How to Reverse Aging with Dr. Eric Verdin - Transcript
Dr. Mark Hyman
Coming up on this episode.
Dr. Eric Verdin
So aging is the accumulation of disorder. And and that disorder is caused by a whole series of external forces over which we have essentially no control. Think about gravity. Think about the gamma rays coming from, you know, interstellar radiation. Think about UV.
Think about, oxygen stress. All of these forces are there, and they're always gonna be with us. And and we know that they are the driving forces of the aging process.
Dr. Mark Hyman
Before we jump into today's episode, I'd like to note that while I wish I could help everyone via my personal practice, there's simply not enough time for me to do this at this scale. And that's why I've been busy building several passion projects to help you better understand, well, you. If you're looking for data about your biology, check out function health for real time lab insights. If you're in need of deepening your knowledge around your health journey, check out my membership community, Hyman Hive. And if you're looking for curated and trusted supplements and health products for your routine, visit my website, supplement store, for a summary of my favorite and tested products.
Welcome to The Dr. Hyman Show. I'm doctor Mark Hyman. And today's conversation matters because it affects all of us, and it's about how we age and perhaps how we may be able to slow down that process. And we're talking with one of the world's experts on aging, doctor Eric Burdon, who's the president and CEO of the Buck Institute For Research on Aging, a pioneering biomedical research institute dedicated to aging and age related disease.
He's a native of Belgium. He received his MD degree there from the University of Liege and then completed his clinical research training at Harvard Medical School, and he's published over 280 scientific papers in aging and metabolism. He's the guy, who knows more about aging than most people on the planet. He's worked on the molecular mechanisms of aging, mitochondrial function, inflammation, caloric restriction. He's a pioneer in so many ways, and is a really interesting great guy.
We had a deep conversation today about some really key elements that you probably heard about in the news, like mitochondria or the role of our own healing and repair system in activating longevity pathways. We talked about how do we diagnose, in a sense, the rate of aging, how do we look at our biological age as opposed to our chronological age. We talked about some of the exciting new developments in therapies from things like NMN and R, which help increase NAD in the body, to some of the key molecules that are being researched on reversing aging, like quercetin and pisetin. We get deep into so many topics. We literally could have talked for hours and hours.
I had to cut it after a while, but I think we're gonna have him back for a round 2 of the podcast because we didn't get to cover all of these I wanna cover, and you know I'm very interested in this topic. So go ahead and and, fasten your seat belts. This is gonna be a very interesting and deep conversation. You might have to look up a few things, but we're gonna put everything in the show notes, and, let's dive right in. Well, Eric, it's been so long that I've wanted to have you on the Doctor's Pharmacy podcast.
Your work has been an inspiration for me and the Buck Institute, which is basically the one of the few places in the world that's dedicated to study aging, is doing extraordinary work. And you're the president and CEO of that institute that now I think is leading the way in helping us understand the biology of aging, how to measure aging, and to understand the underlying mechanisms that are driving us to age rapidly and that lead to chronic disease. So I'm so excited to have you on the podcast and to dive deep into the science around it. It might get a little geeky, everybody, but I want you to stay with us. We're gonna explain everything as we go along, and and hopefully, you'll leave understanding the whole science of aging in in a much deeper way.
Dr. Eric Verdin
Thanks thanks for having me, Mark. Delighted to be here with you and looking forward to the next hour.
Dr. Mark Hyman
Yeah. Me too. So okay. So let's just start with with high level. You know, the there's there's a lot of research on aging happening now, but it's not always been that way.
Aging essentially was a neglected area of medicine, and in fact, you were ridiculed or dismissed if you even thought about studying aging because it was thought to be something that just happened that you couldn't do anything about. And now there's this whole field of longevity research and what we call geroscience, like gerontology, looking at the science of how we age, even thinking about describing aging as a disease or what we see as typical aging, which is, I think, abnormal aging as a disease. And and so the question is really, how do we need to think differently today given the science that we have, particularly around the underlying root causes of dysfunctions that happen as we age, the hallmarks of aging? How do we need to think differently about aging and disease going into the next decade or so?
Dr. Eric Verdin
That that's a good question, actually. And, the way the way I I think about it, and it's true, about 20 this is something that's relatively recent. About 25, 30 years ago, aging was considered sort of the backwaters of biology. This was an area that you did you did not go there because it was considered too messy. And and the way people use It was
Dr. Mark Hyman
bad for your career.
Dr. Eric Verdin
Bad for your career. Exactly. Well, people used to think about aging as chaos. So think about if you have a little bit of a background in physics, entropy. So aging is the accumulation of disorder.
And and that disorder is caused by a whole series of external forces over which we have essentially no control. Think about gravity. Think about the gamma rays coming from, you know, interstellar radiation. Think about UV. Think about, oxygen stress.
All of these forces are there, and they're always gonna be with us. And and we know that they are the driving forces of the aging process. What people had not appreciated, is the degree to which we actually resist these forces. And this is where the potential is. So think about, you know, we're not gonna change the fact that we're living in oxygen or that there is gravity and and gamma rays surrounding us.
But what had not been appreciated is the degree to which we resist these forces. For example, if you're lacking DNA damage repair, which is one of the consequences of of gamma radiation or UV radiation, you you're going to live to about 20 years old and you you're going to show in in those 20 years, very accelerated form of aging. And so, what people had not appreciated again, is is this idea of all of these repair mechanisms and how we can actually activate them. So what happened about 20, 25, 30 years ago is the identification of a whole series of mutations that could actually increase lifespan. And so this ran counter to everything we had ever thought about biology.
People thought about mutation that's typically deleterious. You get a mutation, you get a disease. And here were a number of mutations that were identified in in animal models, in in C. Elegans, the little worm that we study, or in in fruit flies, or in mice, they could actually double your life expectancy. So that really put the whole world of aging up on its head and highlighted the potential of, identifying novel interventions including lifestyle or drugs that could actually significantly increase lifespan.
And so initially, of course, these findings were met with a lot of resistance. People thought, well, this is an exception. This is only applying to c elegance or to fruit flies or mice. But over the last 20 years, you know, the work has really shown that there are a large number of genes and proteins that you could target and interfere with that will result in an increase in lifespan and health span. And and we are, right now, at a stage where this is slowly percolating into humans.
And I predict the next 10 to 20 years are gonna be transformative in our ability to bring all of this basic knowledge on on the biology of aging to humans.
Dr. Mark Hyman
I mean, that's pretty exciting what you're saying. I just wanna highlight something that I think is really important, is that historically, we've just thought that, you know, the body degrades over time and that there's no mechanisms to actually stop it or reverse it. And what you're saying is that the discovery of some of these mutations has led to an understanding that we have these built in what I call longevity switches, which is sort of a term that I kind of came up with, but built in repair, renewal, regenerative, and healing mechanisms that we have neglected that we can learn to activate through various interventions from lifestyle to nutraceuticals, to phytochemicals, to prescription medications, pharmaceuticals, or maybe even hormetic interventions, stresses to the body like hot and cold therapy. There's there's all these ways in which the body can actually activate these processes. And there's very there's very few of them, but they're influenced by so many things we do.
So there's so many redundant mechanisms that actually can activate these longevity pathways that we're now discovering. And to me, it's one of the most exciting times in science because for the first time, we're not really looking just at the downstream diseases that we typically look at in medicine based on diagnostic codes. We're looking at the upstream causes and the mechanisms. And the hallmarks of aging is sort of description that that kind of tries to describe some of these underlying causes and mechanisms. But sometimes I don't think they go far enough because they only talk about, well, these are the things that go wrong, not what are the causes of the hallmarks.
So the causemarks are the causes of aging on diseases. What are the causes of the hallmarks going awry? Right? So that's kind of an interesting inquiry. So I think this is such an exciting time.
And we're going to get in during this podcast. We're going to get into discussion of some of the ways in which we can regulate these ancient preserved, conserved pathways that exist across everything from worms to, to humans. Right?
Dr. Eric Verdin
Yes. It is. You're completely wrong. This is this is a really exciting time. You know, as a as a physician, and I mean, by training, I went to medical school, even though I did most of my my career in research.
I've always, you know, once a physician, always a physician. So I've always been intrigued by the relevance of what we're studying in these animal models to humans. And, it is truly a a a a an exciting time, this idea that something that we've always thought was, ineluctible and and and over which we had little control is is becoming another tractable problem. And and this is, you know, the excitement that you see in the field is a reflection of this. You know, one one number that I I like to remind people of is when we think about our own longevity, we, you know, many of us have a sort of a fatalistic approach to it.
We think, you know, my my parents didn't live very old, and therefore, you know, I might as well have another cigarette, another glass of wine,
Dr. Mark Hyman
and show them
Dr. Eric Verdin
enjoy life while it's there. But it it turns out that, you know, about 93% of our longevity is determined by our lifestyle factors.
Dr. Mark Hyman
93? That's a very specific number.
Dr. Eric Verdin
Well, that that's the result of a, of, of a great study by Calico, looking at ancestry.com, they were able to sort of revise a number which used to be about 80%. People used to think about 80% of lifestyle was determined, was determining, health span and lifespan. But the number they came up based on millions of people and and records appears to be 93% lifestyle, 7% genetics. That's true only if you and the only exception to this is if you have an ancestor, someone in your first degree relative who has lived above a 100. Then there's some likely genetic factors.
It means you're most likely protected, and you you can have another cigarette than a Well,
Dr. Mark Hyman
I have an Apo I have ApoE 2 as one of my ApoE leads. So I call that the jackpot gene.
Dr. Eric Verdin
You're one of the lucky ones.
Dr. Mark Hyman
Yeah. So I don't know what that means exactly, but I have APOE 2, 3. So I think I don't know how far I can go. How much ice cream can I actually eat before I get into trouble? That's kinda what I wanna
Dr. Eric Verdin
know. Probably more than me. I'm I'm I'm I'm I'm E3 E3, which is already good.
Dr. Mark Hyman
That's that's average. That's good. Okay. So let's let's get into the conversation around 2 two aspects, which one is, what are these mechanisms and pathways? Let's and then let's talk about how we how we and the research at the Buck Institute is actually uncovering ways in which we regulate these.
But before we do that, I wanna go into sort of a conversation that was preceding that, which is how do we measure aging? How do we know if what we're doing is working? And this is the whole discussion around how do we measure biological age and how do we look at our biological clocks. And there are so many out there. I think you were on a paper that I read that listed all of the different kind of clocks and the pros and cons of each one, which I was great.
It was great because I I was like, well, I don't know. This is very overwhelming, but it really helped for me to understand that. And, you know, personally, I did the true diagnostic DNA methylation test. I don't have any affiliation with them, but I just did it 2 years ago and when I was 62. And then I implemented a whole bunch of interventions, including more aggressive lifestyle change, different nutraceuticals, analytic supplements, which we'll talk about, as well as different kinds of treatments like plasmapheresis and exosomes and stem cells.
I just kinda went. I did it all. And then I also did rapamycin. And I was like, how far can I change this biomarker? And so I just throw the kitchen sink at it, which is not very scientific.
I get it. But I wanna I'm gonna end up 1, so I thought it was you know, we're trying. And I went back even though I got 2 years older, and I'm 64. On the same test, I went to from 43 when I was 62 to 39 when I'm 64. So I bent back 4 years even though I got 2 years older.
And so how reliable are these clocks? You know? Am I just falsely enthusiastic about my own result? And what are the things we should be looking at? Is it the need and pace of aging?
Is it demethylation? Which, you know, what are the what are the things that actually are worth looking at?
Dr. Eric Verdin
Yeah. That's a the whole idea of biomarkers of aging is going to be critical, and and and here's the reason. We, we go through life right now, sort of hoping, you know, that things are gonna work out for the best. And traditional medicine essentially waits for you to get sick, to really start intervening. So there is a need, a crying need for, what we call surrogate markers.
Markers that would be able to predict, you know, how well are you aging. And when we talk about biological aging, or biological age, this is in contrast to chronological age. So, you know, just for your audience, you you can be 40 years old, but your your body can be behaving more like the body of a typical 30 year old, or like the body of a typical 50 year old. That would be your biological age. And by the way, we, you know, we are also able to generate an estimate of biological age.
