• njikomes

Nathan Price: Metabolism, Aging, Microbiome, Blood Sugar, Diet & Personalized Medicine | Transcript

Full episode transcript below. Beware of typos!

Nick Jikomes

Nathan Price, thank you for joining me.


Nathan Price 3:45

Pleasure to be here. Thanks for having me.


Nick Jikomes 3:47

Can you start off by just telling everyone who you are and what your background is what you're working on today?


Nathan Price 3:53

Yeah, so um, so I'm Nathan price. I have a PhD in bioengineering from the University of California, San Diego. I've been working as a scientist for about about 15 years that I've run an independent lab. First was an assistant professor at the University of Illinois in Urbana Champaign, then moved from there and became a professor and Associate Director at the Institute for Systems Biology in Seattle. The last several years of which I co directed with Lee hood, the hood price lab for integrated biomedicine. And so we've worked on systems biomedicine, I should say. And then about a year ago, I moved to become CEO of longevity, which it was a startup that was co founded by a real good friend of mine, Joel Dudley as well as Chris Mason at Cornell, which really focused on AI in health. We then merged that company together with another company called thorn to form a company called Thorn Health Tech, which we took public a couple of months ago. And then I'm moving now with the merger to become Chief Science Officer for Thorn Health Tech, and running the science as we're trying to build what we call a big integrated scientific wellness company. And so that's a little bit about me, I also work in just trying to push forward a number of things, and a few national groups, I serve on something called the board on Life Sciences for the National Academies of Sciences, Engineering, and medicine, and do a number of things to try to keep a foothold in academia while primarily now moving into the, into the business world and running science from that side.


Nick Jikomes 5:40

So you mentioned something called systems biology, what is systems biology or systems medicine?


Unknown Speaker 5:48

Yeah, so systems biology is is really about how do you take the pieces that we've identified in biology? And how do they operate together as a whole, so that the properties that come out of that are, you know, more than the sum of the parts? So it's really kind of a yin and yang with molecular biology that, you know, went into biology and kind of figured out all the pieces, right, what is a gene, what is a protein, etc. Then, in systems biology, it's really about getting into omics, which is alright, what now we can measure all of the genes. So through the Human Genome Project, we can measure all the proteins, how do they operate together in a system to give us life? And that's what systems biology is really about.


Nick Jikomes 6:28

Interesting. There's a couple other terms that I want to ask you about that, that I've been hearing more, and that I've read in association, in association with your work and with other people's work. So that's systems medicine, how do they how do all the parts we've identified work together? There's also digital phenotyping. And then this notion of personalized medicine. So what are those things mean? And how does this all start to kind of tied together?


Unknown Speaker 6:51

Yeah, a lot of new terms. So personalized medicine. And we actually talk a lot about something we call P for medicine, which is a little bit broader, which is predictive, preventive, personalized, and participatory. And so when we talk about that form of medicine, what we're really talking about is one a shift, more towards being able to anticipate problems. And we'll talk more about it, even a different concept called Scientific wellness, maybe a little bit. So we want medicine that's predictive, right? So anticipatory of something that might go wrong, that you don't want to go wrong preventive, right, how do you stop those things from happening? Personalized in the sense that, especially as you're thinking about chronic disease, that has they're very diverse paths into chronic disease? And it's, you know, the medical term idiopathic, right, but it's very specific to the individual. And so you want to be very personalized. And then participatory is where we think about how do you empower people with knowledge so that they can really incorporate into their lives, you know, some of the deep science that has been developed, so they can make an impact on their health. And then you also asked about, I think, digital phenotyping, we use two terms, I'll bring it up. So one, digital phenotyping is really, what can you do in the digital space to monitor your health. So this wearables is kind of the most obvious example of that. And then we also have a concept that we refer to as deep phenotyping, which can include all that information from wearables, but it also goes through all those kind of omics data, so you get your genome done. You're looking at your proteome, and your microbiome and your metabolism, and just starting to generate a lot of that kind of data, which is just not really happening in the research space, primarily, although some of it is now available to people. But you go in and try to understand in some depth, a lot of these systems that we just couldn't profile until quite recently.


Nick Jikomes 8:53

So maybe to start to talk about this and think about this. We can talk about something like blood sugar regulation. So I think everyone knows, you know, knows about sugar at at a very high level, we know that our blood sugar is probably tightly regulated. Most people do. A lot of us probably know some with diabetes, where that part of our metabolism is not functioning the right way. And you know, that you're even starting to see now glucose monitoring tools, not just for diabetics, but for everyday people that want to start doing this sort of digital phenotyping personalized medicine stuff. So before we get into some of that, can you just give us like a metabolism 101 here for blood sugar regulation?


Unknown Speaker 9:38

Sure. So for blood sugar regulation, the the primary idea is that turns out your body is very sensitive to the amount to the concentration of glucose that's coming into your system, or that exists in your system. And so what happens is that as your glucose levels build up, your body secretes a hormone called insulin that suppresses the glucose levels. And so you've got this control system in your body, that's always trying to get you back to a baseline. So if you eat a big meal, right, your glucose will spike up, your insulin will come up, will lower your glucose until you come back to a steady state. And conversely, if you if your blood sugar goes low, then it will release stores of glycogen, so that you can get your glucose back up. And so you just got a control system like that in your body, everyone does. Unless you're, unless you're type one diabetic, in which case you don't make insulin. And that's the problem.


Nick Jikomes 10:40

Okay, so that's basically, that's basically what diabetes is, you don't have the insulin there. And so you're not able to bring back down blood sugar levels, like another person, there's


Unknown Speaker 10:49

two types, two types of diabetes. So there's, there's type one diabetes, which generally means that you don't have the ability to make insulin can be likely a genetic defect, a missing piece that you can't do that. And so that's why, you know, diabetics have to walk around and, you know, poke themselves with insulin and watch that carefully, because they essentially have to take on the role of regulating their own blood sugar. You know, one of my best friends in high school is diabetic. So, you know, I know he's gone through that, you know, for a long time, as of many, many people. And then the term what was the other question? What will happen to diabetes, type two, type one diabetes, you have no insulin, type two diabetes is a little bit different. So Type Two Diabetes means that you lose your sensitivity to insulin. So you have the ability to make it it's in there genetically. But that's more triggered by environmental factors. So if you so one of the big problems is if you're in an environment, where you're not getting enough exercise, you're eating too many really high sugary foods that we have, you know, processed foods that we have now, you put a lot of stress on that system. So if you're always swamping it with you know, with massive amounts of sugar, your body, and so it means you're flooding your system with insulin. And as you do that, over the years and decades, your body becomes less sensitive to insulin. And there is some debate about the exact mechanisms of that and so forth. But at a high level, you become resistant to responsive to that insulin. There's also this notion that certain cells just become so full of sugar that they can't react to the insulin. So there's a couple of different modes of thought about what it means to be insulin resistant. And so that becomes a problem. And so then someone develops type two diabetes, because they gradually get worse at being able to deal with sugar. And as they cross the threshold, then they become diabetic, because they just their insulin system doesn't operate as it needs to, and they lose the ability to control their own blood sugar.


Nick Jikomes 13:02

So how important is prevention here in the context of the reversibility of this is, is this something that is reversible for type two diabetes,


Unknown Speaker 13:14

it certainly is reversible in the early stages. So prevention is an area that I'm super interested in. And, and, you know, we can get into, you know, a lot of the big studies we've done around this, but diabetes is a great example. Because not only can we think about reversal of diabetes of type two diabetes, but there's also what's called pre diabetes, so you can monitor so if you're measuring, you know, out of your blood, you can monitor what you can wear these days, like a continuous glucose monitor, right? So you could actually look at the degree to which your body responds to a particular meal to a particular foods to particular times of day, and you can actually map that and I've worn these continuous glucose monitors, not a massive amount, but for some months, you know, I've worn them intermittently all aware, I'm on and off just to check in. And, and you can, you can watch this. And if you simultaneously if you're also getting measurements of insulin, you can get a sense for I know what your sensitivity is, and you can look at just kind of what it is also, if you're just in a fasted state, and so based on measures like something called a Homa IR, or insulin, then you can get diagnosed actually, as being pre diabetic. So what that means is you haven't lost the ability to to control glucose, you're not diabetic yet. But you can see that you're on the path. And so that is really important. So I was pre diabetic actually, some years ago, and was able to reverse that by diet and lifestyle, which many people have. It's not that complicated to do if you look at it early, just change your diet, you know, grace, your activities, some basic things, but as you get further down the road It becomes quite irreversible. And I don't know if it's ever irreversible, but you start having serious problems. So if you're at the late stage of diabetes, you become insensitive to pain. So what happens is that a person will step on a nail, for example, and not know it. And it festers. And so and I forget, I saw this gruesome, I'm not going to get it exactly right, because I looked at a little while ago, but but foot amputations, for diabetics, were up something like 40%, over the last five years, it was some some crazy number like that. And you can imagine that you've gone all the way from something that you can cure, an essence by, you know, slight modifications of diet and walking to something that's going to require cutting off a limb. And so the the starkness or the difference in diabetes between doing something early and prevention, which is actually pleasant to do, and in many ways, compared to something that's gruesome at the end is incredibly Stark. And it's one of the areas that we want to see across all these different diseases, which is to actually gain an appreciation for what pre disease means, in Alzheimer's disease, or, you know, in cardiovascular disease, we also, we also know that that one's been mapped out pretty well, and so forth. And we could get into any of those those kinds of issues.


