Can We Reverse Aging? The Answer May Surprise You | Dr. Eric Verdin

So aging is the accumulation of disorder. 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 interstellar radiation, think about UV, think about oxygen stress. All of these forces are there and they're always going to be with us. And we know that they are the driving forces of the aging process.

Well, Eric, it's been so long that I wanted to have you on the Doctors Pharmacy podcast. Your work has been an inspiration for me. And the Buck Institute, which is basically 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 going to explain everything as we go along and hopefully you'll leave understanding the whole science of aging in a much deeper way.

Thanks for having me, Mark. Delighted to be here. with you and looking forward to the next hour.

Yeah, me too. So, okay, so let's start with high level. You know, 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 called 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?

That's a good question, actually. And the way I think about it, and it's true, 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 not go there because it was considered too messy. And the way people used to think about aging.

It was bad for your career.

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 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 interstellar radiation. Think about UV, think about oxygen stress. All of these forces are there and they're always going to be with us. 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 going to change the fact that we're living in oxygen or that there is gravity 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 gamma irradiation or UV irradiation, you're going to live to about 20 years old and you're going to show in those 20 years a very accelerated form of aging. And so what people had not appreciated again 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 brand counter to everything we have ever thought about biology. People thought about mutation that's typically deleterious. You get a mutation, you get a disease. disease. And here were a number of mutations that were identified in animal models, in C. elegans, the little worm that we study, or 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. Elegans or to fruit flies or mice. But over the last 20 years, 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 we are right now at a stage where this is slowly percolating into humans. And I predict the next 10 to 20 years are going to be transformative in our ability to bring all of this basic knowledge on the biology of aging to humans.

I mean, that's pretty exciting what you're saying. I just want to highlight something that I think is really important, is that historically we just thought that 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 all these ways in which the body can actually activate these processes. And, 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 in 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, but sometimes I don't think they go far enough because they, they only talk about, well, these are the things that go wrong, not what are the causes of the Hallmark. So if the cause marks are the causes of Aging on diseases, what are the causes of the Hallmarks going awry? Right. So that's kind of an interesting, you 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 humans, right?

Yes, it is. You're completely right. This is a really exciting time. You know, as a physician and I mean by training, I went to medical school, even though I did most of 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 an exciting time, this idea that something that we've always thought was ineluctable and over which we had little control is becoming another tractable problem. And this is, you know, the excitement that you see in the field is a reflection of this. You know, one number that 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 parents didn't live very old and therefore, you know, I might as well have another cigarette, another glass of wine and enjoy life while it's there. But it turns out that, you know, about 93% of our longevity is determined by our lifestyle factors. 93.

That's a very specific number.

Well, that's the result 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 determining health span and lifespan. But the number they came up based on millions of people and records, appears to be 93% lifestyle, 7% genetics. That's true only if you, and the only exception to this, if you have an ancestor, someone in your first degree relative who has lived above 100, then there's some likely genetic factors. It means you're most likely protected and you can have another cigarette.

Well, I have APOE2 as one of my APOE alleles.

Fantastic.

So I call that the jackpot gene.

You're one of the lucky ones.

Yeah. So I don't know what that means exactly, but I have 8.02.3 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 kind of what I want to know.

Probably more than me. I'm E3E3, which is already good.

That's average. That's good. Okay. So let's get into the conversation around two aspects, which one is what are these mechanisms and pathways? And then let's talk about how we we and the research at the Buck Institute is actually uncovering ways in which we regulate these. But before we do that, I want to go into a conversation that almost is 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 was like, well, I don't know. This is very overwhelming, but it was really helpful 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 two years ago. Oh, and when I was 62, and then I implemented a whole bunch of interventions, including more aggressive lifestyle change, different nutraceuticals, analytic supplements, which which we'll talk about, as well as different kinds of treatments like plasma feresis and exosomes and stem cells. I just kind of went, I did it all. And then I also did rapamycin. And I was like, how far can I change this biomarker? And if I just throw the kitchen sink at it, which is not very scientific, I get, but I want. I'm gonna end up one. So I thought it was, you know, worth trying. And I went back, even though I got two years older, now I'm 64. On the same test, I went to. from 43 when I was 62 to 39 when I'm 64. So, I've been back four years even though I got two years older. And so, how reliable are these clocks? Am I just falsely enthusiastic about my own result? And, what are the things we should be looking at? Is it the need in the pace of aging? Is it the methylation? What are the things that actually are worth looking at?