If you've if you've met someone who's 70 years old and you think that person looks younger, you have you have you have defined in your own head that this person is biologically younger. And and this by the way, these these are true, variables. They're actually algorithm that will predict your age simply based on facial recognition, just like we do. And, so there's been a lot of interest in the field, of generating more precise and more predictive biomarkers of biological age. The reason being, not just to be able to, you know, to tell you where you are on your trajectory, but also to assess the efficacy of our interventions.
And you you just described, you know, your n of 1, which is critical, which is okay. You start a whole series of interventions. How do you know you're actually helping yourself versus hurting yourself? And so this is where the these clocks are coming into play. Now we are right at the beginning of of a whole field.
So, I did, you know, the same thing as you did. TruDiagnostic, I I don't have any affiliation with them. We collaborate with them. I think they are the best company right now in terms of, providing a large number of, assays. And I say, large numbers is I think, is key.
They are right now, there's a proliferation of these clocks. Many of them are epigenetic clocks. They're measuring, methylation in DNA. The reason is not that these clocks are better than others, it's just that historically, they were the first one. And this is work pioneered by Steve Horvath and his colleagues.
So I did the same thing as you did. I measured all my clocks, I'm 67 years old, and my clocks came between 2567. And of course, I I look at the 20 the 25 year old clock, and I say, that's a really good clock.
Dr. Mark Hyman
That's good. So I'm jealous now.
Dr. Eric Verdin
And and that's that's gly glycan age for whatever reason. Yeah. But the other clocks, you know, frankly, varied between 42 and 67. So the question is, you know, how do you how do we sort through this? And Well, you just pick
Dr. Mark Hyman
the best one. Don't you? Just pick the best one.
Dr. Eric Verdin
Well, I picked
Dr. Mark Hyman
the best one. Exactly.
Dr. Eric Verdin
So, so I mean, there's obviously, there are some significant problem with this. These are not, approved, clinical tests. But I still think that they have value. And their value really comes back in in repetitive measurement, just like you said. So you you you you first, you need probably to measure many of them.
The paper that you're referring to is a paper in which we did, plasmapheresis and a number of patients, with a company called Circulate. And and we found on on a global scale that most of the clocks actually went back, when these patients underwent, plasmapheresis. So but again, there was extreme variation between the different clocks. So I tell people, if you if you wanna use the clocks, companies like TruDiagnostic will give you many numbers, they will be all over the place, but the true value comes in looking at how they change over time. Now the the prediction is that over time, we we will not only have these epigenetic clocks, we will have proteomics clock, metabolomics clock, facial recognition clocks.
You know, there there's a proliferation of these clocks right now, and they paint a pretty complex picture, and I think they will allow us to do truly preventative medicine. Some of these recent clocks, for example, proteomics clock by Tony Whisqueray at Stanford, are able to measure organ specific aging, which is gonna be really critical. Because of course,
Dr. Mark Hyman
you
Dr. Eric Verdin
know, as we age, we are always limited by the, what I call, the rate limiting organ. It could be your liver that's gonna fail first, and you would wanna know and and do, you know, an intervention that favors your liver versus your brain versus your heart and so on. So I think we're right on the cusp of a rev revolution in diagnostics, and these epigenetic clocks is the first the first symptoms, going in this direction.
Dr. Mark Hyman
So basically, it's it's all getting shaken out right now in the research. Yes. Exactly. And and we're gonna learn which are the best clocks, and we'll learn more and get better. But in the meantime, what what I hear you saying is stick to one assay and repeat it over time based on what you're doing.
Because if it's off, it's off by the same amount every time. And what you're looking at is a change from the baseline, either worse or better. So
Dr. Eric Verdin
But interestingly, you know, another anecdote, for example, someone did an interesting experiment where they they measured, the clocks at different times of the day in the same person. And they found they found over the 24 hour period, the clock would vary by 5 years. So that's
Dr. Mark Hyman
because I'm older at night. I know that. I feel older at night. In the morning, I'm good. I'm, like, 25.
By the time my night comes, I'm 70.
Dr. Eric Verdin
Mean meaning that, you know, if if you're gonna do this, do it every time at the same time of the day because there's obviously there are no variation in there.
Dr. Mark Hyman
Great. Okay. So so now we have these clocks. Let's say we can measure these these changes that happen as a result of interventions. Let's talk about some of the most exciting work at the Buck Institute looking at the the sort of underlying things that that really regulate aging around, we call cellular senescence, which is zombie cells, the cells that kinda spew out inflammation throughout the body, are, looking at our metabolism and how our nutrient sensing pathways work, which I think I wanna get into fair fair fairly deeply, stem cell and stem cell biology and protein, protein function.
And then how do we sort of make sense of it all through bioinformatics and systems biology? And I know you've recently partnered with Leroy Hood, who's just a brilliant scientist. So I'm curious about, like, how how you start to think about where where are the most leverage points that you're seeing in the data that you're looking at, in the research you're doing at the Bunk Institute about what's working, in all these different areas?
Dr. Eric Verdin
So maybe I'll I'll just take it one step backwards, and and just to alert your audience to the fact that there are no there will be no magic pill. Aging is an incredibly complex mechanism, and, you hired you alluded to earlier in our discussion to these hallmarks of aging, which is think about it as a catalog of all of these abnormalities that happen during aging, and that includes epigenetic dysregulation, senescent cells, nutrient failed nutrient sensing, defective stem cells, defect in mitochondrial biogenesis. There's all kinds of problems that happens during aging. By the way, they're all connected to each other. And when we think about aging and and solving it, I think, if you study it, you will realize how complicated a process is.
And and that, you know, we at the Bak Institute, we have about 300 people working on aging. We don't take sides in a way that I I cannot predict what's going to be more important. So we we study pretty much every one of the hallmarks of aging. We obviously have a big emphasis on senescence because it was mostly discovered, through the work of Jenny Campisi at the back. So many of us are still working on senescence, but we have people working on mitochondria, we have people working on stem cells.
We have people working on metabolism, and so on. So I I think, one of the the the things that is really emerging right now is is the complexity.
Dr. Mark Hyman
And I think that's so important that you point that out.
Dr. Eric Verdin
It's important it's important because, you know, frankly, I have I've I've sometimes been called the grumpy man of of longevity research, because I I I I refuse the hype of work. I think, there's a lot of really exciting things happening in in Asian research, but I'm not deluding myself. I I don't tell people I'm gonna live to a 150 or a 170, like some of my colleagues do. I I think, you know, right now, we are focusing on on things that are really tangible. For example, you might be surprised to to to hear that most of us could live to 95 years old in good health, if only we would sort of deploy everything that we know.
That's already a lot better than what we have today, where we most of us would live to 65 in good health. So, you know, that's an extra 30 years of healthy life. And right now, we are really focused on on 2 things at the back. We on the basic biology of aging, again, we don't take sides. We study all of these processes and how they relate to each other.
The the bigger, aspect, that is being grown at the Bak Institute is the whole human aspect. Really, taking all this basic knowledge and translating into actionable interventions that I can tell you and other people, this is what you should be doing if you wanna live the longest
Dr. Mark Hyman
possible. Yeah. I mean, I think it's so important what you just said around the the nature of nature, which is and it just reminds me of a quote from John Muir, who was a naturalist in the 1800s who said, when one tugs at a single thing in nature, he finds it attached to the rest of the world. And and essentially, what what I see happening often in research is the reductionism even within the science of aging, Where, oh, it's this hallmark, or I'm gonna focus on mitochondria, or I'm gonna focus on inflammation, or I'm gonna focus on deregulated nutrient sensing, or I'm gonna make something that's gonna lengthen telomeres or kill zombie cells. And that's where things get into this reductionist mindset that doesn't understand that all these interact.
They're all dynamic. It's a web of connections and interrelationships that all either positively reinforce each other or negatively reinforce each other. And so and and a lot of these ancient longevity pathways, and I think and when I think of this, and I would love to hear your opinion about this, is is that they there's kind of a a way to kinda influence a lot of it through the same kinds of interventions, obviously, the lifestyle stuff. But when I think about, for example, the the 4 d regulated nutrient sensing pathways that tend to go wrong, mTOR, insulin signaling, AMPK, and sirtuins, which I know is a lot of mumbo jumbo. We'll explain all that, I promise.
But these are these are what I call the longevity switches. And it seems that they they they're affected by what we eat, but they're also affected by various kinds of other things like exercise or various hormetic stresses or other factors and that they affect all these other hallmarks. So like mTOR, m p a, all these things affect mitochondria. They affect inflammation. They affect oxidative stress.
They affect your epigenetic regulation. They affect DNA repair. They affect senescent cell. I mean, this is when you sort of start to dig into it, it's like it's everything is affecting everything. So what's the highest leverage point?
And and and and and, again, I'm not a longevity researcher. I'm just sort of a doctor trying to make sense of all this. Is is the it seems like the deregulated nutrient sensing is one of the most important, almost meta hallmarks because when you address those 4 pathways, it it downstream benefits all the others. Am I am I off, or does that make sense to you?
Dr. Eric Verdin
I I agree. I'm not sure.
Dr. Mark Hyman
Okay. Because this I made this up. I made this up. So
Dr. Eric Verdin
No. I I I do agree. Although, there are you know? So when I think about the the buckets of in which you should invest if you want to maximize your longevity, nutrition is clearly one of the top ones. And, but equally important is exercise.
But by the way, exercise or physical activity affects all of the same pathways that we just discussed, you know. So it's it most of the time, I I I sort of reduce this to the fact that we're dealing with energy generation. And and, you know, so if you think about, exercise and nutrition have this in common, they are both profoundly dependent on your ability to generate a lot of energy, and and so and and the proper energy. And there's one theory of aging that posits that one of the things that happens as we age is our ability to generate energy decreases. And since, you know, for example, the repair function that we were discussing earlier, our ability to repair DNA, to repair proteins, and so on, is also incredibly dependent on energy.
So as energy supplies dwindle, our ability to make sufficient energy becomes limiting, then, you know, and if you have the choice between repairing your DNA or actually walking, your body is gonna is gonna is gonna favor the walking. And, so so there's there's, there are lots of common threads between all of these variables, and, I'm happy to to dive into this.
Dr. Mark Hyman
Yeah. Yeah. Let's dive into it, because I think I agree with you. I think the mitochondria are central. It's really about the the how we create and make energy as well as how we protect, preserve, and improve the number and function of our mitochondria.
And and I would say that sort of the difference between a 2 year old who's, you know, running around like crazy and can't stop moving versus a 92 year old who's just sitting in the chair, barely can move is the health and function of their mitochondria. And and a lot of your research has focused on on mitochondrial function aging and, particularly around the, role of NAD and, ketogenic diets, for example, and the role of of, the role of sirtuins in regulating mitochondrial function as well. So, and I I think I'd love to dive into this whole topic with you a little bit more because you're such an expert in it. You know, what what have you learned about, how mitochondria are regulated and how they play a role in aging? And what are the most, salient things we've learned about how to improve the number and function of mitochondria from lifestyle all down to nutraceuticals and even medication?
Why don't we dive into that? Because you're you're, like, the world's expert here.
Dr. Eric Verdin
Lots of drawers to to open there. Yes. So when when we think about energy so let's backtrack. So, you know, our energy we generate energy from essentially burning food in the presence of oxygen. Think about, when you throw coals into a fire, if you blow air on it, you know, the fire will get more intense.
So this is the same thing. We burn carbohydrates, lipids, or fats, and and proteins in the presence of oxygen to generate energy. And, you know, this process takes place at many places in the cell, but predominantly in the mitochondria, which by the way are are sort of commensal bacteria which have become incorporated into our cells. So this is something of fusion that happens, you know, billions of years ago. Quite quite interesting biology.
So these mitochondria are generating the ATP that we use as energy, and also the NAD, which we use as a it's not a it's a form an intermediate form of energy, and we can come back to this later. Now it turns out that, mitochondria numbers dwindle with aging, and and their ability to generate energy dwindles with aging. And there are multiple variables that that are causing this. Some are mutations in the DNA. So the mitochondria have their own DNA, which is an ancestral bacterial DNA.
They accumulate mutations, their numbers decrease, the NAD levels, which is this critical intermediate, dwindles as well. All of these factors lead to a progressive and and worsening, energy deficit as we age. So there's a lot of interest in trying to understand how do we reverse this and how do we how do we prevent this from occurring at the first place.
