Episode 76: How to Solve an Age-Old Problem, with Dr. Lee Hood

Robert Rountree:

This is The Thorne Podcast, the show that navigates the complex world of wellness and explores the latest science behind diet, supplements, and lifestyle approaches to good health. I'm Dr. Robert Rountree, chief medical advisor at Thorne and functional medicine doctor. As a reminder, the recommendations made in this podcast are the recommendations of the individuals who express them and not the recommendations of Thorne. Statements in this podcast have not been evaluated by the Food and Drug Administration. Any products mentioned are not intended to diagnose, treat, cure, or prevent any disease. 

Hi everyone, and welcome to The Thorne Podcast. I'm honored to have with me returning guest, Dr. Lee Hood, a scientist whose work is led to new advances in the fields of human genomics, cancer, and Alzheimer's research. Before we get started, Dr. Hood, how are you doing today?

Lee Hood:

I'm in great shape. How about you, Bob?

Robert Rountree:

I'm pretty darn good. I'm enjoying the first snows of the winter season. We got a big dump last night and we're always happy to have moisture.

Lee Hood:

Absolutely. Yeah.

Robert Rountree:

So why don't we talk a little bit about your background, so that people can understand why you're the guy that we would want to talk to about aging? How did you get interested in anti-aging research? Or maybe we don't use that word, “anti-aging,” but “healthy aging” research.

Lee Hood:

Well, I think it's the accumulation of a lot of different interests. I have, early in my career, been very interested in developing technologies like automated DNA sequencing that made The Human Genome Project possible. The importance of these technologies is this idea that humans are terribly complicated. And if we're to decipher these complications, we have to be able to generate an enormous amount of data on humans. And obviously determining your DNA sequence generates a lot of data. But we, and others, have also developed technologies that will let you assess what the genome is actually doing to you, as well as the environment and your own behavior, by analyzing the proteins and metabolites and blood and the gut microbiome – that is the billions of micro-organisms that live in your gut and have an enormous impact on both your health and, it turns out, the process of aging and everything.

Robert Rountree:

We've gone from it taking how long to sequence the human genome, to machines that could do it in maybe a week, to now these little hand-held devices that could do it pretty quickly.

Lee Hood:

Well, they're getting to the point where they'll be able to sequence genomes in one or two days. And that is the remarkable departure from the first genome, which overall was a 13-year project, The Human Genome Project. And even more remarkable, the cost of sequencing has come down more than a million-fold in the last 20 years. So you can now do genomes for a few hundred dollars a genome. Of course, the first genome probably cost north of a billion dollars. So it was really the creation of these new opportunities of deciphering complexity in humans that got me initially interested in the process of aging. I had a colleague at ISB, Nathan Price, whom you know, who also was very interested in this area. And together we joined our labs, and we attacked longevity and aging and Alzheimer's and precision population health, and a whole series of different kinds of things. But with regard to aging, I think it's really a remarkable process to study. What is most remarkable is that the mechanisms that induce aging appear to be highly conserved from a single-cell organism like yeast, all the way up to human beings.

So I think the problem of aging is maybe 100 times simpler than the problem of cancer. I think it lays itself out in a conserved way and a very simple kind of way, that lends its analysis to not only thinking about how to assess aging but how to optimize aging, so we can either slow the process down or perhaps in the future be able to reverse the process. And of course, those are two absolutely fascinating questions.

Robert Rountree:

Your discussion brings up a core issue, I think, which is that one way to look at aging is that it's just wear and tear. Right? You live long enough, everything's going to break down and fall apart. And then there's another perspective which says, aging is a thing in and of itself. That you can study worms and yeast and, quote, “lower” organisms, and you actually see that there's some kind of genetically driven, metabolic pathway or set of pathways that are controlling aging. I think one of the obvious implications of that is that certain animals seem to live forever. You and I've talked about that before. You've got these naked mole-rats that seem to not get older when their chronological age is older. I wonder if you could talk about that distinction between chronological age and biological age and what that means exactly, because I know you've studied biological age.

