November 28, 2019
[00:00:45] Podcast Sponsors
[00:03:26] Guest Introduction
[00:05:38] What does a typical day look like for a scientist at Harvard?
[00:07:56] Dr. Sinclair's method of speeding up the aging process in mice
[00:14:30] Cellular Reprogramming 101
[00:23:24] A device that determines a human genome via a USB connection
[00:25:13] Whether you can predict your lifespan with your current DNA data from 23andMe
[00:29:11] The correlation between protein consumption and longevity
[00:33:17] Podcast Sponsors
[00:36:42] cont. The correlation between protein consumption and longevity
[00:49:17] The effects of NMN on fertility
[00:52:43] Uncoupling proteins, and whether DMP supplements are a good idea
[00:57:56] Resveratrol, stressed wine and fruit, and longevity
[01:03:13] Cancer breakthroughs in which Dr. Sinclair is currently interested
[01:10:21] David's personal protocol
[01:24:29] Closing the Podcast
[01:26:25] End of Podcast
Ben: On this episode of the Ben Greenfield Fitness Podcast.
David: Eyes in those old mice went back in time. And you might say, “Well, that's just a clock. It doesn't mean anything.” But guess what, the cells literally became young and functional as though they were young again. No one knows exactly the best path to longevity. So, what I'm going to tell you is my best guess currently based on having read thousands and thousands of papers and worked on this my whole life. I've never hesitated before, but this is really key and I wanted to make sure everyone who's listening gets it.
Ben: Health, performance, nutrition, longevity, ancestral living, biohacking, and much more. My name is Ben Greenfield. Welcome to the show.
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Hey, folks. It's Ben Greenfield, and I was actually just telling my guest on today's show that probably he's one of the most requested guests that I have really had folks reach out to me and asked me to have on the show over the past couple of months. So, I figured, what the hell, it's high time, I actually got this cat on and picked his brain about all things anti-aging and longevity because that is his forte. He just wrote a book called “Lifespan.” I have the book right here with me. It's dog-eared, plenty of pages folded over. And I always love to be able to dive down into the deep dark rabbit holes I discover within a book whenever I manage to get somebody like this on the show.
And he's really considered to be a leading world authority on longevity and genetics. He's been researching this stuff for a long time. He has a lab at Harvard and all of his research is primarily focused on everything from genetic reprogramming to discovering these genes that may assist us with longevity and the ability to be able to increase both our lifespan and our health span. And as he writes in the book, aging is a disease. That disease is treatable and he's on the cutting edge of making that happen. His name is Dr. David Sinclair, and in addition to everything I just told you, who's actually named as one of times most influential people. So, that in and of itself is an honor. And David, welcome to the show, man.
David: Ben, thanks for having me on.
Ben: Yeah. I'm super stoked to talk to you just because, like I said, so many people are interested in this stuff. And as you probably know, it's something that seems to be taking the world by storm, this whole idea of how to stop aging, or as you say in the subtitle of the book, Why We Age—and Why We Don't Have To. So, I'm just curious though, man, before we dive into some of the goodies within the book, for you as a Harvard scientist, I'm just kind of curious what a typical day in the life of David Sinclair is like. So, what does your life look like? Are you just spending time in a white lab coat poking needles into mice all day, or what exactly do you get up to?
David: Yeah. Well, there is no typical day. I do maximize what I'm able to do during the day with one mission in mind besides being a good father and husband, and that is to leave the world a better place and I found it. Sometimes I get under the skin of my colleagues because I'm not a typical scientist. I do spend a lot of time in the lab and with students. I teach them. We've got also about 15 companies that I'm helping to run, and I've started. I lecture around the world and chairman and adviser to a bunch of companies. I'm an entrepreneur and I keep myself busy.
So, a typical day would be either being in a lab, or being on a plane, or giving a lecture somewhere, or writing a book. These are all the things that I do, but one thing I think you and your listeners will find interesting is I try not to waste a second of my life. My grandmother who co-raised me with my mother said that my job is to leave the world better. Then I found it and I took on aging and changing medical practice as best I could, which is a big thing. It's like saying, “I'm going to go to the moon in 1920.” And that takes a lot of effort. It's not easy. I've had a lot of ups and downs in my career. There's a lot of people who say that this is a fool's errand or think that there's no way we can keep publishing in the world's top journals without making stuff up. And that all hurts when colleagues say that shit, but I'm actually proud to say that I've maximized my life so far and I'm not [00:07:44] ______ to slow down at all.
Ben: Yeah, yeah. You definitely seem to be all over the place. So, kudos for that and for pursuing to keep yourself put together pretty well in the process. And actually, in the book, you delved into a little bit of your own personal anti-aging protocol, and I definitely want to get into that later on, but I just think the back story of how you discovered some of these vital takeaways when it comes to aging, it's pretty intriguing. And I think one of the things that really left out to me in the book as I was reading early on in it was not the idea of slowing down aging, but the idea of speeding it up and what we can learn from that in the book. You talked about how you figured out how to make mice age more quickly. Can you get into that, like what did you do to actually make ice or make mice rather get super old super-fast?
David: Well, I have a theory on aging, which is that it's not the DNA that changes as we get older, so much as the ability to read the code. And essentially, what's happening we think is that the loops of DNA that allow genes to come on when we're young get lost, and that program actually gets messed up. We call this the epigenome. And one of the things that causes this unraveling of the DNA and cells eventually losing their identity and checking out of the system and causing us to age, one of the main drivers is a broken chromosome. And what that causes the cell to do is to freeze, to have to unravel a lot of its chromosomes to try and respond to this threat. They stick the DNA back together and then they have to repackage everything back to being young again. And they don't do that very well, we don't think.
To test this hypothesis though, we need to break [00:09:40] ______ some DNA. And so, we created a mouse in the lab that we could turn on a DNA cutting enzyme so that we could cause this to happen and ask if we were right or wrong. And as a good scientist, you're always trying to prove yourself wrong. And if you can't, then [00:09:58] ______ says you might be right. And so, what we expected to happen was that we'd get aging, and that's exactly what happened. And when that happened, that was now 10 years ago, it was quite a remarkable thing to see. We have mice in the lab that we've been studying where you can, if you came to the lab, then you'd see that the mice have wrinkled skin and every organ in their body is essentially old.
But here's the important thing. Just a few years ago, researchers realize that you can take a mouse's DNA–in fact, I could take your DNA and tell you exactly, well, within a few percent error, how old you are biologically without hand waving, without just saying, “Oh, that looks like an old blood or an old mouse. So, we did that to these mice and they don't just look old, they are literally 50% older based on this measurement of that chemical that accumulates on the DNA and causes the cells to, we think, get old.
Ben: So, do you have to actually create a special mouse, or can you take any mouse and do this? Like, do you have to make that mouse susceptible to being able to go in and alter its DNA from the get-go?
David: Right. These have to be genetically altered mice that we've made from cells. So, we start with stem cells in which we engineer them. And so, they're born normal. They're quite happy, healthy, and then we've engineered them so that we can feed them a drug, just an antibiotic or some other molecule that's harmless, but it turns on this program. And we turn it on when they're young, and they don't feel it. It's like getting an x-ray, breaks the DNA, they heal. We switch it off after three weeks and then we just let time take its course. And what we see is that they're aging 50% faster having set this, what we think is an epigenetic program. The best analogy I could–well, one of the analogies I can give is a DVD. It's when you're young, you put it into a player, it can read the movie or read the music. But if you scratch it up, it's going to have trouble, and that's what we've done to these mice, we scratch their DVD.
Ben: So, the only way that you age them was to basically affect their DNA specifically?
David: Well, we didn't create mutations, so the information should all still be there in the genome, but the ability of the cells to read it was missed and the cells eventually forgot what type of cells they were. And we think that's what aging is, the cells forgetting their identity.
Ben: Okay. And that would be due to DNA damage?
David: Yes. It's not the only driver, we think, but it's a major one. And what the broken DNA does is it distracts the proteins that read the DNA, and they go to help with the break and get distracted, but then they don't always go back to where they came from. And over time when you do this over a lifetime, which happens in every cell at least once a day so it's 26 billion times in your body every day, then it accumulates. Much like if you unwrap a present, you can re-gift it a few times by rewrapping it. But if you try to do that thousands of times, it's going to look really messy.