Dr. Mark Hyman
So so so clearly, the mitochondria are key, and and the question then is, what what can we do to help our mitochondria? Because if if what you're saying is true that they're central to aging, both healthy aging as well as unhealthy aging, then it seems like they're a major target for intervention. And, there's a lot of stuff floating around there in this sort of literature and also in the sort of cultural zeitgeist around interventions that help to regulate mitochondria from, you know, fasting or ketogenic diets to things like rapamycin or other phytochemicals that may be able to regulate mitochondrial function like urolithin a. And I just, you know, just wonder how you how you sort through all the massive data and information around around all of this, and where you start guiding people practically around how to make sense of the data.
Dr. Eric Verdin
Yeah. So, you know, as I mentioned, so there there's loss of mitochondrial number, there's loss of mitochondrial function, and there's loss of mitochondria, you know, key metabolites like NAD. And so I think when I think about, you know, what can you do, it ranges from lifestyle intervention all the way down to some of the drugs that we're actually working on. So I I the the two ways in which I think you can maximize your mitochondrial function as you age is fasting, And fasting, as as I mentioned earlier, activates a process called autophagy, which means self eating. So and the beauty of autophagy when you're fasting is that your body is able to sort through the garbage and the and and the well functioning mitochondria to discard the poorly functioning mitochondria and to keep the ones that are most efficient, so the process called mitophagy.
So intermittent fasting, I think, is is part of, you know, the ability that your body has to shift between feeding and fasting is is a process that we call metabolic flexibility, and I think it is really an integral part of health. So, I encourage people to, you know, to incorporate this into their daily routine. Another way in which you can process
Dr. Mark Hyman
What you mean is, just to what you're asking is to give people a break between dinner and breakfast is essentially what you're saying, like
Dr. Eric Verdin
Well, yes. That's one way to do it, actually. And, you know, right now, we're at the stage where there are a whole bunch of different fasting modalities have been, explored and tested, and, I I don't think there's clear evidence that any of them is is is more beneficial than another. Some people will do, you know, a deep fast every 3 months, some people will do, some fasting every day. I think there are, we're still at the stage where these different modalities are being compared and and and trying to decide what is the best way.
But any of them is better than none. That would be the the rule that I would and practically for me, I do, you know, I do a 5 day fast, every 3 months, and then I do I do sort of what people call restricted time feeding, which meaning I I try not to eat for 12 to 16 hours every day, so to at least have a a period of fasting. There are also, a number of interesting supplements that are emerging that are, supplements or drugs. You know, there's, the interest in fasting came out of the realization that animals, on calorie restriction, so who whose calorie intake was limited, actually showed the increased lifespan. That that's pretty much a universal feature.
So that led to study of fasting, but also led to the discovery of what we call these fasting mimicking or calorie restriction mimetics. So drugs that are fooling your body into thinking that you are under calorie restriction or fasting. And those drugs, you know, some of your audience are
Dr. Mark Hyman
Well, running around starving all the time.
Dr. Eric Verdin
Exactly. Exactly. So, you know, metformin, you you I'm sure you've heard about metformin or rapamycin, our calorie restriction pneumatics. So they they fool your body to think that you're fasting, and they induce, parts or all of the protective response. And this is why some of these drugs are being explored for their potential, anti aging effect.
There are also supplements that are emerging. There's a process called mitochondrial biogenesis, which is the process by which you are making new mitochondria. And we know, you know, we know the pathways, the biological pathways that lead to this, and and some of them can be activated by drugs or supplements, Supplement, for example, that, activates, mitochondrial function would be, the urolithin a. I'm sure you've heard, product, sold by
Dr. Mark Hyman
Oh, I take it every day.
Dr. Eric Verdin
Yep. I I take it every day too. And, you know, it's a supplement, so it it it's not going through the same process that a a FDA approved drug would be, but the company that, you know, commercializes this called TimeLine has has a very proactive approach to testing, you know, doing clinical trials, and demonstrating the efficacy of of what they are claiming. And we've collaborated with with them, so I can I can I can attest to some of the results that we've published with them? So really interesting supplement.
And the last one, I mean, that I you know, physical activity exercise is is certainly a very strong way to activate mitochondrial function in your muscle. And we know, you know, your muscle mass is a very strong predictor of your life expectancy. So anything that benefits your muscle, having strong mitochondria, bulk, frankly, also of your muscle will will lead to protective effect on your brain and other organs as well. So, obviously, you know, when are we talking about anything related to aging? Reductionist approach works for a while to try to simplify the models, but once you start thinking about anything, it's connected to everything else.
Dr. Mark Hyman
That's right. And and the, you know, the thing around the the the mitochondria, also that you've done research around is, NAD and and, you know, NAD plus. And there's a lot of, you know, controversy around this particular compound. You know, some say it's kind of the data isn't there. Some say it's God's gift to mankind, then we should be all taking it.
What's your kind of, you know, sort of down and dirty on the science behind NAD and taking NAD either as a NMN product, NR product, or sub q NAD or IV NAD. I mean, this is all these people are doing these things, including me. So I'm I'm curious about what your perspective is, someone who's actually done the research.
Dr. Eric Verdin
Yeah. Happy to talk about this, because, frankly, it's it's once you are involved in the research and you see some of the stuff that's being sold, it's sometimes I shake shake my head in disbelief. But, that being said, there's like, in any story, there's always an element of of truth to to to the whole NAD story. So just a a word about NAD is a molecule that allows you to shuttle energy, between different parts of the cell. So this is a purely intracellular molecule.
So this is not something that lives in the blood, and so, you know, this will be important because there's a whole fad right now of intravenous NAD, which frankly does not make any sense to me biologically. But, so NAD is an intracellular, and it doesn't cross from the blood into your cells. So it just, it's, you know, it is an intracellular metabolite. Why is it important? Because it allows you to shuttle energy between different parts of the cells, from the mitochondria to the cytoplasm and so on, or different different from different molecules, within the cell, more correctly.
So it's also known that NAD levels decrease during aging, and and this is, that's really well established in humans and in animal models. So out of this came the idea that maybe this is one of the reasons why we have this global energy deficit as we age. Maybe we're not able to manipulate. So when I think about, you know, NAD, you think about Brinkman, you know, the trucks that carry, money. So think about if they all went on strike, all of a sudden, you know, the energy of the economy, which is money, would be stuck in in the supermarket and nothing moves anymore.
So this is the same thing. And so, I think about them as the the the the the fund carriers. So out of this can be ideal, maybe we can just reestablish NAD levels, and so people will see a benefit. And and in animal models, you can do this using, what we call NAD precursors. And there are 2 of them that are you know, you're familiar with, nicotinamide riboside, n r, or nicotinamide mononucleotide, n n n.
And both of them essentially do almost the same thing. Some colleagues will argue vociferously on whether one is is superior to the other. At the end, they both reestablish NAD levels. They might have additional signaling properties in addition to this, but, and in animal models, they do remarkable things. So, you know, we've published we and many other people in the field have published a number of papers showing that NAD supplementation in older animals really alleviates some of the, effects of aging.
It does not increase lifespan, I should say, but it certainly alleviates many of the disease complications and so on. So out of this came came the interest, well, maybe we should bring this to humans. Now, and a number of companies are selling NR and NMN. One significant issue is that the amounts that are being sold as supplements are much lower by a fact by a factor 10 of what we use in the laboratory setting. So, you know Like, the most bottles have,
Dr. Mark Hyman
like, 250 milligrams if you
Dr. Eric Verdin
need to. But you're saying
Dr. Mark Hyman
you need more, like
Dr. Eric Verdin
We used 2 to 3 grams. 5 grams. Exactly. Wow. So we used precursors.
Yes. We used a lot more. And those of us who take NMN or NR typically take a lot more than the the 200 milligrams, a day.
Dr. Mark Hyman
Well, would you say, take 2 grams or 1 gram, or
Dr. Eric Verdin
Well, that's I take a gram when when I most of the time. Now the obviously, what we need is more clinical data in humans. And, a lot of noise has been made about a couple of initial studies that failed, and, you know, and and that's, you know, that's true, Peter. TI is highly skeptical, and and there are, you know, there are really good reasons to be skeptical about some of the claims that have been made for NMN and NR, but I think my argument is that's not through the baby with the bathwater. And there is, there's enough compelling evidence in model systems that, NMN and NR actually are having interesting effect that pursue the studies and to conduct the clinical trials.
Now one one of the biggest problems I have is why is asking the question, and it's something my lab has been working on, why are NAD levels decreasing during aging? And that really has not been studied by many people except us and and Eduardo Chaney, who was at was at Mayo Clinic. And what we both found is that the reason why NMN NAD levels decrease during aging is because there's another molecule called CD 38, which is activated during aging for reasons that are not entirely clear, but in in part because of the senescent cell burden. So the CD 38 is itself as NAD hydrolase. It chews up NAD.
And so when you give, NR It's an
Dr. Mark Hyman
enzyme like Pac Man that kinda eats up your NAD.
Dr. Eric Verdin
Exactly. So the think about your NAD pool, like water in a sink. The problem that we're having is a leaky sink. So there's something that's chewing up the NAD. And when you give NMN or NR, you're essentially filling up more water in the leaky sink.
And so which is not a very satisfying way to solve a problem. So the the way we are going about it, and a growing number of companies are are doing this as well, is to actually identify small molecule inhibitors of CD 38. And so I have a startup called, NAPA Therapeutics, which, you know, has a large number of these novel molecules. We're testing them. Some of them some of these inhibitors, and not not ours, but others have been shown to increase lifespan, and to correct, some of the aging associated energy deficit much more, sort of, efficiently than than the precursors.
So my prediction is that if you think about NAD defect in the future, in the long run, we probably will be looking for, you know, these CD 38 inhibitors rather than filling up the tank with with more water.
Dr. Mark Hyman
Interesting. So it's in essentially stopping the breakdown of NAD rather than just taking more precursors of NAD. Exactly. The hole in the bucket. You can keep filling the bucket faster, but at some point, it's kind of diminishing returns.
Better just put the hole in the bucket.
Dr. Eric Verdin
You got it. You got it. And, you know, one one reason, you know, for doing this is and and this is it speaks also to the the importance. A lot of people are taking a lot of supplements these days, and they're not being followed appropriately by physician. As I was taking a lot of NMN, I was always concerned because we know that, NMN, as its being, if you take a large amount of it, will consume your, your one carbon, your methyl groups.
And so I was as I was doing this, I was always following my homocysteine levels. And actually, I found it to, you know, to rise significantly in the presence, of large amount of, NMN intake. And and, you know, and if I if it goes too high, I stop my NMN for a while. So speaking to the fact that all of these processes are connected, and I I I'm I'm somewhat worried about, you know, the proliferation of of supplements that are being touted and sold to some somewhat naive public hoping, you know, this is gonna increase my lifespan. There are a lot of there you know, there are very few molecules that have absolutely no consequence, and and I think, you know, if you go down go down this route, do it with someone, you know, that knows, understands the biochemistry, and can follow you appropriately.
Dr. Mark Hyman
It's interesting. I mean, basically, just to summarize what you said is that the precursors, NR and NMN, which are available, and we don't have to talk about which companies produce the best ones, but let's just assume you're getting the best one, will actually lead to an increase in NAD levels. But if you do intravenous or subcutaneous NAD plus, it won't, and that you might be wasting your money.
Dr. Eric Verdin
Yes. You are you know, a typical NAD infusion costs about $700. There are studies showing what happens when you inject NAD intravenously. It goes to your liver, and it is cleaved into nicotinamide, NADP Ribose. Now the nicotinamide is essentially niacin.
You know? You can buy this for, you know, 20¢ or whatever. So this $700 injection, I I I really have no idea. Actually, no one has any idea what happens to it. Most of it is likely very quickly degraded.
Dr. Mark Hyman
And And that's why you feel that kinda weird flushing feeling when you get the NLP?
Dr. Eric Verdin
Well, niacin, niacin, as you know, will activate these flushing receptors. This was one of the, you know, the limiting use of niacin as a as a a drug, but at cholesterol lowering, a few a few decades ago, people had, had some flushing issues. It's the same thing that you're feeling when you're taking intravenous, nicotinamide. Yeah.
Dr. Mark Hyman
There there's an anecdote, and I don't know what to make of it, was I I had a I did a retreat, on longevity, and one of the the the local companies who's in Turkey, offered NAD as part of this. And there was a woman who had Parkinson's who was quite severely affected. And we know that Parkinson's is a mitochondrial disease. And her her response was pretty remarkable. Like, her tremor stopped.
