The Dr. Hyman Show - Reverse Aging Now: The Latest Longevity Breakthroughs | Dr. Eric Verdin

Episode Date: December 4, 2024

What if aging wasn’t inevitable, but something you could slow—or even reverse? In this episode of “The Dr. Hyman Show,” Dr. Eric Verdin, the president of the Buck Institute for Research on Aging, and I dive deep into the science of longevity. Discover how lifestyle choices, mitochondrial health, and cutting-edge research are transforming our understanding of aging. From fasting and nutrient sensing to emerging therapies like CD38 inhibitors, this episode reveals actionable insights to help you live a longer, healthier life. In this episode, we discuss: The Role of Mitochondria in Aging The Critical Role of NAD Levels and Aging Lifestyle Interventions for Longevity Gene Therapy The Importance of CD38 and Enzyme Inhibition View Show Notes From This Episode Get Free Weekly Health Tips from Dr. Hyman Sign Up for Dr. Hyman’s Weekly Longevity Journal This episode is brought to you by Rupa Health, BIOptimizers, LMNT, and Fatty 15. Streamline your lab orders with Rupa Health. Access more than 3,500 specialty lab tests and register for a FREE live demo at RupaHealth.com. Don’t let stress take over your holidays. Try Magnesium Breakthrough from BiOptimizers. Head to Bioptimizers.com/Hyman and use code HYMAN10 to save 10%. LMNT is giving listeners a FREE eight-count sample pack of their vital electrolyte drink mix with any purchase. Just visit DrinkLMNT.com/Hyman today. Fatty15 contains pure, award-winning C15:0 in a bioavailable form. Get an exclusive 15% off a 90-day starter kit subscription. Just visit Fatty15.com and use code DRHYMAN10 to get started.

Coming up on this episode. 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. Hey everyone, it's Dr. Mark. As functional medicine practitioners, we need to get to the heart of root causes behind our patients' health concerns. And let's face it, ordering labs to get the data can be an administrative nightmare. Luckily, Rupa Health is here with the solution. Rupa's simple lab ordering platform helps you access and order from thousands of tests from over 35 different lab companies in one place. And better yet, it won't cost you a cent. That's right. There are no hidden fees, subscriptions, or complicated billing systems

when you use Rupa Health. So if you're tired of juggling multiple invoices or dealing with administrative headaches, do what I do. Make the switch to Rupa Health. Sign up free at rupahealth.com and take control of your lab ordering process today. That's rupahealth.com. The holiday season is here and with it comes all the stress of shopping, hosting, and endless events, which is why I always recommend magnesium breakthrough from Bioptimizers. This isn't your standard magnesium. It contains seven forms of magnesium to support every system in your body. Most of us are low in magnesium, which can make it hard to manage stress, stay calm, and get a good night's sleep. Magnesium Breakthrough helps restore your levels, letting you handle holiday stress with resilience. With forms like citrate, glycinate, and taurate,

it ensures maximum absorption and total body support from relaxation to energy production. Don't let stress take over your holidays. Try Magnesium Breakthrough from Bioptimizers. Head to bioptimizers.com slash hymen and use the code hymen10 to save 10%. That's bioptimizers, B-I-O-P-T-I-M-I-Z-E-R-S dot com slash hymen. And if you subscribe, you'll get discounts, free gifts, and a guaranteed supply each month. Before we jump into today's episode, I'd like to note that while I wish I could help everyone by 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 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 Doctors Pharmacy. I'm Dr. Mark Hyman. That's pharmacy with an F, a place for conversations that matter. 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, Dr. Eric Burden, 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 Leeds 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 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 as a very 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 and 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, NR, 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, and I had to cut it after a while. But I think we're going to have back for a round two of the podcast because we didn't get to cover all the things I want to cover. And you know, I'm very interested in this topic. So go ahead and fasten your seatbelts. This is going to be a very interesting and deep conversation. You might have to look up a few things, but we're going to put everything in the show notes and let's dive right in. 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 and 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. 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's 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 so the question is really, how do we need to think differently today, given the science that we have, particularly around the underlying 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, 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 not go there because it was considered too messy.