Ben: Okay. So, basically, what you're saying is with these mice, you didn't take out their mitochondria or alter their mitochondria, you didn't affect the telomeres in any way, you didn't take out stem cells or nuke stem cells or anything like that, all you did was make a change in the DNA that cause the DNA to become slightly damaged, and that's what caused them to age. I think at the book, you said like 50% faster or something like that.
David: Yeah. So, there are various hallmarks about aging, mitochondrial dysfunction [00:13:49] ______. But what we found is if we disrupt the epigenome in the way that I described by cutting [00:13:56] ______ but not mutating it as far as we can tell, then the other hallmarks come as a consequence. So, what we're arguing with this theory, and it needs to be challenged and tested, and there's going to be a lot of people who try to prove us wrong, is that this is a very upstream cause. Essentially, what I'm saying in my book is aging is due to a loss of information over time, and you can accelerate that loss by cutting DNA, damaging it. But it's not the DNA itself that's the problem, it's the packaging of the DNA that tells which genes to read at what time.
Ben: Okay. So, taking this scratched DVD analogy forward, you get in the book into this idea of cellular reprogramming. It's kind of like the opposite strategy, like how you would actually fix this DNA damage. And I found this to be really intriguing. Can you fill folks in on what cellular reprogramming is and how that works?
David: Yeah. The Nobel Prize in 2012 was awarded to a Japanese professor whose name is Shinya Yamanaka, and he discovered what are called Yamanaka factors. These are genes that come on when we're baby actually earlier in embryos, and they instruct cells what to become. And it turns out if you take skin cells or really any adult cell from the body of a person or an animal, you can reprogram cells to be really young again. In fact, so young that they become stem cell, old reprogramming, or IPSCs to generate, induced pluripotent stem cells.
That was a great discovery, deserved a Nobel Prize, but no one in their right minds with a few exceptions, this lab being included in that camp, thought that it would be sensible to try to reprogram an animal, right? What are you going to do, create the world's biggest stem cell pool or giant tumor? It seems very safe. And in fact, the first experiments to try this were done in a lab at the Salk Institute in San Diego. And they actually ended up finding that the mice didn't survive for a couple of days after turning these genes on, which probably would have ended there if it weren't for their tenacity, and they realized, or at least they hypothesized that if they turn those reprogramming genes back off and let the mouse recover, and they repeated that every week, then they could have a mouse that wouldn't die. And what they found was that this short-lived mouse strain that they had in a lab, it lived about 30% up to 40% longer by turning on these reprogramming genes.
Now, scientists are always skeptical. That's our job. And a lot of people said that that's just a bunch of BS because if you make any mouse die every week, it's probably [00:16:48] ______ longer. We call this hormesis. Anything that doesn't kill you makes you stronger. But, we've been working on this theory for more than a decade and it made perfect sense to us that this was right. We'd been already trying to figure out how to take the age back [00:17:05] ______ using these factors and we hadn't made a lot of progress because of the toxicity.
But the real breakthrough came when a student of mine, [00:17:14] ______, he decided to leave out one of those four genes. And one of those four turns out to be toxic. It's called MiCK, and it also is known to drive cancer. So, when he left it out and tried reprogramming an animal, he found out that it didn't cause cancer, it didn't kill them. Actually, the mice in the tissues that he tested in got younger. He could actually measure the clock of those tissues. And in this case, the experiments were done on the eye, that the retina of the eyes in those old mice went back in time, and you might say, “Well, that's just a clock. It doesn't mean anything. It's like a clock on the wall. If you turn the clock back, it's not going to actually change time.” But guess what, the cells literally became young and functional as though they were young again, and all the genes that were supposed to be played or turned on when the animal was young went back to how they were. And so, the mice that blind when they were old were able to see again after we reprogrammed their nerves.
Ben: How's the Yamanaka factor, these three, not the one that causes cancer but the other three that you talked about, how are those actually working? Is it fixing DNA damage or is it via some other mechanism?
David: Yeah. It's not, as far as we know, fixing DNA damage. Let me use another analogy that I think will be useful here. Think of the genome as a piano, but instead of having 100 and so keys, you've got 20,000. And when we're young, [00:18:50] ______ how the piano player can play or read note perfectly. And then as we accelerate aging in my lab or as we just live our daily lives, there are mistakes played. And eventually, it's just a complete cacophony of ROM notes being played. So, it's not fixing the piano, we're fixing the player, okay? And so, these reprogramming genes, what they do is they help the pianist remember what the concertos should sound like. And when we do that, these are the three genes that instruct other genes to reverse the program. And I'm hesitating here because I don't know how technical to get. And usually, I don't ever hesitate.
Ben: Yeah. You can get technical. I'll reel you back if I need to.
David: Well, I've never hesitated before, but this is really key and I wanted to make sure everyone who's listening gets it. Those loops of DNA that I talked about, that tell a cell whether it's going to be a skin cell or a brain cell. As I mentioned, over time we lose that structure and cells lose their ability to read the right genes the right time. There's a chemical modification on the actual DNA that instructs the cell as to what that program looks like, which genes should be on in the brain and which genes should be on in the skin. And those change over time in very predictable ways so much so that I can read those what are called DNA methylations and say exactly how old that person is within a few percent error. And in fact, tell that person when they're going to die in at least predicted–not if they're going to cross a busy street and get hit by a bus, but essentially, I can say when all of the aging are going to come crashing down on that person.
Ben: Wait, so you could project, like you could look at my DNA methylation patterns and tell me, “Yow, Ben–” for example, “David, I'm 37 years old.” You could say, whatever, 47 years from now, that's when enough of this DNA methylation issues or DNA damage is going to accrue to the point where that's when you'll kick the can?
David: But it's not DNA damage, all right? It's DNA modifications that change. And they change we think in response to this DNA damage response. And we know this because in those mice that we aged with DNA damage, they accumulated this crust on the genome. We can even do this in the dish. We can grow cells, we can damage the chromosomes, and then we see this cross this methylation accumulate. And based on that, we can say those cells are actually older than they were the day before by a lot. But it's really interesting because then we can ask the question, “Are those reset eyes? Are those retinas that we've reprogrammed?” They might be healthier and the mice can see, but are they unambiguously younger? And the answer was yes, they are.
Ben: Wow. Okay. So, this test that you're talking about to be able to predict how old somebody's going to be when they die, is that something that's currently available? Because I've interviewed Dr. Bill Andrews from Sierra Sciences about telomere testing, and that seems like a very rough approximation of biological age. But what you're talking about sounds way more precise.
David: It is and there's a fellow who–his name is Stephen Horvath. He's the namesake of this test, so it's also called the Horvath clock, or you could call it the epigenetic clock. It's much more accurate. We use machine learning in my lab and in his lab, too, say which of these crusty areas are important to predict age, and it's very accurate. It's revolutionizing our ability to study aging because it's–for once, it's very accurate. And you can even use it to tell the age of a piece of somebody if you find them in a forest. I don't want to be morbid, but it is Halloween over here in the U.S. But also, I've just heard yesterday someone in my department is looking at old bones thousands of years ago and they seem to be able to tell how old that person was when they died, too.
Ben: So, can people actually get this test? Is this commercially available?
David: I'm aware of at least one company that's trying to commercialize this in the U.S. I'm also working on this with Stephen Horvath to see what we can do to make this available because he and I are asked every day if people can have this test. The one thing that we're working on that will really help is to reduce the cost. Right now, it's at least a few hundred dollars, probably closer to $1,000 retail to do this. But I'm holding in my hand right now a DNA sequencer that's about the size of a candy bar.
Ben: Oh, is that the mini ion one that you talked about?
Ben: Okay. How's that work?
David: Well, I'm opening it up. Okay. And inside, there's a little cartridge that you put in, and you squirt the DNA into that, close it up, and you plug it into your computer, it's a USB connected, and it will pull your DNA through millions of little pores in a membrane. And the DNA is streaming through there very rapidly that a membrane can tell you whether it's in A, T, C or G, and even whether there's a methyl on there. And so, very rapidly, we can run your DNA through this little device and tell you your entire genome, and how old you are, and when you're likely to die.
Ben: Holy cow. I assume that's not something somebody could just like buy on Amazon.