Her gait improved immediately. Like, it was like an immediate shift, like, someone taking l dopa. And I was like, well, that's interesting. Wow. I don't know.
I don't know. This is an anecdote, but I I I imagine it's doing something. And, yeah, it's a it's not a fun way to take it, you know, intravenously, subcutaneously. You can also do it the same thing. It seems like it would lead to the same kind of result, but it's it's fascinating data.
So what you're saying about NED is that it and the precursor essentially is it doesn't necessarily extend lifespan, but it improves quality of life and health span. Would that be accurate?
Dr. Eric Verdin
That that's the prediction, and that's what we although, you know, the there's evidence that CD 38 inhibition or deletion actually increases lifespan, so that might be one way to put back this whole pathway in the context of longevity.
Dr. Mark Hyman
Wow. And that's what NAPA Therapeutics is working on, right?
Dr. Eric Verdin
This Yes. Yes. Absolutely.
Dr. Mark Hyman
Incredible. Amazing. The the, God, I mean, I I feel like we need to go have another one of these podcasts. I might do this in 2 parts because go go on forever.
Dr. Eric Verdin
Any anytime. Happy to come back.
Dr. Mark Hyman
I I I there's so much more I wanna get into on inflammation, around nutrition, around, the microbiome and aging and many, many other topics. But I I would love to kind of just finish up for the last few minutes on 2 topics. 1 is what are the all star molecules for longevity? And I and I I have a list that I wanna sort of get your thumbs up, thumbs down on. And 2, what do you do, not as a scientific kind of, kind of clear scientific protocol, but as your own self care based on what you know as someone who's an insider.
Like, it's almost like insider stock trading. Right? Like, what are you what are you doing? So the the the molecules that I I think, you know, seem to me to be the most promising are, around the rapamycin molecule, which is a drug that we've talked about in the podcast before essentially is inhibits mTOR, which is one of these longevity switches that regulates everything from muscle protein synthesis to autophagy to inflammation to mitochondrial function to DNA repair. That's one.
Then there, you know, the metformin question, which I think is a little probably a little longer than we have to get into, but I'm I'm a little dubious about it. And I don't know if we're gonna get to the TAME trial now, which is a randomized trial that's gonna give us the answer, unfortunately. And then there's all the sort of phytochemicals like quercetin, fisetin, curcumin, green tea extractor, epigalactylcatacin, gallate, phytochemical that can be derived from pomegranate. Among all these sort of players, you know, which are ready for prime time, which have sort of low risk potential benefit, which should be we careful with, like, how do we think about this?
Dr. Eric Verdin
It it's a tough one. I tell people, you know, if you wanna
Dr. Mark Hyman
In 5 minutes or less.
Dr. Eric Verdin
Okay. So I'll I'll start. 1st, I think, before taking any supplement, I think, people should optimize the rest of their lifespan because there's nothing you know, if you have a wound that's infected with a bacteria, you don't put a Band Aid on it. You you start getting
Dr. Mark Hyman
So let's assume everybody's exercising, eating perfectly, sleeping great, managing stress, and removing toxins from their life. Okay. We've done all that. Now we're gonna
Dr. Eric Verdin
Very, very few people do this. So the next step would be to have once you've optimized all of this the best you can, and I think about them as buckets, you know. And I
Dr. Mark Hyman
agree with you, by the way. I agree.
Dr. Eric Verdin
You can make in because a lot of people, you know, will go to supplements. They don't wanna do any of the other things, and the and they're missing, you know, they're missing the really powerful stuff. This is where you know, the reason I'm bringing I'm making this point so strongly is that the the we we do not have and will not have for the next 20 years an antiaging medicine or supplement that is better than physical activity. And I you know, mark mark my words, for 20 years, in 20 years, we will still not have something that works as well as physical activity.
Dr. Mark Hyman
It's a miracle drug.
Dr. Eric Verdin
It is a miracle drug. And so, if if you are sort of not paying attention to that one, well, you can sort of put a band aid on on some issues, but you'll never really get to the core problems. Now, thinking about the rest, first for me is blood draw. You know, are you are you balanced in terms of vitamin d, vitamin b 12? This would be the first the first big ones.
And I'm I'm surprised how many people tell me, friends and colleagues, no, I don't know what my vitamin d is. So that's number 1. Number 2,
Dr. Mark Hyman
there are some By the way, that's why I started Function Health, which was to give people access to their own data, including all the things we've talked about, inflammatory markers, the inflammation markers that we talked about as well as vitamin d and methylmalonic acid and homocysteine, all the things that we wanna know. Right?
Dr. Eric Verdin
Exactly. You're also you're you know, I don't know if you're measuring this, but your omega fatty acid. Levels.
Dr. Mark Hyman
Omega 3 fats, a 100% ratio. Omega 3 fats, insulin, lipid fractionation, all the things that you should be measuring to see what your metabolic health is and your mitochondrial health is.
Dr. Eric Verdin
Critical. So, you know, there are a few supplements that have documented efficacy. One of them is omega fatty acids. And, you know, especially if you are like most people in the western world, and you are you don't have access to enough of them. So omega fatty acid would be one of the top ones for me for everyone to take every morning and every night.
If you're exercising, you know, carnitine is is really one of the well recognized supplement that that people take. Now we talked about a whole variety of flavonoids, quercetin, curcumin, fitsetin, all of those. The problem with many of those is, bioavailability. So much of what has been shown about their efficacy is is based on studies where the the the chemicals are added directly to cell. The problem is, you know, before the chemicals get to your cells, they have to go through the gut and have to be absorbed and all this.
Most of those have extremely low bioavailability. Now some companies are trying to remedy this by making them into phytosomes and all of this, but most of the time, the data is just not there that these things are getting absorbed to a significant level. So I I have, you know, I have my doubts.
Dr. Mark Hyman
Take the pill, and then your blood levels don't reflect
Dr. Eric Verdin
Don't change.
Dr. Mark Hyman
Your pill.
Dr. Eric Verdin
Right. It just it just goes through. So, there are, you know, for example, one thing you didn't talk about, which I think is really critical, is fiber and probiotic, that which I think for me, you know, I'm I'm a firm believer in the whole gut health, being a critical determinant of your health and brain function. And so optimizing your bacteria in your gut, not by eating the bacteria, but by eating the fibers that feed them, is really, a critical part. So I I I have a a special concoction of prebiotics that I I make myself, and I think that's, to me, is really one one of the central components of having a healthy healthy digestive system, which will determine your immune system and and so on.
As I told you earlier, I I believe in, urolithin a. That's one of the few well documented supplements that, has been shown to have an increase, an effect on your VO 2 max on on other immune function. We published on on the effect on immune function. I don't know. Any any other ones that I I I forgot the list of all the the compound that you mentioned.
One one thing that I wanna mention also is is the whole concept of, as a physician, you know about polypharmacy. The idea of polypharm well well, people you know, polypharmacy is the idea that once you start you start with 1 compound, you have a series of positive effect, but you also have a series of, side effects. The idea of polypharmacy is when you start adding things on top of each other, you generate responses that are unpredictable and not always beneficial. And I I do worry about the tendency, in the field of what people call stacks, you know, where you're taking 5, 10, 20 supplements together and hoping that all of this magically is going to work together. I can tell you one experiment that, some colleagues have done in the lab.
So in C. Elegans, the little worm that we study, we can, we can identify readily small molecules that increase the lifespan. So this experiment was done. It generated to, a whole series of molecules that increase lifespan. So let's say we have 10 compounds that all increase lifespan.
So what they did then okay. So they combine each of these 10 compounds pairwise, and what you'll find is they were actually able to identify a number of pairs that actually had synergistic effect, where the the lifespan effect was bigger than the sum of the 2 drugs. So that's very exciting. So then they took these pairs and then screened again the whole library to see, okay, what can we add? And what they found is that when you actually so they have these pairs with 2 drugs that increases lifespan.
Whenever they added another drug that also increased lifespan, all of the effects went away. And so and that's that's not good. And, you know, I hear about Brian Johnson taking a 120 supplements, and I'm thinking, you know, it cannot be good what's happening at this mixture of all of these drugs, you know, all of this byproduct, I don't know. It just it worries me, in general. And I tell people, you know, so how do you solve this problem?
One way would be to do sequencing. So you would go, for example, for 3 months on on this compound, and then another 3 months on this other compound. So I I think we are right at the beginning of of a of a of a new land that we do not understand.
Dr. Mark Hyman
Do you think that that the the advent of our, understanding of systems medicine biology with AI is gonna help us sort through this?
Dr. Eric Verdin
Absolutely. Absolutely. And, you know, the whole area that we are pursuing is the whole idea of phenomics. This is the idea of deploying to the clinic these tests that allows us to to measure tens of thousands of variables instead of a 100. And so the the BAC right now, you know, has a whole program with Lee Hood and Nathan Price called Phenomics, which is really going to the next frontier in terms of measuring.
You know, typical medicine, as you mentioned, relies on on on a 100, 200,
Dr. Mark Hyman
maybe Not even. Not even. Your annual checkup is, like, 20 or 30 biomarkers. Your CBC, chemscreen, cholesterol, and a urinalysis.
Dr. Eric Verdin
Exactly. And and if you take all of the tests that medicine can today conduct, maybe it's a 100 or 200, you know, in one of these samples, we can measure 5,000 proteins, and we can measure 10,000 metabolites, and we can measure, you know, 10,000 transcripts, so and and 20,000,000 CPG sites. So, really, the idea is now to use artificial intelligence and these deep, you know, deep phenotyping assays that we and try to extract, you know, all of the information that we can get on, you know, how do these drugs work, what pathways are they activating. This is the next frontier. And I think, yeah, we're we're we're tremendously excited by this.
You know, it's not not for direct consumption for the public, but it's important for people to know that this is where medicine is going. It's it's it's ramping up to next stage data and gathering and and processing.
Dr. Mark Hyman
I think that's really a a good place to end, which is the future of medicine is something we can't even imagine right now, and the level of data we can get on each individual is, you know, orders of magnitude more than we've ever been able to get in in a way that we haven't been able to apply clinically. But now given the advent of, one, the capacity to measure omics at every level. I mean, there's a 100,000 petabytes of data just in our microbiome. Yes.
Dr. Eric Verdin
Exactly. But I
Dr. Mark Hyman
don't even know what a petabyte is, to be honest with you, but it still sounds like a lot of data. And and that's just one part of our biology. And the complexity of those interactions, the dynamic is the the dynamic way they interact, how they they actually are affected by various inputs from lifestyle, from nutraceuticals, from drugs. We're we're we're in the most, to me, the most exciting era. It's almost like we finally figured out, like, how to look at the stars and, you know, look at what's going on in the universe in a way we never could before.
And I I I'm just so excited, and I I, you know, even though I'm, like, 65 almost, I'm gonna be 65 this year, I just feel like a kid in a candy store, and I just can't wait to see what's gonna happen. And I'm gonna try to keep myself alive long enough so I can actually take advantage of it all.
Dr. Eric Verdin
That's the, you know, that's the whole philosophy that I tell people. You know, the reason why you should optimize your your health plan today using everything that we know is that, first, there there's 35 years of extra healthy life for you to be gathered using this. And 30 years from now, God knows, you know, where we will be in terms of our ability to, you know, to interfere in these pathways and to keep you healthy even longer. So the the key is, you know, while we're working at gathering all of this data and and defining what are the safest and and most effective, you know, lifestyle changes, or or drug and so on, just keep yourself healthy, and and, and and you will you will reap the benefits now and in the future.
Dr. Mark Hyman
Oh, that's so exciting. Well, thank you for your work, for pioneering all this data and science. It's really tremendous, and, you know, there there's not that many people working at the level you're working. And it just to hear what you're saying, to understand the implications of it, to know that you you've come to the same conclusions that someone in the clinic working with your patients has come to is just very heartening. So, I'm very excited.
I I'm definitely gonna make it out to the and I promise I'll get there.
Dr. Eric Verdin
And Absolutely.
Dr. Mark Hyman
We'll see we'll see you around the next morning. And I'm gonna have you back because I didn't get to ask, like, at least half of what I wanted to ask you. So we'll find another another time to have part 2.
Dr. Eric Verdin
Take care. Bye bye.
