines in most labs these days. We’ve got one that's the size of a little candy bar. It's quite an amazing technology. And if we read all those little methyls, those cloverleaves as I’ve just called them for the first time. As they accumulate on the DNA and occasionally get subtracted by TET enzymes, that is a – If you look at the right places in the genome, not all of them, not hundreds of thousands of them, but there are about a few hundred that reproducibly, time and time again, in humans, in mice, in dogs, they serve as a clock. If I was to read your DNA methylation pattern, Matt, I can plug that into an algorithm that we’ve develop using machine learning by looking at hundreds of humans, and I could tell you if for your chronological age, whether you are doing better or worse for your biological age, and that is a better predictor of your longevity than anything else. In fact, if you look at the biological age based on this clock, you can predict whether somebody smoked or not even better than they remembered.

[00:18:40] MB: How much variance can there be between your biological age and your chronological age just from the data that you've already seen? Assuming people who haven't necessarily taken a lot of these interventions to either slow or reverse aging.

[00:18:53] DS: Well, I've seen data points where people are a decade younger [inaudible 00:18:57] 20 years younger. And these are people typically that have eaten the right things, stayed lean, exercise, all those good stuff the doctors figured out through other means that these are healthy for you. But, yeah, it can make a massive difference. By the way, just doing those things that I mentioned as well as getting good sleep, and there’s a fifth one. I think it might be have a community around you for mental health. You extend your life by 14 years on average. By doing this really rigorously like I do, I think that 14 years is just the beginning. 

[00:19:27] MB: It’s so funny, things are often simple, but not easy. And from a variety of disciplines, I mean, if you look at the book blue zones, what you're just talking about, all of these different methodologies. If you get a lot of sleep, if you eat relatively healthfully, if you take care of your body and stay physically active. Those things go such a long way towards pretty much reducing all caused mortality, increasing your happiness, increasing pretty much everything you can imagine. And everybody, it's so obvious that people almost ignore it. 

[00:19:56] DS: Well, I think that the time we are in with COVID-19, people are paying more attention to their health, because when you're young, and I still feel young. I’m 50. Death and sickness is so far in the future. We don't think about it. But if you are obese right now, you can be quite susceptible to COVID-19. Same for any condition. And so it's not just something in the future. It can actually affect your life now. 

I have a friend who spent two weeks on a ventilator who was in his 40s. He wasn't particularly unhealthy, but still I think we’re in a time where we shouldn't be ignoring our health and putting it off into the future. The other thing that's important to know is my field and my lab have studied rodents and dogs for many years. It's very clear to us that the sooner you start healthy living, the better it is and the bigger impact you have. You can't say, “Okay. I'll go to the gym when I'm 65.” That's not going to work as well as if you do it your whole life.

[00:20:53] MB: So I want to tie this back in to the epigenetic reprogramming. Some of those lifestyle interventions are obviously ways that you can start to take some steps to reprogram your epigenome, to change your lifestyle, to reverse or decrease the impact of aging in some form or fashion. But tell me a little bit more about how that reprogramming is actually happening and what are some of the factors that drive that and can actually move that lever. 

[00:21:19] DS: The main one we've discovered is broken DNA. Now, when you chromosome breaks, it's a do or die, fix or die problem for the cell. You’ll either rip your chromosomes to shreds when you try to copy it and divide, or you might become a humor, both of which you don't want. So the cell has to really mount a massive response to even just one piece of broken DNA in each cell. And each cell has at least one broken chromosome per day, which is pretty incredible, right? What's that? 26 billion breaks in your body a day. Your body has to react to that. 

And what it does in its reaction is send proteins from key areas, like the sirtuins, are normally holding those bundles together so that genes don't get read. Then we see the move to the break or breaks. They do their job, but then they have to find their way back to where they came from. And that happens 99.9% of the time. That's why we don't grow old within a few days. But it's cumulative, because if .1% of those proteins don't make it their way back and they up staying where they were or they off and do something else, cells eventually, as we see in mice and in human cells, they lose their identity, because genes that shouldn't be on start coming on because of this reshuffling of these silencing proteins, the sirtuins and others as well. So that's one thing. 