Lee Hood:

We know that some people age very rapidly and other people age extremely slowly. So it is utterly clear, chronologic age is not an index of how rapidly or slowly you're aging. Nathan and I started thinking about this whole process of – we need a metric that assesses how rapidly we're aging. He and I studied together a population of 5,000 individuals, where we did their genome and their blood analytes and their gut microbiome and digital health measurements. They ranged in age from 21 to greater than 90. We were able to divide them into 10-year bins, 21 to 30, 31 to 40, so forth. We were able to show beautifully that as you age, the envelopes of control for the expression of the analytes in your blood, decrease in efficiency in a linear fashion. And without getting into any details, this led us to an algorithm that could determine one's biological age. So biological age is the age your body says you are, rather than the age your birthday says you are. And obviously your biological age, the lower it is relative to your chronologic age, the better you're aging. OK? So one of the first –

Robert Rountree:

So that's a good thing.

Lee Hood:

That's a good thing. Lower is better. So one of the first things we did to confirm that is, we looked at this population. And basically this was a population where we were trying to optimize their wellness and not their aging, in the initial stages. But what we demonstrated strikingly enough is, over the four years that we studied this population, women actually lost a year and a half of their biological age per year they were in the program. So over the program, they lost six years of biological age. And the implication is, they were aging better and better as they did it, and men lost about a year. We think the difference might have been more due to compliance than biology, but we don't really know. But the important point was, this biological age is a metric for aging, and at the same time a real metric for wellness. We went on to demonstrate beautifully that you could also assess the biological age of your major organs like the liver and the heart and the kidney and so forth.

And because the algorithm used metabolites in the blood, we were able to deduce actionable possibilities for different individuals that uniquely lets them optimize their biological aging. So I think this whole idea of slowing aging is one of the really major factors to dealing with chronic disease. In fact, a young scientist at Harvard, David Sinclair, who's one of the key pioneers in studying aging, made the calculation that if we can – in the human population as a whole – delay the aging process by just one year, we can save something like $13 trillion in the health-care process over time.

Robert Rountree:

So you're saying a lot of really important things here. One that stands out kind of at the top, is that aging is some kind of process, that it's a physiological mechanism that we can unlock with the right kind of information and data, and that we can do something about it. We can affect it. I remember that discussion being held around Alzheimer's disease is that maybe if you live long enough, you'll eventually get Alzheimer's disease. But if you change the curve even slightly and you don't get Alzheimer's disease until you're 125 years old, then you may not care. So it's not about us eliminating these diseases or stopping aging. It's not about living forever, it's just about slowing down the curve. So I hear that as part one. And then part two is, you say there are all these metrics that we're discovering. I know from reading your papers that the things that you're using to determine biological age are not esoteric. They're not things that you can only get at one lab in Belgium. They're things that most any lab can measure.

I wonder if you could talk about that, because I think that's a really important take-home issue for people, that the stuff you're talking about measuring is not hard to do.

Lee Hood:

Well, I can talk about it. One way to talk about it is saying that by manipulating the metabolites in your blood, at least certain of them, you can change the whole aging process. And that's one approach that we're really interested in exploring in detail. But another absolutely fascinating study that we carried out a couple of years ago, was looking at 9,000 individuals that are older, in the 60-, 70-, 80-plus year age, and analyzing their microbiomes. And what we discovered was, if you are a healthy person and are aging in a healthy manner, two things change in your gut microbiome. The first is that the core populations of microbes that populated your gut in your 20s and 30s and 40s disappeared. And the second thing is, each healthy individual carved out a unique microbiome that looked absolutely unique for different healthy people. In contrast, the unhealthy people, one, never lost those basic core microbiomes, and two, did not individually differentiate into these unique species.