Dr. Mark Hyman
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Coming up on this episode.
Dr. Eric Verdin
So aging is the accumulation of disorder. And and that disorder is caused by a whole series of external forces over which we have essentially no control. Think about gravity. Think about the gamma rays coming from, you know, interstellar radiation. Think about UV.
Think about, oxygen stress. All of these forces are there, and they're always gonna be with us. And and we know that they are the driving forces of the aging process.
Dr. Mark Hyman
Before we jump into today's episode, I'd like to note that while I wish I could help everyone via my personal practice, there's simply not enough time for me to do this at this scale. And that's why I've been busy building several passion projects to help you better understand, well, you. If you're looking for data about your biology, check out function health for real time lab insights. If you're in need of deepening your knowledge around your health journey, check out my membership community, Hyman Hive. And if you're looking for curated and trusted supplements and health products for your routine, visit my website, supplement store, for a summary of my favorite and tested products.
Welcome to The Dr. Hyman Show. I'm doctor Mark Hyman. And today's conversation matters because it affects all of us, and it's about how we age and perhaps how we may be able to slow down that process. And we're talking with one of the world's experts on aging, doctor Eric Burdon, who's the president and CEO of the Buck Institute For Research on Aging, a pioneering biomedical research institute dedicated to aging and age related disease.
He's a native of Belgium. He received his MD degree there from the University of Liege and then completed his clinical research training at Harvard Medical School, and he's published over 280 scientific papers in aging and metabolism. He's the guy, who knows more about aging than most people on the planet. He's worked on the molecular mechanisms of aging, mitochondrial function, inflammation, caloric restriction. He's a pioneer in so many ways, and is a really interesting great guy.
We had a deep conversation today about some really key elements that you probably heard about in the news, like mitochondria or the role of our own healing and repair system in activating longevity pathways. We talked about how do we diagnose, in a sense, the rate of aging, how do we look at our biological age as opposed to our chronological age. We talked about some of the exciting new developments in therapies from things like NMN and R, which help increase NAD in the body, to some of the key molecules that are being researched on reversing aging, like quercetin and pisetin. We get deep into so many topics. We literally could have talked for hours and hours.
I had to cut it after a while, but I think we're gonna have him back for a round 2 of the podcast because we didn't get to cover all of these I wanna cover, and you know I'm very interested in this topic. So go ahead and and, fasten your seat belts. This is gonna be a very interesting and deep conversation. You might have to look up a few things, but we're gonna put everything in the show notes, and, let's dive right in. Well, Eric, it's been so long that I've wanted to have you on the Doctor's Pharmacy podcast.
Your work has been an inspiration for me and the Buck Institute, which is basically the one of the few places in the world that's dedicated to study aging, is doing extraordinary work. And you're the president and CEO of that institute that now I think is leading the way in helping us understand the biology of aging, how to measure aging, and to understand the underlying mechanisms that are driving us to age rapidly and that lead to chronic disease. So I'm so excited to have you on the podcast and to dive deep into the science around it. It might get a little geeky, everybody, but I want you to stay with us. We're gonna explain everything as we go along, and and hopefully, you'll leave understanding the whole science of aging in in a much deeper way.
Dr. Eric Verdin
Thanks thanks for having me, Mark. Delighted to be here with you and looking forward to the next hour.
Dr. Mark Hyman
Yeah. Me too. So okay. So let's just start with with high level. You know, the there's there's a lot of research on aging happening now, but it's not always been that way.
Aging essentially was a neglected area of medicine, and in fact, you were ridiculed or dismissed if you even thought about studying aging because it was thought to be something that just happened that you couldn't do anything about. And now there's this whole field of longevity research and what we call geroscience, like gerontology, looking at the science of how we age, even thinking about describing aging as a disease or what we see as typical aging, which is, I think, abnormal aging as a disease. And and so the question is really, how do we need to think differently today given the science that we have, particularly around the underlying root causes of dysfunctions that happen as we age, the hallmarks of aging? How do we need to think differently about aging and disease going into the next decade or so?
Dr. Eric Verdin
That that's a good question, actually. And, the way the way I I think about it, and it's true, about 20 this is something that's relatively recent. About 25, 30 years ago, aging was considered sort of the backwaters of biology. This was an area that you did you did not go there because it was considered too messy. And and the way people use It was
Dr. Mark Hyman
bad for your career.
Dr. Eric Verdin
Bad for your career. Exactly. Well, people used to think about aging as chaos. So think about if you have a little bit of a background in physics, entropy. So aging is the accumulation of disorder.
And and that disorder is caused by a whole series of external forces over which we have essentially no control. Think about gravity. Think about the gamma rays coming from, you know, interstellar radiation. Think about UV. Think about, oxygen stress.
All of these forces are there, and they're always gonna be with us. And and we know that they are the driving forces of the aging process. What people had not appreciated, is the degree to which we actually resist these forces. And this is where the potential is. So think about, you know, we're not gonna change the fact that we're living in oxygen or that there is gravity and and gamma rays surrounding us.
But what had not been appreciated is the degree to which we resist these forces. For example, if you're lacking DNA damage repair, which is one of the consequences of of gamma radiation or UV radiation, you you're going to live to about 20 years old and you you're going to show in in those 20 years, very accelerated form of aging. And so, what people had not appreciated again, is is this idea of all of these repair mechanisms and how we can actually activate them. So what happened about 20, 25, 30 years ago is the identification of a whole series of mutations that could actually increase lifespan. And so this ran counter to everything we had ever thought about biology.
People thought about mutation that's typically deleterious. You get a mutation, you get a disease. And here were a number of mutations that were identified in in animal models, in in C. Elegans, the little worm that we study, or in in fruit flies, or in mice, they could actually double your life expectancy. So that really put the whole world of aging up on its head and highlighted the potential of, identifying novel interventions including lifestyle or drugs that could actually significantly increase lifespan.
And so initially, of course, these findings were met with a lot of resistance. People thought, well, this is an exception. This is only applying to c elegance or to fruit flies or mice. But over the last 20 years, you know, the work has really shown that there are a large number of genes and proteins that you could target and interfere with that will result in an increase in lifespan and health span. And and we are, right now, at a stage where this is slowly percolating into humans.
And I predict the next 10 to 20 years are gonna be transformative in our ability to bring all of this basic knowledge on on the biology of aging to humans.
Dr. Mark Hyman
I mean, that's pretty exciting what you're saying. I just wanna highlight something that I think is really important, is that historically, we've just thought that, you know, the body degrades over time and that there's no mechanisms to actually stop it or reverse it. And what you're saying is that the discovery of some of these mutations has led to an understanding that we have these built in what I call longevity switches, which is sort of a term that I kind of came up with, but built in repair, renewal, regenerative, and healing mechanisms that we have neglected that we can learn to activate through various interventions from lifestyle to nutraceuticals, to phytochemicals, to prescription medications, pharmaceuticals, or maybe even hormetic interventions, stresses to the body like hot and cold therapy. There's there's all these ways in which the body can actually activate these processes. And there's very there's very few of them, but they're influenced by so many things we do.
So there's so many redundant mechanisms that actually can activate these longevity pathways that we're now discovering. And to me, it's one of the most exciting times in science because for the first time, we're not really looking just at the downstream diseases that we typically look at in medicine based on diagnostic codes. We're looking at the upstream causes and the mechanisms. And the hallmarks of aging is sort of description that that kind of tries to describe some of these underlying causes and mechanisms. But sometimes I don't think they go far enough because they only talk about, well, these are the things that go wrong, not what are the causes of the hallmarks.
So the causemarks are the causes of aging on diseases. What are the causes of the hallmarks going awry? Right? So that's kind of an interesting inquiry. So I think this is such an exciting time.
And we're going to get in during this podcast. We're going to get into discussion of some of the ways in which we can regulate these ancient preserved, conserved pathways that exist across everything from worms to, to humans. Right?
Dr. Eric Verdin
Yes. It is. You're completely wrong. This is this is a really exciting time. You know, as a as a physician, and I mean, by training, I went to medical school, even though I did most of my my career in research.
I've always, you know, once a physician, always a physician. So I've always been intrigued by the relevance of what we're studying in these animal models to humans. And, it is truly a a a a an exciting time, this idea that something that we've always thought was, ineluctible and and and over which we had little control is is becoming another tractable problem. And and this is, you know, the excitement that you see in the field is a reflection of this. You know, one one number that I I like to remind people of is when we think about our own longevity, we, you know, many of us have a sort of a fatalistic approach to it.
We think, you know, my my parents didn't live very old, and therefore, you know, I might as well have another cigarette, another glass of wine,
Dr. Mark Hyman
and show them
Dr. Eric Verdin
enjoy life while it's there. But it it turns out that, you know, about 93% of our longevity is determined by our lifestyle factors.
Dr. Mark Hyman
93? That's a very specific number.
Dr. Eric Verdin
Well, that that's the result of a, of, of a great study by Calico, looking at ancestry.com, they were able to sort of revise a number which used to be about 80%. People used to think about 80% of lifestyle was determined, was determining, health span and lifespan. But the number they came up based on millions of people and and records appears to be 93% lifestyle, 7% genetics. That's true only if you and the only exception to this is if you have an ancestor, someone in your first degree relative who has lived above a 100. Then there's some likely genetic factors.
It means you're most likely protected, and you you can have another cigarette than a Well,
Dr. Mark Hyman
I have an Apo I have ApoE 2 as one of my ApoE leads. So I call that the jackpot gene.
Dr. Eric Verdin
You're one of the lucky ones.
Dr. Mark Hyman
Yeah. So I don't know what that means exactly, but I have APOE 2, 3. So I think I don't know how far I can go. How much ice cream can I actually eat before I get into trouble? That's kinda what I wanna
Dr. Eric Verdin
know. Probably more than me. I'm I'm I'm I'm I'm E3 E3, which is already good.
Dr. Mark Hyman
That's that's average. That's good. Okay. So let's let's get into the conversation around 2 two aspects, which one is, what are these mechanisms and pathways? Let's and then let's talk about how we how we and the research at the Buck Institute is actually uncovering ways in which we regulate these.
But before we do that, I wanna go into sort of a conversation that was preceding that, which is how do we measure aging? How do we know if what we're doing is working? And this is the whole discussion around how do we measure biological age and how do we look at our biological clocks. And there are so many out there. I think you were on a paper that I read that listed all of the different kind of clocks and the pros and cons of each one, which I was great.
It was great because I I was like, well, I don't know. This is very overwhelming, but it really helped for me to understand that. And, you know, personally, I did the true diagnostic DNA methylation test. I don't have any affiliation with them, but I just did it 2 years ago and when I was 62. And then I implemented a whole bunch of interventions, including more aggressive lifestyle change, different nutraceuticals, analytic supplements, which we'll talk about, as well as different kinds of treatments like plasmapheresis and exosomes and stem cells.
I just kinda went. I did it all. And then I also did rapamycin. And I was like, how far can I change this biomarker? And so I just throw the kitchen sink at it, which is not very scientific.
I get it. But I wanna I'm gonna end up 1, so I thought it was you know, we're trying. And I went back even though I got 2 years older, and I'm 64. On the same test, I went to from 43 when I was 62 to 39 when I'm 64. So I bent back 4 years even though I got 2 years older.
And so how reliable are these clocks? You know? Am I just falsely enthusiastic about my own result? And what are the things we should be looking at? Is it the need and pace of aging?
Is it demethylation? Which, you know, what are the what are the things that actually are worth looking at?
Dr. Eric Verdin
Yeah. That's a the whole idea of biomarkers of aging is going to be critical, and and and here's the reason. We, we go through life right now, sort of hoping, you know, that things are gonna work out for the best. And traditional medicine essentially waits for you to get sick, to really start intervening. So there is a need, a crying need for, what we call surrogate markers.
Markers that would be able to predict, you know, how well are you aging. And when we talk about biological aging, or biological age, this is in contrast to chronological age. So, you know, just for your audience, you you can be 40 years old, but your your body can be behaving more like the body of a typical 30 year old, or like the body of a typical 50 year old. That would be your biological age. And by the way, we, you know, we are also able to generate an estimate of biological age.