Nick Jikomes 16:21

I see. So with diabetes, and with a number of things, there's this sort of pre disease state before you have full fledged diabetes or something else. And I guess the point of the digital phenotyping, or monitoring your physiology is that you can actually see that and then take the necessary changes.


Unknown Speaker 16:39

Yeah, so I give you an example. So let's say cardiovascular disease. So cardiovascular disease, is probably along with diabetes, the best disease that we've mapped out those risk factors or what comes before, a big reason for that is a real famous study, that called the Framingham Study, which monitored for many decades, people who lived in Framingham, Massachusetts, and followed, you know, what was happening in their lives, and did it for long enough that you could observe, know, who got heart attacks, and you know, who got strokes and who didn't and, and was able to really look at a lot of warning signs. So one warning sign is there's nuances to this, but one warning sign, for example, is LDL cholesterol, right? LDL cholesterol being high is considered a bad thing. HDL cholesterol, so called good cholesterol being high, it's considered, you know, a good thing. And so you can monitor for those. And that's done for millions of people, right? We intervene on those and statins and things of that nature. Now, one of the really fascinating elements there, and this is actually a study that we did a couple years ago, is if you take some of the new technologies like genomics, so if you measure, you know, genes out of an individual, you can create what's called a polygenic risk score. So just summing up the contributions from a number of different genetic variants. And it turns out, you can predict blood levels of LDL cholesterol and people pretty well, from the genome, there's a lot of the information is is encapsulated there. And so we had done an analysis, where we had we had taken about 5000 people through a wellness program over the course of about four years. And we looked at individuals going through that wellness program and whether or not they were able to lower their LDL cholesterol, right, and thus, presumably lowering their risk of cardiovascular disease or not. And it turned out that you could predict who would be successful and who wouldn't on that measure, based on genetics. So if someone was had high LDL cholesterol, and their genome predicted they'd be high, we saw no statistically significant ability for them to lower their LDL cholesterol by lifestyle, you can do it with statins and so forth. But if there was a gap, in other words, if their LDL cholesterol in their blood was high, but their genome predicted it should be low, they could lower their LDL cholesterol very significantly, by lifestyle intervention. And so some of the really fascinating things going forward, or that you can create a new category of information in medicine, which is this delta, this gap between what your genome predicts and what your measure is. And if there's space there, those are the easiest things that appears to be able to change and to move. And as you then think about doing that, for all the different measures that we use in medicine, you can create a, a map for an individual of all the things that are easiest for them to change. They could that would make a material difference in their health aimed at predictive and preventive personalized medicine. So that's where we're going.


Nick Jikomes 19:55

So so if you have all of this information, you get your genome sequenced, you are mentioned In various aspects of what your body's doing, let's just say you find 10 things where this kind of gap exists, maybe your doctor could look at this data and say, okay, for five of these, I don't even need to give you a drug, you can just do simple things, and here's what they are. And then for another five, maybe it's not so simple, and you know, that that's where you need to give a drug, instead of giving a drug for all 10 or something like that.


Unknown Speaker 20:24

Yeah, and this is an area that we're, you know, really interested in, and it's one of the things that I'm doing a lot, you know, with foreign Health Tech now, is, you know, so I'm, I'm not anti drug, by any, by any stretch of the imagination, if drugs are what are necessary, and that's what's you know, are the evidence points, we should use them. But by the same token, drugs are primarily developed for late stage disease, that usually come with side effects. And, and, and you're making a trade off, right. And depending on the severity of the disease, the tolerance for side effects goes up with that. So if someone is has late stage cancer, like we'll actually give them chemotherapy, chemotherapy is horrible, right, it's gonna, it's gonna kill every fast growing cell in your body, and you're hoping it kills the tumor, right? But it's also going to destroy the lining of your gut, it's gonna kill, you know, your hair, your hair is gonna fall out, it's gonna kill all that. And so we'll tolerate that. But what we're really interested in are, what are the kinds of things that you can do in the prevention space. And as you move into, the more you move into prevention, obviously, the fewer side effects that you're willing to tolerate, and you've got to have an incredible safety profile. And this is where we're very interested in lifestyle interventions. And also things like, like nutraceuticals, or natural products, or things of this nature, where you can have some of the similar effects to a lot of drugs, but you're going to, but you hit the target more softly, but without a lot of side effects. And so you're trying to have this trade off between, you know, you have this really serious issue that you're trying, you're kind of willing to take a hammer to it, versus where you are trying to nudge it in certain directions. You know, just like we talked about in diet, you know, once you're at late stage diabetes, you're going to have to, you know, you're going to have to do something drastic to try to make a difference. Early stage, you can do things that are pretty easy.


Nick Jikomes 22:22

So you mentioned at one point, you are pre diabetic yourself, but you reverse that through lifestyle and diet changes. So what were those changes? And what are, you know, what are the general rules of thumb for things like diet and blood glucose? My understanding is right, some foods will make you spike bigger in your blood sugar levels, and some will be a much more prolonged and softer spike. So what are some of those general rules there?


Unknown Speaker 22:48

Yeah, so we can talk. I mean, they're at a high level, it's really simple stuff, it's, you know, cutting out as much of the processed, you know, high sugary foods as you can, and, and getting more activity. If you can spend some amount of time you know, there's a lot of interest in, you know, intermittent fasting or things of that nature, which we could talk a little bit about if we want, but basically, anything that just allows you to, you know, have an opportunity to process out some of the sugar in your, in your bloodstream, basically, all of that works. To get a little more personalized, you know, with the continuous glucose monitor that I mentioned, it is quite interesting to look at what foods in particular spike you a lot, so, so one that was surprising to me, is, if I compare, there's a beef stew that my wife makes, and it's got white potatoes in it and carrots and beef. And you know, it's it's a, it's a good, you know, a nice stew. I ate that in my blood, like, my blood sugar spiked massively. If I compare that to say ice cream, which got a little fat in there. It spiked about double what the ice cream did. Like the bloodspot, which I was surprised by that was one of the things that I


Nick Jikomes 24:06

was yeah, you wouldn't naturally think that. Yeah. So how, um, so a lot of this is common sense. So something that's got a lot of sugar in it will tend to make your blood spike more, on average, although there are surprises, as you just mentioned, how much how much of the individual reaction that one would see is going to depend on that person. So we've already sort of talked about the genetic differences between people, how common would it be for two different people to have a very different blood glucose spike.


Unknown Speaker 24:37

So you can definitely have quite different blood glucose glucose spikes across individuals. And in fact, probably the coolest study on this that I've seen was done by Iran, Seagal and Iran Lnf out in Israel, probably aware of this study. It's very famous, but it's a where they looked at the impact of the microbiome, and it turns turned out that you could pretty predict from people's microbiome certain foods that would have, you know, a higher impact in one person and not another. And they use this to create these kind of two diets for people where it was a little hard to guess, like, which was the healthy and which is the unhealthy, because we all have a pretty good sense of, you know, generically a healthy diet and generically and unhealthy, or there's no healthy diet, that's, you know, 100% Twinkies or something that doesn't exist. But they did do it where, you know, one of the diets had ice cream, and the other had chocolate and the other you know, and that was go back and forth, where it was a little hard to eyeball and say, which was which. And then they would predict, which would be better for certain individuals, and they were actually able to get quite a good signal off that, where some people a cookie would spike them massively to another person, a banana would would spike more than the cookie, and something would be the opposite, and so forth. So we didn't know about a number of those kind of specific responses, at least as mediated in that that regard.


Nick Jikomes 25:57

I see. So, to a first approximation, a lot of this is common sense. But I mean, you've now mentioned a couple examples where, you know, maybe a banana makes you spike a lot. And for someone else that doesn't, which, you know, you probably would never guess that if you didn't know anything. So it sounds like if you really want to know, you do actually have to monitor your blood glucose. And so I guess my next question is, how accurate? Are these monitor monitoring devices? And How expensive are they? And how easy are they to use?


