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Aging is a normal developmental program that involves discrete expression of specific genes leading to particular physiological changes. There is growing evidence that many types of long term disease, like certain cancers or neurodegenerative disorders, are not just happening in old age, they are caused by old age-- specific changes that induce a state where these problems may manifest. If aging has a discrete biological program, can that serve as a target for therapeutic intervention, to block aging as the first step in preventing age-related disease? Dr. Eric Morgan of BioAge describes the concepts of healthspan vs lifespan, and discusses the concept of aging as a gateway to disease, along with potential therapeutics that could slow the process.
Talking Biotech is a weekly podcast that uncovers the stories, ideas and research of people at the frontier of biology and engineering.
Each episode explores how science and technology will transform agriculture, protect the environment, and feed 10 billion people by 2050.
Interviews are led by Dr. Kevin Folta, a professor of molecular biology and genomics.
Talking Biotech Podcast 380 Stopping Long Term DIsease by Arresting Aging
Dr. Eric Morgen, BioAge
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[00:00:00] Kevin Folta: Hi everybody, and welcome to today's Talking Biotech podcast by Colabra. Now, I don't know about you, but I'm in an age where I see many folks around me tending to elderly parents that are in health declines. I, I have one myself. And medicine has gotten really good at patching up heart's, kidneys, and other failing organs, and we've learned a lot about combating infectious.
And so what this means is that if you're lucky enough to avoid a tragic accident, you're going to have to wrestle with long-term disease, and that's the point of today's podcast, that presentation of diseases like cancer, neurodegenerative disease, it happens as we progress into our older years. . So is there some sort of biochemical, cellular, physiological gait, some sort of a restriction point that somehow pushes back against those disorders that eventually breaks as we age and research in humans and animal models suggests that it's likely so.
So what is that gate? and if it's discovered, could new drugs be designed to help uncouple our physiological age from the calendar, in essence allowing us to live longer before those terminal illnesses set in. And this is the topic of today's discussion. We're speaking with Dr. Eric Morgan. He's the COO and co-founder of Bio Age.
Welcome to the podcast, Dr.
Morgan.
[00:01:34] Eric Morgen: Thanks very much, Kevin. It's a pleasure to be here.
[00:01:36] Kevin Folta: Yeah, this is really cool to me too because just reading about the company and getting familiar with the website, I learned a lot about how to rethink this idea. Aging and, and this contribution to disease, along with some potential, um, remedies that we'll talk about today.
So most people are concerned about living longer. This is the idea of lifespan, but what is healthspan and why is that potentially more important than lifespan per se? .
[00:02:05] Eric Morgen: Yeah, absolutely. So lifespan of course is how long you live, and Healthspan is just how long you live in good health, essentially, you know, prior to developing your first major age related disease.
Uh, and of course, what all of us care about is, uh, living with a healthy. Good quality life. And so that's what, uh, the idea of health span captures. Um, that we'd like to basically the, our, our real priority, all of us is to live a longer, longer, healthier life. And that's what health Span captures.
[00:02:36] Kevin Folta: Um, but this idea of health span is really connected perfectly with the aging process.
Mm-hmm. . And so what's going on at, say, the developmental level, maybe molecular level that really is defining what aging is. .
[00:02:53] Eric Morgen: Mm-hmm. . Absolutely. So at. You know, fundamental molecular level aging is basically the process by which all of the metabolic, um, processes and molecular pathways that normally keep you, you know, functioning well and robustly, um, as a young person.
all of those pathways and processes gradually break down as you get older. And it's that breakdown at a cellular level that causes cellular level dysfunction that then, uh, eventually manifests at, you know, a tissue level, at an organ level with a specific disease, uh, and ultimately at the level of your whole body, um, where you become increasingly susceptible to all kinds of diseases and ultimately have an increased risk of disability.