And what was really remarkable is, we looked at healthy and unhealthy individuals in their 80s over a period of four years, and we determined that the unhealthy people were three to four times as likely to die over that period of time as the healthy one. So one of the really interesting questions is, can we identify drugs or molecules that affect these master switches, and in doing so would affect multiple of these features of aging? And indeed, it does appear that there are two drugs, according to animal studies, rapamycin being one, and metformin being the second and those affect two different control mechanisms. But they both have some very interesting effects on the hallmarks of aging. And big clinical trials have been carried out in dogs, in mice, in yeast, in a whole variety of different things. And the results are, I think especially for rapamycin, really quite remarkable. Of course, the really key thing is having clinical trials in humans that assess not only the positive effects of rapamycin toward aging, but whether it has side effects and complicating factors that we don't know about. These are things that will take a few years to determine.

But I will say, there are across the country a number of physicians who are actually subscribing these drugs to sets of their patients, with the proper warning and following the results in appropriate fashion. I think this opens up the very exciting possibility that in the future we will really be able to have very profound effects on the aging process. And as we can see, that's going to have a big influence on preventing chronic disease.

Robert Rountree:

This is all really exciting. I think having followed that rapamycin research for a number of years, I get very curious about how we can mimic that effect maybe by using diet, maybe other agents that alter that mTOR pathway that rapamycin seems to affect. So I'm always curious about how to reverse-engineer these things and say, is there some other way besides the drug that we can do it? But first we got to understand how the drug works, which I think is... Was it Dr. Matt Kaeberlein that's doing a lot of that research in Seattle?

Lee Hood:

In dogs, yeah.

Robert Rountree:

And these dogs are living longer and healthier.

Lee Hood:

It was really interesting, he just published a paper I read about in the last few days, where he has a very large population of dogs that he's followed now for... I don't know what it is, probably 10 years or so. But what he was able to demonstrate that was very interesting is, the dogs really can make people healthy because they force people to get 10,000 or more steps a day, and that really improves your health outlooks if you can do that. Having dogs that age well and people that age well can be very complimentary.

Robert Rountree:

Yeah. It makes a really good case for going out and getting a dog now. You talk about these three regulatory pathways. It seems like they're all tied up in nutrient metabolism, either blood sugar, blood glucose metabolism or protein metabolism. I know that the mTOR pathway's involved in construction of things, like building proteins, etc. Is it fair to say that this aging process is all wrapped up in those two things, glucose and protein? It may be a gross exaggeration.

Lee Hood:

I think it's fair to say, they're very fundamental parts of this process. The explanation David Sinclair in his wonderful book Lifespan, is that primitive organisms very early had to learn when nutrients and the environment was hostile, to shut things down. And conversely when life was good, to open them up and have DNA replication and reproduction and all those things. He argues, it's the shutting down of these phenomena that is what walks the aging process.

Robert Rountree:

All right. I think we're going to need to take a break right now, and when we come back, we'll answer some questions from our listeners. 

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And we're back, so now it's time to answer some questions from the community. Our first question this week comes from a listener who asks, what are the markers that you look at to determine biological age as opposed to chronological age? Obviously chronological age is based only on your birthdate.

But when you talk about gathering big data, multi-omics, genomics, are there ones that really stand out as being particularly important?

Lee Hood:

Well, there are two ways to determine biological age. One, I described earlier and that is actually taking a small amount of blood and analyzing certain metabolites that are in the blood, that are a part of the algorithm that gives that individual's biological age. A second approach to biological age is to actually look at the epigenetic modification of an individual's white blood cells, and their levels of modification that correlate with different degrees of age and the aging process and so forth. The enormous advantage of the first measurement, the blood metabolite measurement is, it leads to actionable possibilities that will let you make your biological aging more effectively as an individual. What is different between the metabolic determination of biological age and the epigenetic determination of biological age, is that the former also leads to actionable possibilities that will let you facilitate the aging process and hopefully increase the distance between your chronological age and your biological age. And it will do that for some of your major organs as well, which is very useful. You can have a very reasonable biological age globally.

Thorne is a company to which Nathan and I actually licensed the algorithm for determining biological age now. They have a test that can determine your metabolic biological age, assess your organ biological ages, and give you recommendations about how you can improve them. So I think the biological age is going to be a very useful concept for optimizing and assessing how we can optimize the aging process.