Yeah, that's a, The whole idea of biomarkers of aging is going to be critical. And here's the reason. We go through life right now sort of hoping 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 how well are you aging? When we talk about biological aging or biological age, this is in contrast to chronological age. Just for your audience, you can be 40 years old, but 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. By the way, we are also able to generate an estimate of biological age. If you've met someone who's 70 years old and you think that person looks younger, you have defined in your own head that this person is biologically younger. By the way, these are true variables. They are actually algorithms that will predict your age simply based on facial recognition, just like we do. 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 tell you where you are on your trajectory, but also to assess the efficacy of our interventions. And you just described your N of one, 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 these clocks are coming into play. Now, we are right at the beginning of a whole field. So I did the same thing as you did. True Diagnostic, 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. 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 25 and 67. And of course, I look at the 25 year old clock and I say, that's a really good clock.

That's good. I'm jealous now.

And that's glycine 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 we sort through this?

Well, you just pick the best one, don't you?

Well, you pick them up. 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 repetitive measurement, just like you said. So you, you know, First, you need probably to measure many of them. The paper that you're referring to is a paper in which we did plasma pheresis in a number of patients with a company called Circulate. And we found on a global scale that most of the clocks actually went back when these patients underwent plasma pheresis. But again, there was extreme variation between the different clocks. So I tell people, if you want to use the clocks, Companies like True Diagnostic 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 prediction is that over time, we will not only have these epigenetic clocks, we will have proteomics clock, metabolomics clock, facial recognition clocks. 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 Wyss-Coray at Stanford are able to measure organ specific aging, which is gonna be really critical. 'Cause of course, as we age, we are always limited by what I call the rate limiting organ. It could be your liver that's gonna fail first. And you would wanna know and do an intervention that favors your liver versus your brain versus your heart. so on. So I think we're right on the cusp of a revolution in diagnostics. And these epigenetic clocks is the first symptoms going in this direction.

So basically, it's all getting shaken out right now in the research. And we're going to learn which are the best clocks and we'll learn more and get better. But in the meantime, 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.

But interestingly, another anecdote, for example, someone did an interesting experiment where they measured the clocks at different times of the day in the same person. And they found over the 24-hour period, the clock would vary by five years.

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, Night comes, I'm 70.

Meaning that, you know, if you're going to do this, do it every time at the same time of the day because there's obviously a dermal variation in there. Great.

Okay. So now we have these clocks. Let's say we can measure 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 sort of underlying things that really regulate aging around we call cellular senescence, which is zombie cells and cells that kind of spew out inflammation throughout the body, are looking at our metabolism and how our nutrient sensing pathways work, which I think I want to get into fairly deeply. Stem cell and stem cell biology and 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 how you start to think about 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 Buck Institute about what's working in all these different areas?

Maybe I'll just take it one step backwards and just to alert your audience to the fact that there will be no magic pill. Aging is an incredibly complex mechanism. 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. That includes epigenetic dysregulation, senescent cells, 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 solving it, I think if you study it, you will realize how complicated the process is. And that, you know, we at the Buck Institute, we have about 300 people working on aging. We don't take sides in a way that I cannot predict what's going to be more important. So 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 Giacomo Campisi at the Buck. 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 think one of the things that is really emerging right now is the complexity.

I think that's so important that you point that out.

It's important because, you know, frankly, I have sometimes been called the grumpy man of longevity research because I refuse the hype or work. I think there's a lot of really exciting things happening in Asian research, but I'm not deluding myself. I don't tell people I'm going to live to 150 or 170 like some of my colleagues do. I think right now we are focusing on things that are really tangible. For example, you might be surprised to hear that most of us could live to 95 years old in good health if only we would deploy everything that we know. That's already a lot better than what we have today where most of us would live to 65 in good health. That's an extra 30 years of healthy life. Right now we are really focused on two things. the Buck 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 bigger aspect that is being grown at the Buck 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 want to live the longest possible.