And the way people- 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. 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 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 animal models, in C. elegans, the little worm that we study, or in fruit flies, or in mice, that 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 sea elegans or to fruit flies or mice. But over the last 20 years, you 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 healthspan. 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 and the mechanisms. And the hallmarks of aging is sort of description 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 hallmarks 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 humans, right? Yes, it is. You're completely wrong. 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 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, many of us have a sort of a fatalistic approach to it. We think, my parents didn't live very old, and therefore, I might as well have another cigarette, another glass of wine, enjoy life while it's there. But it turns out that 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 healthspan 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 a hundred, then there's some likely genetic factors. It means you're most likely protected and you can have another cigarette. Well, I have an APOE2 as one of my APOE. 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 APOE-23, 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 E3-E3, which is already good. That's average. 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 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 sort of 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 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 we'll talk about, as well as different kinds of treatments like plasmapheresis 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 so I just throw the kitchen sink at it, which is not very scientific, I get. But I'm an N of one. So I thought it was, you know, we're trying. And I went back, even though I got two years older, now I'm 64.

On the same test, I went from 43 when I was 62 to 39 when I'm 64. So I bent back four years, even though I got two 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 things that actually are worth looking at? Yeah, that's it. The whole idea of biomarkers of aging is going to be critical. And and here's the reason we we go through life right now, sort of hoping, you know, that things are going to work out for the best. And traditional medicine essentially waits for you to to get sick,

to really start intervening. So there is a need, a crying need, for what we call surrogate markers, markers that will 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 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. And 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. And by the way, these are true variables. They're actually algorithms 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 just described, you know, 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, 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 Horvat 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, look at the 20, that 25 year old clock and I say, that's a really good

clock. That's good. I'm jealous now. And that's, that's 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 the best one, don't you? So, I mean, there's obviously there are some significant problems 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 first you need probably to measure many of them. The paper that you're referring to is a paper in which we did plasma phoresis and 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 plasmapheresis. 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. You know, 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 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 Wiskoray at Stanford, are able to measure organ specific aging, which is going to be really critical. Because of course, you know, as we age, we are always limited by the what I call the rate limiting organ. It could be your liver that's going to fail first, and you would want to know and do 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 revolution in diagnostics, and these epigenetic clocks is the first the first symptoms are going in this direction so basically it's all getting shaken out right now in the research like and 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. So that's... 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 diurnal 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 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 Buck Institute about what's working in all these different areas? So 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. And 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, 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 Gigi 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 aging 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, you know, 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 sort of deploy everything that we know.

That's already a lot better than what we have today, where most of us will 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 two things at the back. 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. Let me ask you a question. What do you reach for after you finish a workout? If you're like most people, you probably reach for a sports drink to replenish the water and electrolytes you lost. And that's great, except that most of these drinks are also filled with sugar, food coloring, and other junk. When I want to get the benefits of a sports drink without all the nasty stuff, I reach for Element. Their tasty drink mix has everything I need to give myself a science-backed the nasty stuff I reach for Element. Their tasty drink mix has everything I need to give myself a science-backed electrolyte boost whenever I need it.

And there's no sugar, coloring, artificial ingredients, gluten, or fillers, which means it aligns perfectly with my dietary choices. Element is one of the most important tools in my health and fitness toolkit, and I know it can be for you too. Right now, Element is offering my listeners a free sample pack with any purchase. That's eight single serving packets free with any Element order. This is a great way to try all eight flavors or share Element with a friend. Get yours at drinkelement.com slash hymen today. That's l-m-n-t dot com slash hymen. I want to tell you about a groundbreaking discovery that could be a game changer for your health. Cellular fragility syndrome. What the heck is that? Well, this

condition just identified in a recent study is caused by a deficiency in an essential fatty acid called C15, the first new essential fat discovered in over 90 years. As many as one in three people may be low in C15, leading to weaker cells that age faster, impacting your metabolic, liver, and heart health. Do you have fatigue, poor sleep, and are you feeling older than you should? Well, these might be signs of a C15 deficiency. Now, C15 is a unique fat that keeps our cells strong and resilient.

Without it, our cells can become fragile, accelerating the aging process, and that's where Fatty 15 comes in. A pure vegan C15 supplement designed to replenish this critical nutrient, repair your cells, and restore your long-term health. Not only does Fatty 15 help repair age-related cellular damage, but it also protects against future breakdown, boosting your energy, improving your sleep, and reporting healthier skin, hair, and joints. It's like giving your body a daily dose of resilience. Want to learn more? Head to fatty15.com slash drhyman10 and use the code DRHYMAN10 for 15%

off their 90-day subscription starter kit. That's F-A-T-T-Y-1-5.com slash D-R-H-Y-M-A-N-1-0 and take control of your health today and give yourselves the support they need. Yeah, I mean, I think it's so important what you just said around the nature of nature, which is, you know, 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 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

deregulated 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 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'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 senescent self. 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, 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. 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 are dealing with energy generation. And 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 so, 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, 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. And 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, and particularly around the role of NAD and ketogenic diets, for example, and the role of sirtuins in regulating mitochondrial function as well. So, and I think I'd love to sort of dive into this whole topic with you a little bit more because you're such an expert in it.