Our diseases
[00:03:41] Kevin Folta: like Alzheimer's and cancer, are they really established by events that are happening during aging? Meaning that aging kind of sets the stage for these disorders, that it's kind of a prerequisite that you don't see children walking around with Alzheimer's disease? What's going on there?
[00:03:58] Eric Morgen: Yeah, absolutely. Outside of some, you know, very specific rare hereditary diseases, um, you don't get neurodegeneration, uh, until you're quite old. Uh, and that's the case with many of these diseases, which are aptly named age related diseases. You know, the risk of Alzheimer's goes up exponentially with age.
Um, and it's really, you know, it's your age. The, you know, number one risk factor for developing, uh, diseases like Alzheimer's. So, um, so it's clear that there is this underlying biological process of aging that is driving the increased risk for, you know, not only Alzheimer's and cancer, but you know, heart disease, chronic lung disease, um, you know, degenerative eye disease, et cetera.
You know, there's a very long list. Um, There's this underlying principle here that, you know, there's this wide, you know, vast variety of diseases that, you know, share this underlying etiology. And, uh, that's actually what, you know, we find really compelling. It's why we work on aging. It's that, um, it's this very potentially huge impact you can have if you can really modulate the aging process, you can, you know, affect the, you know, decrease the risk, uh, of developing all sorts of diseases and really improve health and quality of life for, um, you know, for people in the population.
[00:05:19] Kevin Folta: Yeah. You see, I could, I could go all day just on aging alone because it's, it's intriguing to me that, uh, you know, small things like mice to age at one rate. Mm-hmm. and tor tortoises at another, and dogs at another, humans at another. It's a really interesting kind of innate developmental, Pathway. It seems like it's something that's already, uh, designed into our d n a.
And does it appear that this is a common pathway among humans that all, that everyone goes down at the same rate? Or are there different ways that humans have, uh, genetically maybe more accelerated or slower programs? .
[00:05:57] Eric Morgen: Yeah. So it's clear that different people are aging at different rates. Um, another way of saving that saying that is that some people age more successfully, and some people age, you know, less successfully.
I they get, you know, diseases at a younger age, they get disability at a younger age, and they die at a, at a younger age. Um, and there's really this. This really close link, as we were mentioning before, between, um, you know, healthspan and Lifespan. It's really as your health deteriorates, that leads to a shortened lifespan in most cases.
Um, and so you have these, uh, amazing examples within the population of people who are, you know, aging more or less successfully. And, uh, at the really good end of that spectrum, you have these amazing examples of, you know, centenarians and supercentenarian. Um, you know, to give just one example whose, uh, name is Lila Denmark, um, who is a pediatrician who practiced until the age of 103, um, which is, you know, a working lifespan that's, you know, probably double, uh, that of, you know, most of us.
Um, and she, you know, lived until 114. And a really, you know, important thing about these people who are very, who live a long time, who live beyond a hundred or 110 is that, um, they don't age in poor. , they actually have a much shorter, uh, period at the end of their life where they're in poor health than the rest of us.
So, um, so these people who have a long life also have a really long health span. And so, um, that's actually a really fundamental concept to, uh, how we, uh, do our research and find our, our targets and, and what pathways we wanna modulate to improve human health. , we look at this variation, we look at these people who have these amazing long lives, and the people who, you know, who age more poorly and try to figure out the root causes, um, of those differences in terms of biology.
Um, and that's what we target with our therapeutics. .
[00:07:49] Kevin Folta: What's really interesting about this, and I've been through your website and some of the publications and news releases, is that most of the targets that you're looking at are not the traditional molecular and cellular events that have been described.
Things like telomere shortening, things like that. And so what are some of the, the events that, uh, that we've classically looked at as the molecular underpinnings of, of aging, and are those really just correl. ,
[00:08:18] Eric Morgen: right? So there's, there's quite a lot of things that go wrong as you age. Um, I think you've alluded to that as well.