Unknown Speaker 26:24

Yeah, that's a great question. Um, I think they're, they're quite accurate, they're certainly easily accurate enough to be highly useful. You know, you're not surprised by it. If you never eat a meal, and it doesn't spike up. And it's, you know, they're quite reproducible, it goes back, as far as I can tell the data on them is very good. You know, there might be some sort of gold standard device you could compare against, there's a little deviation, but for the average person, their their way worth it in terms of being able to see what what's going on. Cost wise, I think the one I, well, they're still a little bit difficult to get, because you've got, unless they've changed it very recently, and it probably depends partly which state you're in, you do have to get a doctor to prescribe it,


Nick Jikomes 27:12

I think so


Unknown Speaker 27:13

the most difficult part is finding a doctor, that's kind of okay with, you know, the notion that you don't have diabetes, but you just are curious about your body, and you want to figure out how to optimize. Now, I'm a huge proponent of preventive medicine, so and, and personalized medicine, and I'm, so I'm very happy for people to say, you know, I'm pre diabetic creative, I'm not pre diabetic, there's a lot of really healthy people that just want to know what the impact is and learn about their body. And there's a, there's a ton of interest in that. In the early days, it was harder to get because there were just kind of a limited supply of them. So they restricted them to diabetics. Now, if you get the right, you know, a doctor that's, you know, aligned with your wanting to just understand your body, then you can get a, you can get a prescription for them. And then you can buy them, I can't remember exactly what the cost is on them. But the one that I used was a two was basically it's a, it's a patch that you put on or not a patch, it's a you know, you put this little sensor into your, into your arm totally painless, they have a little gun, you push a button and it goes right in. And then the cool thing is you can hold your phone up to it, and it will immediately tell you your blood glucose level at any moment of the day. And it also tracks it passively. So I think it makes a measure about every, every few minutes or so. And you get a trend. But if anytime you want to see where it is, I found that super useful because I you know, I might be eating something. And, and especially if I'm introducing new things into my diet, I can I can try it, and then I can do the measurement and look and see, you know, did it did it spike me, you know, I did I did I go to a level I really didn't want to go to because I'd like to keep my you know, my blood sugar a little more controlled. And the other thing I like is you can test out you know, products, there's a lot of products that will claim that they've got, you know, health benefits or that, you know, they have, you know, maybe they've got a little sugar in them, but they add fiber to it. And so you can monitor and see, okay, how much of a difference does it actually make for you. And there are things you can do that make a big difference. So let's say you are going to indulge in something sugary, for whatever reason. Like one of the things you can do is you can you can observe, like if you just eat that, you know what your what it does to your blood. And you can also look at, well what if I choose to drink a fiber drink or something like that, right? You say okay, I'm going to I'm going to down 20 grams of fiber before I eat this and you can observe that in fact it does blunt the amount of sugar uptake it slows it down. Right because when you fruit there, there's a bunch of fiber in there too, which is why it doesn't spike you quite as much as say eating something that is just processed. straight up, which basically doesn't, which in our natural in that kind of a natural diet would kind of not happen, right, you'd be eating fruit that has something in there.


Nick Jikomes 30:10

I see. So like if you drink so it is true if you drink a glass of like Sunny Delight orange juice, it's not got pulp in it, it's probably got added sugar versus an organic orange juice with pulp, it really will have it would have a difference in your blood glucose level peak, even if they had the same amount of sugar in them, because one has the pulp and one doesn't. Yes. And


Unknown Speaker 30:31

you'd be much better off eating the orange right? Because that's really has much more of the fiber in it as soon as you juice it. Right in then Jason with both Jason without poll would be even worse. But you know, but the juice? Yeah, the juicing is going to is going to spike you much more than is, you know, the eating of the fruit itself.


Nick Jikomes 30:48

Hmm. Yeah. So what about? So what effect is exercise itself have on blood glucose levels? And how does that interact with diet? So for example, if you just go exercise strenuously, is that going to take down your blood sugar? or change it at all?


Unknown Speaker 31:06

Yeah, it, it can actually go both ways depending on where you're at. Because sometimes people are surprised because they'll go exercise and they'll see their blood sugar go up. And the reason for that is you're recruiting energy. So it's pulling glycogen, you know, out. And so it's flooding some glucose into your system that said, if you're like, if you're super high glucose, and you say, Okay, I'm going to go out and walk or something like that, you'll see it come down. So it is context dependent. The what you'll see happen in your, in your blood glucose. If you're if you're exercising, you know more when you're fasted, and that's when I was monitoring myself, that was more the the norm, which is I'd exercise in the morning, I would, you know, I would see the blood glucose actually go up, because it's recruiting some, you know, some energy from, you know, from the fat stores?


Nick Jikomes 31:56

I see. So it depends. So, so it really is useful if you can get your hands on one of these glucose monitors, too. Yeah, yeah. Interesting. Yeah, I'm about to try, I haven't tried one. But I'm going to try one, I think in a week or two. And just for people listening, the what I had to do is a it's not open to everyone the one that I'm going to try. So it's not like fully publicly available. The retail price, I think, is something like $200 for like a three month period where you'd be able to monitor it. And what I did have to do is I did have to, so you mentioned you had to get a prescription. So I had to input like my basic medical history, my medical stats and stuff. And then someone through the app approved it a physician that was licensed for the state that I'm in. And that's what I had to go through. So


Unknown Speaker 32:45

people have been working on making it easier. I


Nick Jikomes 32:47

know. Interesting. So you mentioned, you mentioned that study about the microbiome, and I did want to talk about microbiome stuff. Can you start off by just defining for people that don't know, what the microbiome is, and why it's such a big focus of research right now?


Unknown Speaker 33:04

Sure. So the microbiome refers to essentially all the microbes that live in a particular environment. So one of the most common that we think about is the gut microbiome. So what this means is that in your body and your gut, are basically, tons of microbes that live there reside there, they and they, under they perform metabolic transformations, and that are essential to a lot of what goes into making you healthy or not healthy. So it can incorporate so the microbiome is is really looking at all these other living organisms that are on us, and you know, and inside us, it is really an important thing to understand, because microbes are what first of all, you know, the life the first evolved on this planet. So the vast majority of life actually exists as microbial species. And so that is just the interface kind of the so every interface that we have, whether it's our skin, our mouth, our gut, basically, everything we have that interfaces with the outside world, in some way, is coated with with these microbes.


Nick Jikomes 34:22

Interesting. So with the gut microbiome, can you give people a sense for like, you know, I've heard and I don't know if this is true that, you know, there's more microbes in your gut than there are cells in your body? What's like the level of diversity and volume that we're talking about here?


Unknown Speaker 34:38

Yeah, there was it was kind of a lot of analysis of that at one point. But basically, yes, if you look at the number of cells in your body and the number of, you know, microbial cells that you have in your gut microbiome in your microbiome, I believe that the latest numbers are that it's about equal Yeah, initially the way it was thought to be about 10 to one, and then people looked at a little ones, well, it's probably a little bit too much, but you know about about the same number. So you've got a massive number of these if you do the count differently, but if you count, you know, the total genetic content of your microbiome is vastly higher, I think it's 100. To one I been a little while since I looked at that number, but I think it's about 100 to one, the amount of kind of genetic content that you have in your microbiome compared to your human genome. So there is a huge amount of information that's there. And what we're finding is that it is incredibly relevant to health. And, and it is still very much a cutting edge area. And, you know, we can go, we've done a number of studies on this, and I'm sure we'll talk about a few of them here in a second. But it is an area that people are just really trying to get their minds wrapped around and push out as much information as they possibly can, you know, this is, you know, we actually have a, you know, a gut microbiome test now, so people can take that, and they can go through that and get a measurement of microbiome. And it gives back a whole host of information about you know, relevant to health, both good science and bad science and things you can do to make an impact on it.


Nick Jikomes 36:16

I think let's first talk about what these microbes are doing and what we know about that. And then talk about things like, like the health impact and the variation between people and across across lifespan. So So in general, what exactly are these microbes doing in a physiological sense? Are they pre digesting certain nutrients for us? Are they secreting things that are beneficial for the body? Or that we need for different things? Like what do we know there?


Unknown Speaker 36:43

Yeah, it's all the things that you just talked about. So they do create certain compounds that have been associated with health butyrate endles, things like this have been shown to have positive health effects. They also make molecules that have a negative health effect. So one example of this is if you have certain species of bacteria, they will utilize material that they'll find in things like like red meat, and eggs and different aspects of the diet. And they create a compound called trimethylamine or TMA for short. And then TMA will get into your bloodstream. And then your liver actually converts it into trimethylamine oxide TMA, oh, and TMA O is a risk factor for cardiovascular disease. And so one of the things that happens there, then is you can actually have compounds that in the absence of this bacteria actually beneficial to you. But if you have those bacteria makes us TMA creates the tml in the liver, and you end up with problems from that. And so there's this whole network of, of metabolic transformations that are mediated by the microbiome, for both good and bad. And I give you I give a couple other examples. So another one is that the microbiome actually interfaces with drugs we take as well. So there was a really fascinating study that came out in I think it was INCEL, earlier this year. And they went through and did a really deep dive on one particular individual's microbiome. And then they tested it against a whole host of drugs, to see what happened when that those drugs were exposed to the microbiome. And what it turned out was that 13% of the drugs were inactivated, or they were just eaten or changed into some other substance or made a nerd or, you know, whatever it was, that so you inactivated 13% of drugs. So one of the things you know, we talk to drug companies about this quite a lot, is, you know, so if you're, you're developing a drug, you're running a trial, if you're not measuring the microbiome, then you have this huge black box, that could be deactivating your drug. So some of the people that you're testing aren't even on your drug, really, I mean, they're gonna put it in their mouth, but it's getting changed to something else. They're not, you know, so that. So you've got this big black box. And so one of the things that, you know, I'm a big proponent of is, if you're testing drugs, you should absolutely be monitoring the microbiome and understanding, you know, are those drugs being deactivated by the microbiome because you could fail the trial, not because of the drug not being good, but especially if you're doing maybe do it in a part of the country where the kind of bacteria that eat that drug are really prominent? You'd have no idea? You don't how many things could that have happened to is really fascinating question.


Nick Jikomes 39:55

Yeah. Well, so you just mentioned another thing that's interesting, you said in a certain part of the country where that bacteria is prominent. So does the microbiome composition of people systematically vary from region to region?