You know, 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 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, the fire will get more intense. So this is the same thing. We burn carbohydrates, lipids, or fats 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 sort of commensal bacteria which have become incorporated into our cells. So this is something, a fusion that happens billions of years ago, quite interesting biology. So 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 dwindles with aging. And there are multiple variables 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? So, so, so clearly the mitochondria are key. And, and the question then is, um, 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, um, 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 sort through all the massive data and information 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 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 the two ways in which I think you can maximize your mitochondrial function as you age is fasting. And fasting, as I mentioned earlier, activates a process called autophagy, which means self-eating. And 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 the 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- What you mean is, just what you're asking is to give people a break between dinner and breakfast. It's essentially what you're saying.

Well, yes, that's one way to do it, actually. Right now we're at the stage where a whole bunch of different fasting modalities have been explored and tested. 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 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 I at least have a period of fasting. There are also a number of interesting supplements that are emerging that are supplements or drugs.

You know, the interest in fasting came out of the realization that animals on calorie restriction, so whose calorie intake was limited, actually showed increased lifespan. That's pretty much a universal feature. So that led to the 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 running around starving all the time. Exactly, exactly. So, you know, metformin, I'm sure you've heard about metformin or rapamycin

or calorie restriction pneumatics. 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 mitochondrial function would be the urolithin A. I'm sure you've heard a product sold by... I take it every day. Yeah, I take it every day too. And, you know, it's a supplement,

so it's not going through the same process that an FDA approved drug would be. But the company that, you know, commercializes this called Timeline has a very proactive approach to testing, you know, doing clinical trials and demonstrating the efficacy of what they are claiming. And 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 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 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 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 and 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, 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, sometimes I shake my head in disbelief. But that being said, there's 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. So NAD is an intracellular, and it doesn't cross from the blood into your cells. So it is an intracellular metabolite. Why is it important? Because it allows you to shovel 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. 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 manage. So when I think about NAD, you think about Brinkman, the trucks that carry money.

So think about if they all went on strike, all of a sudden the energy 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 fund carriers. So out of this came the idea, maybe we can just reestablish NAD levels, and so people will see a benefit. And in animal models, you can do this using what we call NAD precursors, and there are two of them that you're familiar with, nicotinamide riboside, NR, or nicotinamide mononucleotide, NNN.

And 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. So 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, 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 most bottles are like 250 milligrams exactly but you're saying you need more like we use two to three grams exactly so we use yes we used a lot more and those of us who take nmn or nr typically take a lot more than the 200 milligrams a day what What would you say, take two grams or one gram?

Well, I take a gram 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 is enough compelling evidence in model systems that NMN and NR actually are having interesting effect to pursue the studies and to conduct the clinical trials. Now, one of the biggest problems I have 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 Eduardo Cini, who was at Mayo Clinic. And 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 RNA... It's an enzyme like Pac-Man that kind of chews up NAD. And so when you give an RNA... It's an enzyme like Pac-Man 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. And when you give NMN or NR, you're essentially filling up more water in a leaky sink, 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 has a large number of these novel molecules. We're testing them. Some of these inhibitors are not ours, but others have been shown to increase lifespan

and to correct some of the aging-associated energy deficits much more sort of efficiently 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 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. You can keep filling the bucket faster, but at some point,

it's kind of diminishing returns. Better to 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 actually I found it to, you know, to rise significantly in the presence of a large amount of NMN intake. And, you know, and if it goes too high, I stop my NMN for a while. So you're speaking to the fact that all of these processes are connected. And I'm somewhat worried about, you know,

the proliferation of supplements that are being touted and sold to a somewhat naive public, hoping, you know, this is going to increase my lifespan. There are a lot of, you know, there are very few molecules that have absolutely no consequence. And I think, you know, if you're going to go down this route, do it with someone, you know, 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 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+, it won't and that you might be wasting your money. Yes. plus it won't and that you might be wasting your money yes you are you know a typical nad infusion costs about 700 dollars uh 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 that? Yes.

Well, niacin, as you know, will activate these flushing receptors. This was one of the limiting use of niacin as a drug. But 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. I did a retreat on longevity, and one of the local companies, it was in Turkey, offered NAD as part of this.