And, um, you know, one way of, uh, breaking these into sort of fundamental biologic processes is to think of them as the hallmarks of aging. Um, there was a famous paper published under that name, but these sort of categories of things that go wrong. And so, uh, you know, for example, one thing that goes wrong, You know, cell signaling, if cells are not able to, you know, talk to each other in a way that, um, is as well controlled as when you're younger, that causes, you know, breakdown in tissue functioning.
Um, which includes, you know, stem cell functioning, which is another actually major hallmark of aging is that as we get older, um, the stem cells, uh, these sort of, you know, more, more powerful cells in a way that live in, in each of our. Um, that are able to help regenerate those tissues when there's damage, you know, that they, they get less able to do that as you get older.
So, um, and so this breakdown in cell signaling and stem cell function is actually addressed directly by, you know, one of our programs, uh, which is our, our AON program. Um, another really classic aspect of aging is infl aging. The idea that, you know, Uh, have a more inflamed physiologic state as you get older.
And that's a really, you know, key component of aging and causes a lot of other problems. Um, and we're addressing inflammaging through, um, through a different, uh, program that targets the, uh, N L R P three uh, inflammasome pathway. Yeah, we'll
[00:09:54] Kevin Folta: catch up on that in just a little bit, um, with some of the therapeutics that are potentially coming down the line.
Um, one of the intriguing parts about aging in my mind has been, and we touched on this briefly, is the variation we see among animals and animal models. Yeah. Yeah. And so you got mice that live, you know, however long a mouse lives. But then you have things like, uh, uh, tortoises and some bats, like the variation with them bats is huge.
Mm-hmm. in terms of how long they have a lifespan mm-hmm. . And so how much have we learned from animal models about the aging process and how have those, uh, studies really informed human
[00:10:30] Eric Morgen: health? Yeah. Yeah. This is, it's really interesting because there's a few. I think really high level points here, and one, um, is as you alluded to, there's a massive diversity in lifespan, uh, among animals.
You know, when you go from, you know, rodents to, um, to humans to uh, to really long-lived species, um, like, uh, you know, Greenland sharks, you know, or, or certain types of tortoises. And so really, You know, blatant proof that there's nothing set in stone about, you know, the human lifespan, that it should be 80 or 90 years, for example.
Um, and that it's really, you know, certain aspects of, you know, evolutionary happenstance, that specific, um, organisms have specific lifespans. And, um, so that's one point, uh, that lifespan is clearly. , there's examples of all sorts of lifespans that we can potentially achieve. Uh, 0.2 is that, um, experiments in model organisms have clearly shown that we can intervene in aging, that we can take an animal that's aging at its natural rate and that we can administer a therapy.
And there's a few good examples of this that, um, extends that, uh, animals lifespan and healthspan. Uh, and if we can do it in animals, you know, there's no fundamental reason why we shouldn't be able to do that. Uh, and then 0.3 is that, um, you know, specifically using, um, animal models as a way to test therapeutics.
You know, that's clearly we do a lot of that. Um, and that has classically focused on animals that are very different from us. So, you know, we e established that we can change the rate of aging in, in. You know, sea elegans or, or in flies, uh, drosophila. And, um, you know, the things that work in those an, uh, animals are gonna be quite different in many cases from the things that will work in humans.
Uh, and so, you know, the, the actual use of model organisms, um, has not resulted to date in a therapy, uh, that. You know, was discovered in those model organisms and is translated into people, um, and is on the market of course. And so, um, you know, there's this really important point that, that we care a lot about at bio age, which is, you know, starting with evidence from human biology, uh, in our case from healthy, you know, human aging cohorts and figuring out what are the best targets there.
Uh, and kind of starting with that to have the greatest chance of, you know, having a therapy that really works in. .
[00:12:56] Kevin Folta: Yeah. And we'll talk about that, uh, says that's a really important part of the approach. But when we talk about, uh, limiting aging, you know, as a prerequisite to heading off disease, it's, you, we've discussed this already today in other podcasts, that it, it's multifactorial.
