Understanding Genetics of Aging with Harvard Professor Dr. David Sinclair

Harvard scientist and NYT best-selling author David Sinclair, PhD and I take a tour around the science of aging. If aging is THE root cause of all of the chronic diseases of aging, then arguably, if we focus on the aging journey itself, we might be able to stop playing “whack-a-mole medicine.” A lot of complex environmental, genetic, epigenetic and biochemical processes go into the aging journey, however, as Dr. Sinclair discusses, it looks like a very heavy lifter in aging is epigenetic changes – specifically, DNA methylation and demethylation (plus histone acetylation). In this episode of New Frontiers, learn about the amazing research going on at Dr. Sinclair’s lab, hear what’s getting translated to humans, and what you can do NOW to stop the epigenetic clock from ticking…. Listen and learn, leave us a 5 star review if you’d be so kind, and be sure to share with your colleagues! ~DrKF

Understanding the Genetics of Aging with Harvard Professor Dr. David Sinclair

What is aging? Is it a disease? Is it inevitable? What processes in the body are responsible for aging and can they slowed or reversed with the correct interventions. Dr. David Sinclair is a Professor of Genetics at Harvard Medical School and the author of the book Lifespan: Why We Age — And Why We Don’t Have To. In this episode of New Frontiers, he talks with Dr. Fitzgerald about the genetic and epigenetic controls of aging and lifestyle interventions for slowing the aging process.

In this episode of New Frontiers, learn about:

David A. Sinclair, Ph.D., A.O. is an entrepreneur and world leader in aging research. He is a tenured Professor of Genetics at Harvard Medical School, co-Director of the Paul F. Glenn Center for the Biology of Aging Research at Harvard Medical School, Professor and Head of the Aging Labs at UNSW, Sydney, and an honorary Professor at the University of Sydney. He is best known for his work on genes and small molecules that delay aging, including the Sirtuin genes, resveratrol and NAD precursors. He has published over 170 scientific papers, is a co-inventor on over 50 patents, and has co-founded 14 biotechnology companies in the areas of aging, vaccines, diabetes, fertility, cancer, and biodefense. He serves as co-chief editor of the scientific journal Aging, works with national defense agencies and with NASA. He has received 35 honors including being one of Australia’s leading scientists under 45, the Australian Medical Research Medal, the NIH Director’s Pioneer award, TIME magazine’s list of the “100 most influential people in the world” (2014) and the “Top 50 people in Healthcare” (2018). In 2018, he became an Officer of the Order of Australia for his work in medicine and national security.

Instagram: @davidsinclairphd

Twitter: @davidasinclair

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Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine, and today is no exception. I am very excited to be talking to Dr. David Sinclair. You’re familiar with his book. And actually, you’re likely familiar with some of the cool research that he’s written about in Lifespan, and we’re going to get an update. But let me give you his background. He’s a tenured Professor of Genetics at Harvard Medical School, Co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard. He’s conjoint professor at the University of New South Wales in Sydney.

He’s best known for his work on genes and small molecules that delay aging, including the sirtuins, NAD precursors, and other epigenetic modifiers. He serves as co-chief editor of the scientific journal Aging and he has received many, many, many honors. Incidentally, David, you look quite young. So this list of honors, well, including one of them being a leading scientist under the age of 45. I mean, it’s just amazing what you’ve been able to achieve. What else? He was voted, let me see, NIH Director’s Pioneer Award. So he was given that. Time magazine, one of the most 100 influential people in the world and top 50 people in healthcare. So lots of cool accolades, lots of great research over at your lab. And I just look forward to diving in and talking about it today.

Dr. David Sinclair: Well, hey, Kara, it’s great to be on.

Dr. Kara Fitzgerald: We’ll just start at the top and then we’ll kind of drill down. You’re focusing on aging, maybe a snapshot as to why. I mean, it is ironic. You’re one of the leading scientists under 45, so you’re really interested in it, the background on why, and then what it is, a definition of what aging is to you.

Dr. David Sinclair: Sure. Well, I’m now 50, so I don’t qualify anymore.

Dr. Kara Fitzgerald: Oh really? You still look it.

Dr. David Sinclair: But I used to be. Okay. Thank you. Thank you. In videos now, you can blur it slightly. I think that’s the secret. Anyway, very kind introduction. Thank you. It’s really great to meet you. I’ve been interested in aging since I was four years old when I realized nobody was really talking about it much and the consequences are horrific. All the diseases that we associate with old age, cancer, heart disease, Alzheimer’s, frailty, diabetes, the list goes on. People don’t talk about it, but to me it’s obvious that you don’t get these diseases when you’re a kid. And why is that? So I’ve been trying to figure that out. And if I could give people the biology, the physiology of someone who’s younger or maintain their youth, then we wouldn’t get those diseases, at least that the prevalence would be much less and we could live much healthier.

As a consequence, we would live longer, of course. The goal is not to live forever. People misunderstand that. It’s about how to have a big impact on human health. And so, aging I think is defined incorrectly. We’ve been spending the last 200 or more years as scientists and doctors trying to research and fix and cure the end result of aging, those diseases. I call it, in my book, you’ll remember, whack-a-mole medicine. I think you and your listeners will appreciate that we do far less to prevent those diseases.

One of the analogies I make is that aging… Well, let’s start with diseases. Diseases are what cause you to fall off the edge of the cliff. But why don’t we talk about, why don’t we research what drives us to the edge in the first place? And I’m screaming, I’ve been screaming from the top of the mountain, from the ivory tower, you could say, for the last 25 years. And in the end, I just said, “Okay, I have to write this book because it’s just not getting through to the people who make decisions.” It seems to be working. So the definition of aging as it currently stands is that it’s separate from disease.