Yeah, I mean, I think it's so important when you just said around the nature of nature, which is, it 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, essentially, 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 going to focus on mitochondria or I'm going to focus on inflammation or I'm going to focus on deregulate nutrient sensing, or I'm going to make something that's going to 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 a lot of these ancient longevity pathways, and I think when I think of this, and I would love to hear your opinion about this, is that there's kind of a way to kind of influence a lot of it through the same kinds of interventions, obviously the lifestyle stuff. But, when I think about, for example, the four deregulated 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 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, mPA, all these things affect mitochondria, they affect inflammation, they affect oxidative stress, they affect your epigenetic regulation, they affect DNA repair, they affect senescence self. I mean, this is when you start to dig into it, it's like everything is affecting everything. So, what's the highest leverage point? And again, I'm not a longevity researcher. I'm just sort of a doctor trying to make sense of all this. It seems like the deregulated nutrient sensing is one of the most important, almost meta hallmarks because when you address those four pathways, it downstream benefits all the others. Am I off or does that make sense to you?

I agree.

Oh, wow. Okay, because I made this up. I made this up. So.

No, I do agree, although there are, you know, so when I think about the buckets in which you should invest if you want to maximize your longevity, nutrition is clearly one of the top ones. But equally important is exercise. But by the way, exercise or physical activity affects all of the same pathways that we just discussed. So most of the time, I sort of reduce this to the fact that we're dealing with energy generation. And so if think about exercise and nutrition have this in common, they are both profoundly dependent on your ability to generate a lot of energy. 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, 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 or ability to make sufficient energy becomes limiting, then, you know, if you have the choice between repairing your DNA or actually walking, your body is going to favor the walking. And so, there are lots of common threads between all of these variables. I'm happy to dive into this.

Yeah, yeah. Let's dive into it because I agree with you. I think the mitochondria are central. It's really about how we create and make energy as well as how we protect, preserve, and improve the number and function of our mitochondria. And, I always say the difference between a two-year-old who's 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 a lot of your research has focused on mitochondrial function aging, particularly around the role of NAD and ketogenic diets, for example, and the role of sirtuins in regulating mitochondrial function as well. And, 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. 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 like the world's expert here.

Lots of drawers to open there. Yes, so 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 fat and proteins. in the presence of oxygen to generate energy. This process takes place at many places in the cell, but predominantly in the mitochondria, which by the way are commensal bacteria which have become incorporated into our cells. This is something a fusion that happens billions of years ago. Quite interesting biology. These mitochondria are generating the ATP that we use as energy, and also the NAD, which we use as an intermediate form of energy, and we can come back to this later. Now it turns out that mitochondria numbers dwindle with aging, and their ability to generate energy dwindle with aging. 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 worsening energy deficit as we age. And so there's a lot of interest in trying to understand how do we reverse this. and how do we prevent this from occurring at the first place?

Clearly, the mitochondria are key. The question then is, what can we do to help our mitochondria? Because 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.

Yeah. So, you know, as I mentioned, so that there's loss of mitochondria 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. The two ways in which I think you can maximize your mitochondrial function as you age is fasting. Fasting, as I mentioned earlier, activates a process called autophagy, which means self-eating. The beauty of autophagy when you're fasting is that your body is able to sort through the garbage and the well-functioning mitochondria to discard the poorly functioning mitochondria and to keep the ones that are most efficient. So that process called mitophagy. So intermittent fasting, I think is part of the ability that your body has to shift between feeding and fasting is a process that we call metabolic flexibility. And I think it is really an integral part of health. So I encourage people to incorporate this into their daily routine. Another way in which you can- Just.

To what you're asking is to give people a break between dinner and breakfast is essentially what you're saying.

Well, yes, that's one way to do it actually. And right now we're at the stage where there are a whole bunch of different fasting modalities have been explored and tested. And I don't think there's clear evidence that any of them is more beneficial than another. Some people will do a deep fast every three 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 trying to decide what is the best way. But any of them is better than none. That would be the rule that I would, practically for me, I do a five-day fast every three months and then I do sort of what people call restricted time feeding, which means I try not to eat for 12 to 16 hours every day. so that at least have a period of fasting. There are also a number of interesting supplements that are emerging that are supplements or drugs. The interest in fasting came out of the realization that animals on calorie restriction, so whose calorie intake was limited, actually showed the increased lifespan. that that's pretty much 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, well, I'm running around starving all the time.