Robert Rountree:

I have to say that I did the Biological Age test through Thorne, and was pleased to find out that I was about 10 years younger biologically according to those markers. And then I also did an epigenetic aging test through another company and got very similar results. So that was pretty gratifying, to see that concordance between the data. As you point out, the biggest difference was that with the Thorne test there were some specific things that were recommended, some dietary strategies, etc. Whereas with the epigenetic clocks, which were developed by Steve Horvath – that I believe is at UCLA and now a lot of other people have gotten on that bandwagon – it's not quite as clear what one needs to do to change epigenetic age. There is some research along those lines but I think it's less straightforward.

Lee Hood:

I agree with that.

Robert Rountree:

So mainstream medicine says one thing about “aging” supplements. I assume that that one thing they're saying is... in mainstream medicine they say supplements are not even worth pursuing, because in the animal studies they haven't really shown benefit. But the next part of the question is, isn't all of this on a spectrum? So maybe at one end of the spectrum you've got powerful drugs like rapamycin or I think there's a derivative called everolimus. So rapamycin is sirolimus and then there's everolimus that does very similar kind of things. This person is saying, isn't it possible that supplements do something, maybe not as powerfully as the drugs?

Lee Hood:

Well, my own view is supplements are an important window through which we can optimize health. I think the challenge in dealing with the general question of supplements is, some individuals would like to test many and say none of them do anything. Just as it would be impossible with a drug, if you tested 50 or 100 at one time to say, what did what? Similarly with supplements. And that means, if you're arguing supplements don't work, you have to understand that the test was carried out, was it done in the context of a single supplement or all sorts of supplements? And most of the studies I've seen had multiple supplements. And gosh, I think the complexity there makes it impossible to draw any conclusions, unless you're extremely clever about it. And that's why all I'd say is, if people make those general statements, go back and look carefully at what they've done and determine whether that really makes sense or not. But it's one thing to say, X doesn't work because you can test X very carefully.

I'd be very skeptical about global statements that a whole class of compounds don't work with regard to facilitating health and optimizing wellness and balancing out to healthy living.

Robert Rountree:

So a lot of people when they get older, they talk about how easy it is for them to bruise. They just bump into something, and they suddenly have this big bruise on their arm or their leg. What are some of the factors that lead to these extrinsic indicators of aging like fragility? What do you think are the biggies that could actually accelerate this aging process?

Lee Hood:

Well, I think it's major systems that become dis-balanced, OK? For example, one very classic one is the immune system. It's a very complicated system that not only deals with protection against foreign invaders, but a part of it also is a very complicated system, a cascade system called complement, and that leads to blood clotting and to fragility of skin and things like that. I think another area that can certainly go out of kilter... And my view is that Alzheimer's in the end is going to turn out to be a metabolic disease very similar to diabetes, and its causative factors are going to be abnormalities in metabolism. They aren't going to be driven by things like tau and amyloid proteins that are a consequence of the process and not a cause of the process. In that regard, we've had now almost 15 years of more than 500 failed drug trials, and almost all of them were pointed toward these amyloid and tau kind of proteins. And frankly, no one pill that can modulate those things is going to be able to deal with Alzheimer's.

Alzheimer's is going to require multimodal therapies, because that's how we're going to redress the metabolic balances that are consequence of this disease.

Robert Rountree:

Now, I've heard the phrase bandied about for years that Alzheimer's disease is diabetes of the brain. Do you think there's some truth to that?

Lee Hood:

Absolutely. And just as we learn to deal more effectively with the metabolic abnormalities of diabetes... And frankly we don't do a very good job now with diabetes, which is a disease 11 percent of Americans have diagnosed type 2 diabetes. Almost a third of them have pre-diabetes, which is the foreshadowing moving to an active diabetes. We need to think of ways of much more effectively dealing with diabetes early and reversing its causative factors at an early stage, before you have frank clinical type 2 diabetes. The same is true of Alzheimer's. We wanted to be able to say, you are on a pathway that's going into Alzheimer's in five years or 10 years, and we'll take you off this pathway right away. OK?