We as scientists and doctors say that a disease is something that causes a decline in the body’s function often leading to death, but it has to happen to less than half the population. If it happens over time to 51% of people, we call it aging. And the problem with having that artificial separation between disease and aging is that we tend to think of disease as something we should throw billions of dollars to cure, but aging, because it’s more common, we say, “Oh, that’s natural and therefore acceptable.” Whereas I think it should be opposite, that because it happens to almost everybody, it’s first of all unacceptable and that we should be working more on it.

Dr. Kara Fitzgerald: Well, and I think that the whole whack-a-mole idea, I’m familiar with the future elderly model. I think Goldman wrote about that some years ago, about if we actually devoted energy more intentionally towards aging as you’re doing in your work, we would reduce. Yeah, we would stop playing the whack a mole as far as our science goes and our interventions.

Dr. David Sinclair: Yeah. Jay Olshansky. Yeah. Do you know about Jay? So Jay just wrote an interesting article in the Wall Street journal yesterday. He’s debating Steve Austad how long we’re all going to live. But what Jay is famous for, or at least I love him for, is his way to say things that are snarky but humorous. And one of the things that he said, and I hope I don’t screw it up, but he said something like, “The way we practice medicine is to find an illness, prescribe a medicine, push the patient out the door, repeat until failure.” And I thought that’s a beautiful way…

You’re an ND, but a special one. But I do think that’s how we are treated. We’ll give you a medicine. Come back with another disease, we’ll give you another medicine. Come back with another disease.

Dr. Kara Fitzgerald: Absolutely. Yes. That’s right. Of course. Yeah. You have to meet a certain set of diagnostic criteria to actually be labeled and treated. That’s right. Yeah. Yes. The idea of prevention of starting earlier is just gaining traction, obviously. And in my world, we’re thinking about it all of the time. But you know what? Even us in integrative/functional medicine, us advanced thinkers who are practicing whole person medicine, we’re still siloing. We’re still making the diagnoses, which I think are important and useful. But you’re backing up and considering aging as the underlying cause of the diseases.

Dr. David Sinclair: Well it is. But I’m not saying anything that isn’t a fact. It’s just that we’ve put it into a different box from really where it should be. Let me give you an example of how frustrating this can be. Let’s say we had a medicine that could give people an extra five, even 10 years of healthy life, delay cancer, delay frailty, delay Alzheimer’s, and delay diabetes. Now, we think we have a medicine already, very safe medicine that can do that. This is Metformin, of course, Metformin being the leading drug for type II diabetes.

It’s a little pill. It’s cheap. Now, just grant me that it does those things. There’s a lot of evidence that it does, but it’s hard to prove those things. But in tens of thousands of patients who’ve received this medicine, they are relatively protected from these diseases. Right now. You cannot be prescribed this medicine unless, like you said, over a threshold. HBA1C levels have to go over whatever it is, five something. If you’re 4.8, forget it. Most doctors will not give you a medicine that could prevent diabetes before you actually get it, which frustrates me tremendously. If I invented a medicine that delayed aging and gave everyone 50 years of extra life, imagine that you couldn’t be prescribed that medicine.

Dr. Kara Fitzgerald: That’s right. That’s right. We exist in this disease care model versus healthcare model. Yeah, it’s-

Dr. David Sinclair: And often it’s too late to do something about it.

Dr. Kara Fitzgerald: So why is it so uncomfortable? Why hasn’t this paradigm shift happened? Why isn’t this in the collective medical establishments epigenome, shift that this is what we need to do?

Dr. David Sinclair: I think you’re in a better position to answer me. I work at Harvard Medical School surrounded by doctors who look at me like I have two heads. It’s very hard to change the course of a conservative institution like medical practice. Even things that we discover in the lab now don’t make it into the consciousness of your average MD until 20 years.

Dr. Kara Fitzgerald: Yes. At least. Yeah. I have to say, it’s been an aha process for me, a relatively recent one. And the more I kind of sink into this idea of having a focus, I could focus my energy on reversing the aging trajectory in my patients and have great outcome with all of the chronic diseases that we’re facing all of the time. Who are the major players in aging? Like the genes that we want to think about, maybe the epigenetic influences. What are you thinking about biochemically as the major players that you want to impact on the aging process?

Dr. David Sinclair: Well, about 20 years ago, I and dozens of other labs, were finding genes that extend the life span of simple organisms, yeast, and nematode worms, and flies, and mice. And there were lots of genes flying around, and in fact, we scientists were at each other’s throat, conferences basically, my gene is more important than your gene. That was the theme. It was really vicious. There was a lot of angst, people crying. It was horrible. The field has settled down now. We’re now into our second and third generation of the field. And the new people, thank goodness, are calmer.

But I raise that because it was chaotic in the beginning. And what we’ve settled on is that there are three, probably more, but three main pathways that are part of a survival network that sense the environment, both inside the body and out and tell the body when it’s time to hunker down, protect itself, survive, and when it’s time to grow and reproduce and don’t worry about keeping the body that healthy. Unfortunately, the world we’re in, of course, keeps us in that state of being satisfied and the body doesn’t worry that much about protecting itself.