Unknown Speaker 40:07

Yeah, it does. You know, and there are commonalities, of course, not like it's 100% Different or something, but it varies a lot. They did a study this was there's a Nature Medicine paper from 2018, out of China. And in that case, what they did is they took signatures that they would learn from the microbiome in one province, you know, and associated with health, like this is a healthy microbiome, this is unhealthy, and they would look you know, the machine learn these things. And then you would apply it in the next province over. And what happened is that the accuracy of that went down substantially, because of this variation between micro biomes, and where they are in different places, and in different people. So a couple of things, though, that are that are quite interesting. So we wrote ourselves in Nature Biotechnology paper in 2019. And what we were able to show is that you could capture about 50% of the variance in the diversity of the microbiome, that would filter down into information and about 40 metabolites that you would see in the blood. So one aspect is that you've got this massive diversity in the species. But it does funnel down to a much more manageable number of things to look at in terms of what do you find in the blood, that are products of the metabolism that's going on in the microbiome, and it's cool metabolism, right? It's happening both in our bodies, and they're much like the TMA example. So you can see that. And then a second item that we did, we published a paper in Nature, metabolism earlier this year, where we we monitored, I think it was in close to about 10,000 people, microbiome is as you get older. And so as we did that, what we found was that if people stay healthy, your microbiome actually becomes increasingly unique, meaning that it looks less like anyone else's microbiome, right. So everyone's microbiome, if you stay healthy, it goes away if you get on a bunch of drugs, or if you get hospitalized, or things like that. But if you don't, if you stay healthy, your microbiome is kind of going along your life with you, and it starts looking more like your microbiome than anybody else's. And they kind of diverge a little bit. And but even as that divergence in the microbiome species is happening, we looked at the metabolites that were associated, again, as they appeared in the blood. And you saw certain commonalities of the kinds of things that would change as and through the course of life. And there was a commonality to that, even though the species themselves change. So what this means is that there's, there's a lot that you can delve in on by trying to understand the reflections of the microbiome in the host right in the person like, what what do we see that's coming out of that? That's good, and that's bad. And, you know, that's why we incorporate a lot in our testing predictions about, you know, what are the metabolic effects that we expect to see, given the species and the gene content, you know, that we measure out of your microbiome, for example.


Nick Jikomes 43:15

So basically, you know, the microbiome is huge, you know, millions and millions, billions of cells of bacteria and other things living inside of our bodies on our bodies. There's many different species and types of microbes, that'll be part of that microbiome, the exact composition of that whole population could be relatively similar in me and you, it could be relatively different. But depending on what that full population looks like, what that full microbiome looks like, that's going to have that's going to mean that certain nutrients, certain metabolites, either are in my body or not, in my body, as a consequence, are different


Unknown Speaker 43:51

levels, right? are different levels, not an on off necessarily, right could be different levels.


Nick Jikomes 43:56

So this is another area where you know, it sounds like you really can't know unless you actually measure it. So how, how easy is this to do these days. So this


Unknown Speaker 44:05

is super easy. So, you know, there's a number of tests out there. Ours is out there as well. The Thoran gut health test, and you can get in what we do is what's called meta genomic sequencing. So this means you're not only getting the species, you're actually measuring all of the gene content. So you can get that and then what that allows you to do or calculations about what kind of metabolisms do we see represented in that microbiome? And you can relate that back to a number of conditions. We actually did a trial on personalized recommendations from the gut health test for people that were suffering from irritable bowel syndrome, which we published in personalized medicine. Two year ago, I think was one night 2019 or 2020. And when we looked at that You know, what we were able to see was that you could get very significant amelioration of symptoms by following personalized recommendations. These were lifestyle and supplement type things, you know, so, you know, not drugs. Basically, you could take natural approaches, you could modify the microbiome, and you could get rid of a lot of the symptoms of IBS in this case.


Nick Jikomes 45:25

So it sounds like the microbiome is relatively easily modifiable. And I'm interested in how easy it is in terms of like physical exercise versus diet versus like probiotics.


Unknown Speaker 45:41

Yeah, so you can definitely modify it. It's more modifiable by prebiotics than it is by probiotics. But I'll give a little bit of a caveat. So so. So one product, that we've got the prebiotic plus we call it but the reason that, and it's, it's basically, it's a two dimensional printed disc. And what it has on there are three things and this is this is one of the issues because oftentimes, if you just take a probiotic, it is. Oftentimes, it won't change your microbiome. And the reason for that is that the species that are existing in your that are there already in your gut, for example. They're there because they out they competed to be there, like they're good at doing what they're doing and surviving there. And so you introduce a new species, and it can be hard. So one of the things that we did is we actually, in this product, we incorporate what are called bacterial fascists. And so if you take a book, if you take a bacteria phage, then basically what you can do, and that's a virus. Yeah, and it kills bacteria. It's a virus that kills specific bacteria. So it's aimed at, at at, you know, bad classes of bacteria to use a simple term. So what you're doing there is you're creating an ecological niche. So you're creating some space, then you put in a probiotic, right, the good spaces that you want to get in there, and then incorporate it on the same disk, or prebiotics. So the fibers that we know that the probiotics most like to eat, so what you're doing is you're creating a space, you're adding in what you want to now fill that niche, because now there's a little bit of space for them to compete. And then you give them this stuff they grow on best to help them out compete and change your microbiome in that way. So that those that we think about, so you can get a microbiome to change, but you do have to create, you've got to create some space, or prebiotics, just because you are changing the structure of the food sources, right, that can have a more persistent effect, usually than the probiotic. But that combination approach is what what I see.


Nick Jikomes 47:51

I see. So if you were trying to like grow a garden in your backyard, and you wanted roses growing in it, you could just sort of blindly throw seeds in the yard, but it might not grow because you've got a bunch of weeds and other stuff back there. But if you pull out the weeds and make sure the soils right for that plant or that flower, then it can grow. Is that the basic idea? perfect analogy. Yep, that's exactly right. So that's the difference between prebiotic and probiotic. Probiotic is like you're adding something and prebiotic is like you are pre emptive li creating the right environment.


Unknown Speaker 48:22

That's exactly right. The probiotic is essentially your the flowers, you're going to plant the prebiotic probiotics, you know, the flowers you're going to plant the prebiotic is the soil the fertilizer that is optimized for the plant that you put in basically the food that most likes?


Nick Jikomes 48:38

So you said that you guys at Thorne you have you have one of these products? What can you describe? Just physically describe it and how much it costs and how you actually use it? Yeah,


Unknown Speaker 48:49

sure. So we've got we've actually got a whole suite of products that are associated with the microbiome test to get personalized recommendations for people, I think there's something like 40 or 50 different products that can be recommended, depending on what the issue is. But the the more general ones we do. So one is with a brand called a Fusio. Which actually I quite like these. So these are an actually take this everyday myself, but it's a it's a, it's a two dimensional printed disc. So and so what you do is you take the disc and you just drop it in water, it could be hot or cold. I typically do it cold, you drop it dissolves. And basically it's a beverage and it's quite good. Steven Phipps, who's the guy who's our chief innovation officer, and he really makes all the products, but he was also a chef and his younger days. So it's kind of funny. He's like a chemist. But he also has a good good sense of some of these things. Really good guy but but basically as you drop that in, and so it just becomes a bit it's a berry flavored drink. I forget the exact costs. I think it's something like $40 for a month supply something like that, and it's just something that you drink. So that that's one. And that's the one I mentioned, that has the bacterial Figes, the, the probiotics and the probiotics kind of all in one. So that's an element. We've also got other products, one called fiber men and enteral men, which essentially have a bunch of nutrients that are good for your microbiome and adds fiber. So if you're having an issue, this is actually how I first became aware of form before I work there, because I was having this you know, in turn, TMI, here I was having very painful daily constipation, it was really unpleasant and, and someone, you know, turned me on to the thorn, the thorn product and he said, Hey, you should take this intro man and fiber man, and I got on it. And two days later, it was gone. And been plaguing me for months. I stayed on it, I then quit using the product. And for about a month, and it came right back, and then I got on it. And then I you know, I switched to take in the non fiber just dis later. And I've never had to come back since so which has been nice. But that was one of the things that got me interested. And then when they reached out about a year later, I actually knew who they were I was, I was impressed with what they had made.


Nick Jikomes 51:14

So you mentioned earlier, this idea that the microbiome, the composition of your microbiome will change as you age, not only not only is it going to change as a function of your lifestyle, but it's probably just gonna, it's gonna age in some sense, just like you age, and you mentioned something about the uniqueness of this microbiome being a kind of marker for general health status. Can you say a little bit more about what what The finding was there?


Unknown Speaker 51:43

Yeah, that it's kind of a, the uniqueness score, it's a little bit of a more difficult one to use, and sort of a, you know, an actionability setting because it is a property within a cohort. But we did see that when we use that uniqueness score, we looked in an A, in this case was an elderly population of man and something called the Mr. Ross cohort. So it was a cohort that we had access to working with Eric or wall at the Oregon Health Sciences University. And basically, if you just took that uniqueness score, it predicted mortality, it predicted who would live within the next four years in a really elderly cohort. And so it was a it was a really big differential, depending on your microbiome. And if all you knew about them was their microbiome, you could predict with a lot of a lot of signal, like who was likely to, to survive, you know, to the later stage, these are all people in their age 80 to 100. So it was a, you know, an older population. So so we know there's a lot of signal that is, you know, that is in that in that system. And so there are these then fundamental changes, you know, that are ongoing. And what we'd really like to understand, and this becomes really important, because it means that, you know, if you're thinking about personalized medicine, at least as it regards the microbiome, you actually have to be more and more personalized as you go through age, because your micro biomes are becoming more and more, you know, because they're sort of CO evolving with you as you go as you go along. Or maybe not quite exactly the technical term, but they're, you know, they're changing along with you, you know, as you as you go along. And so those, those were the elements that really jumped out at us, you know, it was just that fact that you could use this, you know, uniqueness score as a means of, you know, predicting all cause mortality.