So what I would say practically speaking is try to avoid DNA damage. Now, you can't avoid DNA breaks completely, because it's part of life. That will happen. And even if you lived on the bottom of the ocean in a led box, you’d still have DNA breaks. But there are things that exacerbate DNA damage and DNA breaks, certain chemicals. The ones that are known to cause cancer are good examples. Going in the sun will create what are called thymine dimers, which also can lead to breaks. Don't microwave plastics. Yellow die out of inkjet printers is pretty toxic for this kind of stuff. X-rays and CT scans will break your DNA. I try to avoid X-rays, for example, that are frivolous. 

I’ve had a minimal amount, what I would call the necessary amount of dental X-rays, but no more than that. And every time I go into the dentist, I have a fight with my dentist. And in the end, I win, because I think that I have a right to refuse something. But, I mean, I still have X-rays. Don't get me wrong. I'm not that crazy. I don’t wear tinfoil in my head. But I don't like excessive radiation exposure. 

[00:23:51] MB: That makes total sense. So, we avoid some of the causes of DNA damage. What are some of the strategies for making your sirtuins more effective?

[00:24:02] DS: Good question. We found in yeast that just by putting in an extra copy of the gene sirtu, they lived 30% longer, and that mimic the effects of fasting or caloric restriction as it used to be called more commonly. And that's how we figured out how this all works. That the environment is stressful or at least perceived adversity in the environment like low amounts of sugar for a yeast cell would activate the sirtuins and make more of it or we could genetically modify those cells within a few days, and that was sufficient too. 

So what turns on those genes naturally, because we can't easily genetically engineer ourselves. One way is to take what are called sirtuin-activating molecules. Those are molecules we’ve discovered over the years will bind to the enzyme and make it work more effectively, like speeding up a Pac-Man. You can also just have foodstuffs that have these chemicals in them. So there's a little bit in red wine [inaudible 00:25:00], which was the first activator that got some press from our lab. Olive oil now, oleic acid turns out to be an activator. 

But ideally you want to have more than just a trace amounts that are in red wine. I’ve admitted, but I don't endorse products, that I take resveratrol and I've done so for about 14 years now. But in daily life, let's say you’re opposed to taking any pills of whatsoever. Exercise will dilute certain types of high-intensity exercise as well as weightlifting, both of which I do. You can fast, be hungry for a little bit of the day each day. I try to skip breakfast. Well, I always skip breakfast. I try to skip lunch. I eat a regular dinner with a bit of a wine, and that's fine. I haven't admitted this publicly, I don't think ever before. But I struggle with this diet. I mean, I love food. My brain is like everybody else's. I like to eat. And occasionally at night, especially if I’ve had a glass of wine, I might grab some snacks. But really, I don’t do that every night. But I am only human. I say that because it's important to try. And even if you are not perfect at these diets, it's the mere fact you’re trying that’s really important. 

So those are all the things. There’re also some saunas and cold plunges that are a little bit less proven. But there is all evidence for these things turning on the sirtuins. 

[00:26:24] AF: This episode of the Science of Success if brought to you by our partners at the Business Casual Podcast. Business Casual is a new podcast by Morning Brew that make news enjoyable, relatable, and dare I say even fun. Host, Kinsey Grant, interviews the biggest names in business program topics like how technology is changing the fitness industry, to the economics of influencer marketing. It’s the business podcast that makes you smarter and makes you laugh. It’s that mixture of entertainment, but also information. Listen to Business Casual wherever you get your podcasts today. 

[00:27:03] MB: You've talked a lot about fasting, and even if you go on some of your social media profiles, one of the most predominant themes that you share is that the importance of fasting and increasing your longevity. Tell me a little bit more about how that works and why it's so effective. 

[00:27:19] DS: We've known for over 80 years that caloric restriction extends the lifespan of many animals. It started in rats. It’s been done in mice, and everything from a spider to a dog. Caloric restriction works, and caloric restriction, the way it used to be done was you give an animal about 70% to 80% of what it would normally eat. That means they’re pretty hungry for most of the time. So that's not enjoyable, and what used to be only about a thousand people that I knew of that did this rigorously. They even had a website, it was calorierestriction.org. They have some really good recipes, mostly salads, say. 