If you've if you've met someone who's 70 years old and you think that person looks younger, you have you have you have defined in your own head that this person is biologically younger. And and this by the way, these these are true, variables. They're actually algorithm that will predict your age simply based on facial recognition, just like we do. And, so there's been a lot of interest in the field, of generating more precise and more predictive biomarkers of biological age. The reason being, not just to be able to, you know, to tell you where you are on your trajectory, but also to assess the efficacy of our interventions.
And you you just described, you know, your n of 1, which is critical, which is okay. You start a whole series of interventions. How do you know you're actually helping yourself versus hurting yourself? And so this is where the these clocks are coming into play. Now we are right at the beginning of of a whole field.
So, I did, you know, the same thing as you did. TruDiagnostic, I I don't have any affiliation with them. We collaborate with them. I think they are the best company right now in terms of, providing a large number of, assays. And I say, large numbers is I think, is key.
They are right now, there's a proliferation of these clocks. Many of them are epigenetic clocks. They're measuring, methylation in DNA. The reason is not that these clocks are better than others, it's just that historically, they were the first one. And this is work pioneered by Steve Horvath and his colleagues.
So I did the same thing as you did. I measured all my clocks, I'm 67 years old, and my clocks came between 2567. And of course, I I look at the 20 the 25 year old clock, and I say, that's a really good clock.
Dr. Mark Hyman
That's good. So I'm jealous now.
Dr. Eric Verdin
And and that's that's gly glycan age for whatever reason. Yeah. But the other clocks, you know, frankly, varied between 42 and 67. So the question is, you know, how do you how do we sort through this? And Well, you just pick
Dr. Mark Hyman
the best one. Don't you? Just pick the best one.
Dr. Eric Verdin
Well, I picked
Dr. Mark Hyman
the best one. Exactly.
Dr. Eric Verdin
So, so I mean, there's obviously, there are some significant problem with this. These are not, approved, clinical tests. But I still think that they have value. And their value really comes back in in repetitive measurement, just like you said. So you you you you first, you need probably to measure many of them.
The paper that you're referring to is a paper in which we did, plasmapheresis and a number of patients, with a company called Circulate. And and we found on on a global scale that most of the clocks actually went back, when these patients underwent, plasmapheresis. So but again, there was extreme variation between the different clocks. So I tell people, if you if you wanna use the clocks, companies like TruDiagnostic will give you many numbers, they will be all over the place, but the true value comes in looking at how they change over time. Now the the prediction is that over time, we we will not only have these epigenetic clocks, we will have proteomics clock, metabolomics clock, facial recognition clocks.
You know, there there's a proliferation of these clocks right now, and they paint a pretty complex picture, and I think they will allow us to do truly preventative medicine. Some of these recent clocks, for example, proteomics clock by Tony Whisqueray at Stanford, are able to measure organ specific aging, which is gonna be really critical. Because of course,
Dr. Mark Hyman
you
Dr. Eric Verdin
know, as we age, we are always limited by the, what I call, the rate limiting organ. It could be your liver that's gonna fail first, and you would wanna know and and do, you know, an intervention that favors your liver versus your brain versus your heart and so on. So I think we're right on the cusp of a rev revolution in diagnostics, and these epigenetic clocks is the first the first symptoms, going in this direction.
Dr. Mark Hyman
So basically, it's it's all getting shaken out right now in the research. Yes. Exactly. And and we're gonna learn which are the best clocks, and we'll learn more and get better. But in the meantime, what what I hear you saying is stick to one assay and repeat it over time based on what you're doing.
Because if it's off, it's off by the same amount every time. And what you're looking at is a change from the baseline, either worse or better. So
Dr. Eric Verdin
But interestingly, you know, another anecdote, for example, someone did an interesting experiment where they they measured, the clocks at different times of the day in the same person. And they found they found over the 24 hour period, the clock would vary by 5 years. So that's
Dr. Mark Hyman
because I'm older at night. I know that. I feel older at night. In the morning, I'm good. I'm, like, 25.
By the time my night comes, I'm 70.
Dr. Eric Verdin
Mean meaning that, you know, if if you're gonna do this, do it every time at the same time of the day because there's obviously there are no variation in there.
Dr. Mark Hyman
Great. Okay. So so now we have these clocks. Let's say we can measure these these changes that happen as a result of interventions. Let's talk about some of the most exciting work at the Buck Institute looking at the the sort of underlying things that that really regulate aging around, we call cellular senescence, which is zombie cells, the cells that kinda spew out inflammation throughout the body, are, looking at our metabolism and how our nutrient sensing pathways work, which I think I wanna get into fair fair fairly deeply, stem cell and stem cell biology and protein, protein function.
And then how do we sort of make sense of it all through bioinformatics and systems biology? And I know you've recently partnered with Leroy Hood, who's just a brilliant scientist. So I'm curious about, like, how how you start to think about where where are the most leverage points that you're seeing in the data that you're looking at, in the research you're doing at the Bunk Institute about what's working, in all these different areas?
Dr. Eric Verdin
So maybe I'll I'll just take it one step backwards, and and just to alert your audience to the fact that there are no there will be no magic pill. Aging is an incredibly complex mechanism, and, you hired you alluded to earlier in our discussion to these hallmarks of aging, which is think about it as a catalog of all of these abnormalities that happen during aging, and that includes epigenetic dysregulation, senescent cells, nutrient failed nutrient sensing, defective stem cells, defect in mitochondrial biogenesis. There's all kinds of problems that happens during aging. By the way, they're all connected to each other. And when we think about aging and and solving it, I think, if you study it, you will realize how complicated a process is.
And and that, you know, we at the Bak Institute, we have about 300 people working on aging. We don't take sides in a way that I I cannot predict what's going to be more important. So we we study pretty much every one of the hallmarks of aging. We obviously have a big emphasis on senescence because it was mostly discovered, through the work of Jenny Campisi at the back. So many of us are still working on senescence, but we have people working on mitochondria, we have people working on stem cells.
We have people working on metabolism, and so on. So I I think, one of the the the things that is really emerging right now is is the complexity.
Dr. Mark Hyman
And I think that's so important that you point that out.
Dr. Eric Verdin
It's important it's important because, you know, frankly, I have I've I've sometimes been called the grumpy man of of longevity research, because I I I I refuse the hype of work. I think, there's a lot of really exciting things happening in in Asian research, but I'm not deluding myself. I I don't tell people I'm gonna live to a 150 or a 170, like some of my colleagues do. I I think, you know, right now, we are focusing on on things that are really tangible. For example, you might be surprised to to to hear that most of us could live to 95 years old in good health, if only we would sort of deploy everything that we know.
That's already a lot better than what we have today, where we most of us would live to 65 in good health. So, you know, that's an extra 30 years of healthy life. And right now, we are really focused on on 2 things at the back. We on the basic biology of aging, again, we don't take sides. We study all of these processes and how they relate to each other.
The the bigger, aspect, that is being grown at the Bak Institute is the whole human aspect. Really, taking all this basic knowledge and translating into actionable interventions that I can tell you and other people, this is what you should be doing if you wanna live the longest
Dr. Mark Hyman
possible. Yeah. I mean, I think it's so important what you just said around the the nature of nature, which is and it just reminds me of a quote from John Muir, who was a naturalist in the 1800s who said, when one tugs at a single thing in nature, he finds it attached to the rest of the world. And and essentially, what what I see happening often in research is the reductionism even within the science of aging, Where, oh, it's this hallmark, or I'm gonna focus on mitochondria, or I'm gonna focus on inflammation, or I'm gonna focus on deregulated nutrient sensing, or I'm gonna make something that's gonna lengthen telomeres or kill zombie cells. And that's where things get into this reductionist mindset that doesn't understand that all these interact.
They're all dynamic. It's a web of connections and interrelationships that all either positively reinforce each other or negatively reinforce each other. And so and and a lot of these ancient longevity pathways, and I think and when I think of this, and I would love to hear your opinion about this, is is that they there's kind of a a way to kinda influence a lot of it through the same kinds of interventions, obviously, the lifestyle stuff. But when I think about, for example, the the 4 d regulated nutrient sensing pathways that tend to go wrong, mTOR, insulin signaling, AMPK, and sirtuins, which I know is a lot of mumbo jumbo. We'll explain all that, I promise.
But these are these are what I call the longevity switches. And it seems that they they they're affected by what we eat, but they're also affected by various kinds of other things like exercise or various hormetic stresses or other factors and that they affect all these other hallmarks. So like mTOR, m p a, all these things affect mitochondria. They affect inflammation. They affect oxidative stress.
They affect your epigenetic regulation. They affect DNA repair. They affect senescent cell. I mean, this is when you sort of start to dig into it, it's like it's everything is affecting everything. So what's the highest leverage point?
And and and and and, again, I'm not a longevity researcher. I'm just sort of a doctor trying to make sense of all this. Is is the it seems like the deregulated nutrient sensing is one of the most important, almost meta hallmarks because when you address those 4 pathways, it it downstream benefits all the others. Am I am I off, or does that make sense to you?
Dr. Eric Verdin
I I agree. I'm not sure.
Dr. Mark Hyman
Okay. Because this I made this up. I made this up. So
Dr. Eric Verdin
No. I I I do agree. Although, there are you know? So when I think about the the buckets of in which you should invest if you want to maximize your longevity, nutrition is clearly one of the top ones. And, but equally important is exercise.
But by the way, exercise or physical activity affects all of the same pathways that we just discussed, you know. So it's it most of the time, I I I sort of reduce this to the fact that we're dealing with energy generation. And and, you know, so if you think about, exercise and nutrition have this in common, they are both profoundly dependent on your ability to generate a lot of energy, and and so and and the proper energy. And there's one theory of aging that posits that one of the things that happens as we age is our ability to generate energy decreases. And since, you know, for example, the repair function that we were discussing earlier, our ability to repair DNA, to repair proteins, and so on, is also incredibly dependent on energy.
So as energy supplies dwindle, our ability to make sufficient energy becomes limiting, then, you know, and if you have the choice between repairing your DNA or actually walking, your body is gonna is gonna is gonna favor the walking. And, so so there's there's, there are lots of common threads between all of these variables, and, I'm happy to to dive into this.
Dr. Mark Hyman
Yeah. Yeah. Let's dive into it, because I think I agree with you. I think the mitochondria are central. It's really about the the how we create and make energy as well as how we protect, preserve, and improve the number and function of our mitochondria.
And and I would say that sort of the difference between a 2 year old who's, you know, running around like crazy and can't stop moving versus a 92 year old who's just sitting in the chair, barely can move is the health and function of their mitochondria. And and a lot of your research has focused on on mitochondrial function aging and, particularly around the, role of NAD and, ketogenic diets, for example, and the role of of, the role of sirtuins in regulating mitochondrial function as well. So, and I I think I'd love to dive into this whole topic with you a little bit more because you're such an expert in it. You know, what what have you learned about, how mitochondria are regulated and how they play a role in aging? And what are the most, salient things we've learned about how to improve the number and function of mitochondria from lifestyle all down to nutraceuticals and even medication?
Why don't we dive into that? Because you're you're, like, the world's expert here.
Dr. Eric Verdin
Lots of drawers to to open there. Yes. So when when we think about energy so let's backtrack. So, you know, our energy we generate energy from essentially burning food in the presence of oxygen. Think about, when you throw coals into a fire, if you blow air on it, you know, the fire will get more intense.
So this is the same thing. We burn carbohydrates, lipids, or fats, and and proteins in the presence of oxygen to generate energy. And, you know, this process takes place at many places in the cell, but predominantly in the mitochondria, which by the way are are sort of commensal bacteria which have become incorporated into our cells. So this is something of fusion that happens, you know, billions of years ago. Quite quite interesting biology.
So these mitochondria are generating the ATP that we use as energy, and also the NAD, which we use as a it's not a it's a form an intermediate form of energy, and we can come back to this later. Now it turns out that, mitochondria numbers dwindle with aging, and and their ability to generate energy dwindles with aging. And there are multiple variables that that are causing this. Some are mutations in the DNA. So the mitochondria have their own DNA, which is an ancestral bacterial DNA.
They accumulate mutations, their numbers decrease, the NAD levels, which is this critical intermediate, dwindles as well. All of these factors lead to a progressive and and worsening, energy deficit as we age. So there's a lot of interest in trying to understand how do we reverse this and how do we how do we prevent this from occurring at the first place.