David: No. You can buy it, I think. It's commercially available, but this thing I think will set you back tens of thousands of dollars at this point. Eventually, it'll be cheap. It shouldn't be that hard disposable cartridges, probably. What we're working on in my lab is to bring the tests down to about $5 a pop. I've got a couple of people in the lab who are making some good progress there. And then we can have ourselves tested every few months if we want to see how we're doing.
Ben: And when you say you're squirting your DNA into it, are you talking about like a blood spot?
David: Well, yeah. You need to purify the DNA. And so, there's just some little kits that you can–first, you have to prepare the DNA a half an hour and then you squirt what's left into there. So, that's what pure DNA sample goes in.
Ben: Wow. That's fascinating. Now, for people who may not have access to something like that, are there–because a lot of people will test, for example, on 23andMe. Some people even do the whole genome sequencing, or at least more SNPs than what 23andMe is looking at. Could you take your genetic data, like if somebody's listening in and they have their genetic data, and go and look at specific genes that might at least help to predict the potential for accelerated aging or the potential for increased lifespan?
David: Yeah, you can. There are a number of genes that are believed to control how fast we age, and many of them come from studies of worms and flies and yeast cells. There's one called FOXO3, which seems to predict some aspects of longevity, and I've got one good copy and one average copy. My wife the same and our two girls actually inherited both good copy. So, all things being equal, they could live longer than we do. And anyone can take that test and have a look, 23andMe or one of the other companies that does that.
But before everyone rushes and says, “Oh, that's essential for me to know about my future,” bear in mind that longevity is only 20% genetic and the rest is up to us how we lead our lives, which to me tells us that the epigenome, the reading of the genome is probably more important than the actual variation within our DNA.
Ben: Now, that FOXO3 in terms of what someone would look for if they were looking at that, you say that you would want to have a certain variant of it. Would that be like a CC versus a CT versus a TT, or what would people actually look for?
David: Yeah, that's right. You want to see a particular letter at that spot. Now, I don't remember exactly where in the genome it is among the billions of letters. I did mention it in my book in how to look that up.
Ben: I wrote it down, it's RS276426.
David: Okay. So, Ben, have you checked yourself?
Ben: No, I haven't. And I was waiting until I talk to you to spend any time doing that, but basically, I would want to look for a CC at position RS2764264, and that would indicate that if I have to seize at that position, then I could have a greater odd of living a longer time.
David: Yeah, exactly.
Ben: Cool. Okay. Interesting. What do you think about those telomere tests, by the way?
David: I think what you said is the right thing. There's no consensus in the field and there are a lot of skeptics that telomeres play a major role. I think that the truth is somewhere in between that telomeres play a role. Those tests though, like you said, they're highly variable and they change often. And even from week to week, month to month, you can get different results, which is why instead of using telomeres in my lab, we have switched to this DNA methylation clock.
Ben: Okay. Got it. Interesting. Well, I can't wait to see these aging clocks become more available. I did go down to San Diego at one point a couple of months ago and they actually ran a bunch of aging clock measurements on me that I think are similar to what you're talking about. I didn't get the results back or anything like that yet, but yeah, it does seem like a lot of this stuff just isn't that commercially available or at least financially palatable for a lot of people yet.
But you referred to something obviously very profound and important a few moments ago when you said that only, I think you said 15% or 20% of our aging potential is related to genetics, and the rest of it is epigenetics, our lifestyle and the type of things that we do or we don't do. And you actually have a lot of things in the book that you discuss that could influence this pretty dramatically. And one of the first things I want to talk to you about was this idea of amino acids. There's a lot going on right now with like the movie “Game Changers” and the back-and-forth about red meat, about amino acid restriction, or at least methionine restriction and branched-chain amino acids, et cetera. And I'm curious to hear your take on amino acids and meat restriction or anything related to protein and longevity. Have you studied this in your lab at all?
David: Somewhat, somewhat, and I have a lot of friends who've studied it, and I've studied their work. Here's the big picture to think about. What we're learning with longevity is that there's no one particular daily diet that you should stick to. What's better at least based on all these animal studies is to mix it up. Okay. You don't want to say, “Every day, I'm going to eat this and this and this” and repeat that 1,000 times. It's better, we think, to be hungry for periods and then eat, and then try diets for a few days and then switch it up.
But I'll tell you there's a general rule what we think we're learning. First of all, anyone who says they have an answer and knows 100% what the right thing to do is lying or BSing, okay? No one knows exactly the best path to longevity. So, what I'm going to tell you is my best guess currently based on having read thousands and thousands of papers and worked on this my whole life. I try to avoid eating a lot of meat. Now, I know Joe Rogan and others don't like this news, but I'll tell you why I do that. The meat contains a lot of branched-chain amino acids, and in general, a lot of amino acids.
And there's a defensive pathway in the body called mTOR, which senses in particular branched-chain amino acids. And when they're abundant, the goal of that pathway in the body is to build muscle and grow, which is why bodybuilders prefer to drink things that have a lot of branched-chain amino acids into them and eat meat that's natural. But we think that comes at the expense of long-term health. mTOR is actually this genetic pathway that you can find even in yeast cells and worms and flies, and it's the most potent pathway to extend lifespan. When you have a mouse that doesn't have a lot of mTOR, it'll live longer. If those mice are given a drug that inhibits mTOR activity, they will live longer. And even humans that are elderly who take low doses of rapamycin have this boost to their immune system that indicates they might be getting youthful.
If you're always eating meat and a lot of it, you'll have the opposite effect. You'll be switching off your body's defenses against long-term health. So, that's why I rarely eat a steak and I try to focus on plant-based aminos where they're large abundance of these branched-chain amino acids. But there's one more thing that I wanted to mention, which I read this morning. You asked me what has my day start. I didn't actually tell you a typical day, but most times, I'm reading scientific papers starting at around 6:00 a.m., and that was true today. Today, I've read that there was a study out of Australia that showed that at least in mice that these branched-chain amino acids, they don't just mess up your mTOR, they also mess with your brain and make the mice hungry. They change the serotonin levels. And the mice that ate a lot of branched-chain amino acids became obese and lived shorter lifespans unless they were restricted in their calories. So, I would say if you're eating a lot of meat, try to avoid eating a lot, and you could probably counteract that by being hungry.
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I've never been a fan of BCAAs particularly due to the high amounts of leucine because the only three amino acids you're getting in a BCAA supplement or compound is leucine and isoleucine and valine. Leucine, I know, in particular, is a big-time contributor to the activation of this mTOR pathway, but they're also not that great, in my opinion, at maximizing muscle protein synthesis or anything that people are taking them for because they really are only a small set of the building blocks that would be necessary for, say, something like muscle gain, or recovery, or muscle protein synthesis.
And so, I'm not a fan of them from the get-go, but I think one of the other amino acids that isn't part of the BCAA complex is methionine. And I know that there has been research showing that methionine restriction is associated with longevity. In my opinion, the big problem with a lot of these people who are doing a meat or a carnivore-based diet is they're getting massive amounts of methionine in the absence of glycine, which you'd get from eating a properly structured nose-to-tail type of meat diet that includes a lot of organs, and bone marrow, and bone broth, and some of these glycine-rich sources that balance out the massive amounts of methionine from a meat-only diet. Have you looked into like methionine-glycine balance or anything along those lines, or what happens if that higher intake of methionine is actually accompanied by something like glycine?
David: Yeah, not since I was a kid doing my Ph.D. I was working on genes, discovered genes actually that process glycine. But I haven't looked at it in the context of longevity. Now, the methionine is really interesting. We have looked at methionine restriction and we've found that it does slow down frailty, it keeps animals much healthier for longer, but exactly the ratio. We haven't messed with that yet. So, it sounds like something we should be focused on.
Ben: Yeah. As a matter of fact, I'll try and find a link to it and I'll put it in the shownotes, which are going to be, by the way, for those of you listening in, at BenGreenfieldFitness.com/sinclair, S-I-N-C-L-A-I-R, BenGreenfieldFitness.com/Sinclair. But my friend Chris Masterjohn, who's a pretty smart nutritionist, he actually put together a whole database of methionine versus glycine in different foods. And in that database, he actually gets into some of the effects in terms of balancing that excess activation of mTOR when methionine is balanced with adequate amounts of glycine.