Exactly. Exactly. So, you know, metformin, I'm sure you've heard about metformin or rapamycin are calorie restriction mimetics. so they fool your body to think that you're fasting and they induce part 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 the pathways, the biological pathways that lead to this. And some of them can be activated by drugs or supplements. A supplement, for example, that activates a mitochondrial function would be Urolithin A, I'm sure you've heard, product sold by- I.

Take it every day.

Yeah, I take it every day too. It's a supplement, so it's not going through the same process that an FDA approved drug would be, but the company that commercializes this called Timeline has a very proactive approach to testing, doing clinical trials and demonstrating the efficacy of what they are claiming. We've collaborated with them, so 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 certainly a very strong way to activate mitochondrial function in your muscle. And we know, you know, 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, whenever we're talking about anything related to aging, the 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.

That's right. And, you know, the thing around the mitochondria also that you've done research around is NAD and NAD+ and There's a lot of controversy around this particular compound. Some say it's kind of the data isn't there, some say it's God's gift to mankind and we should be all taking it. What's your kind of sort of down and dirty on the science behind NAD and taking NAD either as an NMN product, NR product, or sub-Q NAD or IV NAD? all these people are doing these things, including me. So I'm curious about what your perspective is, someone who's actually done the research.

Yeah, happy to talk about this because frankly, once you are involved in the research and you see some of the stuff that's being sold, it's sometimes I shake my head in disbelief. But that being said, there is like in any story, there's always an element of truth to the whole NAD story. So Just 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. 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 from different molecules within the cell more correctly. So it's also known that NAD levels decrease during aging and this is that's really well established in humans and in animal models. So out of this game, 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 manage. So when I think about NAD, you think about Brinkmann, 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 the supermarket and nothing moves anymore. So this is the same thing. So I think about them as the, the, the, the fund carriers. So out of this came the ideal. Maybe we can just re-establish NAD levels, and so people will see a benefit and. In animal models, you can do this using what we call NAD precursors. There are two of them that you're familiar with, nicotinamide riboside, NR, or nicotinamide mononucleotide, NMN. Both of them essentially do almost the same thing. Some colleagues will argue vociferously on whether one is superior to the other at the end. they both reestablish NAD levels. They might have additional signaling properties in addition to this. And in animal models, they do remarkable things. 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 the interest, well, maybe you 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 factor 10 of what we used in the laboratory setting. so, you know, like, no, most bottles.

Are like 250 milligrams.

Exactly.

But you're saying you need more like.

What?

Use two to three grams.

Exactly.

Wow. Precursors.

Yes. We used a lot more. And those of us who take an amen or NR typically take a lot more than the, the 200 milligrams a day.

What would you say? Take two grams or one gram or.

Well, that's. I take a gram when I, most of the time. Now, 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.

That'S true. Peter Tia is highly skeptical. And 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 let's not throw the baby with the bath water.

And.

There is enough compelling evidence in model systems that NMN and NR actually are having interesting effect that to pursue the studies and to conduct the clinical trials. Now, one of the biggest problems I have is asking the question and something my lab has been working on. why are NAD levels decreasing during aging? That really has not been studied by many people except us and Eduardo Chini, who was at Mayo Clinic. What we both found is that the reason why NAD levels decrease during aging is because there's another molecule called CD38, which is activated during aging for reasons that are not entirely clear, but in part because of a senescent cell burden. So, the CD38 is itself as NAD hydrolase. It chews up NAD. And so, when you give an enzyme.

Like Pacman that kind of eats up your NAD.

Exactly. So, 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. when you give NMN or NR, you're essentially filling up more water in a leaky sink. And so, which is not a very satisfying way to solve a problem. So the way we are going about it, and a growing number of companies are doing this as well, is to actually identify small molecule inhibitors of CD38. And so I have a startup called Napa Therapeutics, which as a large number of these novel molecules. We're testing them. Some of these inhibitors, not ours, but others have been shown to increase lifespan and to correct some of the aging-associated energy deficit much more efficiently than the precursors. My prediction is that if you think about an AD defect in the future in the long run, we probably will be looking for these CD38 inhibitors rather than filling up the tank with more water.