There's so many things that are happening. Mm-hmm. , how can it effectively be treated? It is there, are you treating multiple factors or is it potentially that there is some sort of master regulator that can, uh, kind of slow that
[00:13:26] Eric Morgen: clock? . Yeah, no, there's clearly no single master regulator. And as a result, there's gonna be no, you know, single silver, silver bullet for aging.
That's, I think, pretty clear from the literature and, you know, very compatible with what we've seen in our healthy aging cohorts, that there's no, there's no one pathway to rule them all. Um, but, uh, So there's many pathways. Um, but at the same time, you know, those pathways have a structure and some pathways are regulated by others.
And so there's clearly, you know, pathways that are very important for aging. And, um, you know, in the way that aging drives kind of disease and ultimately lifespan, um, we are confident that, you know, treating specific pathways will have, you know, individual substantial effects. You know, if you, if you pick the right pathways, targeting that pathway alone is, Um, in improve health in certain ways and likely improve lifespan.
Um, but that fixing only, only that one pathway is not gonna, you know, have an indefinite benefit. Eventually the other pathways kind of catch up with you. And so there's this, you know, strong likelihood that there's gonna be a, you know, a, a sequential, uh, approach where, you know, at first you target one pathway and then you target another, and then maybe you have a combination therapy that targets both at the same time.
And so, you know, You know, long-term vision would be to ultimately have a, a suite of therapies potentially, you know, potentially combined that, um, cover large parts or ultimately all of these, you know, different aging pathways that are, you know, really driving, uh, disease and death. So, um, so there's a lot of, a lot of potential pathways to drug and a lot of potential in that approach.
And
[00:15:03] Kevin Folta: what about this, uh, discussion around caloric restriction? Because that's been, at least in my, in my mind, probably the most compelling way to slow the process. And how does that tie
[00:15:14] Eric Morgen: in? . Mm-hmm. . Yeah. It's really, you know, interesting studies that show that, you know, at least in a number of model organisms, if you, you know, decrease the, the caloric intake, you can increase lifespan.
And, um, you know, certainly that could translate to humans, but I think there's a number of ways in which it might not translate well. Um, first of all, there's, you know, a theory that. , you know, clear restriction may have evolved or the effect of clear restriction may have evolved such that say, you know, you're an animal, uh, in a particularly hard winter, there's no food around.
Um, it's a way to kind of redirect biological, uh, priority from things like reproduction to things like let's just survive, um, until, you know, the next time we can, we can start to get to food and, and reproduce. Um, and just thinking of it that way, it makes sense that a really robust effect and a. You know, where them extending their lifespan by, you know, uh, a couple of seasons would be a really large percentage extension in their life, but it might be much less, um, in people.
There's also a really interesting point that, you know, these observations have been primarily in lab mice and lab mice are very unique organisms in particular ways. In particular, they were bred for, um, really high fertility rates so you could breathe them quickly. Um, just a practical consideration and, um, and that.
You know, a priority for these reproductive pathways over things like, you know, sort of, you know, survive, uh, and weight pathways. And, um, and so they may be particularly susceptible to benefit from something like lu restriction lab. Mice also are very, you know, prone to obesity and it's clear that, you know, if you're a very obese creature, whether an animal or a person, um, it's good for your.
To clerically restrict and, you know, and normalize that. Um, so, so there's a lot of, you know, cool findings. Um, there's been, you know, there were primate studies that, uh, didn't have major findings that rec recapitulate the, the, the mouse findings. So, um, so I think one point here is that this is kind of a good example of why.
It's really important if you wanna have a therapy that's gonna work in people and to be confident that it, that it will, um, that you should start with, um, data and observations in humans. Um, so that's what we're excited about. Mm-hmm. . Well,
[00:17:33] Kevin Folta: that's a really good stepping off point. Um, we'll come back on the other side of the break.