The three main pathways that respond to the environment, what we’re eating, all those kind of things, exercising, the one that I work on is called the sirtuins. You mentioned them. These are seven genes in the body that respond to adversity. If you exercise, if you’re hungry, if you’re cold, they’ll come on and protect the body in variety of ways. The second group are feeding into AMPK or AMP kinase, it’s called, and this revs up metabolism, makes more energy for the body. And that’s the pathway that is revved up by Metformin. And then the third pathway, which seems to be one of the most impactful in animals, but the most dangerous to play with is called mTOR, little M, capital T-O-R.

Rapamycin is a drug that you’ll be familiar with, that people take it to stop transplant injections. But if you take a little bit of it, what you’re doing is mimicking the body in a state of low amino acid intake and that also induces the body to recycle old proteins and fight against aging.

Dr. Kara Fitzgerald: All right. I’m wondering where to go. I want to talk about epigenetics, and I want to get over to the epigenetic clock. But do you want to maybe just expand a little bit on these three genes and… Well, you mentioned AMPK and Metformin, and then the sirtuins, and just maybe some of the things that you’re thinking about, like the key sirtuins that you’re interested in and what they do.

Dr. David Sinclair: Well, let’s start with the paradigm that we’ve come up with over the last 20 years. There are three levels going down. At the top level, you’ve got the environment and what you eat and how you live. The second level are these longevity genes, AMPK, sirtuins, mTOR, and others, of course, hundreds of others that play into that network. And those genes are talking to each other. So if you tweak one, the others will kick into action as well. So the old idea of my gene’s more important than yours is a bunch of BS.

Then the bottom part, third lowest, the lower layer, are the causes of aging, the processes that go awry as we get older. There were about eight well established what we call hallmarks of aging. We scientists, we’re always scared to say causes, because you can be wrong, but hallmarks is very safe. Essentially these are the causes of aging at the later stages. They’re not the regulators, but these are the effects. So some of them, if I list them, you’ll recognize them. Telomeres shortening, so the ends of chromosomes get shorter. Misfolded proteins. Nutrient signaling gets defective, that’s why Metformin is helpful.

We have senescent cells, the zombie cells that accumulate in the tissue, which cause havoc and make other cells malfunction and cancerous. We have the epigenome, which the sirtuins are also part of. And there are other things, STEM cells and factors in the blood. So all of those things are known to go awry and it’s knowing that if you prevent or slow down one of those, you can actually have remarkable health benefits. Question is, is there something controlling all of those? And I think at least I’ve put forward a hypothesis that says that the epigenome is the master of all of those problems and have some evidence to back it up.

You asked me about the sirtuins, what do they do? So there are seven. Three of them are in the government in the nucleus of the cell. The others are mostly found in the mitochondria. And there’s one in the cytoplasm, which is number two. And they all do interesting things. I can’t go through hundreds of their functions, but, for example, Sirtuin 1, which is the one that is most conserved across life. It’s mostly nuclear and it controls gene expression. It also controls DNA repair, inflammation out in the mitochondria. It’ll boost mitochondrial activity, reduce free radical production.

So it’s doing a lot of things. And the way it does that is that it either does it directly by deacetylating histone, packing proteins, but it also controls other proteins that do things. Like it deacetylates the inflammatory transcription factor, NF Kappa B. It also deacetylates the cell cycle protein P53, which is well known for its role in cancer. And the list goes on, right? But you get the idea, that these are master regulators of cellular health and survival. And you can let them fade away by not exercising and not eating the right foods and always being satisfied, tons of hunger, or you can activate them either through lifestyle and chemicals.

Dr. Kara Fitzgerald: Let’s see. So entering into the anti-aging process, engaging it, you would be thinking about influencing all of these. But as you said, so all of these levels, so environment, the genes, and then the hallmarks of aging. You might sort of map out all of these guys, but then there’s much interrelation. Well, there’s major interrelationships. So I’m assuming in environment, if you’re a smoker, obviously, you’re going to be damaging all of these various genes and pathways.

Dr. David Sinclair: Exactly, including epigenome.

Dr. Kara Fitzgerald: Yeah, right, right. So, let’s see. I’m just dying to get over to talking about methylation and ten-eleven translocases and some of the cool work you’ve done. Let’s talk about that particular hallmark, epigenetic alterations. You did mention histone deacetylation and sirtuins. Well, talk about the ICE mouse study. Then recently you… Well, actually in, I guess, July of 2019, you published another really interesting study, or it’s nearing publication, looking at the changing epigenetic expression. And so, the ICE mouse study you wrote about in your book and you accelerated aging aggressively I think in a genetic/epigenetic model. Then this more recent paper that’s going to be published soon, you actually reverse aging.

So maybe talk about epigenetics of aging and those studies and thinking about DNA methylation and demethylation. Those are good questions. A long one.

Dr. David Sinclair: Yeah. How long have we got?

Dr. Kara Fitzgerald: I know, I’m sorry. I know I’m just throwing out too much, but I’m just so curious to hear what you have to say.

Dr. David Sinclair: All right. Well, so what we’ve got is a set of tools now that we can read the epigenome, not just in one dimension, which would be in relation to the ATCG code. And of course that’s important. We can modify the CpG islands, they’re called. We can modify those with methylation. That’s one dimensional information. But now we’ve got these amazing tools which are only just being used widely. Some of them we just developed this week, actually. I was on-

Dr. Kara Fitzgerald: Oh my goodness.

Dr. David Sinclair: … talking to my lab this morning. But we can look at the epigenome in its true form, which is in three dimensions over time. And some of these technologies are called Hi-C and HiChiP and ATAC seq. RNA seq is an older one, but these are genome-wide analyses that any graduate student can do now. And not just on a tissue or in a cell culture dish, but on single cells. What that’s giving us is incredible insights into what’s going on during aging and disease, and in response to DNA damage. These are, I think, fundamental processes that we didn’t really have a good handle on until very recently.