Nick Jikomes 53:45

Interesting. Yeah, that's, that's interesting that you, you would need more and more personalization as you age, because you're becoming more dissimilar from other people overtime,


Unknown Speaker 53:55

at least in terms of the microbiome. Now, we actually did another study, which looked very broadly at biochemistry, because there's other ways that you're becoming more similar. The differences between the sexes, for example, at a molecular level, at least in the blood, right, they become attenuated as you get older, right, because you know, you're not pumping out as many sex hormones and things like that. So there's, there's certain axes where you're becoming more similar. I see other axes where you're becoming more distinct. And microbiome is one of those.


Nick Jikomes 54:24

Are there any, like big? Are there any major differences that you tend to see reliably between relatively healthy versus unhealthy people in terms of the species of bacteria present, and what the downstream effects are? And I guess the practical thing here would be like, are there specific species of bacteria that for most people, most of the time are good, versus ones that are bad, and those would be ones that you'd want to try and facilitate the emergence of?


Unknown Speaker 54:52

Yeah. Yeah, so I'll just mention a little bit about we're actually going through right now and looking at the In a lot of detail as we're, as we're trying to work on our version three report and kind of what the next, you know, next big phase is going to be on some of these things. There. There's one strain of bacteria, which is really interesting, because what we did is we went through, we did a meta analysis. And I'm not going to go into it in too much detail, because it's pretty new. And I'll just do the things I remember really clearly. But basically, we did a meta analysis that went through tons of published papers, and categorized you know, whenever a whole host of different species were either associated with the good outcome, or the bad outcome and how often it was mixed, right? In other words, because we all know the notion of a good bacteria bad bacteria is only good to a point right? It's a it's a gross simplification. But there there are certain cases where that's very obvious if you have C difficile which is terrible pathogen that's a bad bacteria right? I don't know any situation that it's good. There's another bacteria


Unknown Speaker 56:02

feet Callie feet, Callie bacterium, prows, Nitze, I got there eventually, perfectly bacterium prows Nuzzi, I, which


Unknown Speaker 56:16

has come up as a good bacteria. In every single analysis that we've run. So far, the only one that we found that like 100% of the time so far has come up to be really good. I don't believe it's available from anyone yet as a as a probiotic. I think people are trying to get at it. Another species that turns out to be really good, over and over again, is akkermansia. And this is actually sold by a company called pendulum, which led by Colleen Cutler, and she really done a nice job with this. So you know, it's, it's a relatively recent startup, but it's a very hard bacteria to culture, but it it's, it's very involved in the mucus layer of the gut. And it turns out that it helps control symptoms of pre diabetes, for example. So it lowers hemoglobin a one C, by, you know, kind of enhancing in, there's more to it, I suppose, but you know, but by enhancing that, that mucous layer, and so that, you know, that's another one that's really in the, you know, in the good category, and has some good clinical clinical data behind it. So that's, that's another really, really nice one, and do those things out there?


Nick Jikomes 57:31

And so do we just sort of broadly know that these species are correlated with what we consider, you know, good outcomes? Or do we know specifically that they're producing some sort of metabolite that's doing something in particular?


Unknown Speaker 57:45

Yeah, um, sometimes we know that sometimes we don't there's, there's a lot of the, you know, we mentioned some of the bad ones, for example, that we know, you know, create TMA, and the TMA Oh, and things of that nature, there is a fair bit that's known about the biology around akkermansia, that I mentioned. And so, you know, and how it actually blunts the sugar uptake, you know, through that mucus layer, and then has an effect on hemoglobin, I would say, although it's not a super area of expertise of mine, so I'm going. So I'm going on, you know, the bit that I know about that. There is, so in some of these cases, we really do. So I'll talk about so one of the really interesting areas, is, you know, how the microbiome may play a role in things like weight loss, which really hot topic area, right? We all a lot of us care about that. And, and it's definitely not a solved problem. I want to be very clear about that. But but there's some really interesting things that have come out, at least in my opinion on this. So we actually did a paper that we published a couple of months ago, with this was a lot that really led by Sean Gibbons, who's a great collaborator, and friend of mine at the Institute for Systems Biology, you know, where, where I've been for a long time, before Thorne, and so the. And so in this paper, it was we took data from this. So previously, I had co founded a company called I didn't we didn't get into this called Air avail, that ran a scientific wellness program for many years. About well, about four years. And then we had 5000 people have gone through this program. And so we have these really dense datasets of genomes plus microbiomes, proteomes metabolomics, clinical labs, wearable devices like this, these huge data clouds that we we've used over and over again, to go from the people that gave research consent, to really look at, you know, use that deidentified data to learn. So one of the things we did is we went back into that population and looked at there was a subset of people who had really lost a lot of weight. And then we did a control set or a match, you know, kind Have a retrospective, but you know, did a propensity score matched set of individuals who had not lost weight, you know, but were matched on other kinds of criteria, you know, sex and, you know, starting BMI and things like that. And so when we did that, we then compare the microbiomes at baseline, to see if we could see something there that looked like it was predictive of the set, you know, what was different between the set of people lost weight and those who didn't. And there were a number of things that came out. And what I like about it is that they seem to make a lot of sense from a mechanistic point of view. So one element is, we looked at the growth rate of the microbiome, so just the aggregate growth rate. So there's this trick that you can use, it's actually really a really cool trick, I think, was around Seagal that figured this out initially, which was, again, really interesting. So you know, in bacteria, you've got a chromosome. And so as you're replicating, right, you're going to measure that from one side to the other as you divide into two cells. And so it turns out that because in a population, it means you'll have more material, more genetic material stacked up at the beginning of the replication than at the end. And it will be higher, the faster the growth rate is. So you can actually just use sequencing at one time point. And then you take this what's called the peak to trough ratio, right? So how high you're stacked up at the beginning as you get down to the the minimum part. And if you do that, you can get an estimate of growth rate. So we use that, you know, that analysis trick. And basically, what we were able to show was that the people who lost the most weight, had micro biomes, that appeared to be growing the fastest according to that metric. And so


Nick Jikomes 1:01:55

no one not independent of the composition of the biome, just the aggregate growth


Unknown Speaker 1:01:59

rate, CAGR the growth rate. And composition matters, too, but I'm talking about in second, but the first thing that mattered was just how fast like right now makes some sense, because every calorie you eat is consumed either by you, or by your microbiome. And so if it's growing faster, maybe it's churning more, we haven't, we've still got to go down and really look at the magnitude of that, you know, that possible effect is an explanation, but it's the one that immediately springs to mind is that well, you know, maybe there's something to that it's it's revved up higher, for whatever reason. So that's one. Second is, when you're eating complex carbohydrates, they go into your microbiome, it breaks them down. And the two dominant ways that it can break it down, is it can break it down into some simple sugars, which are going to trigger the insulin response, as we talked about at the beginning. Or it can turn it into short chain fatty acids, which aren't going to have that same kind of effect. And the other thing that turned out was that the people who lost a lot of weight, had microbiomes, that preferentially made short chain fatty acids from their carbohydrates, instead of sugars, not 100%, or it's not digital, and or but it's just a, you know, which is the preponderance of the species that are there. And so we thought that was really interesting. And then the N amongst those were species that were high butyrate producers were spent. I mentioned that before, because that's been in many, many studies associated with better health outcomes. So as we look at that, that's gotten us pretty interested, you know, we're kind of figuring out where we want to go with this. Because if you if you look in the literature, it turns out that you know, so people have done these experiments in mice. Where Washington say people are on Sigulda. I love Iran, as you can tell, he's very smart. I think I mentioned his favorite three dots. But so he did this really fascinating experiment, where he looked at, he took mice, right, we gave them took a population of mice, and he gave them put one of them on a really high calorie, high fat, I think it was a high fat kind of diet, anyway, made them all fat. So you had a fat mice, and you had these thin mice, that he died in them, right? calorie restricted, brought him down. Now, if you took these mice that had lost weight, so he took half of them, and then half of them, he did nothing to them, and then the other half, he obliterated their microbiome basically. And then he gave them the microbiome of the Finn mouse that he'd never made fat. Mm hmm. And what happened as you went forward was that all the mice that had their original microbiome became fat again, and the ones that had the microbiome, the thin Mouse did not when you put them back in the cages and just Let them eat. And they're eating the same diet. Yeah, yeah, my understanding is that they were eating the same diet. And so the thing that was just striking was that it was causal to weight regain if they had a microbiome with the memory of being fat, rather than one that didn't have that memory. And so, so that got me really excited, because we know, because we're not talking about like taking a molecule, you know, some small molecule that works in a mouse and saying, Oh, let's see if it does the same thing in a person, which is, of course, a very general path for, for pharma, and so forth. And sometimes it works. And sometimes it doesn't, right. So we're a different system. Here, we're talking about just taking a very general concept that your microbiome matters to being able to keep off weight. And say, do we think that's also trained human? I can't. And we don't know, to the same degree, but I can't think of a reason that it would be different. And so then when we look in, as we did with the air avail dataset, it was really interesting, because there we can see that, you know, there are these features, right, that were different between the people that lost and who didn't. And so, you know, one of the things I'm really interested in now, is trying to triangulate down on, well, how could we actually make a difference in the microbiome, that would help you know that as a category for people, because obviously, it is, you know, an incredibly, incredibly impactful area, right? We have I don't know the exact number, but we have a massive number of obese and overweight people in the in the country in the world.