But the modern way of doing it, more modern, and I think easier way to do it, is to – Of course, not eat during the night. So you have an early-ish dinner. I tend to eat around 7PM, and then try not to eat after that. For breakfast, the most I would have would be a spoon or two of homemade yogurt partly for the micro-vein, partly to dissolve my resveratrol, which is like eating brick dust, and then skip lunch. So what’s happening to the body when you do that is that, first of all, there is the obvious things that all doctors will tell you, and probably most people know already, which is that blood sugar levels will come down and your body will start to make its own blood sugar out of the liver, or sugar glucose, and it will start to burn fat. All good things. 

But here's the thing that most people don't understand, at least two really important things happen during that. One is that you’re going to make oleic acid, which is a breakdown product of white fat, white adipose tissue, and that has just been discovered to activate the enzyme, SIRT1, and that’s going to stabilize your epigenome and help repair the telomeres and broken DNA and fix the misholded proteins and dampen inflammation that leads to disease. Yeah, just being hungry and burning fat is actually healthy. I don't think anybody that I know of understands this very well. 

And the second thing that happens is that you will have low levels of glucose that trigger insulin, and then that state will actually turn on the SIRT1 enzyme as well through insulin signaling, which has been linked to aging for many years ever since Cynthia Kenyon discovered that worms, nematode worms that are mutant in insulin signaling live twice as long. 

Yeah, what we’re learning is that these things that we’ve bumped into like eating Mediterranean diets, being hungry that people probably knew thousands of years ago were actually correct at the fundamental molecular level of slowing aging down. 

[00:29:58] MB: Another one that I find really fascinating that I know you've talked about previously as well is cold exposure. Tell me a little bit about how cold exposure works to reverse or slow the aging process.

[00:30:09] DS: So when I started writing my book, the editor said, “You've got to put more of the pop culture stuff, the –” What is it? Cryotherapy? And this is going back three years ago now. It wasn't very scientific at all to say the least. And I rebelled and I said, “I don't want to put that kind of stuff in my book. This is going to be the best science that you’ll ever read.” But I looked into it, and interestingly, there is some validity to cold therapy and also saunas. Again, I thought probably BS, but it actually looks good. It's not as clear as the fasting that I just talked about. But cold therapy, what it'll do is it'll turn on or activate white fat to become brown fat, or beige fat, which is an intermediate form. 

So what is brown fat? Brown fat is found in babies, because babies for the first few weeks cannot shiver, and instead they use brown fat to heat themselves, and that's how they stay warm. But it was thought that after we become little toddlers, we lose out brown fat. But people recently, maybe the last five years, have discovered that adults also have brown fat. And the way to turn on, activate the brown fat brown your existing fat just under the skin is to be called. And I'm not talking about walking out in a windy day for two minutes. That's probably not going to do it. What you need to do is to shock the system. You need to expose the skin to really tough cold. 

In a mouse, what we do is we put them at 4°C, like put them in a fridge for a little bit, and we see they can get brown fat. Possibly, pull them out again and warm them up. Don’t worry, we don’t hurt them any more than us going out on a winter's day. But you can do a cold plunge. You can do cryotherapy. These things potentially are very good for us. 

Getting back to my work and the sirtuins, one of the – So let me tell you, there are seven sirtuin genes in our body, and I've mostly been talking about number one, six and seven, which are found on DNA. But there are others that are floating around outside the nucleus. And number three, four and five are in the mitochondria, which I'm sure you all know is that power packs, the energy-generating system of the cell. And those sirtuins actually are controlling particularly number three sirtuin, controls the browning when it's cold. 