There are a variety of ways of changing the structure of the epigenome. And by that I mean the code, which can be on the DNA or on the histones themselves, through methylation, and in the case of histones, methylation and acetylation, and a whole panoply of different modifications, which are relatively minor, but still I should mention them, they complement what’s happening in three dimensions, which is that there are proteins that loop out the DNA or spool it up tightly like a hose rail. And then those loops are interacting with other loops, and they might not even be near each other in one dimension. They might be very close in three dimensions, and we can now see that.

It’s really quite amazing. Once you have these new technologies, it’s fun to do the equivalent of going into a cave and switching on the light and you see all these diamonds. That’s how I feel right now in the field. What we’re seeing, just to cut to the chase, is when you disrupt cells, in particular the most potent disruption that we can do to a cell right now or an animal, is to cut the chromosome and have the cell freak out trying to repair it. And we see that has not just very acute early major effects on the epigenome in its structure, but long-term permanent scarring of the epigenomes so that those loops and bundles are permanently affected by having the cell go through this panic of trying to repair the chromosome.

Dr. Kara Fitzgerald: That’s fascinating. Would you translate that into like DNA damage from like UV exposure or some of the environmental things that we’re inundated with, chronically bad diet? I mean, are we causing some of those same stressors?

Dr. David Sinclair: I think we are. The most potent insult is the double-stranded DNA break, of DNA double strand break, but probably other types of DNA damage are causing these as well. We’ve done most work on the broken DNA, but there’s no question in my mind that every time the cell has to readjust its epigenome to deal with a large shock, it has trouble resetting the system. There’s the concept, of course, of hormesis where if you don’t do lasting damage to the body, or in this case the epigenome, it’s actually beneficial. You can turn on a stress response and reset, turn it on, reset. But there are certain types of damage that if they’re overwhelming, let’s say you go get a really bad sunburn, yeah, you’ll get mutations. No question. That’s what is believed and proven to cause skin cancer. But nobody I know… But I don’t know everybody, but nobody I know except our lab is understanding what’s happening at the epigenetic level, which seems to be just as important to get the cells into a certain state of metabolism and gene expression that also predisposes for diseases, including cancer.

Dr. Kara Fitzgerald: Can you just walk through what you showed in the ICE mouse model?

Dr. David Sinclair: Yeah. So the ICE mouse, this is the decade-long experiment that we’ve been doing. All these papers that we’ll talk about today on accelerating aging and reversing it are up online. You can go find them. They’re up on Biorxiv, B-I-0-R-X-I-V.

Dr. Kara Fitzgerald: We’ll link to that on our show notes, folks. We’ll link to that and just any other pertinent info from Dr. Sinclair. Okay. Keep going.

Dr. David Sinclair: Yeah. And so, the ICE mice, so the ICE mice stand for inducible changes to the epigenome. In 2008, we published a paper. Or it’s 2009, we published a paper in Cell that said that we could see that chromatin regulators like sirt 1, one of the sirtuins, are part of a DNA damage response. So they move to the DNA break when it’s created. And you don’t have to be exposed to an X-ray or Chernobyl to get DNA breaks. They’re happening all the time. Every cell gets a few every day, which means 20 or more trillion in the body every day. So this is not minor and you can’t prevent them.

These proteins, they move to repair the damage, but they don’t always find their way back again. And we call this the relocalization of chromatin factors, hypothesis of aging, and presented a lot of evidence that that seemed to be true in cells and in the mouse brain. And if we increase the amount of sirt 1 protein in the brain, we could actually prevent the changes in aging caused by the epigenetic change. So we’ve got early evidence, but the ICE mice was a real swing for the fences. What we created was an actual animal that we could induce DNA breaks without causing mutations. Of course, if we had mutations, it would confound interpretation. We wouldn’t know if it was DNA damage or it was actually the epigenome causing it.

We induce that in those mice when they’re young, about four to five months of age. And then we could ask the question, in the absence of mutations, but in the presence of epigenetic changes, what happens to those mice? And we got the result, the one in a million result, that at least the hypothesis predicted, which is that those mice developed a very similar phenotype effect that looks like aging. And not just at the gross level. I mean, you look at the mice, they look old. They’ve got a bent spine. They’ve got gray hair. They don’t see well.

But if you look at the physiological parameters and histological parameters, and even the molecular changes in terms of gene expression and these chromatin changes, epigenetic changes, it looks like aging, which is the first time I believe that aging has been mimicked in a mouse to this extent. But there’s one last thing that’s really important because only until recently could we unambiguously say these mice are old, and that’s the DNA methylation clock or the Horvath clock. And so, we did that test on these mice and they didn’t just look 50% older than their brothers and sisters. They were literally 50% older.

Dr. Kara Fitzgerald: Yeah. That’s amazing. Wow. Okay. It just seems that, yeah, at every turn you induced aging and you would say that aging is an epigenetic phenomena.

Dr. David Sinclair: Well, I’m inclined to believe that that hypothesis is true, speaking as a scientist.

Dr. Kara Fitzgerald: I know, that’s great. There’s layers of qualification in that.

Dr. David Sinclair: You have to remember, nothing’s ever proven. I can’t prove the sun will come up tomorrow even.

Dr. Kara Fitzgerald: Right.