Nick Jikomes 1:06:42

Yeah. So let's, let's just say you're the average American, you might not be in terrible, terrible health, but you've got room for improvement. You know, you want to you want to do better than you're doing now. So obviously, you know, the ideal situation is your genome sequence, your microbiome sequenced? You have a private conversation with Nathan price, you get every single, every single, like personal recommendation you can think of, that's the ideal state. But we're obviously not there is there in terms of where knowledge is at today? Are there very generic things one could do using some of Thorens technology or products or anything else that are virtually guaranteed to at least move you in the right direction. So for example, let's just say you know nothing about the person except they want to get in better shape, or lose a little bit of weight, you know, nothing about their microbiome, is there a prebiotic probiotic combination that is very likely to be better than whatever they have right now?


Unknown Speaker 1:07:43

Yeah, for sure. And we do try to make it as easy as possible, certainly on@thorne.com, there's, you know, different questionnaires people can take in terms of like, what are the, you know, what are the issues that they may be, you know, suffering for, we do have, you know, the tests that people want to dive in more of the Thorne gut health test, we also have a biological age test that measures a lot of, you know, highly used clinical labs, you know, and points to where those are at relative to, you know, the age that you are, and the sex that you are, and so forth. There are a lot of things that people can do. You know, I hesitate to say generically, because I do think it really matters, you know, exactly what your goals are, where you're at, but there are just a whole host, like we've got, there, there's just a whole host of things that you can do that make that make a difference. In terms of health, maybe, you know, maybe a little bit we'll talk about, you know, aging, which I think has has a ton of really interesting elements to it as well. I do, you know, I do, like, you know, the, the probiotic product that I mentioned, you know, I use that everyday, I take a bunch of stuff everyday, just because I'm interested in various elements, but I really liked getting measurements from you know, my doctor, you know, often work with, you know, a knock, or personalized medicine type doctor that likes to, you know, that will measure a ton of things, Am I blind and let me know, kind of what's what's going on. But there are a host of things that people people can do, you know, depending on on what their what their interest is, and what their you know, what, what, to make an impact in their gut and there is I think something like 30% of people suffer from that problem. And we've had really good success for people coming in with you know, whether it's diarrhea or constipation or bloating or and you know, there's there's kind of a tree that people can go through if they want that will kind of help guide you know, what we think might be useful to them. Interesting. And then and then you can read reviews and and give feedback and all those things.


Nick Jikomes 1:09:50

So when you started taking the prebiotic probiotic combination thing that you talked about earlier, what did you actually notice? Did you feel like one of the first things you notice cuz you We feel a difference.


Unknown Speaker 1:10:01

Yes, it made a big difference for me, I have to say. So I've, I have had gust issues for what so I mentioned, you know, the constipation, you know, from a few years ago, that was, you know, a big problem. But the other thing is I often get, I have, I'll get gas gas build up. And I'll notice that like, if it pushes more my motion sickness, like if you know, I don't like, anyway, I get motion sick and cars and things like that often, I think a lot of people do not massively, but you know, enough that it's uncomfortable. And a lot of that comes from buildup, at least for me of just sort of gas, I think, you know, from jiggling around or something causes some issues. Sometimes during exercise, things of that nature. And it's interesting, because the, when I started doing the prebiotic plus that I talked about, it really reduced those symptoms significantly. And in fact, I had a chance. So I've been on it for a while and feeling quite good. And it was interesting, because I recently when I moved from, you know, my primary appointment from ISP, where I'm still on, you know, on leaves, I'm still connected to them a little bit, but I knew my primary appointment from ISP, to first one devotee, and then Thoren HealthTech s, as we did the merger. There, it because I moved across the country from Seattle to New York, I didn't take the prebiotic for about two months, just because, you know, we're ordering and then I had, you know, the way this stuff was transferred, I stayed with my family for a little so I didn't have it for a little while, and I had to reorder it, anyway. And what was really amazing to me was, I started getting back all the old body, and I started feeling, you know, queasy and my stuff. And it was it was kind of shocking to me, because I realized that I had not felt that way in a long time. And I and then I reminded me, I'm like, Oh, I used to always feel this way. And I didn't know that it was like, it's just the way I felt, right? I'm just like, that's life, right? You're just sort of, and then. So for me, it absolutely made a big difference, because I just didn't have that problem. And I got off, and then I got re on it a couple months ago, it's gone away again. So I feel much, much better. So I decided that it makes a difference for me. Not in one day, but you know, as I as


Nick Jikomes 1:12:21

I Yeah. So this is something that you just use continuously now.


Unknown Speaker 1:12:25

They I basically, virtually every morning, whenever I take, you know, I take a bunch of stuff, because I'm interested in these things. And, you know, for longevity, and you know, I'm always trying to monitor, you know, different things that might be useful. But I basically take the probiotic in the morning, this is


Nick Jikomes 1:12:41

the thing that also contains the bacteria phage that kills bacteria. Does anyone is Yeah. And is that the type of thing where those, those phages that you're using those viruses, they are killing bacteria, they're gonna be bad for anyone.


Unknown Speaker 1:12:56

For the most part, yeah, I mentioned that, like the personalization. I'm always, you know, I'm a scientist, so I'm a little hesitant to say always or never. But in general, they are targeted at, you know, at bacteria that we think of as being, you know, overwhelmingly likely to be negative. And the probiotics or, you know, we think are overwhelmingly likely to be positive. And so I've never seen everybody but you know, we think in the vast majority of people, that's true. And what is this product called? It's called pre biotic plus, and it's lifeless, and it's a few CO by Thorn. So if you, you know, it's again, available on the thoran.com website. And also, I just, I'm, I really like the disk. There's another disk, I use quite a lot called Sleep plus, which, if I'm traveling, or I need to get to sleep. And again, people, you know, can you know, they'll have their own experiences. I had often taken melatonin pills in the past. I never felt like they did anything for me. You know, I'd usually go to something much stronger. In that case, a drug where I was taking Ambien to like, knock me out if I was going to Europe or something. I was just trying to get to sleep off cycle. But this sleep plus that we've got has really been great for me. It's a It's melatonin l theanine. And chamomile, and I don't you know, Steve Phipps is the guy that really, you know, developed all that. But for me, I really like nice blueberry tea, and you know, and I drink that and, you know, usually about 15 minutes later I start feeling sleepy in it makes it makes a difference for me. So that's, that's the other one. So I those are the only two things we've got on these discs at the moment. But I really do love the disc because they're just there. I like, you know, their drinks rather than pills, which I prefer and they and you know, they dissolve in there. They're good. So anyway,


Nick Jikomes 1:14:48

interesting. I'm Tom. There's a couple other areas I want to hit in the time we have left. So one is I want to talk about the general interfacing between metabolism generally, and immunity and what the immune systems doing. Because I know that there's a lot of connections there. And I also don't know a lot about it. So I noticed that you guys did a study that had to do with COVID recently that you were a part of, and it looked like you basically took blood from people, and he measured a bunch of stuff. And you seem to find some clear metabolic differences in the individuals that had more mild versus more severe COVID. Can you talk about what that was and what you were finding there?


Unknown Speaker 1:15:34

Yeah. So when COVID First, you know, really hit all of us. The person I really I've got to give a ton of credit to here is Jim Heath, who's the president of IASB. And Jim really just jumped into action in a major way. And, and Lee hood, you know, really connected, Jim in with, you know, people that he knew Roger Perlmutter, in particular at, at mark, and they really stepped up and you know, they kind of did an emergency, I, you know, gave us a really nice grant to dive in and start studying this. And as an aside, I'll just mentioned that, it, we've never seen, like collaboration without IP constraints in the way that we saw right after COVID. However, when just sort of, you know, jumped in together and started working on things, it was actually really beautiful in many ways. So Jim really got into that we started doing this deep phenotyping that we talked about. So we took COVID patients from the Providence St. Joseph health system was awesome at nastic partners and all of this, and started to delve in and make measurements of their metabolomes, their proteomes, a bunch of different clinical labs, really deep profiling of immune system. So including single cell immune populations that we were looking at, particularly Jim. And what we found that was interesting, and this was, this was part of what I've been interested in a while. And part of my contribution was that, if you looked at the metabolites, what we saw was that in people that had no moderate to severe COVID, there were sets of amino acids and lipids that were depleted to near zero, that you didn't see in mild COVID. And the reason that's interesting, this is actually related to kind of a lot of how I think about, you know, some of these areas now, which is that basically, you can never get away from the fundamentals in science, like mass balance. And so if you have to fuel a major immune response, if you have to fuel a major immune response, you have to build the building blocks. So you've got to have the amino acids, the proteins, the lipids, and so forth to build cells. Yeah, what we see is just that in the blood, you would see this massive depletion of the elements that you would need to do that, because it's fueling this major immune response. So, so we became interested in the notion that, you know, maybe one of the problems that comes up is as you start ramping up this really severe response, that you might actually hit up against nutrient limitations. And I'll just share kind of, you know, what really triggered me to start thinking about just that is a general topic, like separate from COVID. was just a little bit before COVID, the end of 2019, I guess. I'm sorry, then. Yeah. In 2019. It's, I had given a keynote at Cornell and the precision nutrition meeting. And one of the women that was there who gave just a spectacular talk, she had gone through these cases with mice. And they I forget what it was, they gave him some terrible disease, it removed their hippocampus, but it fueled this big immune response. And what she showed was that these mice would metabolize away at something between 10 to 30% of their muscle mass in less than a week. And they wouldn't do it if you supplemented them with one amino acid. And that just blew my mind because I thought, you know, what that saying is that they are scavenging because they need that immune response to stay alive. They are scavenging for these, this one building block, and they'll know everything for it.