We're speaking with Dr. Eric Morgan. He's a co-founder and coo o of bio age, and we're talking. Aging and how it's the gateway to preventing long-term disease. This is the Talking Biotech podcast by Col Collabora, and we'll be back in just a moment. And now we're back on collabs talking Biotech podcast.
We're speaking with Dr. Eric Morgan. He's the co-founder and c o o of Bio Age, and we're talking about the idea that aging. Is really the prerequisite to disease that it, uh, sets the stage. Essentially, the changes that are happening developmentally, physiologically, at the molecular level provide a basis by which these other diseases can take hold.
So if there were ways to prevent or slow down these particular facets of. The aging process, it could uncouple the propensity to develop disease from the calendar, which is really a pretty exciting approach. Uh, so, uh, let's talk specifically about bio age in your approach. So you've been using Biobank, which ha have data from large numbers of patients to identify specific drug targets.
Can you tell us more about that
[00:18:52] Eric Morgen: process? Yeah, for sure. So, one key kind of point, starting off point here is that, you know, what we wanna do as a company is develop therapies that target fundamental mechanisms of aging to treat disease. Um, and if you want to figure out what the right mechanisms are to improve health in people and improve aging in people, you need to one, start with humans.
And so that's why the, you know, these are cohorts that we're using and not starting with animal. And two, um, aging in humans is a process that happens over many decades. And so, um, you need to start with data that encompasses many decades of aging. And so we have partnered with some very special biobank that have samples collected longitudinally over many years, and, uh, and health outcomes connected, collected also longitudinally over many.
So we can take a look at people who are middle-aged, don't really have any diseases yet. Um, and they're, they're, uh, and we can ask this really fundamental question, um, by, Going into the blood samples that have been collected over time, we can deeply profile those samples and measure all the molecules and biological processes that are happening, uh, in those blood samples and relate to the health of the overall person and ask this question.
What's different about two people where both healthy and middle-aged, one of whom goes on to age relatively quickly, developed diseases quickly and die quickly. And the other one who is very robust and lives a really long time in great health, um, you know, essentially people who age quickly and people who age.
[00:20:26] Kevin Folta: Yeah. So what kind of data are you looking for? Are these, uh, proteins that are different between the different samples and stages, or are you looking at gene expression changes or all the
[00:20:35] Eric Morgen: above? Yeah, all the above. Um, we particularly like proteomics and metabolomics that's measuring the circulating proteins and metabolites and blood.
But we, we look at, um, you know, these other types of molecules are gonna be measured as well. Transcriptomics, uh, methyl omics, and, um, . And so yeah, at a, at a fundamental, at a very simple, simple level, let's say it is exactly that. It's sort of saying, you know, what are the, you know, proteins or metabolites that are, you know, we are observing in, you know, different, different levels and different people who go on to have different outcomes.
Um, of course it's very complicated data. Um, so there's, you know, many thousands of data points just for the biology from these samples per patient, per per blood sample actually. And we're following, you know, thousands of patients over decades, you know, up to, up to, you know, more than 45 years. .
[00:21:26] Kevin Folta: Yeah. But one of the big problems I would think is how do you separate, uh, correlation from causality?
You know, you've got mm-hmm. , a snapshot of a blood sample or some sort of, you know, metabolite profile and how do you know, or how do you use maybe AI or whatever to be able to separate what is just there as a, as a function of some sort of long-term developmental breakdown from something that kind of.
Causing
[00:21:52] Eric Morgen: it. Mm-hmm. . Absolutely. Yeah. So, um, there's, it's a, it's a fundamental, um, challenge that you're describing, um, in getting to good targets. And, and so there's a number of ways we think about that. And so one is that there's a benefit to having longitudinal samples here. And so our, um, Our modeling that we do to kind of find the drug targets, takes that into account and I, you know, and ask this question or, or demands of the, of the, of the targets that the association be consistent over time so that, uh, you can observe essentially the pathway is going awry as the, um, clinical outcomes.