Dr. Mark Hyman
So so so clearly, the mitochondria are key, and and the question then is, what what can we do to help our mitochondria? Because if if what you're saying is true that they're central to aging, both healthy aging as well as unhealthy aging, then it seems like they're a major target for intervention. And, there's a lot of stuff floating around there in this sort of literature and also in the sort of cultural zeitgeist around interventions that help to regulate mitochondria from, you know, fasting or ketogenic diets to things like rapamycin or other phytochemicals that may be able to regulate mitochondrial function like urolithin a. And I just, you know, just wonder how you how you sort through all the massive data and information around around all of this, and where you start guiding people practically around how to make sense of the data.
Dr. Eric Verdin
Yeah. So, you know, as I mentioned, so there there's loss of mitochondrial number, there's loss of mitochondrial function, and there's loss of mitochondria, you know, key metabolites like NAD. And so I think when I think about, you know, what can you do, it ranges from lifestyle intervention all the way down to some of the drugs that we're actually working on. So I I the the two ways in which I think you can maximize your mitochondrial function as you age is fasting, And fasting, as as I mentioned earlier, activates a process called autophagy, which means self eating. So and the beauty of autophagy when you're fasting is that your body is able to sort through the garbage and the and and the well functioning mitochondria to discard the poorly functioning mitochondria and to keep the ones that are most efficient, so the process called mitophagy.
So intermittent fasting, I think, is is part of, you know, the ability that your body has to shift between feeding and fasting is is a process that we call metabolic flexibility, and I think it is really an integral part of health. So, I encourage people to, you know, to incorporate this into their daily routine. Another way in which you can process
Dr. Mark Hyman
What you mean is, just to what you're asking is to give people a break between dinner and breakfast is essentially what you're saying, like
Dr. Eric Verdin
Well, yes. That's one way to do it, actually. And, you know, right now, we're at the stage where there are a whole bunch of different fasting modalities have been, explored and tested, and, I I don't think there's clear evidence that any of them is is is more beneficial than another. Some people will do, you know, a deep fast every 3 months, some people will do, some fasting every day. I think there are, we're still at the stage where these different modalities are being compared and and and trying to decide what is the best way.
But any of them is better than none. That would be the the rule that I would and practically for me, I do, you know, I do a 5 day fast, every 3 months, and then I do I do sort of what people call restricted time feeding, which meaning I I try not to eat for 12 to 16 hours every day, so to at least have a a period of fasting. There are also, a number of interesting supplements that are emerging that are, supplements or drugs. You know, there's, the interest in fasting came out of the realization that animals, on calorie restriction, so who whose calorie intake was limited, actually showed the increased lifespan. That that's pretty much a universal feature.
So that led to study of fasting, but also led to the discovery of what we call these fasting mimicking or calorie restriction mimetics. So drugs that are fooling your body into thinking that you are under calorie restriction or fasting. And those drugs, you know, some of your audience are
Dr. Mark Hyman
Well, running around starving all the time.
Dr. Eric Verdin
Exactly. Exactly. So, you know, metformin, you you I'm sure you've heard about metformin or rapamycin, our calorie restriction pneumatics. So they they fool your body to think that you're fasting, and they induce, parts or all of the protective response. And this is why some of these drugs are being explored for their potential, anti aging effect.
There are also supplements that are emerging. There's a process called mitochondrial biogenesis, which is the process by which you are making new mitochondria. And we know, you know, we know the pathways, the biological pathways that lead to this, and and some of them can be activated by drugs or supplements, Supplement, for example, that, activates, mitochondrial function would be, the urolithin a. I'm sure you've heard, product, sold by
Dr. Mark Hyman
Oh, I take it every day.
Dr. Eric Verdin
Yep. I I take it every day too. And, you know, it's a supplement, so it it it's not going through the same process that a a FDA approved drug would be, but the company that, you know, commercializes this called TimeLine has has a very proactive approach to testing, you know, doing clinical trials, and demonstrating the efficacy of of what they are claiming. And we've collaborated with with them, so I can I can I can attest to some of the results that we've published with them? So really interesting supplement.
And the last one, I mean, that I you know, physical activity exercise is is certainly a very strong way to activate mitochondrial function in your muscle. And we know, you know, your muscle mass is a very strong predictor of your life expectancy. So anything that benefits your muscle, having strong mitochondria, bulk, frankly, also of your muscle will will lead to protective effect on your brain and other organs as well. So, obviously, you know, when are we talking about anything related to aging? Reductionist approach works for a while to try to simplify the models, but once you start thinking about anything, it's connected to everything else.
Dr. Mark Hyman
That's right. And and the, you know, the thing around the the the mitochondria, also that you've done research around is, NAD and and, you know, NAD plus. And there's a lot of, you know, controversy around this particular compound. You know, some say it's kind of the data isn't there. Some say it's God's gift to mankind, then we should be all taking it.
What's your kind of, you know, sort of down and dirty on the science behind NAD and taking NAD either as a NMN product, NR product, or sub q NAD or IV NAD. I mean, this is all these people are doing these things, including me. So I'm I'm curious about what your perspective is, someone who's actually done the research.
Dr. Eric Verdin
Yeah. Happy to talk about this, because, frankly, it's it's once you are involved in the research and you see some of the stuff that's being sold, it's sometimes I shake shake my head in disbelief. But, that being said, there's like, in any story, there's always an element of of truth to to to the whole NAD story. So just a a word about NAD is a molecule that allows you to shuttle energy, between different parts of the cell. So this is a purely intracellular molecule.
So this is not something that lives in the blood, and so, you know, this will be important because there's a whole fad right now of intravenous NAD, which frankly does not make any sense to me biologically. But, so NAD is an intracellular, and it doesn't cross from the blood into your cells. So it just, it's, you know, it is an intracellular metabolite. Why is it important? Because it allows you to shuttle energy between different parts of the cells, from the mitochondria to the cytoplasm and so on, or different different from different molecules, within the cell, more correctly.
So it's also known that NAD levels decrease during aging, and and this is, that's really well established in humans and in animal models. So out of this came the idea that maybe this is one of the reasons why we have this global energy deficit as we age. Maybe we're not able to manipulate. So when I think about, you know, NAD, you think about Brinkman, you know, the trucks that carry, money. So think about if they all went on strike, all of a sudden, you know, the energy of the economy, which is money, would be stuck in in the supermarket and nothing moves anymore.
So this is the same thing. And so, I think about them as the the the the the fund carriers. So out of this can be ideal, maybe we can just reestablish NAD levels, and so people will see a benefit. And and in animal models, you can do this using, what we call NAD precursors. And there are 2 of them that are you know, you're familiar with, nicotinamide riboside, n r, or nicotinamide mononucleotide, n n n.
And both of them essentially do almost the same thing. Some colleagues will argue vociferously on whether one is is superior to the other. At the end, they both reestablish NAD levels. They might have additional signaling properties in addition to this, but, and in animal models, they do remarkable things. So, you know, we've published we and many other people in the field have published a number of papers showing that NAD supplementation in older animals really alleviates some of the, effects of aging.
It does not increase lifespan, I should say, but it certainly alleviates many of the disease complications and so on. So out of this came came the interest, well, maybe we should bring this to humans. Now, and a number of companies are selling NR and NMN. One significant issue is that the amounts that are being sold as supplements are much lower by a fact by a factor 10 of what we use in the laboratory setting. So, you know Like, the most bottles have,
Dr. Mark Hyman
like, 250 milligrams if you
Dr. Eric Verdin
need to. But you're saying
Dr. Mark Hyman
you need more, like
Dr. Eric Verdin
We used 2 to 3 grams. 5 grams. Exactly. Wow. So we used precursors.
Yes. We used a lot more. And those of us who take NMN or NR typically take a lot more than the the 200 milligrams, a day.
Dr. Mark Hyman
Well, would you say, take 2 grams or 1 gram, or
Dr. Eric Verdin
Well, that's I take a gram when when I most of the time. Now the obviously, what we need is more clinical data in humans. And, a lot of noise has been made about a couple of initial studies that failed, and, you know, and and that's, you know, that's true, Peter. TI is highly skeptical, and and there are, you know, there are really good reasons to be skeptical about some of the claims that have been made for NMN and NR, but I think my argument is that's not through the baby with the bathwater. And there is, there's enough compelling evidence in model systems that, NMN and NR actually are having interesting effect that pursue the studies and to conduct the clinical trials.
Now one one of the biggest problems I have is why is asking the question, and it's something my lab has been working on, why are NAD levels decreasing during aging? And that really has not been studied by many people except us and and Eduardo Chaney, who was at was at Mayo Clinic. And what we both found is that the reason why NMN NAD levels decrease during aging is because there's another molecule called CD 38, which is activated during aging for reasons that are not entirely clear, but in in part because of the senescent cell burden. So the CD 38 is itself as NAD hydrolase. It chews up NAD.
And so when you give, NR It's an
Dr. Mark Hyman
enzyme like Pac Man that kinda eats up your NAD.
Dr. Eric Verdin
Exactly. So the think about your NAD pool, like water in a sink. The problem that we're having is a leaky sink. So there's something that's chewing up the NAD. And when you give NMN or NR, you're essentially filling up more water in the leaky sink.
And so which is not a very satisfying way to solve a problem. So the the way we are going about it, and a growing number of companies are are doing this as well, is to actually identify small molecule inhibitors of CD 38. And so I have a startup called, NAPA Therapeutics, which, you know, has a large number of these novel molecules. We're testing them. Some of them some of these inhibitors, and not not ours, but others have been shown to increase lifespan, and to correct, some of the aging associated energy deficit much more, sort of, efficiently than than the precursors.
So my prediction is that if you think about NAD defect in the future, in the long run, we probably will be looking for, you know, these CD 38 inhibitors rather than filling up the tank with with more water.
Dr. Mark Hyman
Interesting. So it's in essentially stopping the breakdown of NAD rather than just taking more precursors of NAD. Exactly. The hole in the bucket. You can keep filling the bucket faster, but at some point, it's kind of diminishing returns.
Better just put the hole in the bucket.
Dr. Eric Verdin
You got it. You got it. And, you know, one one reason, you know, for doing this is and and this is it speaks also to the the importance. A lot of people are taking a lot of supplements these days, and they're not being followed appropriately by physician. As I was taking a lot of NMN, I was always concerned because we know that, NMN, as its being, if you take a large amount of it, will consume your, your one carbon, your methyl groups.
And so I was as I was doing this, I was always following my homocysteine levels. And actually, I found it to, you know, to rise significantly in the presence, of large amount of, NMN intake. And and, you know, and if I if it goes too high, I stop my NMN for a while. So speaking to the fact that all of these processes are connected, and I I I'm I'm somewhat worried about, you know, the proliferation of of supplements that are being touted and sold to some somewhat naive public hoping, you know, this is gonna increase my lifespan. There are a lot of there you know, there are very few molecules that have absolutely no consequence, and and I think, you know, if you go down go down this route, do it with someone, you know, that knows, understands the biochemistry, and can follow you appropriately.
Dr. Mark Hyman
It's interesting. I mean, basically, just to summarize what you said is that the precursors, NR and NMN, which are available, and we don't have to talk about which companies produce the best ones, but let's just assume you're getting the best one, will actually lead to an increase in NAD levels. But if you do intravenous or subcutaneous NAD plus, it won't, and that you might be wasting your money.
Dr. Eric Verdin
Yes. You are you know, a typical NAD infusion costs about $700. There are studies showing what happens when you inject NAD intravenously. It goes to your liver, and it is cleaved into nicotinamide, NADP Ribose. Now the nicotinamide is essentially niacin.
You know? You can buy this for, you know, 20¢ or whatever. So this $700 injection, I I I really have no idea. Actually, no one has any idea what happens to it. Most of it is likely very quickly degraded.
Dr. Mark Hyman
And And that's why you feel that kinda weird flushing feeling when you get the NLP?
Dr. Eric Verdin
Well, niacin, niacin, as you know, will activate these flushing receptors. This was one of the, you know, the limiting use of niacin as a as a a drug, but at cholesterol lowering, a few a few decades ago, people had, had some flushing issues. It's the same thing that you're feeling when you're taking intravenous, nicotinamide. Yeah.
Dr. Mark Hyman
There there's an anecdote, and I don't know what to make of it, was I I had a I did a retreat, on longevity, and one of the the the local companies who's in Turkey, offered NAD as part of this. And there was a woman who had Parkinson's who was quite severely affected. And we know that Parkinson's is a mitochondrial disease. And her her response was pretty remarkable. Like, her tremor stopped.