Nick Jikomes 1:19:40

They're basically digesting their own muscle mass just to get those components to fuel the immune response.


Unknown Speaker 1:19:46

Exactly. Exactly. And this is this is a slight aside, but I'll just I'll mention this, which is the week after that I had gone to the Burroughs Wellcome Fund to this pregnancy meeting. And you know, it got us because we've launched, we're launching a couple of big clinical trials on this right now, which is actually what I spent most of this week talking about at this pregnancy meeting at Magee women's for the last couple, couple days. But the other aspect is, if you look at that kind of big metabolic perturbation, you know, which which, you know, a woman, growing a baby inside here is kind of the, the biggest one that we have, and just kind of our normal our normal life, then what that what we can see there is, there's probably a, the same thing has to happen, you have to have a recruitment of all of these factors, all of these nutrients, just fundamental mass balance. So we're really doing this really deep dive study now over longitudinally in pregnancy, to look at if there are ways to mitigate certain negative outcomes, right problems that arise in pregnancy, as a function of just monitoring, what are the building blocks that you need optimally, to make each next step in the baby's evolution, you know, the baby's development? You know, how do you actually do that anyway, so that was the backdrop. And then when we went into COVID, we started to see the same sort of phenomenon. And I only mentioned it because I think that a ton of disease comes back to metabolic factors in different ways, as just a fundamental consequence of, you know, just mass energy balances, and the fact that you have to, you have to satisfy that basically, all the time. I'm actually quite convinced that Alzheimer's is mostly about this, I just another aside. And so, you know, there's, there's just a ton that I think goes into this. And so it's one of the factors that can get left out. And sometimes, but that's what we saw on COVID was just, you know, if you're if you're really feeling these huge immune responses, you see this massive depletion of nutrients in the blood, and it was one of the first times we're able to see that in real start timeframe.


Nick Jikomes 1:22:05

So in this sense, the, this sort of metabolic depletion is a it's not, it's probably not the people were, like, depleted in something already. And that's what made them susceptible, necessarily, but like, they're they're progressing to more severe disease, and their body's just sucking those things into the immune response to power everything.


Unknown Speaker 1:22:25

Yes, exactly. That's what I think.


Nick Jikomes 1:22:28

Okay, interesting. So what are what were some of those into? Were there any particular metabolites? You mentioned some specific amino acids? Which which ones are we talking about?


Unknown Speaker 1:22:39

It was pretty, a pretty broad set after admit, I don't remember right off the top of my head exactly once, but the essential amino acids are


Nick Jikomes 1:22:47

all of the essential ones. Yeah, basically. Interesting. Wow. So I want to get into aging. Because we don't have all that much time left. And we could probably talk about any number of things here. So as we move into aging, well, first, can you just sort of define aging? From a biologist perspective? What exactly is aging?


Unknown Speaker 1:23:12

Yeah. So from my standpoint, so aging, and there's a, there's a particular graph that I really wish I could show that is related to, essentially, every year you get older, there's an increase in the likelihood that you'll get a whole bunch of different diseases. Okay. And so as you monitor that, you know, as you go up, you know, it's more likely you'll get Alzheimer's more like, you'll get heart disease more like you get diabetes. And to me the slope of that, that curve is aging, basically, you know, and one of the things I don't know if this will mean something to someone else's hands, it's just stuck in my brain, because I learned it when I was young. But I remember when I was first studying engineering, and there was a class and we went through and we talked about the concept of light bulbs don't age. And when we say light bulbs don't age, what do we mean? And what we mean is that if you have a 30 year old incandescent light bulb, compared to a one year, there's exactly the same probability that they'll blow out, because it's really a function of the energy grid makes no difference. It's not getting older. It doesn't filament doesn't, you know, it's not, it's not getting weaker, it's just a function of when you have a burst. So, you know, so you fast forward that into aging, and we look at but what's happening in our bodies is we do become more and more susceptible to breaking down. So if we talk about something, you know, fairly radical, like the end of aging, and is that a possibility, to me what the end of aging means it would be to flatten that curve. And the reason I bring that up is that there's often you know, is that I want to make it very clear, there's a huge like, enormous chasm between the end of ageing, and immortality, right? Immortality is like a whole other thing that we have no clue about. But the end of aging or the reduction of aging, to me is just the lowering of that slope, the closer it is, you know, if we ever achieved zero, to where it's just as likely that you'll get cancer at 80 as a 20, then that would mean that we have eliminated, aging wouldn't necessarily mean we had eliminated cancer or eliminated anything else that it wouldn't ever happen. But it would mean that we're not progressively just getting higher and higher likelihood, year after year. So to me that that's, that's how I think about that as a concept. And so, to me, then the notion of reducing aging, is very natural. Because there's no, you know, there's no reason to believe that, you know, we're at somehow optimal, or somehow, you know, fated to have this exact slope in the increase of our propensity for all these kind of problems that can be changed, in fact, has already been changed. Right, people used to die when they were 30. And we don't, we don't anymore. Anyway, there's a whole whole whole debate that we could get into there. But what I'm really interested in, is to look at the different factors in hallmarks, you know, the hallmarks of aging, as they're often referred to. And then what can we do that might have an impact on slowing aging, because in animal systems, we know that there are a bunch of different molecules that if you give them to the animals, they live longer, or they have or they have an extended health span, they're healthier for longer, right? Sometimes, you know, you're not extending the absolute end, but you're keeping them healthier for longer. And so what I'm really interested in is mapping as many of those as possible and making them available. So for example, nicotinamide, right beside, or nr is one that's been in the news a fair bit. And it relates to elevated levels of nav in, in your cells. And that is a substrate, you know, it's used for many factors, the main redox element in the body, but it also is used as one of the substrates for DNA repair. And through a class of proteins known as the sirtuins, right, what's your number of people have studied and David Sinclair made very famous recently. Right, and so you can and I actually do take nicotinamide right beside, and you can do that,


Unknown Speaker 1:27:37

you know, we sell, you know, various versions of that, as to other people. But that's, that's one that you can do at high quality. Now, we don't know, we don't know that nicotine amide. Rabbit side will increase healthspan. And lifespan in humans, we know that it does in animal models, we know that it increases any D in the cells. And we know that it's passed safety. And so what I'm going to what I argue, at least for myself is that's kind of what I want to know about the molecules because we won't know. In fact, if it if it increases health healthspan or lifespan for a while, right, because we live a long time. So we have to watch humans take it for 20 years. Yeah. So we'll see that. But that's an interesting one. Another interesting one is that people are running, there's a trial on Metformin, right that has positive aspects of on metabolism. And looks like it is also, you know, has this effect. It's the same kind of thing. We know that it has this these positive effects on health span and animals. It seems to be pretty safe in in humans, we actually use a which I also take, which is a natural product analogue of metformin called Berberine. And so that's something that has very similar effects, except it actually also has better effects on cholesterol. So it was Metformin. So Metformin is a diabetes drug, and people started looking at it. And I can't remember the exact context but someone noticed when they do these big meta analysis that way people that take Metformin, when you look across clinical labs, like electronic medical records, and things like that, look good, like diabetics on Metformin get cancer at lower rates, then people without diabetes, and so people started then Hmm, no, so there are a number of people that actually are interested in that as an anti aging now it's a drug so you know, there's controversy associated with that. But people are evaluated then there's I forget exactly what the acronym stands for. There's a study called Team something something misfortunes this right now. Probably partially Getting ageing through Anyway, time study. And it's, you know, which is looking at this in in a population. Because you know, we see those effects in, in other cases. And if people don't want to do a drug, if you want to do a natural product analog, that's what I mentioned, like Berberine is basically a lot like and there's a lot of new you can dive in the scientific literature, there's a bunch of papers that compare those things together, as they have kind of similar effects. The aquire Sutton is another one that I'm quite interested in. This is a class of molecules that are related to what are called senolytics, which are the preferentially kill so one of the other aspects of aging as you accumulate these senescence cells, which means that they're, they're not, you know, they're not, they're not growing, they're not, you know, they're not active, but they're, they're in senescence. And, you know, we thought that in the past, you know, they're just kind of a NERT wife, what does it matter, but it looks like they have negative effects. And then there are studies that suggest there's a few molecules, but Corson is the one that I'm most familiar with, that have been associated with being a Santa lytic. And there's a little bit of evidence both ways, but I think the preponderance of evidence is in in favor. There was also


Nick Jikomes 1:31:11

some analytic just means that they kill off or destroyed these senescence cells


Unknown Speaker 1:31:15

in Athens cells. Yeah. So you can you can reduce the senescence cells in your body. And so people think that that is good, and there's a whole bunch of people who are working on trying to get drugs, you know, that might, you know, amplify that up, of course, is a natural products and food, you know, that is also a natural Santa lytic. So there are elements like that. Another drug that people are really interested in is rapamycin, again, controversial, but there are doctors that are prescribing rapamycin for anti aging effects.