So, I think that that's part of the key here is just like you wouldn't want to take a whole bunch of unopposed leucine in a BCAA type of compound, like a lot of bodybuilders and fitness enthusiasts do. And it said balance out your amino acids. The same could be said of methionine. You'd want to balance it out with glycine and not do this deal that a lot of people on the meat bandwagon are doing, which is ribeye steaks from Costco for breakfast, lunch, and dinner.
David: Right, right. Well, so I take various sources of glycine, trimethylglycine is one, and that's to just make sure that I'm not depleting my body of methyl groups. And there are various things that I'm doing that run the risk of doing that, and so just as an abundance of caution I'm taking. So, trimethylglycine, Ben, you probably know, listeners may not, that it's also called betaine, and it's been shown over many cytoprotective cells. It's a good source of one carbon, they called, for metabolism. And I don't see any evidence that they aren't going to hurt. And so, in an abundance of caution, I take a little bit of that stuff.
Ben: Yeah. Trimethylglycine or TMG or betaine, and then also, S-adenosylmethionine, I think is the name for that, the SAMe. The interesting thing about those is that both of them when supplemented in correlation with something like NAD, which actually I want to ask a little bit about, they actually–if you're getting like an NAD IV, for example, which a lot of people are doing nowadays, it completely eliminates all of the discomfort, all of the flushing, any of those negative reactions you feel when getting an NAD IV completely disappears if you just take something like oral trimethylglycine beforehand.
David: Yeah. That's super interesting.
David: That IV NAD, I haven't studied it and I'd be curious if you've actually seen some clinical data, a lot of anecdotes people ask me about. I'm taking oral NAD supplements or NAD precursors as supplements with–this is based on my lab's research. If anyone has ever done a search of me on the internet knows that there are thousands of companies using my name and my research to sell products, which I don't do, by the way. But yeah, I'm very interested in NAD supplementation to keep the sirtuins active. So, sirtuins are part of the epigenome regulators that I think prevent the scratches on the DVD of life. And so, I'm trying to make sure that they're always as active as they were when I was young. And we think that in many tissues as we get older, the NAD levels, they're essential for biochemical reactions and these sirtuin protectors to work. They decline, these levels decline as we get older, and the best we can do is if we don't take supplement, exercise helps, fasting seems to help, but [00:42:40] ______ really is the only way to keep those levels high.
Ben: Yeah. It's interesting. I think the form of NAD that I've heard you discuss, you use is NMN, like oral NMN. Is that correct?
David: It is. And please don't confuse that with M&M's. You'll get the opposite effect.
Ben: Well, it is close to Halloween.
David: Yeah, yeah. Well, if you have M&Ms, maybe NMN will counteract on that. What NMN stands for is nicotinamide, which is a form of vitamin B3. And then the M is mononucleotide. Well, and the M and N is the mononucleotide. In any case, it's a complicated name for a very simple small chemical that our bodies are making all the time and turn into NAD. And NAD, as I mentioned, is critically dead without it in 30 seconds. But it's not just important for turning on sirtuins, it's also important for the body's clock.
And often I'm asked about sleep, actually. Is sleep connected to aging? And it absolutely is. Sleep will change the cycle of NAD in the body, and vice versa. We believe, through mouse experiments, that the NAD cycle is contributing to our [00:43:58] ______ clock. And that if we get older and the disruption of the NAD cycle maybe I think is one of the reasons why older people have trouble sleeping.
Ben: That's interesting. Now, I know that there is some effect of NAD. And from what I understand, you might know this, but supposedly, nicotinamide riboside and NMN, those can't actually cross the blood-brain barrier. But NAD is apparently able to enter the hypothalamus intact and have a lot of effects on neural function and the hypothalamus. For that reason, to me, it seems prudent to include something like NAD supplement or NAD IV in addition to something like NMN or NR. So, you're getting kind of the best of both worlds, the effect of the latter on the body and the effect of the former on the brain. Now, when it comes to sleep, do you think that using something like NAD because it can cross the blood-brain barrier would actually be beneficial for sleep?
David: It might be. We've been studying NMN for close to 10 years now. We don't have any evidence that it has trouble raising NAD in the brain. And so, I think that it can work. Now, maybe IV NAD will be better. I don't think we know that. What I'd love to see, but unfortunately it's expensive, is to have a head-to-head clinical trial of NR, IV NAD, and NMN. And then this would, hopefully, settle all of the disputes and discussions that are being had about which molecule was better.
Ben: Yeah. You mean like compare IV NAD to oral NMN?
David: Right, right. I haven't studied IV NAD. What I can tell everybody is that we've been doing clinical trials on NAD boosters for a long while and I have a front-row seat on all of this, and a lot of it's not yet public information. But taking a pill of an NAD precursor like NMN can raise NAD levels in humans. Of course we're not extracting the brain, so I couldn't tell you if that happens. But I would recommend anyone who's reading about this to be suspicious of people who are selling things, and even scientists who have ownership in companies that sell products because they may be great people, but you want to have somebody who has no conflict of interest here. It bugs me that there's this discussion between people who have something to gain from all the–any supplement [00:46:50] ______.
Ben: Yeah, yeah. That's a good point. By the way, the paper that I saw on this, it was by Roh, R-O-H, in 2018, and it was titled Exogenous nicotinamide adenine dinucleotide regulates energy metabolism via hypothalamic connexin 43 or C43. And that was the paper in which I think they use labeled NAD via IV and showed that it crossed the blood-brain barrier and entered the hypothalamus intact in mice and had a lot of effects on things like hunger and energy expenditure and fat burning in mice. And I think they said NR and NMN or N–now you've got me on the M&M kick, the NMN couldn't act in the same fashion. That was the only paper I saw that actually looked into that.
David: Yeah. Yeah, I remember that paper. There have been a couple and more I know that are coming out looking at labeled versions of these molecules to trace where they go. And it's very complicated, actually. The gut will mobilize or metabolize some of these. They'll be taken up by different cells, different transporters. What it'll eventually settle out in my prediction is what always happens in science, is that everybody's a little bit right. The brain will take up NAD potentially better than others, but these other molecules also work, and that NAD is also broken down into these other things and then taken up.
Right now, all I'm saying, Ben, right now is that I know in mice that if you give them NMN in their food or down their throat, they will increase their brain's NAD. This IV NAD itself, I don't know. The other thing that's worth bringing up before we get too stuck in the weeds if you give NAD to neurons today, we'll take it up, whereas many other cell types don't have that capability. First, they have to degrade it and then bring it inside and remake it. And that's often forgotten that there are some cell types that can easily take up NAD. I hear too many scientists saying one blanket statement about the body, and the body is made up of thousands of different cells, and they all behave somewhat differently. There's no one statement that ever proves to be correct.
Ben: Yeah. But there was one interesting takeaway from your book. I think you did this with NMN, and that was looking at the effects on fertility. I found that to be really interesting. Can you talk a little bit about that research on NMN and fertility?
David: Yeah, yeah. This result gets other scientists upset because it goes against what's written in textbooks that nobody wants to rewrite the textbook. It's a lot of work. What we've found was that one of the sirtuins, so there are seven of those sirtuins in our bodies, the one that's called number two, SIR2, actually regulates cell division and make sure that chromosomes are equally segregated between the two cells as one cell divides. And that's very important of course to prevent cancer, but the other thing that we figured out is this role of SIR2 and NAD levels that's essential for producing healthy eggs in female mice.
And what we then eventually showed, and we've now put the paper online if anybody wants to try and check it out, you can find it, is that if you maintain the NAD levels or restore the NAD levels in the ovary, you get much healthier eggs in female mice. And we have some data that is so controversial that some of my colleagues did not even want to publish it, and that is if you destroy all the eggs with chemotherapy of a mouse and then give them NMN, you can find that there are healthy eggs and they can actually breed again. And that goes against all of biology. So, we need to do more work before some of my colleagues are willing to put that out there.
Ben: It's really interesting though because–I mean, if that's true, if it can restore ovarian function, then older women who are trying to conceive could theoretically use something like NMN to boost the activity of that SIR2 enzyme and actually get healthier eggs similar to the research that you did in mice?