Uh, are increasingly accumulating, uh, like poor clinical outcomes, for example. That's one, one aspect. So the longitudinal aspect is important. Um, two is that we can, uh, get a much stronger idea of causality through integrating genetic data, um, and a. Great example of this is using Mendelian randomization where we supplement these observations from proteomics and metabolomics, um, with observations from genetics showing, um, essentially that, you know, people who are born with genetics that predispose them to have particular proteomic or metabolomic profile profiles.
Um, also have the same kinds of. That, you know, we're observing just based on the, uh, the non-genetic data, and that's a link you can use to, to really strongly argue for causality. It's a bit like a, a randomized control where randomization occurs at birth. So it's a cool idea. Um, and, uh, and I'll, I'll just say the last thing that we do, um, which is, you know, we'll ask two things that we do, which are ultimately the most important is one is we, uh, evaluat.
um, these pathways in experimental animal models, um, naturally, uh, sort of, um, age animal models. And two is that we ultimately, uh, evaluate in the clinical trials. So, uh, a lot of, a lot of different ways to get towards causality. Mm-hmm. .
[00:23:49] Kevin Folta: And when you're using animal models, uh, is there anything that we learn from, say, octogenarians are center genes that, uh, can help confirm or maybe refute
[00:23:59] Eric Morgen: a hypothe?
uh, well, absolutely. Like we start with the human data. So we're not even interested in any of these pathways unless they, um, are something that, for example, a healthy 80 year old has that a unhealthy 80 year old doesn't, or actually more specifically that, you know, people when there's a 50, um, have that are different, uh, when they're destined to go on to become that healthy versus unhealthy 80 year old.
[00:24:22] Kevin Folta: Yeah. It's interesting stuff. So, so let's talk about the pipeline. Mm-hmm. . Um, are there any good examples or what is a good example of a small molecule that your group has identified that maybe can slow some aspect of
[00:24:34] Eric Morgen: aging? Yeah, for sure. So, um, so a great example here is our, um, BGE 1 0 5 program, which targets the Alan Pathway.
Uh, and so this is a. Interesting pathway that, again, came over, came out of these, um, longitudinal aging cohorts where, you know, we were interested in developing a drug that benefited muscle aging. And so, uh, you know, we modeled pathways that, uh, looked like they'd be likely to, um, you know, over many decades improve, uh, physical and muscle.
Um, and also improve longevity. And one of the ones that came out on the top of this list was this AON pathway. Um, and, uh, you know, so one of the initial observations, for example, is that if you just plot levels of sort of AON pathway activity, um, in different people at baselines when they're healthy, um, in a middle age, uh, that those levels predict, um, the sort of, you know, muscle aging destiny, these people that people who have higher levels, Um, go on to have much better physical function.
Uh, when they're older, they have faster walking speed, they have better grip strength, um, you know, better ability to kind of use those things to accomplish everyday activities. Uh, and they also live longer. Um, so that was really interesting and, um, that led us to. You know, do obviously a lot more deeper analysis to confirm that, but ultimately to sort of evaluate that in, um, animal models where we observed that, um, when we, uh, interventionally boost, um, the Aon pathway that, uh, animals who are aging have, uh, are, are much more sort of physically active, um, as they get older over the course of a few months.
Um, Separately, we, we, um, applied this as well to an animal model of more rapid muscle atrophies. This is something that happens to people all the time. Uh, older people, um, are, you know, inactive for some reason. Often they get admitted to hospital for something, let's say pneumonia. Um, they stay in a hospital for a week, um, and they come out and they really can't walk very well.
Um, and that's because they've experienced dramatic atrophy during that period. And so we, um, modeled that in a. By, uh, taking older mice and, um, casting one of their limbs. And this works by the same method. You kind of immobilize the limb, the muscles atrophy. And, um, in the mice who, uh, got the, our, our drug BG 1 0 5, um, they showed basically no muscle atrophy, um, after the, after the period of casting, uh, versus, you know, the ones who didn't, who showed, you know, quite traumatic muscle atrophy.