Dr. David Sinclair: That result was one in a million. I’m not that lucky. Things just don’t happen to me. They’re one in a million. So I think more likely the hypothesis is valid.

Dr. Kara Fitzgerald: I know you’ve got this other study I want to talk about where you actually do the reverse, you turn back the hands of times pretty remarkably. But in this ICE model, so you make these mice old. Have you introduced some of the interventions that you talk about to them? I mean, have you been able to reverse age in these old mice? Have you looked at that?

Dr. David Sinclair: Well, we haven’t partly because we still are struggling… Not struggling, but we’re still working hard to publish these papers. After that, I can start doing the next stage, which is what you’re suggesting. We are giving some NMN, which is the sirtuin activator that we work on in part. It’s not done yet. The mice do seem to have less frailty, and that’s true for regular old mice as well. But due to lack of time and funds, we haven’t been able to do that experiment. These are really hard experiments, in my defense. These mice have to be bred, and then induced, and then you have to wait another 10 months. So just getting the experiment done is two to three-year process and hundreds of thousands of dollars, which basically is more than a single grant from the government. So I can’t do so much in parallel that I’d like to be doing. But I’m very keen to apply the technologies we have now, particularly the really new ones that do seem to really be able to, not just slow aging, but reverse it.

Dr. Kara Fitzgerald: All right. I want to talk about those in a second. I just want to let folks know that NMN is nicotinamide mononucleotide, and that’s a cofactor, actually. I think NAD is the cofactor. Is that correct, for the sirtuin?

Dr. David Sinclair: Yep. Sirtuins use NAD as officially a co-substrate, which means they rip NAD apart and attach an acetyl from the histone or the target protein. But yeah, if you don’t have NAD, sirtuins won’t work, but neither will we.

Dr. Kara Fitzgerald: Yeah. So the NMN is something that you’re taking that you think is beneficial for you, that we can take. I think a lot of folks probably listening to this podcast are taking some form of maybe nicotinamide riboside or NMN. Anyway, for sirtuin support. Okay. So initial findings in this group of mice suggests that NMN might be helpful for them. That’s pretty neat. It’s interesting, if we were to light upon the benefit of anti-aging research, you’d certainly have a lot of funds. I mean, you could divert some of the millions and millions and millions or perhaps billions of dollars going into all of the other chronic disease research that we’re engaging in.

Dr. David Sinclair: Yeah, it’s risky. I did write in my book the comparison of investment and return, so that that’s detailed. But I don’t want to be painted with a brush that basically says, “Oh, David thinks we shouldn’t do Alzheimer’s research.” That’s not true. I think any research is better than none. But I think it’s some of the bang for the buck. As a group of medical researchers, we haven’t been very successful in treating Alzheimer’s. And then, Leonard Hayflick, who’s a legend in the field of aging. He discovered cellular senescence. Actually, cellular senescence is called the Hayflick limit of cell reproduction. What he said was curing Alzheimer’s will tell you nothing about aging. “It may allow you to extend lifespan by maybe 14 days,” is his quote.

Dr. Kara Fitzgerald: Wow.

Dr. David Sinclair: And meanwhile, I don’t know exactly the numbers. I haven’t looked recently, but it’s orders of magnitude more in Alzheimer’s versus the biology of aging. Now, because there’s so much money in Alzheimer’s, a lot of people in my field are trying to put the word Alzheimer’s into their grants because it’s the best way to get funding, but it typically doesn’t go to understanding why Alzheimer’s occurs in older people. Put it this way, and we’re doing this experiment right now. If we can take a mouse, and one day maybe a human that has Alzheimer’s, and make their brain young again, would they have Alzheimer’s?

Dr. Kara Fitzgerald: I mean, I would venture, no.

Dr. David Sinclair: Right. I would agree.

Dr. Kara Fitzgerald: Clinically, so.

Dr. David Sinclair: We will know in the next year or so.

Dr. Kara Fitzgerald: Yeah. And so, it could really be of… Yeah. Let’s start talking about that. So you’ve got the ICE model, you’ve made mice age and it seems to be an epigenetic phenomenon, and therefore if you begin to turn the clock back via altering the epigenome… Actually, let me ask you this. In the ICE model, when you look at the epigenetic changes, are there, you would say, their DNA methylation and demethylation, and then histone acetylation? That those are the lion… Or is methylation the lion’s share? I mean, what are you seeing? I guess, if you’re using Horvath’s clock, you’re looking at methylation.

Dr. David Sinclair: We are, so we’re looking at a lot. And if you go to the papers that we put up online, you’ll see there’s a lot of data on this. It just gets more complicated the more you spend on it. But we do see changes in methylation. Not globally, just at these particular clock sites, which is important because it means the cell is actively controlling which of these sites is important to, or which drives aging and which is important to reverse. It’s not just that you can wipe clean, like you would brush your teeth, free of methylation. It’s much more controlled than that, which is very exciting, actually, if it’s a conserved process.

Yeah. But we also see many changes besides that. We see histone acetylation, methylation changes across the whole genome at particular genes. One set of genes that jumped out that’s interesting is the developmental control genes. For example, the Hox locus, H-O-X, these genes control in embryogenesis where your head and your tail are. And we see those get dysregulated during aging, which is something people haven’t thought about. But more and more, I think aging is the dysregulation of embryogenesis late in life, and cells starting to lose their identity.

Dr. Kara Fitzgerald: That’s so interesting. Well, let me ask you this, and then we’re going to talk about reversing aging and some of the other research that you’ve done. Do you think that Horvath’s clock, and there’s actually a few clocks now, but his main one, those changes aren’t just surrogate markers of aging. They actually drive aging.