David: Yeah, it's true. And I have to be careful because I'm here at Harvard Medical School and I'm not supposed to overstep any conclusions. And so, I would say that in mice, it looks promising. We've done a small study in horses, old horses, and that looked promising. What I do is I try to make medicines that are proven to work rather than just hoping. And so, I've started a company in Australia called Jumpstart Fertility, and they're working on making medicines they've worked for about four years now to test if this is true. And I think if anyone's going to make this breakthrough for women, it's going to be them.
Ben: Yeah. It is really cool because I think a lot of women are concerned about the health of their eggs when they're 35, 40 years old, maybe thinking about having another baby. And some of this research on NMN, I think it's very interesting with regards to that. There are some other things I wanted to talk to you about, and one I have a particularly fascination with and practice it daily, and that's this idea of cold thermogenesis. I take a cold shower typically at the beginning or the end of the day. I just worked out in my gym this morning out here in Spokane and I keep that thing at about 35 degrees in the winter. So, I'm basically working out in a giant cryotherapy chamber.
And a big part of that is because I want to upregulate my brown fat production, just because it's so rich in mitochondria and because it can decrease with age. And you talked a little bit in the book about this uncoupling protein that we actually find in something like brown fat. And the fact that there's actually something that is almost like a supplement that I know gets talked about in the anti-aging sector, over on Reddit and some of these underground forums is something that could speed up this conversion even more called DMP. Can you explain a little bit about uncoupling protein and DMP, and if you think this is something that people should look into using or not?
David: No, don't use it. That's the first thing.
David: Definitely don't try it. It's extremely toxic. And there have been deaths caused by trying this.
Ben: Oh, wow.
David: But I'll explain how it works and how I think the future looks. So, the mitochondria are the power packs of the cell. They work by having a chemical gradient between membranes. But essentially, what you can think of as the way these mitochondria make energy, it's similar to a hydroelectric dam, and the water is running down and generating energy. Now, you can circumvent that by poking holes in the dam, or in this case, you make the membranes of the mitochondria leaky, and then they can't make as much chemical energy.
That's what DMP does, and DMP was all the rage in the 1930s. People thought it was the end of obesity. There were millions of pills sold with people losing weight. The problem with poking holes in a dam is that if you do it too much in the body, it generates a lot of heat and it's also fatal. And overdoses led to this product being banned, and it was one of the reasons that the FDA Act was written in the first place was to stop drugs like this from being sold. So, metabolic party didn't last very long and obesity, of course, is now the scourge of the planet. Unfortunately, DMP is off the table.
So, what's the good news? Well, the good news is that you can uncouple–we have proteins that do this naturally, you can boost the levels of uncoupling proteins by being cold. And so, Ben, what you're doing I think is very good for doing that. And actually, building up brown fat is one of the best things you can do for metabolism. There are even whole companies that are based on this trying to find chemicals that'll do it. But just being cold, very cold will do this. I dump myself in a cold bath every weekend after being in a warm sauna and hot tub. And if nothing else, I feel great afterwards. It was actually our friend Joe Rogan who put me onto this. He took me to one of the cryochambers and that was fantastic.
Ben: Oh, yeah.
David: So, getting back to the biology, you want to stimulate these uncoupling proteins. But I think we can do better. I don't think everybody wants to be cold. It's not that pleasant. I don't find it great just sitting in a cold bath every weekend either. So, we're working on a drug that we hope will be able to be as helpful as DMP, but with none of the toxicity. And I'm working with a couple of chemists who have figured out a way to make DMP safe, and it's actually chemicals that haven't have an off safety switch so that even if you were to overdose, it should be fine. And we're finding in animal studies that these mice burn fat. They become thin, they don't get diabetes, it reverses their type 2 diabetes. Continuum Biosciences is the company that's working to make these uncouplers a drug that would treat not just fatty liver disease, but could also prevent and treat obesity, and even extend lifespan by mimicking fasting.
Ben: That's fascinating for all the people who don't actually want to take the cold bath or the cold shower or the cryotherapy chamber. I'm basically looking into a few different companies right now that are producing like these done-for-you cold tubs that get shipped to your house that keep the temperature even in ambient temperatures of like 110 degrees Fahrenheit at 31, 32 degrees where you got to like break through the ice to get into the water.
And actually, I'm very excited about this type of approaches because you get all the benefits of cold water immersion, and the mammalian dive reflex, and the vagal nerve activation. And a lot of this stuff you don't even get with like a cryotherapy chamber from this cold water immersion. So, I think it is really beneficial. I'm pretty excited if you're able to come up with a good mitochondrial uncoupling age and it could probably vastly enhance the effects of something like a cold thermogenesis practice like that.
David: Exactly. And also, there's one of these sirtuin genes that we work on. I mentioned number two for fertility. Number three is beneficial in the mitochondria, and it's turned on by cold. And we think that some of the benefits for longevity in animals and maybe ourselves is in part mediated by this SIR3 protective into.
Ben: Yeah. And that's kind of related to something else that I know you've studied up on, and that's resveratrol, and some of these other plant-based compounds that can increase the activation of SERT enzymes, SERT–I guess the protein, not an enzyme, correct?
David: SERT enzymes, correct, yup.
Ben: Okay. Yeah. So, you talked about different forms of like wine and strawberries, but you actually discussed in the book about how we should be looking into using the forms of these compounds that have been stressed, specifically. Why is that? Why would you want like wine or strawberries or wine from grapes or strawberries that have actually been placed under different forms of environmental stress?
David: Well, before we get into that, let me just update everyone about resveratrol. So, resveratrol comes in and out of the media and often people don't know what to think. We first found resveratrol slows aging by mimicking calorie restriction in mice going back over 10 years ago now. And then there was a kerfuffle between–I was sandwiched between a couple of pharmaceutical companies fighting over patents and they were trying to discredit each other. We fought back with science and have resolved the science.
And so, we were right that resveratrol activates the main sirtuin enzyme, SIRT1. And we know exactly how it works down to the molecular level. But that kind of molecular detail doesn't make the news, but I wanted to update everybody. And I've been encouraged that there are more and more clinical trials that, they don't all show positive results, but there are increasing number of human studies that show with blind, double-blind placebo-controlled studies that you can actually mimic what we saw in the mice, which is that you can reduce the negative effects of a high-fat diet and lower your blood sugar levels like a diabetes drug would.
So, with that all on the table, why would plants make resveratrol and why does it turn out to be healthy for us? What I think is going on is that plants are making resveratrol to turn on their own sirtuin enzyme. Plants all have sirtuins. Every life form essentially has these enzymes to protect themselves. It's very ancient thing. But what I think is that we've evolved, or at least I'm proposing, is that we've evolved the sense when our plant supply, our food supply is running out. All right.
We can see this now with conscious beings. We can see that the leaves are drooping or we can measure the soil quality. But if you're a primitive animal, the only way really to know if you're going to be running out of food is to sense the chemicals in the food. And so, what we see is that resveratrol and a bunch of other molecules that are produced when plants are stressed hits certain pathways in the body that make us healthier. And it probably should come as no surprise to remember that most of the drugs that we take are derived from plant molecules, and majority of those are produced by stress plants.
And so, the theory is called xenohormesis. Xeno means cross-species and hormesis is that term anything that doesn't kill you makes you live longer. And that is the idea that we should be seeking out foods that prior to being picked have been under adversity. So, they're full of these molecules that then we can ingest and trick our bodies into thinking that times are about to be tough. And so, they hunker down as well in order to survive. And ultimately, I think that would lead to healthier and longer life in our bodies as well.
Ben: Yeah. It's fascinating. There's a couple of anecdotes I've come across in the past about this. An author named Jo Robinson wrote in her book, “Eating on the Wild Side” about how if you rip leafy greens up the night before you actually make them into a salad or consume them, you actually can get slightly more of these xenohormetic compounds when you consume these plants that are stressed. Apparently, they think they're being consumed by a wild animal or something like that. And so, I came across that years ago before I was even familiar with the term xenohormesis.
And then I was also speaking with Todd White, who has a company called Dry Farm Wines, and they import these organic wines from Europe, but the grapes are grown in, as the name implies, less irrigated conditions. So, they basically get grapes that are more stressed. And apparently, the resveratrol in these grapes is even concentrated slightly higher if they're grown basically without much water. So, it's like a smaller, less sugar concentrated grape, but it has a higher amount of these antioxidants like resveratrol in it. So, I think this is also a good reason for people who aren't kind of into wild plant foraging or don't go out into nature and gather some of these plants that are more stressed than the big fluffy sugary produce you get at the grocery store. You may want to start to look into that or at least go to a farmer's market and get some of the ugly produce instead of the big beautiful ones that we find in the grocery store.