Interesting. So it's 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.

You got it. You got it. And one reason for doing this is, And this speaks also to the importance. A lot of people are taking a lot of supplements these days and they're not being followed appropriately by a physician. As I was taking a lot of NMN, I was always concerned because we know that NMN, as it's being, if you take a large amount of it, will consume your one carbon, your methyl groups. and so I was, as I was doing this, I was always following my homocysteine levels. And, and, 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'm I'm somewhat worried about the proliferation of supplements that are being touted and sold to some somewhat naive public hoping this is going to increase my lifespan. There are a lot of, there are very few molecules that have absolutely no consequence. And I think if you're going to go down this route, do it with someone that knows, understands the biochemistry and can follow you appropriately.

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 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+, it won't, and that you might be wasting your money.

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 and ADP-ribose. Now, the nicotinamide is essentially niacin. You can buy this for 20 cents or whatever. So this $700 injection, I really have no idea, actually no one has any idea what happens to it. most of it is likely very quickly degraded.

And that's why you feel that kind of weird flushing feeling when you get the NAD.

Yes. Well, niacin, as you know, will activate these flushing receptors. This was one of the limiting use of niacin as a drug, but at cholesterol lowering a few decades ago, people had some flushing issues. It's the same thing that you're feeling when you're taking intravenous nicotinamide.

There's an anecdote, and I don't know what to make of it, was I did a retreat on longevity and one of the local companies was 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 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. And, I don't know, I don't know, it's just an anecdote, but I imagine it's doing something. And, yeah, it's not a fun way to take it, you know, intravenously, subcutaneously, you can also do it same thing. It seems like it would lead to the same kind of result. But this is fascinating data. So what you're saying about NAD is that in the precursor essentially is it doesn't necessarily extend lifespan, but it improves quality of life and health span. Would that be accurate?

That's the prediction and that's what we, although, you know, there's evidence that CD38 inhibition or deletion actually increases lifespan. So, that might be one way to put back this whole pathway in the context of longevity.

Wow. And, that's what Napa Therapeutics is working on, right?

Yes, absolutely.

Incredible. Amazing. I feel like we need to go have another one of these podcasts. I might do this in two parts.

Because going forward, anytime, happy to come back.

There's so much more I want to get into on inflammation, around around nutrition, around the microbiome and aging and many, many other topics. But, I would love to kind of just finish up for the last few minutes on two topics. One is, what are the all-star molecules for longevity? And, I have a list that I want to sort of get your thumbs up, thumbs down on. And, two, 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? What are you doing? So, the molecules that I think 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 the metformin question, which I think is probably a little longer than we have to get into, but I'm a little dubious about it. And, I don't know if we're going to get to the TAME trial now, which is a randomized trial that's going to give us the answer, unfortunately. And then there's all the sort of phytochemicals like quercetin, fisetin, curcumin, green tea extractor, epigallocatechin gallate, berberine, and some of these molecules that seem to be sort of promising as both... and uridine, which you mentioned, which is sort of a mitochondrial supporting phytochemical that can be derived from pomegranate. Among all these sort of players.

Which.

Are ready for prime time, which have sort of low risk potential benefit, which should be careful with, how do we think about this?

It's a tough one. I tell people if you want to-.

In five minutes or less.

Okay, so I'll start. First, 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 bandaid on it. You start get, 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, 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 agree with you, by the way.

I agree with you.

You can make it because a lot of people, you know, will go to the supplements. They don't want to do any of the other things. And, 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 they, we, we do not have and will not have for the next 20 years. an anti-aging medicine or supplement that is better than physical activity. Mark my words, for 20 years, in 20 years, we will still not have something that works as well as physical activity.

It's a miracle drug.

It is a miracle drug. If you are not paying attention to that one, well, you can put a band-aid on some issues, but you never really get to the core problems. Now, thinking about the rest, First for me is blood draw. Are you balanced in terms of vitamin D, vitamin B12? This would be the first big ones. And 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 one. Number two, there are so many- 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 want to know, right?

Exactly. You're also, you're, you know, I don't.