Dr. David Sinclair: We think so. I cheekily wrote in the book, if you can give something to those ICE mice, you could take it away. But really, it’s a philosophy that first we want to understand why aging happens. I think we have some idea now. Using that knowledge, we can target therapies. What we’ve done in general is to figure out where the backup copy of the epigenome is, or at least how to access it and reset the cell. And that required the removal of the DNA methylation sites at these particular genes or regions of the genome.

You mentioned the TET genes. These are used during embryogenesis, important for setting the cell type. If you’re a nerve cell, you have to stay a nerve cell. You don’t want to be turning into a liver cell the next day. But we know that if we don’t have those TET genes or a gene that works downstream of them to finally remove the methyl group that’s called TDG, without those genes, the reprogramming and the age reversal doesn’t happen.

Dr. Kara Fitzgerald: It is really complex. And I can imagine, now that you’ve turned the light on in the cave, it’s just added that much more complexity. Oh my gosh. It’s extraordinary, but it’s-

Dr. David Sinclair: But yeah. I mean, how exciting is it to just walk around and pick diamonds off the wall.

Dr. Kara Fitzgerald: It’s amazing. It’s really cool. I want to talk about what we’re going to be doing, what we need to be thinking about as humans. But now let’s talk about, so you’ve made the mice old. NMN seems to be helpful for them. But then you also have this other remarkable study where you’re regenerating nerve cells, which is a hallmark of aging, optic nerve cells, I think, and using Yamanaka factors. So you’re turning back the hands of time by altering epigenetic expression. Can you talk about that?

Dr. David Sinclair: Right. We spent many years… Well, I should say my graduate student, Yuancheng Lu was ready to quit because he was trying all sorts of ways to reset the epigenome of old cells. And he kept getting cancer cells. He kept getting dead cells. He actually came into my office and he said, “I can’t do this. I have to quit.” And I said, “Well, just try something new.” What he decided to do was to try a combination of three of the Yamanaka transcription factors, which are used these days to make STEM cells out of regular cells, adult cells. And he did that, and he found that aging could go backwards in cell culture.

He was just using fibroblast skin cells. He didn’t use neurons at that point. But then he did something that was extremely brave. He said, “What if we just inject these three genes into the eye of a mouse and see what happens?” Most people don’t jump from basically skin cells to the eye, but he did.

Dr. Kara Fitzgerald: Yeah, why did he do that? What prompted that?

Dr. David Sinclair: He’s fascinated by the eye, anyway. His family is a group of eye experts. His father has a company that is making STEM cell replacements for the eye. And so, he was thinking that already. But in revisionist history, it’s partially true that we thought that the early very young central nervous system, including the optic nerve, can regenerate. But as you become older, it doesn’t anymore. And we thought, well, if we push those cells back to an early state, maybe they would repair themselves or grow back. And so, that was the idea.

The third reason, which really is true 100%, is that we knew that there were drugs about to be approved for treating eye disorders with gene therapy. And we’re both very interested in making translational discoveries, meaning, can we help patients? And if it worked in the eye of a mouse, we could go much quicker in treating a human eye. And so, that was the idea. And so, he went for it and he did one experiment first where he damaged the back of the eye with a pair of tweezers. We had collaborators, Zhigang He’s lab at Children’s Hospital in Boston, were the experts.

This is very difficult stuff, but what we found was after the crash, we could turn on the three Yamanaka factors. And we found that the nerves grew back and survived much better. Like they were young again, which was the first indication that we might be onto something.

Dr. Kara Fitzgerald: It’s amazing. And you actually turned them on, the endogenous Yamanaka factors?

Dr. David Sinclair: No, we don’t have the technology to do that yet, though. That’s what this morning’s lab meeting was about.

Dr. Kara Fitzgerald: Seriously?

Dr. David Sinclair: Yeah. I mean, we want to eventually just take a pill to do this.

Dr. Kara Fitzgerald: Yes. Or like eat an apple or maybe take a couple of grams of vitamin C.

Dr. David Sinclair: Although, vitamin C is one of the inducers of the TETs. Maybe you know that.

Dr. Kara Fitzgerald: Yeah.

Dr. David Sinclair: Yeah. So, yeah, we’re onto it, but we only have primitive technology where we have to use AAV, adeno-associated viruses to turn them on. And in those viruses, we fit the three genes and we put them under the control of the antibiotic doxycycline. So we could now feed those mice doxycyclin, on come the genes, and then we could turn that off three, four weeks later. The reason we wanted to turn them off is for safety reasons. When we go into people, which we hope is less than two years from now, we’ll have a nice safety switch.

Dr. Kara Fitzgerald: Okay. For folks who are just scratching their heads, so these Yamanaka factors, I don’t know a lot about them except that, as you said in the beginning, you can take a fully formed specialized adult cell and just bring it all the way back to pluripotent status. Correct?

Dr. David Sinclair: Yeah. That’s what they do.

Dr. Kara Fitzgerald: Okay. So then if you were to do that, like he’s dealing with regenerating an optic nerve, you don’t want to bring that all the way back to STEM cell status. You want it to stop as a nice, new fresh nerve cell, and regenerating vision. And that’s your hard, that’s why you’re stopping the journey kind of midway.

Dr. David Sinclair: Well, that was the trick, is that how could we do this without turning the eye into a giant STEM cell pool or a tumor? It’s called partial reprogramming. We tell the cell, “Go back to being young, but stop. Don’t go any further.” And we manage to do that by leaving out some of the other Yamanaka factors like c-Myc which is an oncogene. And it seems like we’ve hit upon the correct three-gene combo that’s very safe. We’ve tested this in mice for over a year in the eye and in the whole body. But it does take cells back to a very young state.