David: Yeah. Well-put. It should be cruel to our food.
Ben: Yeah, exactly. Beat it up. Whip your produce with chains. Another thing I wanted to ask you about before I actually do want to pick a little bit into your personal protocol because you've got some interesting things that you do yourself. That would be cancer. I don't think any discussion of longevity would be complete without addressing cancer, which is I think one of the bigger chronic diseases that takes us out early. Are there any cancer breakthroughs currently occurring that you're particularly intrigued with or excited about?
David: Well, definitely. And there's probably going to be a few prizes awarded for these discoveries. It's immune-oncology. I bet many people have heard about this, but it's really a major breakthrough. It's the kind of breakthrough that we were dreaming about in the future. And right now, if we get cancer after, at least many of us have to be subjected to chemotherapy, which is designed to damage DNA. And the reason that works is that cells that are dividing quickly in the cancer are less able to cope with DNA damage.
But for anyone who was paying attention earlier to our discussion will realize that in the process of repairing broken DNA, you will accelerate your age clock, and it really comes as no surprise but it is tragic that people who go through chemotherapy, if they survive, are lucky enough to survive. Then they will be older physically than before that. Now, that's terrible. So, what we need is different approaches that don't have to damage the genome of our bodies to be able to survive cancer. And this is what immune-oncology gives us. It actually stops cancer cells from hiding from the immune system, disables their hiding cloak, their invisibility cloak, and then our body can go and kill those. And we're seeing cancers that were once untreatable melt away. And Keytruda, which is an immune-oncology product looks next year to set to be the world's most profitable product in the world.
Ben: Is that a pharmaceutical, that one you just said?
Ben: And how did you pronounce it again?
Ben: Ketruda. Okay. So, that's an immune-oncology-based cancer drug that specifically is able to target cancer without nuking the body like chemotherapy would?
David: That's exactly right. And there are hundreds of clinical trials around the world testing molecules like this to be able to kill certain types of cancer. President Carter was saved by I think this very drug. He had brain cancer and actually was able to survive it. And he's just the beginning of a whole revolution of drugs that in the future, hopefully, we won't have to go through this ordeal of chemotherapy.
Ben: Wow. Are there side effects to it at this point, known side effects?
David: Yeah. There's one side effect that shows up, and that is that men who are gray end up getting their hair color back.
Ben: That doesn't seem too bad.
David: Yeah. It's tough to live with. Then there may be some side effects I'm unaware of. But in my circles, I haven't heard of any side effects of these drugs.
Ben: Interesting. That's fascinating. I have to keep my eye on that research. By the way, I wanted to ask you about this because I know you have, or you're associated with a journal called aging. Is that something that people could subscribe to to actually keep their finger on the pulse of a lot of these developments?
David: So, this is a journal that I don't run, but I am serving as editor. I think you have to subscribe. So, it's a paid publication. That said, fortunately, most papers are eventually released online so that almost everything that's ever been published in aging is publicly available. If people are interested in learning more about what I think and the research that's coming out, I now have a newsletter because there's by the popular demand and everyone's welcome to sign up for that. And of course, on social media, I try to find the most interesting papers every few days and put those out there for everybody to look at to.
Ben: What's your website for the newsletter?
David: It's called a lifespanbook.com.
Ben: Okay. Cool. I'll link to that in the show notes. And that journal, Aging, is that a print pub or like an online subscription?
David: It'll be an online subscription. I think you can get it privately.
David: I know that most universities have it, but unless you're a student, often it's hard to access that. One thing that's interesting, Ben, is the world of publishing is being ripped apart, not just for print media, but for publications, as well as scientific publications. And it's really chaotic right now, and we're in a world where a lot of papers are posted online before they're even submitted to a journal. And so, we're in an interesting world where the public can read research just as easily as any other scientists in the world instead of waiting two years for this work to be vetted by peers. Eventually, they are published in journals, and those are the actual substances of record. But now, the world is moving so much faster that we can post this research sometimes many years in advance.
Ben: Yeah. It is interesting, and I think that podcasting helps out a little bit, too. I mean, like I talked to so many people, even physicians who are now getting a lot of information just via this rapidly expanding field where stuff's available on audio literally days after research study comes out. I think that that's a medium. It seems to be helping a lot of people, too. Of course, I'm biased, obviously.
David: Let me tell you something very important to me. I spent most of my career talking to the print media and there wasn't one story that I read that wasn't misinterpreted biased or hype. And you get tired of that, but it was a necessary evil. I no longer think it's necessary. I think that podcasts are a saving grace where scientists like myself can talk directly to people and not have their words misinterpreted or intentionally misrepresented.
Ben: And the interesting thing is now Google and Apple podcasts and a lot of these search engines are now using AI algorithms to search the actual audio of every podcast. Meaning that you can very precisely dial in now for specific episodes related to anything that you'd want to discover, and literally use a search engine to search the audio. So, it's only going to get better, I think. I also wanted to ask you, David, about your personal protocol, like you have this yogurt that you make and you drink, and you have specific blood biomarkers that you test. Can you walk folks through, taking things from the science to the streets what your personal protocol is like as far as some of your biggest wins or your must-dos on a daily basis when it comes to your own anti-aging protocol?
David: Yeah, sure. I'm happy to share it. Now, just in full disclosure, I don't recommend anything and we're all different, so it doesn't mean this is perfect for everybody. And what I've done is optimized my protocol based on biofeedback. So, I wear a ring as a sensor, the Oura ring. I have a watch, one of the usual biosensors on the watch, and I've been doing blood tests, had a company called InsideTracker, which I've have invested in. That gives feedback of blood tests. So, more than most people, I know what's going on and what works and what doesn't for me based on N of one, we would say, on a clinical trial. I don't know if I'm going to live longer, but so far so good. I'm 50 years old now and I'm not super wrinkly and I have no gray hair.
Ben: Yeah. Honestly, I'm not just saying this to blow smoke, you actually look–oh, you look younger than 50.
David: Oh, well, thanks. I certainly don't feel [01:11:41] ______. My father's 80 and he doesn't feel anywhere over 40. So, that's all so far so good. But with all that, let me tell you what I do. Now, it's a fairly long list and listeners can jump straight to page 303 of my book if they'd like to get the cheat sheet. But some of the highlights that our page are I start my day with just a couple of spoonfuls of homemade yogurt, which I found is remarkably great product for maintaining what I think is a healthy microbiome. And it's a yogurt that I make myself, which only takes five minutes to make a few week's supply. It's very, very easy. Just mix some sachets with some milk and let it run overnight at body temperature and you end up with beautiful tasting yogurt.
Ben: Yeah. Which strain do you use? What probiotic strain do you use?
David: So, it's a company called Bravo and I order the sachets online.
Ben: Okay. Got it. I also make yogurt, but Dr. William Davis, I don't know if you're familiar with him, he's a cardiologist and he talked to me about a recipe when I interviewed him. He uses a strain called L. reuteri in his yogurt. And apparently, it has an effect on increasing oxytocin and testosterone and preserving bone density. It's got an effect on enhancing deep sleep. I do something similar that you do. I use coconut milk and that L. reuteri strain I just buy on Amazon, and yeah, just basically let it sit in the food dehydrator, in my case, at about 110 degrees for 12 hours or so. But you drink this or you drink or eat this yogurt pretty much every day?
David: Yeah, I do. It tastes better than this commercial stuff anyway. I originally bought it because I wanted my son to have a healthy microbiome. He has a weight issue and I thought this might be one way to fix that. There was nothing else that seemed to be working. But then I found out that it tasted great, so I kept eating it. And I saw various parameters of my body improve seemingly in time with eating this yogurt, including inflammation.
And here's just an anecdote and so anybody who's listening don't–I'm not going to publish this. This is just a story, but it's interesting. All science begins with stories anyway. I haven't been sick in years. Maybe I had a sniffle once since I started taking this. Now, I don't know if it's yogurt or what, but I can tell you, I'm a much healthier person now than I was 10 years ago based not just on that but a whole range of measures. And while people around me are getting sick, I just so far seem to be immune to these viruses that go around.