And, um, and so that brought us to, um, ultimately kind of mirror that study design in a human, uh, phase one clinical trial where we got healthy volunteers, um, who volunteered to be at bedrest for 10 days. So they li they, they were lying in bed all day other than going to the bathroom. Um, and that also, um, you know, If they're not using your muscles.
And so those muscles atrophy, and this is established that, um, you know, other people have done this before and so they experience a lot of muscle atrophy, particularly in their leg muscles. And, uh, we showed via a number of measures that, um, boosting the apon pathway via our drug BG 1 0 5. And these people, um, dramatically protected them from that atrophy.
So, Preserved the, um, circumference of their thighs. Uh, as an one example, uh, preserved the dimensions of specific muscles that we measured by ultrasound. Um, it also, um, preserved the, the rate at which muscle proteins are synthesized, um, which went down a lot in the people who didn't get the drug. Um, and was, uh, you know, Much better preserved than the people who, who got the drug.
So, um, uh, and I, I guess the final aspect is that muscle quality was also, um, again, qual muscle quality. In addition to quantity is known to decline with, uh, with this kind of bedrest atrophy. And, uh, via ultrasound we observed that the muscle, muscle quality was preserved, um, by the drug. So, um, so really exciting result that, you know, mirror.
the animal data, but also kind of reflected these associations that we found initially in the human data that people, you know, over many decades had protected muscle function. And here we're showing it, you know, over a very short period of time and we're very, um, you know, optimistic that this can have some dramatic health benefits for people in very specific health conditions.
Um, and you know, probably the most. A dramatic example of this where muscle atrophy really causes huge problems in a really short period of time, is in the intensive care unit where people are, um, often put on a ventilator. Um, you know, they have a tube down their throat and there's a machine that basically breathes for them.
And so when that happens, that diaphragm, which normally. Does the work of breathing is, um, at rest. Um, and so just in the same way that, you know, bedrest causes your, your leg muscles to atrophy, being on a ventilator causes your diaphragm to atrophy. And, um, it's known from human research that peop, that people who have the most diaphragm atrophy have the most trouble.
Getting off the ventilator at the end once their health is improving. And if you can't get off the ventilator, um, you can't get outta the ICU and you die. So this is a really dramatic example where we think preventing muscle atrophy in older people, um, and older people are, are, you know, more prone to all of the negative consequences of being on the ventilator and being in the ICU u um, that preventing that muscle atrophy of the diaphragm.
Uh, You know, a dramatic implications for people's health. Um, incidentally in the icu they also get super dramatic, um, atrophy of their, of their peripheral muscles, their legs and arms, and so I'll also be able to look at that.
[00:30:27] Kevin Folta: Yeah. I have a million questions on this one, but l maybe just start with a, a basic one is, what is APO one?
[00:30:33] Eric Morgen: Absolutely. So, um, again, very interesting. So Aplin is a peptide, uh, a small protein that circulates, um, in the blood and that is secreted pre primarily by a muscle and is kind of perceived by a number of different tissues in the body, but notably including muscle. Um, and so this is a class of, um, molecules that's known as exer kinds because.
Aon is released by muscle when you exercise, um, along with certain other things, which are also called exer kind. And so it's really interesting that, um, Aon may be a great example of why exercise is good for you and, um, may probably participates in a lot of the signaling that causes exercise to increase and or preserve your muscle.
So, um, that's one way to kind of, you know, hypothesize what's going on in this clinical trial is that people who are at bedrest, they should experience a lot of atrophy cuz they're not exercising at all. Um, and here we're, you know, taking patients who are at bedrest by giving them this drug and boosting this sort of exercise pathway in a sense.