Dr. Kara Fitzgerald: Well, if you’ve tested it in the whole body, you’ve taken old mice and made them young, would you say?

Dr. David Sinclair: Well, no. We didn’t for safety reasons. So we didn’t analyze those mice extensively. We opened them up, so to speak, and had a look at the number of tumors. We didn’t let them get really old, unfortunately, which is what I would have liked to have done. But the reviewers of our paper forced us to kill those mice. So we’re going to have to repeat the experiment. But it’s not a perfect experiment because it’s not easy to deliver AAVs to the whole body evenly. They go to the liver and pile up there. What we’re working on now are new generations of AAVs that we can get more even distribution across the body. And that’ll be a better experiment.

Dr. Kara Fitzgerald: The adeno-viruses.

Dr. David Sinclair: Yeah, the adeno-viruses, because it’s still evolving technology.

Dr. Kara Fitzgerald: That’s so interesting. Will that be the technology that’s used in humans?

Dr. David Sinclair: Well, the AAV2 works fine for the mouse eye and should work fine for the human eye. It’s already FDA approved for that.

Dr. Kara Fitzgerald: That’s really interesting. Oh my goodness. Okay. All right. I’m going to just ground us in what we can do today. What can we do today to slow down our epigenetic changes, to slow down the clock, those methylation sites that Horvath has identified? You started our conversation by these three areas, of course, our environmental inputs, the longevity genes, and then the seven hallmarks with epigenetic alterations, I think you probably put at the top of your list. So what can we do now safely to slow everything down as we wait for adeno virus delivery of the Yamanaka factors?

Dr. David Sinclair: Yeah. Well, so the NMN, which is the NAD precursor, we don’t know if that does anything in humans yet, formally speaking. It’s mostly been in mice. I’m helping to run clinical trials right now with NAD boosters, including NMN. But the results are still early. They’re phase one results. So safety looks good. Efficacy, I’ll have to tell you in about a year from now. Yep. But I take NMN because it’s safe, apparently. And if we wait 10 years for proof, if there is such thing, it’s going to be too late for a lot of people, especially my father who is 80 at this point. He is taking some risk, but very small risk.

So there’s NMN. The other thing that I take is resveratrol. So resveratrol from red wine is the old story. It was controversial back and forth, but now we’ve proven or at shown pretty convincingly that it activates the sirt 1 enzyme directly, as we had said. And that if you give it to mice and to people, it has health benefits including lowering of cholesterol and blood glucose levels.

Dr. Kara Fitzgerald: What kind of dosage, in what form?

Dr. David Sinclair: I take a gram a day. I take it in powder form. Some of the early trials failed I think because it doesn’t get absorbed if you just pop it as dry powder in a capsule. And I know that as a fact. This isn’t just me speculating. So I mix it with some yogurt, a couple of spoons of yogurt in the morning so that it’s dissolved. It’s like trying to eat brick dust, the most soluble drug. It’s not a drug. It’s obviously a plant supplement. The problem with resveratrol is that when it comes straight out of the plant, it’s attached to sugars and it’s nice and soluble. But the processing of it means you purify the plain molecule which isn’t soluble. So that’s the point. I take a gram every morning.

Dr. Kara Fitzgerald: And then you take NMN with that?

Dr. David Sinclair: Yeah. Together. NMN is soluble, so you don’t need food, we don’t think. But yeah, resveratrol is a real trouble, troublesome molecule. We’ve shown other molecules activate sirt 1, going back to 2003, actually. Quercetin which you can get apples and onions, I think. Was it, Fisetin is another activator. I just take mainly resveratrol because I don’t want to take too many things at once. But I should say that I’m monitoring myself carefully to see if things get better or worse.

Dr. Kara Fitzgerald: Right. You talked about that, yeah. How are you monitoring?

Dr. David Sinclair: I have the Apple watch, I have the Oura ring, O-U-R-A. I also do blood tests through a company that I have to disclose I’m involved with and have a small investment in. It’s called InsideTracker. And they can come to your house or you can go to Quest or LabCorp and get a blood test. They measure I think more than 35 markers now. The usual ones, CRP, glucose, testosterone, vitamin D, the usual, but also some extras that are interesting. But what makes them special is, first of all, you can look at the graphs over time. But really their secret sauce is that they have hundreds of thousands of data points now, and they’ve mined PubMed, and they can tell you, first of all, what is optimal for you according to the literature, and also how to get into the optimal zone by changing what you eat and how you exercise.

Dr. Kara Fitzgerald: I love it. Okay. So we’ll link to that on the shownotes page, folks. It sounds really, really cool, David. So resveratrol. You’re doing a gram of NMN. Product quality for resveratrol. You can name brands, it’s fine.

Dr. David Sinclair: Well, actually I can’t.

Dr. Kara Fitzgerald: Oh, okay.

Dr. David Sinclair: No. I mean, I don’t do that for a number of reasons. One is I’ve never tested brands.

Dr. Kara Fitzgerald: Okay, okay. Okay, that’s fair enough. Okay, good.

Dr. David Sinclair: Yeah. The other thing I definitely want to mention is I don’t… What happens if I mention a company, even if it’s neutral, is that, my face, my quote will be up on their website. So I have to be really careful. And you can imagine how Harvard Medical School feels about that.