Ben: Oh, that's surprising. I mean, over 90% of your immune system is in your gut. So, if you've restored a gut lining or balanced your gut bacteria, it has a pretty profound impact on the immune system.
David: Right. And so, anyone who's listening who's curious how they're doing in terms of aging besides measuring your DNA methylation clock, a really great measure is how often you get sick. And I say that for a number of reasons. One main one is that when you look at centenarians, people who live over 100 years old, they say that through most of their life, they rarely got sick, by infections, not just physical ailments. And so, I've really taken that on board.
There's another fact which is when you stimulate the body's protective pathway, this mTOR pathway using rapamycin, best ways to tell if the drug is rejuvenating those elderly people was to look at their resistance to getting the flu, and it works. Basically, older people who get rejuvenated through these mTOR inhibitors resist the flu better. And so, I think that maybe I'm just saying this because I haven't been sick in a while, but now the science really does point to, if you're always sick, assuming you don't have little kids with runny noses, if you're those people who has a bad immune system and always get sick, that's probably telling you something about your body and your lifestyle.
Ben: Yeah, yeah. That or you just fly on planes too much. I do a lot when I'm on planes. I take yogurt almost every day like you do, but man, I'm using like bee propolis and oil of oregano and recently started messing around with even like T-cell enhancing peptides like thymus and alpha-peptide. And yeah, it's always an uphill battle when you're traveling all over the place on planes, but I'm sure this yogurt helps out quite a bit. So, you're doing that. You mentioned you take NMN. You talked about how you do the sauna with the cold pool, and then you test your blood and biomarkers via InsideTracker. Any other things that you do that are big wins for you?
David: Two more that I think are worth mentioning that I've noticed have helped with my body's metabolism and the blood biomarkers. One is resveratrol, which we mentioned earlier, that I've been taking since 2004.
Ben: Do you use a specific brand of resveratrol? I recently saw an article that said that most of it, that most supplement manufacturers using resveratrol from peanut skins, not grape skins, I'm curious if you have a brand that you actually like for resveratrol?
David: Well, I don't use brands. I'm lucky enough to have a basement with resveratrol in it because we did clinical trials years ago. But that's not useful to everyone else. I haven't tested products. There was one that I tried a while ago. I don't like to mention brands on air. Here's what I could say is that most resveratrol is real and look for the highly pure substances. So, you want 98% plus, 50% can even give you diarrhea because there's other stuff that comes along with the molecule. You can get it from–well, companies can buy it from Polygonum cuspidatum, which is a giant knotweed in China and Japan. That's another source besides peanuts.
I think that most of it is real, resveratrol. The one thing that most people don't realize is that it's highly insoluble. Even people who do clinical trials, I would tell them that they should mix it with a bit of yogurt or with a bit of olive oil because otherwise, it barely gets absorbed. We've known this for years. And that's why I think clinical trials are finally working because people have realized that you need a bit of solvent with this stuff. And that's one of the good things about having this yogurt in the morning. I mix it in and it dissolves nicely in this yogurt. It's full cream milk, so I get that in. Now, often people say, “David, you're not fasting if you eat two spoons full of yogurt.” We can argue that. It's not a perfect fast, but a couple of spoonfuls of yogurt I don't think is going to kill me enough. I don't eat 'til dinner. That's pretty long.
Ben: Yeah. That's probably the top question that I get is, does this take me out of fasting or does this take me out of keto? People flip out quite a bit over 10 calories here or 20 calories there, but I think it's a better idea to pay attention to the bigger variables like whether you're putting 400 calories of coconut oil and butter and ghee into your coffee in the morning versus having a spoonful of yogurt.
David: Well, 100%. Rhonda Patrick put me onto the glucose monitors and I wear one on my arm. And so, I can see what works for me specifically when I eat. The yogurt doesn't change my blood glucose levels at all.
David: You really expected to. There's a little bit of protein, but that's gone probably pretty quickly in the body.
Ben: Yeah. And so, you said there was something else besides resveratrol that you're big on for metabolism?
David: Yeah. This one requires a prescription if you live in the U.S. or the U.K. or Australia. It doesn't if you live in Thailand or other similar countries, Uganda. It's metformin. So, metformin is increasingly talked about in longevity circles, in part because there's some compelling studies that were published looking at tens and eventually hundreds of thousands of veterans that were taking metformin to treat their type 2 diabetes. It's a drug that stems from the French lilac. It's just a modified form of that. Again, plants are great for drugs.
But metformin, unfortunately, still is classified as a drug. It's a very safe drug as drugs go. And the World Health Organization actually calls it an essential medicine for humanity. But most doctors don't consider prescribing metformin until you become hypoglycemic or you have very high glucose levels. Often, doctors like to wait 'til you get sick before they give you a medicine. Instead, many of my colleagues, myself included, we take some metformin even before we get diabetes. And that's not just because we think that diabetes is bad and blood sugar is bad for longevity, but also because these hundreds of thousands of people that have been studied are relatively less likely to get cancer, heart disease, frailty and Alzheimer's if they're in high-risk groups. So, many of my colleagues, myself included, think that this is one of the best drugs on the market that you could take or molecules anywhere for slowing down the process of aging.
Ben: Yeah. A lot of the data I've seen on metformin, it's definitely good for a lot of the stuff you're talking about. The only reason I've resisted adding that into my protocol is just because of the exercise component. I'm sure you've seen some of the data on the reduction in VO2 max or, I think it was a couple of months ago, the research on a little bit of the blunting of the satellite cell and mitochondrial proliferation response to exercise. So, for me, when I'm tearing it up in the gym, I don't feel like metformin is going to help me out on that front. But if it's fitness, not in the longevity, it might be a different story.
David: Well, let's dig in a little bit into that study you mentioned because the study was quick to promote the differences, but often in these studies, as Peter Attia points out, they're not that big after all once you really dig in. And actually, all of the people who exercise gain muscle strength and muscle size. There was only a slight difference in the muscle size in the metformin group, which was slightly lower. But they were all just as strong, okay? And so, we're not talking about big difference here.
If your only goal in life is to have big muscles, sure, don't take metformin on the days you exercise and probably a day after. But otherwise, it's not a big deal. I'm still trying to figure out what's the correct answer. I don't think we have a perfect one, but I think that the effective metformin, these “negative effects” were overblown. I've got nothing to gain from metformin of course. It's a cheap drug and I don't really care if it's sales change of course. I've talked to the authors of the paper and my good friend Nir Barzilai at Albert Einstein College of Medicine, who's arguably the world's expert on this, and he was the one to point out to me that this fear of metformin affecting your muscles negatively is far overrated. Now, do I take metformin every day? Do I take it when I'm going to the gym? No. I don't think I need to take metformin every day anyway. I've got my blood in check. But I don't think that we should just avoid metformin and simply want big muscles.
Ben: Yeah. I think it comes down to whether you're like an elite pro athlete or just the average fitness enthusiast looking to get that combination of lifespan and health span. For me, up until last month, and I'm on the fence going forward about this, so I was competing professionally in endurance sports or even just like the slightest decrease in my VO2 max, response to exercise, I really couldn't afford to affect, but you're right. I mean, in terms of the slight downregulation of some of those responses for most people, it's going to be kind of a moot point.
David: Yeah. Well, I was talking more about your [01:24:11] ______ warrior kind of person, not professional of course. If you optimize things down to a fraction of a percent, that's very different. Most people are trying to be healthier and fitter and look a bit–and for those people, that's who I was referring to.
Ben: Yeah, yeah. Well, we've kind of only scratched the surface of all of the information that's in this book, and I mean, it was a fascinating read. And for those of you listening in, again it's called “Lifespan.” I've recently gone to David's website and subscribed to his newsletter because obviously, this science proceeds at a pretty rapid pace. And so, I recommend you get the book, and also recommend you look into his website and his newsletter there to kind of stay on the cutting edge of a lot of this stuff as well. And David, I really appreciate your time in terms of coming on here and sharing all this stuff with us from the yogurt and the cold protocols to the nicotinamide and the metformin and beyond. I mean, everything that you're doing is very fascinating. So, thanks for coming on and sharing all this stuff with us, man.