So, really, you got to think of these sirtuins as the body’s protectors. They’re like the Pentagon. And when there's an emergency or even a potential emergency, they send out the troops and make the body more defensive. Conversely, I want to put this in, Matt, because I don't forget to say, because I t’s really, really important. If you never experience cold, and typically we go from our garage, to our cars, to our houses, to work. If you don't experience hot like a sauna, if you don't ever feel hungry, and you don't need to today. If you barely ever exercise, if you barely ever lift anything heavy, you sirtuin survival circuit is going to just relax and say, “Cool, man. This is great.” And your epigenome is going to degrade and you’re going to find that you have diabetes, cancer, heart disease, and Alzheimer's much quicker than someone else who did all the right things. 

[00:33:21] MB: That's another point that I think is so fascinating, which is the importance of having some kind of external stressor to actually keep your sirtuins – I don't know the right term, but productive, proactive, etc. Tell me a little bit more about that concept and why some level of stress, whether it's hunger, etc., cold, extreme heat and so forth is actually important. 

[00:33:46] DS: Well, from an evolutionary perspective, what I have proposed is that this is a very ancient survival circuit that has been around since life first was in the primordial pond, I guess you’d call it. It’s really a set of genes that responds to perceived threats, whether it's a lack of nutrients on DNA damage, or whatever it is. It could be UV light coming in. It could be a lack of amino acids. And it turns on this survival circuit, and the sirtuins are part of that.

Now, there are other components that are important to know about. One is mTOR, which works best for longevity when there're low amounts of amino acids. So, if all you ate is a steak every night, your mTOR is going to work for you. And then there's one called AMPK, which is short for AMP kinase, which is a protein that senses how much energy we have, and it'll come on when we’re hungry and when our cells don't have enough energy, and it'll switch on the mitochondria and make them more active, which actually turns out to be beneficial for repairing things and living longer. When you have all of those survival genes switched on, whether you’re an early microbe in the primordial soup or a human being 3.7 billion years later, it's all good. In fact, it's better than good. 

[00:35:04] MB: So, in our modern lives of luxury and comfort, relatively speaking, because most people in have things like air conditioning, and so forth, we’re not living like we used to live thousands of years ago. The fact that we have many of these comforts today has actually made us from an epigenetic standpoint more prone to aging and disease. Is that correct?

[00:35:29] DS: It’s 100%, and it's similar to use it or lose it. We live in a world, a modern world, the marketing world, consumer world has decided that the best way to make money is to give us comfort and satiety, lots of sugar, lots of salt, lots of fat, lots of comfy chairs, right? This is what our brain seeks. Our brain doesn't want to be running away from a sabertooth tiger or being hungry, because that's dangerous. So we've evolved, unfortunately, to crave these comforts. But what that leads to in the long run is susceptibility to diseases, including infectious diseases as we’re finding out now.

[00:36:10] MB: I want to come back to something we talked about earlier, because I understand – And it makes total sense to me that somebody who's eating healthy and sleeping well and cultivating healthy stress in their life, all of these things, is going to slow down their aging. But at least from my experience, I haven't seen a lot of people who start eating salad and jogging and suddenly go from being 65 to being 25. Tell me about how does this get into the actual reversal of aging and what is some of the cutting edge science that you're working on? Some the interventions that you're seeing that may eventually emerge that we can start to implement to actually not only just slow our aging down, but really think ultimately about potentially reversing aging.

[00:36:49] DS: Yeah. Well, yeah. Slowing down aging was step one. And I would say that we’re pretty far into that as a field. There are drugs like rapamycin that inhibit mTOR, which extend the lifespan of rodents at least by 20%. That’s a pretty good start. But, you're right. You can't give rapamycin or resveratrol to a mouse and expect it to suddenly go back to being young again. We don't see that. 

Now, I will say that we’ve been somewhat successful. In my lab, for example, we can activate the sirtuin enzymes and get part of their youth back. We published a paper a couple of years ago in the Journal Cell that showed that by activating the SIRT1 enzyme in the lining of blood vessels, the endothelial cells, which by the way are what COVID is seeming to be attacking. Those mice could go from being elderly and weak and unable to run on a treadmill to running up to two times further like a young mouse. So there are aspects. Aspects is important. Not the whole animal, but suspects can be reversed. 