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, 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 the same thing. It seems like it would lead to the same kind of result, but it 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 healthspan. 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. Yes. Absolutely.

Incredible. Amazing. God, I mean, I feel like we need to go have another one of these podcasts. I might do this in two parts because... Anytime. Happy to come back. There's so much more I want to get into around inflammation, 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 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 doing? So the molecules that 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 on the podcast before, essentially 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 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, epigallactylcatechin gallate, berberine, and some of these molecules that seem to be sort of promising as both, and u lithium-A, which you mentioned, which is sort of a mitochondrial-supporting 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 careful with, like, how do we think about this? It's a tough one.

I tell people, you know, 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 Band-Aid on it. You start getting... 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. 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. And I agree with you, by the way. Because a lot of people will go to supplements.

They don't want to do any of the other things. And 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 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. And, you know, mark my words, for 20 years, in 20 years we will still not have something that works as well as physical activity. And mark my words, for 20 years, in 20 years, we will still not have something that works as well as physical activity. It's kind of a miracle drug.

It is a miracle drug. And so if you are sort of not paying attention to that one, well, you can sort of put a Band-Aid on some issues, but never to 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 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 methylmonic acid and homocysteine, all the things that we want to know, right? Exactly. Also, I don't know if you're measuring this, but your omega fatty acid levels. 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 acids. 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, you know, carnitine is really one of the well-recognized

supplements that people take. Now, we talked about a whole variety of flavonoids, quercetin, curcumin, fitcetin, 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. 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 my doubts. You take the pill and then your blood levels don't reflect. Don't change. 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, you know, 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 probiotics 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 the whole concept of, as a physician, you know, about polypharmacy.

The idea of polypharmacy, well, people, you know, polypharmacy is the idea that once you start, you start with one compound, you have a series of positive effects, 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 C. elegans, the little worm that we study, 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 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 combined 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. I hear about Brian Johnson taking 120 supplements, and I'm thinking it cannot be good what's happening at this mixture of all of these drugs, know all of this byproduct i don't know it just it worries me um 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 on this compound and then another three months on this other compound so i 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 100. And so the back 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 100, 200. Not even.

Not even. Your 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 5000 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, deep phenoty and try to extract all of the information that we can get on how do these drugs work, what pathways are they activating.

This is the next frontier. And I think 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 and 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 of the capacities to measure omics at every level, I mean, there's 100,000 petabytes of data just in our microbiome. Yes, exactly.

I don't even know what a petabyte is, to be honest with you, but it 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 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'm just so excited. And I, you know, even though I'm like 65 almost, I'm going to be 65 this year, I just feel like a kid in a candy store. And I just can't wait to see what's going to happen. And I'm going to try to keep myself alive long enough so I can actually take advantage of it all. That's the whole philosophy that I tell people.

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 in 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 key is, you know, 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. Oh, that's so exciting. Well, thank you for your work, for pioneering all this data and science. It's really tremendous. And 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 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 bucket 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 like at least half of what I wanted to ask you. So we'll find another time and have part two.

Take care. Bye-bye. Thanks for listening today. If you love this podcast, please share it with your friends and family. Leave a comment on your own best practices on how you upgrade your health and subscribe wherever you get your podcasts. And follow me on all social media channels at DrMarkHyman. And we'll see you next time on The Doctor's Pharmacy.

I'm always getting questions about my favorite books, podcasts, gadgets, supplements, recipes, and lots more. Now you can have access to all of this information by signing up for my free Mark's Picks newsletter at drhyman.com forward slash Mark's Picks. I promise I'll only email you once a week on Fridays and I'll never share your email address or send you anything else besides my recommendations. These are the things that have helped me on my health journey and I hope they'll help you too. Again, that's drhyman.com forward slash Mark's Picks. Thank you again and we'll see you next time on The Doctor's Pharmacy. and neither myself nor the podcast endorsed the views or statements of my guests. This podcast is for educational purposes only. This podcast is not a substitute for professional care by a doctor or other qualified medical professional.

This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. Now, if you're looking for your help in your journey, seek out a qualified medical practitioner. You can come see us at the Ultra Wellness Center in Lenox, Massachusetts. Just go to ultrawellnesscenter.com. If you're looking for a functional medicine practitioner near you, you can visit ifm.org and search find a practitioner database. It's important that you have someone in your corner who is trained, who's a licensed healthcare practitioner and can help you make changes, especially when it comes to your health. Keeping this podcast free is part of my mission to bring practical ways of improving health to

the general public. In keeping with that theme, I'd like to express gratitude to the sponsors that made today's podcast possible.