David: No. It's been fun and I see my role in life is to improve the lives of everybody. And so, this is an important part of that and I appreciate you having me on, Ben.
Ben: Yeah. Cool. Well, folks, the show notes are at BenGreenfieldFitness.com/sinclair, S-I-N-C-L-A-I-R. I'll link to a lot of the stuff we talked about. I wrote a note to myself about that, methionine, glycine, balanced database from Chris Masterjohn. I'll link to the yogurt recipe that I use and the aging journal at Sinclair's website, a lot of this stuff. So, just go to BenGreenfieldFitness.com/sinclair, where you can also leave your comments, your questions, your feedback, any thoughts that you have about this episode, and until next time. I'm Ben Greenfield along with Dr. David Sinclair signing out from BenGreenfieldFitness.com. Have an amazing week.
Well, thanks for listening to today's show. You can grab all the shownotes, the resources, pretty much everything that I mentioned over at BenGreenfieldFitness.com, along with plenty of other goodies from me, including the highly helpful “Ben Recommends” page, which is a list of pretty much everything that I've ever recommended for hormone, sleep, digestion, fat loss, performance, and plenty more. Please, also, know that all the links, all the promo codes, that I mentioned during this and every episode, helped to make this podcast happen and to generate income that enables me to keep bringing you this content every single week. When you listen in, be sure to use the links in the shownotes, use the promo codes that I generate, because that helps to float this thing and keep it coming to you each and every week.
My guest on today's podcast—Dr. David Sinclair, an acclaimed Harvard Medical School scientist and one of Time’s most influential people—just wrote a paradigm-shifting book.
It’s a seemingly undeniable truth that aging is inevitable. But what if everything we’ve been taught to believe about aging is wrong? What if we could choose our lifespan?
In this groundbreaking new book Lifespan: Why We Age―and Why We Don't Have To, Dr. Sinclair, leading world authority on genetics and longevity, reveals a bold new theory for why we age. As he writes: “Aging is a disease, and that disease is treatable.”
This eye-opening and provocative work takes us to the frontlines of research that is pushing the boundaries on our perceived scientific limitations, revealing incredible breakthroughs—many from Dr. David Sinclair’s own lab at Harvard—that demonstrate how we can slow down, or even reverse, aging. The key is activating newly discovered vitality genes, the descendants of an ancient genetic survival circuit that is both the cause of aging and the key to reversing it. Recent experiments in genetic reprogramming suggest that in the near future we may not just be able to feel younger, but actually become younger.
Through a page-turning narrative, Dr. Sinclair invites you into the process of scientific discovery and reveals the emerging technologies and simple lifestyle changes—such as intermittent fasting, cold exposure, exercising with the right intensity, and eating less meat—that have been shown to help us live younger and healthier for longer. At once a roadmap for taking charge of our own health destiny and a bold new vision for the future of humankind, Lifespan will forever change the way we think about why we age and what we can do about it.
During our discussion in which we take a deep dive into “Lifespan,” you'll discover:
-What does a typical day look like for a scientist at Harvard?…5:45
- No such thing as a “typical” day
- Founded and runs several companies
- Was taught by grandmother and mother to “leave the world a better place than you found it”; this led to his interest in anti-aging and longevity
-Dr. Sinclair's method of speeding up the aging process in mice…8:30
- Theory on aging: it's not the DNA as much as it is the ability to read the code
- Epigenome: a record of the chemical changes to the DNA and histone proteins of an organism
- A broken chromosome is one of the main drivers of the aging process
- Created a genetically altered mouse with a DNA cutting enzyme (cutting but not mutating)
- You can look at a person's DNA and tell how old they are biologically
- Akin to scratching a DVD until it's no longer able to play the movie
- Aging is the result of cells “forgetting” their identity due to DNA damage
- The only change was slightly damaged DNA; no stem cells, alterations to telomeres, etc.
-Cellular Reprogramming 101…14:30
- Yamanaka Factors: genes that turn on in our embryo, and instruct cells what to become
- First tests done at the Salk Institutein San Diego
- Mice with cells turned “on” and “off” lived 30-40% longer
- MiCK gene was left out of mice; this resulted in their tissue becoming younger
- Genome is akin to a piano: Not fixing the piano, you're fixing the pianist
- DNA methylation patterns indicate the age of the cells and predict end of life
- Epigenetic (Horvath's) clock: Much more precise measurements than telomere tests
- Able to determine the age of previously deceased persons
- Not commercially available currently
Want early access to a chapter of my new book coming January 2020?
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-A device that determines a human genome via a USB connection…23:15
-Whether you can predict your lifespan with your current DNA data from 23andMe…25:15
- FOXO3 gene
- Longevity is 20% genetic; the rest is based on our lifestyle
- Epigenome is more important than the actual DNA
- Mixed opinions as to the role telomeres play in longevity
- Tests such as 23andMeare erratic in their accuracy
-The correlation between protein consumption and longevity…29:30
- Focus on variety in diet vs. one particular “perfect” diet
- Anyone who says they know exactly what to do is lying
- Meat contains many branched-chain amino acids (BCAAs); builds muscle
- Comes at the expense of long-term health
- mTOR inhibits longevity
- Plant-based amino acids are preferable
- Importance of maintaining proper methionine/glycine balance
- Trimethyl-glycine alleviates discomfort from a NAD IV
- Nicotinamide adenine dinucleotide (NAD) supplementationkeeps sirtuins active (prevents scratching on the DVD)
-The importance of a proper methionine and glycine balance…38:00
- Chris Masterjohn Methionine Glycine balance database
- Methionine restriction slows down frailty
- Trimethyl glycine (TMG) is also called betaine
- Oral TMG alleviates discomfort from a nicotinamide adenine dinucleotide (NAD) IV
- NAD supplementation keep sirtuins active (prevents the DVD from scratching)
- Oral nicotinamide mononucleotide (NMN) supplement is what Dr. Sinclair uses
- Sleep will change cycle of NAD in the body, and contribute to reversing our “clock”
- NAD can cross the blood-brain barrier; NMN cannot
- Exogenous nicotinamide adenine dinucleotide regulates energy metabolism via hypothalamic Connexin 43 (Roh, 2018)
- Neurons will absorb NAD, whereas other cells will not
-The effects of NMN on fertility…49:15
- Sirtuin #2 regulates cell division
- Restore NAD levels in ovaries resulted in healthier embryos in mice
- Destroy NAD, give NMN, resulted in healthy embryos
- The field is reluctant to embrace this; no one wants to rewrite the textbooks
-Uncoupling proteins, and whether DMP supplements are a good idea…53:10
- DMP is extremely toxic; deaths have been reported after use
- Mitochondria power the cells
- Similar to hydroelectric dam
- Circumvent by poking holes in the dam
- DMP damages mitochondria
- Overdoses resulted in death
- Cold thermogenesis is efficacious in uncoupling proteins
- New drug that's as effective as DMP minus the toxicity is on the horizon – Continuum Biosciences
- Sirtuin #3 is beneficial for mitochondria
-Resveratrol, stressed wine and fruit, and longevity…58:00
- Resveratrol slows aging by mimicking calorie restriction; activates sirtuin #1
- Plants make resveratrol to make their own protective enzymes
- Stressed plants hit pathways in our body that make us healthier
- Most drugs we take are derived from stressed plants
- Xenohormesis: anything that doesn't kill you makes you stronger
- Book: Eating on the Wild Sideby Jo Robinson
- “Be cruel to your food”
-Cancer breakthroughs in which Dr. Sinclair is currently interested…1:03:15
- Chemo is designed to damage DNA
- Repairing DNA accelerates age clock; cancer survivors age tremendously
- Keytruda – a form of immuno-oncology
- Has potential to be the world's most profitable drug in coming years
- Jimmy Carter's life was saved thanks to Keytruda
- Only known side effect is to restore hair color in men
- Aging journalBen and David discuss
- Sinclair's website and newsletter
-David's personal protocol…1:10:30
- Oura ring
- Inside Tracker (blood tests)
- William Davis yogurt recipe
- The frequency in which you get sick is a great measurement for your longevity
- NMN supplement
- Cold thermogenesis
- Resveratrol(98% purity or higher)
-And much more…
Resources from this episode:
– Book: Eating on the Wild Side by Jo Robinson
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