Dr. Kara Fitzgerald: Yeah. I appreciate that. I do, I appreciate that. But this particular podcast isn’t CME or anything like that. So, yeah, I’m absolutely happy to respect that. Any other interventions that you’re doing that you think are important for people to be adopting now?

Dr. David Sinclair: Lots. There’s a whole list on page 304.

Dr. Kara Fitzgerald: Okay. Yep. And we’ll link to the book. So yeah, if you don’t already have it, we’ll link to, I guess, I don’t know, Amazon or something.

Dr. David Sinclair: Yeah. And then, new developments that I see, I put out in a newsletter that’s also on the book’s website. And so, I’m always learning about how to optimize exercise and diet based on the scientific literature, mostly, and clinical trials, importantly.

Dr. Kara Fitzgerald: Good.

Dr. David Sinclair: Yeah. I mean, I can go through some of them if you like.

Dr. Kara Fitzgerald: Well, you know what? Your website is lovely, and it’s accessible, and you can sign up for the newsletter. So I don’t know. We need to kind of bring this home. I could pick your brain all day, but we do need to wrap up. So maybe just some final thoughts, be that you’ve already talked about, gave us some insight into where we’re heading. But if there’s something that we can engage in now, just give me some of your thoughts either on interventions for us to adopt or where science is going.

Dr. David Sinclair: Right. Well, I’m increasingly interested in alpha-ketoglutarate, which is a substrate for the TET enzyme.

Dr. Kara Fitzgerald: Interesting.

Dr. David Sinclair: There’s some preliminary evidence in mice that it extends their lifespan. This is Brian Kennedy’s work who’s over in Singapore, an old colleague of mine. So that’s interesting.

Dr. Kara Fitzgerald: Have you actually started taking alpha-ketoglutarate?

Dr. David Sinclair: A little bit. A little bit. I need to do it more rigorously and see what happens. Right now my life’s like everybody’s, a little bit out of control. So I’ll do it more rigorously later. But yeah, I mean, it tastes fine. It’s nice and acidic. It’s like eating citric acid.

Dr. Kara Fitzgerald: It’s been in our world in integrative medicine. We’ve been using alpha-ketoglutarate forever because it’s a Krebs cycle intermediate. Like that’s how we’ve thought about it. One company in particular would always put a little bit of AKG in an amino acid supplement for that reason.

Dr. David Sinclair: Right. Well, it may have that double benefit. We’ll see. I’m also really interested in oleic acid. O-L-E-I-C. It’s a component of olive oil and it’s in avocados and nuts, right? Everyone knows that. But it may be the reason why those foods are so healthy. And then, what’s happening at the cellular level was shown in a recent paper a few months ago, Doug Mashenek. I might be screwing the name up, but he did a brilliant study with his lab and found that the way resveratrol activates sirt 1 directly by changing how it moves in time and space, is the same way that oleic acid interacts with the enzyme.

So if he’s right, what it means is that, first of all, when we eat these foods where it’s basically like drinking red wine, you get an activation boost like resveratrol. But also what’s important is that oleic acid is a byproduct of fasting. When we fast, or should I say fast, now I’m American, but fasting will generate oleic acid out of your white adipose tissue. And that may be one of the reasons why being hungry is so good for you. And here’s the cool thing. We can test that.

We have a mouse that… Well, at least the mutation we published in science about 2013. We’ve now made a mouse that has the mutation that blocks resveratrol’s ability to activate. And we haven’t published this yet, but I’ll tell you that those mice don’t live longer when you give them resveratrol in combination with a high fat Western diet, which basically nails the hypothesis that resveratrol works through sirt 1 activation. So that’s nice to do because scientists at Pfizer gave me hell for a decade. The other thing about it is that we can now test whether oleic acid gives health benefits to those mutant mice. And if it doesn’t, then I think Doug’s hypothesis could be true.

Dr. Kara Fitzgerald: Isn’t that fascinating? And have you started that yet?

Dr. David Sinclair: Have we? I think we were about to before COVID came by, but we’re getting there. We’re going to start with cells from the mice, which is much easier.

Dr. Kara Fitzgerald: Very exciting stuff. I mean, these are some old school… It’s nice to hear about oleic acid. Of course, we’re all eating as many avocados as we can and certainly using loads of olive oil. But it’s really nice to revisit it, or alpha-ketoglutarate and see that it’s involved in these really key age-reversing, important mechanisms beyond just cell fluidity, which is what we thought about was monounsaturated fatty acids. Like there’s just way more levels to it that you guys are teasing out and in very interesting way as well.

Dr. Kara Fitzgerald: It has been just a pleasure to be able to talk to you today and I thank you so much for your time and just your willingness and your generosity with sharing all the things that are going on over at your lab. Good work. Extraordinary work. Thank you.

Dr. David Sinclair: Well, thanks Kara. Well, you keep up your good work too.

Dr. Kara Fitzgerald: Thanks. Thank you. All right, so we’ll continue this, hopefully, if you allow me pick your brain again sometime in the future. I would love to have you on again.

Dr. David Sinclair: Sounds good.

Dr. Kara Fitzgerald: And that wraps up another amazing conversation with a great mind in functional medicine. I am so glad that you could join me. None of this would be possible, through the years, without our generous, wonderful sponsors, including Integrative Therapeutics, Metagenics, and Biotics. These are companies that I trust, and I use with my patients, every single day. Visit them at IntegativePro.com, BioticsResearch.com, and Metagenics.com. Please tell them that I sent you and thank them for making New Frontiers in Functional Medicine possible.

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