Her gait improved immediately. Like, it was like an immediate shift, like, someone taking l dopa. And I was like, well, that's interesting. Wow. I don't know.
I don't know. This is an anecdote, but I I I imagine it's doing something. And, yeah, it's a it's not a fun way to take it, you know, intravenously, subcutaneously. You can also do it the same thing. It seems like it would lead to the same kind of result, but it's it's fascinating data.
So what you're saying about NED is that it and the precursor essentially is it doesn't necessarily extend lifespan, but it improves quality of life and health span. Would that be accurate?
Dr. Eric Verdin
That that's the prediction, and that's what we although, you know, the there's evidence that CD 38 inhibition or deletion actually increases lifespan, so that might be one way to put back this whole pathway in the context of longevity.
Dr. Mark Hyman
Wow. And that's what NAPA Therapeutics is working on, right?
Dr. Eric Verdin
This Yes. Yes. Absolutely.
Dr. Mark Hyman
Incredible. Amazing. The the, God, I mean, I I feel like we need to go have another one of these podcasts. I might do this in 2 parts because go go on forever.
Dr. Eric Verdin
Any anytime. Happy to come back.
Dr. Mark Hyman
I I I there's so much more I wanna get into on inflammation, around nutrition, around, the microbiome and aging and many, many other topics. But I I would love to kind of just finish up for the last few minutes on 2 topics. 1 is what are the all star molecules for longevity? And I and I I have a list that I wanna sort of get your thumbs up, thumbs down on. And 2, what do you do, not as a scientific kind of, kind of clear scientific protocol, but as your own self care based on what you know as someone who's an insider.
Like, it's almost like insider stock trading. Right? Like, what are you what are you doing? So the the the molecules that I I think, you know, seem to me to be the most promising are, around the rapamycin molecule, which is a drug that we've talked about in the podcast before essentially is inhibits mTOR, which is one of these longevity switches that regulates everything from muscle protein synthesis to autophagy to inflammation to mitochondrial function to DNA repair. That's one.
Then there, you know, the metformin question, which I think is a little probably a little longer than we have to get into, but I'm I'm a little dubious about it. And I don't know if we're gonna get to the TAME trial now, which is a randomized trial that's gonna give us the answer, unfortunately. And then there's all the sort of phytochemicals like quercetin, fisetin, curcumin, green tea extractor, epigalactylcatacin, gallate, phytochemical that can be derived from pomegranate. Among all these sort of players, you know, which are ready for prime time, which have sort of low risk potential benefit, which should be we careful with, like, how do we think about this?
Dr. Eric Verdin
It it's a tough one. I tell people, you know, if you wanna
Dr. Mark Hyman
In 5 minutes or less.
Dr. Eric Verdin
Okay. So I'll I'll start. 1st, I think, before taking any supplement, I think, people should optimize the rest of their lifespan because there's nothing you know, if you have a wound that's infected with a bacteria, you don't put a Band Aid on it. You you start getting
Dr. Mark Hyman
So let's assume everybody's exercising, eating perfectly, sleeping great, managing stress, and removing toxins from their life. Okay. We've done all that. Now we're gonna
Dr. Eric Verdin
Very, very few people do this. So the next step would be to have once you've optimized all of this the best you can, and I think about them as buckets, you know. And I
Dr. Mark Hyman
agree with you, by the way. I agree.
Dr. Eric Verdin
You can make in because a lot of people, you know, will go to supplements. They don't wanna do any of the other things, and the and they're missing, you know, they're missing the really powerful stuff. This is where you know, the reason I'm bringing I'm making this point so strongly is that the the we we do not have and will not have for the next 20 years an antiaging medicine or supplement that is better than physical activity. And I you know, mark mark my words, for 20 years, in 20 years, we will still not have something that works as well as physical activity.
Dr. Mark Hyman
It's a miracle drug.
Dr. Eric Verdin
It is a miracle drug. And so, if if you are sort of not paying attention to that one, well, you can sort of put a band aid on on some issues, but you'll never really get to the core problems. Now, thinking about the rest, first for me is blood draw. You know, are you are you balanced in terms of vitamin d, vitamin b 12? This would be the first the first big ones.
And I'm I'm surprised how many people tell me, friends and colleagues, no, I don't know what my vitamin d is. So that's number 1. Number 2,
Dr. Mark Hyman
there are some By the way, that's why I started Function Health, which was to give people access to their own data, including all the things we've talked about, inflammatory markers, the inflammation markers that we talked about as well as vitamin d and methylmalonic acid and homocysteine, all the things that we wanna know. Right?
Dr. Eric Verdin
Exactly. You're also you're you know, I don't know if you're measuring this, but your omega fatty acid. Levels.
Dr. Mark Hyman
Omega 3 fats, a 100% ratio. Omega 3 fats, insulin, lipid fractionation, all the things that you should be measuring to see what your metabolic health is and your mitochondrial health is.
Dr. Eric Verdin
Critical. So, you know, there are a few supplements that have documented efficacy. One of them is omega fatty acids. And, you know, especially if you are like most people in the western world, and you are you don't have access to enough of them. So omega fatty acid would be one of the top ones for me for everyone to take every morning and every night.
If you're exercising, you know, carnitine is is really one of the well recognized supplement that that people take. Now we talked about a whole variety of flavonoids, quercetin, curcumin, fitsetin, all of those. The problem with many of those is, bioavailability. So much of what has been shown about their efficacy is is based on studies where the the the chemicals are added directly to cell. The problem is, you know, before the chemicals get to your cells, they have to go through the gut and have to be absorbed and all this.
Most of those have extremely low bioavailability. Now some companies are trying to remedy this by making them into phytosomes and all of this, but most of the time, the data is just not there that these things are getting absorbed to a significant level. So I I have, you know, I have my doubts.
Dr. Mark Hyman
Take the pill, and then your blood levels don't reflect
Dr. Eric Verdin
Don't change.
Dr. Mark Hyman
Your pill.
Dr. Eric Verdin
Right. It just it just goes through. So, there are, you know, for example, one thing you didn't talk about, which I think is really critical, is fiber and probiotic, that which I think for me, you know, I'm I'm a firm believer in the whole gut health, being a critical determinant of your health and brain function. And so optimizing your bacteria in your gut, not by eating the bacteria, but by eating the fibers that feed them, is really, a critical part. So I I I have a a special concoction of prebiotics that I I make myself, and I think that's, to me, is really one one of the central components of having a healthy healthy digestive system, which will determine your immune system and and so on.
As I told you earlier, I I believe in, urolithin a. That's one of the few well documented supplements that, has been shown to have an increase, an effect on your VO 2 max on on other immune function. We published on on the effect on immune function. I don't know. Any any other ones that I I I forgot the list of all the the compound that you mentioned.
One one thing that I wanna mention also is is the whole concept of, as a physician, you know about polypharmacy. The idea of polypharm well well, people you know, polypharmacy is the idea that once you start you start with 1 compound, you have a series of positive effect, but you also have a series of, side effects. The idea of polypharmacy is when you start adding things on top of each other, you generate responses that are unpredictable and not always beneficial. And I I do worry about the tendency, in the field of what people call stacks, you know, where you're taking 5, 10, 20 supplements together and hoping that all of this magically is going to work together. I can tell you one experiment that, some colleagues have done in the lab.
So in C. Elegans, the little worm that we study, we can, we can identify readily small molecules that increase the lifespan. So this experiment was done. It generated to, a whole series of molecules that increase lifespan. So let's say we have 10 compounds that all increase lifespan.
So what they did then okay. So they combine each of these 10 compounds pairwise, and what you'll find is they were actually able to identify a number of pairs that actually had synergistic effect, where the the lifespan effect was bigger than the sum of the 2 drugs. So that's very exciting. So then they took these pairs and then screened again the whole library to see, okay, what can we add? And what they found is that when you actually so they have these pairs with 2 drugs that increases lifespan.
Whenever they added another drug that also increased lifespan, all of the effects went away. And so and that's that's not good. And, you know, I hear about Brian Johnson taking a 120 supplements, and I'm thinking, you know, it cannot be good what's happening at this mixture of all of these drugs, you know, all of this byproduct, I don't know. It just it worries me, in general. And I tell people, you know, so how do you solve this problem?
One way would be to do sequencing. So you would go, for example, for 3 months on on this compound, and then another 3 months on this other compound. So I I think we are right at the beginning of of a of a of a new land that we do not understand.
Dr. Mark Hyman
Do you think that that the the advent of our, understanding of systems medicine biology with AI is gonna help us sort through this?
Dr. Eric Verdin
Absolutely. Absolutely. And, you know, the whole area that we are pursuing is the whole idea of phenomics. This is the idea of deploying to the clinic these tests that allows us to to measure tens of thousands of variables instead of a 100. And so the the BAC right now, you know, has a whole program with Lee Hood and Nathan Price called Phenomics, which is really going to the next frontier in terms of measuring.
You know, typical medicine, as you mentioned, relies on on on a 100, 200,
Dr. Mark Hyman
maybe Not even. Not even. Your annual checkup is, like, 20 or 30 biomarkers. Your CBC, chemscreen, cholesterol, and a urinalysis.
Dr. Eric Verdin
Exactly. And and if you take all of the tests that medicine can today conduct, maybe it's a 100 or 200, you know, in one of these samples, we can measure 5,000 proteins, and we can measure 10,000 metabolites, and we can measure, you know, 10,000 transcripts, so and and 20,000,000 CPG sites. So, really, the idea is now to use artificial intelligence and these deep, you know, deep phenotyping assays that we and try to extract, you know, all of the information that we can get on, you know, how do these drugs work, what pathways are they activating. This is the next frontier. And I think, yeah, we're we're we're tremendously excited by this.
You know, it's not not for direct consumption for the public, but it's important for people to know that this is where medicine is going. It's it's it's ramping up to next stage data and gathering and and processing.
Dr. Mark Hyman
I think that's really a a good place to end, which is the future of medicine is something we can't even imagine right now, and the level of data we can get on each individual is, you know, orders of magnitude more than we've ever been able to get in in a way that we haven't been able to apply clinically. But now given the advent of, one, the capacity to measure omics at every level. I mean, there's a 100,000 petabytes of data just in our microbiome. Yes.
Dr. Eric Verdin
Exactly. But I
Dr. Mark Hyman
don't even know what a petabyte is, to be honest with you, but it still sounds like a lot of data. And and that's just one part of our biology. And the complexity of those interactions, the dynamic is the the dynamic way they interact, how they they actually are affected by various inputs from lifestyle, from nutraceuticals, from drugs. We're we're we're in the most, to me, the most exciting era. It's almost like we finally figured out, like, how to look at the stars and, you know, look at what's going on in the universe in a way we never could before.
And I I I'm just so excited, and I I, you know, even though I'm, like, 65 almost, I'm gonna be 65 this year, I just feel like a kid in a candy store, and I just can't wait to see what's gonna happen. And I'm gonna try to keep myself alive long enough so I can actually take advantage of it all.
Dr. Eric Verdin
That's the, you know, that's the whole philosophy that I tell people. You know, the reason why you should optimize your your health plan today using everything that we know is that, first, there there's 35 years of extra healthy life for you to be gathered using this. And 30 years from now, God knows, you know, where we will be in terms of our ability to, you know, to interfere in these pathways and to keep you healthy even longer. So the the key is, you know, while we're working at gathering all of this data and and defining what are the safest and and most effective, you know, lifestyle changes, or or drug and so on, just keep yourself healthy, and and, and and you will you will reap the benefits now and in the future.
Dr. Mark Hyman
Oh, that's so exciting. Well, thank you for your work, for pioneering all this data and science. It's really tremendous, and, you know, there there's not that many people working at the level you're working. And it just to hear what you're saying, to understand the implications of it, to know that you you've come to the same conclusions that someone in the clinic working with your patients has come to is just very heartening. So, I'm very excited.
I I'm definitely gonna make it out to the and I promise I'll get there.
Dr. Eric Verdin
And Absolutely.
Dr. Mark Hyman
We'll see we'll see you around the next morning. And I'm gonna have you back because I didn't get to ask, like, at least half of what I wanted to ask you. So we'll find another another time to have part 2.
Dr. Eric Verdin
Take care. Bye bye.
Dr. Mark Hyman
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