But how far are we from flip a switch and in three weeks you literally get your hair back, your hair color? You get your eyesight back? Your brain works like it was young. Hopefully, you’ll retain all your memories. We’re testing that right now. So, what it needs is something a little bit more potent than just activating sirtuins. You have to get the sirtuins and these other proteins that they work with to go back to where they came from when they started, when we were babies, and get those methyl groups, those cloverleaves to be going back to the pattern that they had when we were young. 

And we don't know all of the workings of the system, but we do know actually how to contact the cell and initiate a program that does exactly that, which is get the sirtuins to go back, we think. But what we definitely see, and we’re going to be publishing this for the first time, is that you can trigger these TET enzymes that I mentioned earlier, these are enzymes that remove those methyls off DNA. And when you trigger those, the clock goes back quite a lot by 50%. But here's the kicker. If you don't have a TET enzymes in your body, or if you're a cell or a mouse, I should say, then reprogramming doesn't work, and the tissues that we’re looking a – Typically we do the eye, the old eye, then reprogramming doesn't work. You don’t get a young eye back. 

If you do have the TETs around, and we initiate this program effectively, in three weeks, we can take an old mouse that’s essentially blind to back to seeing like it was young again. That's where we’re at. And what's exciting about this is that if we can reverse aging in the eye, which is a very complex tissue, it's possible we can reverse aging in any part of the body, and that's what we’re testing now, and that's what we’re working towards in clinical trials to test whether we can reverse the damage that is caused by pressure in the eye, glaucoma. I'm sure you've heard of it. And this is one of the largest causes of blindness on the planet. Right now, there's nothing you can do once you've lost your vision or you’re losing it. You can have a little bit of slowdown by some treatments. But to be truly reversing, that damage is unprecedented. And we’re pretty excited about testing to see if this will work in people as well.

[00:40:10] MB: It’s so fascinating, and I’m definitely going to be watching from the sideline. Anxious to see how this research progresses and hope that in a few years or maybe a decade or two, this is something that really can become mainstream and help people start to actually reverse aging. It will be truly fascinating to see that.

[00:40:27] DS: Well, yeah. Sometimes people think, “Oh! This is just hype, because it sounds too god to be true. But I’ve got some very good people on this. I’ve got a number of companies that I work with and I’ve cofounded. The one I’m reprograming, it’s still in stealth. So I won’t say too much about it. But it's got some really top people from the pharmaceutical industry, from banking. And if anyone can do it, this team can. 

So it's really real, right? I could be wrong. Maybe it only works in mouse size and it'll never work in anything else. But I think that's highly unlikely, because we didn’t choose the eye for any specific reason other than we like a challenge. And my student knows a little bit about the retina, but we could've chosen the liver. We could've chosen the kidney. And we’ll see if we can reprogram an entire animal soon. But you asked what does this mean for us. Clearly, I'm not going to let you come to my lab and inject yourself with the gene therapy that we use. It's a virus, by the way, that will inject into the eye and turn on three reprogramming genes. We call them, OS and K. It's an acronym for four Oct4, Sox2 and Klf4, which people currently use to make stem cells out of adult cells, but we use it to reprogram the animal. 

But, yeah, that's where we’re at. So what we do in our lives? Well, if you can give me a few years, I'll let you know if we’re on the right track for all of us. But until then, what I would say is that you should definitely watch this space. My colleagues and I, my three cofounders, four of us, are working on the next generation. We have now found small molecules. In other words, chemicals, that we can get even in our diet or from a supplement that will hopefully do the same thing, literally, a youth pill. And I hate to use that term, because it sounds like a bunch of BS. But it's true. And these are people who I think could potentially win a Nobel Prize for those kinds of discoveries.

[00:42:19] MB: It’s so fascinating, and it's just such an interesting topic. I'm curious, you touched on one or two of these, but what are some of the – All caveats included in this. But what are some of the supplements or treatments that you take things like resveratrol, metformin, etc. that potentially can mitigate some of the impacts of aging?