Know if you're measuring this, but you're Omega fatty acid. We're measuring Omega 3 fats, 100%. We're measuring 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. Critical. So, you know, there are a few supplements that have documented efficacy. One of them is Omega fatty acid. and especially if you are like most people in the Western world and 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, carnitine is really one of the well-recognized supplement that people take. Now, we talked about a whole variety of flavonoids, quercetin, curcumin, fisetin, all of those. The problem with many of those is bioavailability. So much of what has been shown about their efficacy is based on studies where 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, they 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 this, but most of the time the data is just not there that these things are getting absorbed to a significant level. So, I have, you know, I have doubts.

If you take the pill and then your blood levels don't reflect the pill. Don't change.

Yeah, it just goes through. So, There are, for example, one thing you didn't talk about, which I think is really critical, is fiber and probiotic, which I think for me, I'm a fervent 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 have a special concoction of prebiotics that I make myself and I think that to me is really one of the central components of having a healthy digestive system which will determine your immune system and so on. As I told you earlier, 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 VO2 max on other immune function we published on the effect on immune function. I don't know, any other ones that I forgot the list of all the compounds that you mentioned. One thing that I want to mention also is is the whole concept of, as a physician, you know about polypharmacy. The idea of polypharma, well, people, you know, polypharmacy is the idea that once you start, you start with one 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 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 sea Elegance, the little worm that we study, We can identify readily small molecules that increase the lifespan. This experiment was done, it generated to a whole series of molecules that increase lifespan. Let's say we have 10 compounds that all increase lifespan. What they did then, combine each of these 10 compounds pairwise, and what you find is, they were actually able to identify a number of pairs that actually had synergistic effect where the lifespan effect was bigger than the sum of the two 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 two drugs that increases lifespan, whenever they added another drug that also increased lifespan, all of the effects went away.

So.

That'S not good. And, you know, I hear about Brian Johnson taking 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 three months on this compound and then another three months on this other compound. So I think we are right at the beginning of a new land that we do not understand.

Do you think that the advent of our understanding of systems medicine biology with AI is going to help us sort through this?

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 measure tens of thousands of variables instead of a hundred. And so the Buck right now 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 100, 200, 300 biomarkers.

Not even.

Not even.

Annual checkup is like 20 or 30 biomarkers. Your CBC, chem screen, cholesterol, and a urinalysis.

Exactly. And if you take all of the tests that medicine can today conduct, maybe it's 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 20 million CPG sites. So, really the idea is now to use artificial intelligence and these deep phenotyping essays 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 tremendously exciting by this. It's not for direct consumption for the public, but it's important for people to know that this is where medicine is going. It's ramping up to a next stage of data gathering and processing.

I think that's really 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 orders of magnitude more than we've ever been able to get 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 100,000 petabytes of data just in our microbiome.

Yes, exactly.

But I don't even know what a petabyte is, to be honest with you, but it still sounds like a lot of data. And that's just one part of our biology and the complexity of those interactions, the dynamic way they interact, how they actually are affected by various inputs from lifestyle, from nutraceuticals, from drugs. We're in the most, to me, the most exciting era. It's almost like we finally figured out how to look at the stars and look at what's going on in the universe in a way we never could before. I'm just so excited and 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.

That's the, you know, that's the whole philosophy that I tell people, you know, the reason why you should optimize your health plan today using everything that we know is that first there's 35 years of extra healthy life for you to be gathered using this. And 30 years from now, God knows where we will be in terms of our ability to interfere in these pathways and to keep you healthy even longer. So the key is, while we're working at gathering all of this data and defining what are the safest and most effective, you know, lifestyle changes or drug and so on, just keep yourself healthy and you will reap the benefits now and in the future.

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's not that many people working at the level you're working and it's just to hear what you're saying, to understand the implications of it, to know that that you've come to the same conclusions that someone in the clinic working with real patients has come to. It's just very heartening. So I'm very excited. I'm definitely going to make it out to the Buck Institute. I promise I'll get there. And we'll see you around the next morning. And I'm going to have you back because I didn't get to ask at least half of what I wanted to ask you.

So we'll find another time and have part two.

Take care. Bye-bye. If you love that last video, you're going Love the next one. Check it out here.