Nick Jikomes 1:31:47

And what does it normally used for?


Unknown Speaker 1:31:50

It's normally used as an immunosuppressant. Mm hmm. So the dosage that you that people do when they're trying to use it for longevity is much lower. And typically, I think most people right now think about it as because what, what rapamycin does is it targets mTOR effect. mTOR actually stands for target of rapamycin what how was discovered named, and so when, when you fast mTOR when you you know, mTOR cycles on and off as you go through, like eating fast. And so it's thought, you know, that with our ancestors going through, you know, hunting, hunting for food, finding, you know, kind of the feast famine kind of model, that mTOR cycles naturally, and that we've shifted it, so we kind of just have mTOR shut on all the time. And so, when you look at the effects, you know, again, across lots of animal model systems, basically everything, everything that we've given rapamycin to lives longer. So the suppression of mTOR seem to be really useful. And so


Nick Jikomes 1:33:00

I have a question here, actually. So you mentioned that this was an immunosuppressant, we were just talking about COVID and metabolism immunity stuff. Now we're talking about aging stuff. So so this is this is my understanding, having listened to a number of people in these different areas, tell me if you think this is accurate, when we think the immune system and how it might connect to aging, basically, every time we have an immune reaction, every time there's an inflammatory response, let's say you get an infection, right, the body wants to get rid of it. So you have this you have this immune response, there is inevitably collateral damage to the body, in just in the normal process of fighting that infection. So anytime there's inflammation, there's collateral damage, even though the inflammation is trying to do something beneficial for you. So every time that you have an infection, you get sick. That basically means you're going to take some of this collateral damage to your body, and it's going to contribute to aging. So basically, every time you get sick, even if it's fairly innocuous, it's just a little bit of sort of extra aging a little bit closer you are to to the end of the lifespan, is that a reasonable way to think about the connection between inflammation and aging at a very, very high level?


Unknown Speaker 1:34:14

Yeah, I think I think it is reasonable. You know, I don't know that all those little insults, you know, in inflammation, or, you know, are not reversible, you know, I wouldn't be able to say that like conclusively. But in general, we know that chronic inflammation adds massively to aging. So I think, you know, that thought process you're thinking through is, you know, seems like a reasonable a reasonable one. A reasonable one to me. And yeah, and so this I don't necessarily think of the benefits of rapamycin is being associated with reducing inflammation. I think people have looked into that. I haven't I haven't delved into that in a lot of detail I have to say, but this cycling mTOR is definitely just, it comes up all the time, you know, there's these certain molecules that just come up all the time and aging and mTOR is massively one of them. And so the question is whether or not you can get something that is, you know, maybe like rapamycin, you know, like, you know, some sort of, you know, like a rapper log or something where you can, you could have, you know, an ability to use that, but a lot of people are, are very bullish on it, you know, Matt Gaber line at University of Washington, and certainly been, you know, one of the proponents of, you know, of rapamycin being a very promising molecule, and so forth. So there are, so there's a huge amount of interest in this space. And it gets back to what I was talking about earlier, where if you're trying to do something from a prevention standpoint, or from an, you know, an extension of healthspan. It's a very different proposition than a drug aimed at late stage disease, right? Because you've got to be so careful about what what's the side effect profile, what does it mean to take a drug that we tested for acute use, and now we're thinking about it for chronic use. By the same token there, these tantalizing examples where you can test them, like some of these molecules literally will increase healthspan, when you give them to yeast cells, to worms, to flies to mice.


Nick Jikomes 1:36:23

So that implies that the mechanism at work here is so basic, that it's just shared, it's like, four is


Unknown Speaker 1:36:29

very fundamental. And ad plus, as we talked about before, is very fundamental. You know, so you're talking about really conservative mechanisms in some of these cases. And so, you know, whether or not we'll ultimately see, you know, major benefit from this. And then the other thing that really is, you know, and then whether or not it will have an impact on healthspan, or if it might even also have an impact on longevity, right, is there and that that always gets into be a little bit more of a question of, you know, how far out can that be? be pushed, you know, and there's a lot of people that feel like, you know, you can't push it much farther, and some people feel like, you know, that that's not true. And, you know, I don't think we really know know the answer, I don't know, yet.


Nick Jikomes 1:37:13

Um, what about microbiome stuff here? Are there any connections between people who live especially long and microbiome composition?


Unknown Speaker 1:37:24

Yeah, I'm not aware of it in like four. Doesn't mean it doesn't exist. But it's pretty recent that we've done big studies of microbiome and aging. Ours was one of the first Rob Knight did a big one. I think there was another one that just came out from a group out of China. But it's been pretty, you, there was a cohort that did these in elderly care centers. You know, so there's been, there's been a few of these in aging that people have looked at. But I don't think we know the hallmarks of extreme longevity. We certainly in the uniqueness score, we did, we did go up to people who were up in age to about 100. So we did do that. But I have not seen myself the microbiomes of like, super centenarians, or people who are at really late stage. Maybe it's just come out, and I'm just revealing my ignorance on that topic. I should look that up, I'd be pretty interested in it. But yeah, I don't know, off the top of my head, like what, you know, what would be the the absolute aspects related to extreme longevity?


Nick Jikomes 1:38:28

So you mentioned, you mentioned this idea of an mTOR cycling being related to metabolic cycles that might be how would you say it there might be sort of ecologically natural metabolic cycles. So if we think about our ancestors, they didn't live in the world that we the world of abundance that we live in today. So they may have been eating and fasting all the time, in a kind of cyclical way, just because that was that was life. So were some of those ideas connected to why people are talking so much these days about things like intermittent fasting, that when you fast, you're actually putting yourself into that kind of metabolic state that you mentioned?


Unknown Speaker 1:39:10

Yeah, that's exactly right. Because when you fast, you're essentially inducing this mTOR cycling naturally. And so that's, you know, some of these molecules are really sort of simulating, you know, that effect of, you know, getting your mTOR cycling up and down. So, there is a lot of interest, certainly in that, and there's no doubt that, you know, our genes are pretty mal adopted to our modern society. I mean, just take the obvious, you know, so if you take obesity as an example, right? We live in bodies that are that have taste receptors that are very prone to like things that are not good for them. Right, which makes no sense. And then and then we are well, I mean, it makes sense and historic concept, but I understand where it comes from, buddy. But at some level, but but if you were designing yourself to be optimal today, your body tries to hang on to every calorie it can find. Right? Which makes no sense in a modern society where you have essentially infinite calories at any moment of the day. Right? It loses muscle mass very readily, right? It doesn't try to keep it because it's metabolically expensive. So it tries to get rid of right. So if you're not pumping iron all the time, as everyone knows, it goes away quickly. So there's all these kinds of things that our bodies are set up for, that are just maladaptive, maladaptive to the, to the modern world in to the extent that we have it. So at some level, I think what we're really trying to do is figure out, you know, how do we, how do we help our there's obviously all the lifestyle choices, and all the things we can do to you know, get ourselves in better, you know, better situations, and that's all obviously super important. But are there other ways that we can also try to deal with the biology as it is, and make it easier for people to be able to kind of operate healthy and in our modern society? That that would be a whole other topic, I


Nick Jikomes 1:41:09

guess, to dive in on? So yeah, I'm, I'm gonna have to get going soon. And I know that you probably don't have that much time, either. You know, we've covered we've covered a fair amount on some big topics that, you know, we could probably spend hours and hours and hours talking about each one. But you know, we talked about microbiome stuff. We've talked about metabolism, blood glucose stuff, we've talked about aging, you know, all of this is sort of wrapped in this exciting time we're in of personalized medicine, medicine, and new technologies coming out, and you know, people being able to use technology to really understand and take a better hold of their own health. With all of that stuff in mind is is there any any general recommendations or final thoughts you want to leave people with on how they can start to look into doing this kind of thing for their for themselves?


Unknown Speaker 1:42:00

Sure, yeah. So if people are interested in this you know, we've got a thorn calm, you know, all based I think every, you know, all the different molecules and things that we talked about are all available, I encourage people to do their, you know, their own research and understand, you know, how these things operate. But if people you know, their tests available that we've got a biological age test or the gut health test, there are questionnaires, entry points, things of that nature. So if people are interested in this space, and want to take action on, you know, either optimizing their gut health, trying to take a shot at in increasing healthspan or any of those things that are all very easily accessible, easy to monitor and easy to do.


Nick Jikomes 1:42:48

Can you spell that out for people?


Unknown Speaker 1:42:51

Yeah, Thorne t h o r n e.com.


Nick Jikomes 1:42:56

Well, Nathan price, thank you for your time. We covered a lot of interesting stuff, so I appreciate it.


Unknown Speaker 1:43:01

Right. Thanks so much. Appreciate it.



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