[00:42:40] DS: Right. I'll refer listeners to my book, because it's a list and that's all explained why I do and what I do. Page 304 if you want to go to the cheat sheet, but do read the book as, well because it explains in more detail about the things we’ve talked about like exercise and diet in more detail. But some of the main ones that I will tell you now, a gram of resveratrol, just basically teaspoon of a powder. I got to say upfront, because everyone will want to know this. Unfortunately, I have to be very careful. I'm not a doctor. I’m a Ph.D. I'm at Harvard. Very conservative. I don't have companies. I'm not making money off this. I definitely don't mention companies. And the reason is that my name and Harvard are used all the time, unfortunately, to sell products. And Harvard gets very upset. So do I.

So I'm not to mention products. But I will tell you in general what to look for, and I also explained a bit in my book that you want high quality supplements, which means that the resveratrol should be gray or white in color, not brown. 

The next one I take is NMN, which is what's called an NAD precursor. And we haven't talked about NAD today, but NAD is the fuel for sirtuins. Without it, sirtuins don't do any of their job. They don’t spool up the DNA. As we get older, we think we make less and less of this NAD. And we need NAD also for life.  Mitochondria need it to make energy, for example. I supplement with – What is it? About 750 to a thousand milligrams of NMN every morning as well to boost my NAD levels up. Now, that’s some proven – There haven't been a lot of clinical trials with NMN yet, as supposed for resveratrol, where there’s a pretty good literature. So it’s still – I'm giving all the caveats. So I’m a scientist after all. But I am doing clinical trials with hospitals around Boston to test this. And for the last two years, we've never seen anything that's being a worry in terms of safety. So I feel quite comfortable talking about it. 

The other kind of things I do, let's say I do the usual aspirin, which I'm now convinced is protecting against many types of cancer. You just have to careful to get the coated ones. You don’t want to hurt your stomach lining in the long run. What else do I do? I take a metformin, you mentioned. Metformin is a severe – Well, not severe. It's a potent molecule. It's used to treat type II diabetes. It's a derivative of a molecule out of a French lilac client. It's been used in millions of people and it's very safe in general, but it's not 100%. So you got to be careful if you take it. You could get lactic acidosis, which could damage your body. 

But in general, it's pretty safe. But it also requires a prescription. So you need to talk to you doctor. I’ll tell you ahead of time that most doctors are not happy prescribing metformin to a young or a healthy individual. They’re trained to wait and to actually get type II diabetes. And as soon as you cross that threshold, they’ll give it to you or prescribe it. 

I get frustrated. I understand where they’re coming from. But still, it is frustrating that metformin is so safe, so cheap and can prevent type II diabetes. But you have to get a disease for most doctors to treat the symptoms. Anyway, good luck with your doctors there. Not much we can do about that at this point. But I'm trying to educate doctors that metformin looks like one of the best molecules for delaying diseases of aging in tens of thousands of people that have been looked at with type II diabetes that turn out to be relatively resistant to cancer and heart disease, and frailty, and Alzheimer's even compared to those who never had type II diabetes, which is quite an amazing proposition. 

I'm trying other things. Alpha-lipoic acid is something that's used in mitochondria. I take that. I’m on regular drugs. I’ve have had high cholesterol most of my life since I was in my 20s. So I take Lipitor. Much to the chagrin of Joe Rogan who thinks that I might be hurting myself. But I've got a condition. So I have to do that. But to compensate, you should know that should be taking CoQ10, the soluble form of it, because you can deplete your CoQ10. Without CoQ10, your mitochondria are a less effective. Actually, without CoQ10, you’re dead. But you don’t want to be depleted in it at all. That some of what I do, but what I've found is that combination of the first three, metformin, NMN and resveratrol really had a big impact on my body. I measure my body as a scientist should to see what's happening, especially if I’m going to talk about it in my book and on podcast. It's really been quite beneficial to my body. My cholesterol levels have never been better. My bad cholesterol, actually, it's lower than my good cholesterol. I still can't believe it. HDL levels are usually a fraction of your LDL, and you try to get them closer at a ratio of five or less. I have a ratio of less than one, which is quite a thing to think about. 