Robert Rountree:

So it seems like we're on the verge of being able to come up with a kind of virtual model that mimics the processes involved in Alzheimer's, and use artificial intelligence to actually predict what effect a certain intervention might have. Am I correct about that?

Lee Hood:

Yeah, that is true. There is a model called digital twins. And basically what this digital twin model does is, it integrates from the top down our mechanistic understanding of Alzheimer's, together with the physiology of Alzheimer's, and from the bottom up the biochemistry and genomics and phenomics of Alzheimer's. And what we get then is a detailed model of the abnormalities that are embedded in Alzheimer's. And what these digital twins can do that are really interesting is, you can digitally create a million twins, which represent different variants on this metabolic picture for a million virtual people. We can look at how changing aspects of this picture changes the outcome of diabetes. Alternatively, we can actually take all of the data of an individual and put it into this digital twin, and it can begin to make an assessment of where the abnormalities are and the kind of things we'd have to do to restore metabolic normality. So the digital twins can both create a gazillion models and test all sorts of things, and they'll be able to take in the complicated detailed data from individuals and make assessments and recommendations about prevention, optimization, modification and the like.

Robert Rountree:

It seems to me that... I mean, this is fascinating and amazing, actually. This is going to change how medicine is practiced, being able to use these digital twins. And that addresses the issue you brought up earlier when we were talking about supplements. We can't really study one supplement at a time and think that that means something. We've got to look at an entire lifestyle intervention, which I think you called scientific wellness.

Lee Hood:

Here what we could do is, take the million virtual people and we could give them each different supplements and see what that did, right? Those are the kind of experiments we'll be doing in the future.

Robert Rountree:

It seems like that's really where this whole notion of scientific wellness is going to go too.

Lee Hood:

Yeah, absolutely. We're going to be making the digital twin that will optimize all the features for wellness. I mean, the interesting thing about wellness is that most of us... Healthy people now probably represent 30 percent of our potential wellness, and there are many things you can do to further optimize that. And the benefits of optimizing it – the energy it takes is not trivial – but to optimize those benefits means for sure you're going to be moving into the 90s and 100s mentally alert, physically capable. You're not going to have to think about retirement if you don't want to. But if you're mentally alert up into the 100s, playing golf and tennis for 40 years of your life as your major activity, I think would get terribly boring. But [laughs] maybe I could be criticized for that. Maybe people love doing that. I mean, the point I'm making is, this gives us the chance to be creative and original, and to use what we've learned in a lifetime to fashion new opportunities and new possibilities, and all of these kinds of things.

Robert Rountree:

Well, I've got to say, talking to you really opens a lot of doors of possibility for me. It seems like the sky's the limit on how we can use these new discoveries about biology and aging, to help our patients and to help improve health span, not just lifespan.

Lee Hood:

What's going to be a really critical part of this whole new regimen that we will have for aging and for Alzheimer's and for wellness is, we each have to realize that in the end we are the captains of choosing the pathway for our health trajectory. And that takes on a lot of responsibility, if you want to do it well. Nathan and I have actually just written a book on what 21st century medicine should be, at Harvard University Press, that'll come out in April. I would urge people who care about these things to read that book, because it says clearly the many different kinds of things you can do to take responsibility for guiding the trajectory of your own health, your own wellness.

Robert Rountree:

And the title of that book is going to be?

Lee Hood:

It's The Age of Scientific Wellness. It's by Nathan and myself.

Robert Rountree:

The Age of Scientific Wellness. We'll be on the lookout for that, for sure. And meanwhile, if people want to follow what you're up to, because it seems like you're on to some very exciting things, how do they keep track of what you're doing?

Lee Hood:

Well, I think the best way right now is, I've created a nonprofit called Phenome Health that's proposing a second genome project that'll be paid for by the government. Phenome Health has a website that has lots of these things described.

Robert Rountree:

Wonderful. Well, folks, that's all the time we have this week. Dr. Hood, thank you so much for coming on the podcast. We'd love to have you back on someday in the future.

Lee Hood:

We can do it. OK.

Robert Rountree:

Excellent. As always, thanks everyone for listening. Until next time. 

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