[00:47:32] MB: Some great suggestions, and obviously, again, all of that with extreme caveats. And read the book, because it actually goes much more detailed explanation of the science, the warnings, all the things you should pay attention to. So don’t just jump in to the ship without doing a little more homework, but those are some things that I'm certainly going investigate and see if it makes sense to get into.

[00:47:53] DS: There’s another thing I want to say. It's good point. Thanks, Matt, for saying that. The other reason that you shouldn't just take a list and go with that is that everybody's different. And if you don't understand why something works or measure it, you don't know. I mean, most people are not like me. I would bet that most people listening to this are not Hungarian derived 50-year-old males with ADHD and sleeping issues. That’s me, right? But my microbiome is also quite personal. So it's going to – I think everybody should try things if they’re into it. Do it in a stepwise fashion. Make sure that it doesn't hurt them. Make sure they feel well. Make sure their liver is still functioning well, if not better, and then work up from there. It's really important to know. You don't just take a handful of pills and hope it's going to work. That's not the point. 

[00:48:44] MB: So, for somebody who's listened to this whole conversation and wants to start with some first action step, what would be the first thing you would recommend that they do to begin slowing down the aging process in their bodies?

[00:48:58] DS: Gee! Well, if you’re aiming on only one thing, I would say it would be less often. But importantly, I'm not talking about any eating disorders. I'm not talking about malnutrition. You’ve got to eat well, and you can actually eat about the same amount of calories as normal. But space out the meals and don’t snack in between.

I have a beef with nutritionists who are under – Many of them are under the impression and telling their clients or customers or patients that you shouldn't feel hungry. It's bad to feel hungry. I think that goes against all the science that we have right now. It’s actually good to be hungry. It’s not good to be too hungry. It's not good to be too thin. It’s not good to be deficient in vitamins and minerals, but it is good to feel hungry. 

[00:49:45] MB: David, for listeners who want to find out more about Lifespan, about you, about your work and everything you've got going on, so much interesting stuff that we didn't even get to jump into much of it. Where can they find you online?

[00:49:57] DS: Well, I have a newsletter which comes out every 10 or 15 days now. A lot of it is on the current situation of the world, I'm right in the middle of all of this. Surprisingly, aging is just part of what I do. Lifespanbook.com, lifespan book.com, you can sign up for that. There’re links to my podcast. There are blogs that I've written, and you can get the backdated copies of my newsletter as well, which have all the little tips that you may not find in the book like have a cup of hot water. It actually makes you no longer feel hungry. So those kind of things are all in there. I'm also on social media pretty often with new things that I'm reading over time, including ways to get through the next couple of years with COVID. That’s who I am.

The book, I really encourage people to read it mainly because the people who have given me feedback have said it has been life-changing for them, which is great to hear. But also because it's a really unusual book, and I'll tell you why. I'm a tenured professor at Harvard. So, unless I do something really outrageous, I'm not going to lose my job. So I can take risks. And the risks that I took that most scientists, probably nearly all scientists would not have taken, would be to write a book about the research that we were doing before we published it, right?

You can read about details in my lab and what it was like to discover reprogramming of the body and reset the age of the eye and make nice run twice as far. That's all in the book. A lot of that is only coming out now to the scientific world, and I'm proud of that, because I think that the public has a right to know what goes on behind the scenes. They have a right to because they paid for it, right? My salary comes out of the National Institutes of Health, which is paid by all the taxpayers in the US. So I'm here talking tonight not because I like to hear my voice. In fact, it’s the opposite. But because I love the idea that everybody can get interested in science and learn how to live longer better lives. 

[00:51:57] MB: Well, David. Thank you so much for coming on the show, for sharing all this wisdom. So many great insights and a really deep look at how our bodies age and what we can do to combat that. 

[00:52:09] DS: Well. Thanks, Matt. It's been great being on. 

[00:52:12] MB: Thank you so much for listening to the Science of Success. We created this show to help you, our listeners, master evidence-based growth. I love hearing from listeners. If you want to reach out, share your story, or just say hi, shoot me an e-mail. My e-mail is matt@successpodcast.com. That’s M-A-T-T@successpodcast.com. I’d love to hear from you and I read and respond to every single listener e-mail.

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