And they have preserved muscle. So, um, so it's a very, you know, interesting pathway with a lot of implications. And, and of course we ultimately hope to, you know, not only develop it in these acute indications, but really apply this to the aging population at large, um, and prevent a lot of the really severe, you know, disability and quality of life problems, uh, that have to do with, you know, age related muscle loss or, you know, also called sarcopenia or frailty.
[00:32:10] Kevin Folta: That's a really, really good point because it seems to me that that's kind of a downward spiral that once you can't exercise, you can't, you start secrete or stop secreting April and now you don't exercise even more. It seems like you, like, you know, it's kind of a, a self-feeding problem, but one of the places where I think this is huge, and maybe you've thought about this, maybe not, but what about, um, uh, interactions with NASA and astronauts who, because of the fact that there's no gravity mm-hmm.
come back and can barely. . Mm-hmm. .
[00:32:39] Eric Morgen: Yeah, absolutely. I mean, that's another great, essentially model, human model of, um, muscle atrophy is that, you know, in bedrest you're kind of unloading your muscles and when you're in zero G, you're also unloading your muscles. So, you know, astronauts have to do quite a lot of exercise just to kind of, you know, not have really profound atrophy and they, you know, they, nonetheless, they decondition.
So, um, that would be definitely a potential application. . Yeah.
[00:33:06] Kevin Folta: This is really neat. So what about, uh, chronic inflammation? You've mentioned this before and that this idea of chronic inflamma, uh, inflammation becomes more common with age and uh, now we see more and more data that show this connection with, uh, pathology.
And are there strategies in place to slow or specifically target. chronic inflammation.
[00:33:27] Eric Morgen: Mm-hmm. . Yeah, absolutely. So we have, um, a pathway that's targeting, uh, increased inflammation with aging, uh, which targets the NLRP three pathway, um, and. So there's a lot of things that go wrong with your immune system with age, and in some ways your immune system gets, you know, less effective and is less active.
Um, for example, the ability to produce antibodies or respond to new, you know, uh, new diseases or new sort of infections that you encounter, um, in terms of antibody response. But there's other aspects where the immune system is just overactive, and that's this idea of inflammaging and, uh, the main culprit here.
The innate immune system, and that's exactly where the NLRP three pathway comes in. It's like the key driver of innate inflammation. And so, um, as people get older, they have, you know, increased levels of innate inflammation. Um, great example of this is neutrophils and, um, and it's bad to be chronically inflamed and it's also bad to be acutely inflamed.
So older people have a much harder time surviving pneumonia. And in large part that's because, um, there's an overactive immune response, uh, in the lungs of, uh, older people with pneumonia. And so they damage their own lungs. Um, and, uh, you know, it's clear also that chronic inflammation drives things like cardiovascular disease where it damages the lining of the blood vessels and, uh, neurologic diseases, which, um, you know, neurodegeneration, uh, appears to be driven in part by chronic inflammation.
Uh, and so, um, N L R three, uh, is our program targeting chronic inflammation. And again, it was, um, you know, the genesis was observations in our human. Where, you know, people who had higher levels of this over time, um, had worse outcomes. In particular, you know, they had shorter lifespans and of course they had more inflammation.
Um, and so this is, uh, an example. Um, In the, you know, previous case with, um, the Aon program. We, we didn't make that drug ourselves. We, uh, in licensed it, uh, essentially bought it from, uh, Amgen and in this case with L R P three, this is a molecule we made from scratch. After kind of making this observation that, uh, it would be a really.
Powerful pathway for aging. We, um, screened billions of compounds using a cool approach called DNA encoded libraries, which I won't go into, but, but very neat. Um, and came up with a drug that targets this pathway that has really, you know, awesome. Drug properties, you know, where it's, you know, not only absorbed well, but um, but it, uh, you know, gets into the brain, it passes the blood-brain barrier, and so has this, you know, potential for, um, you know, being applicable to, uh, to help with neurodegeneration, which is a, you know, a massive problem associated with aging.
[00:36:15] Kevin Folta: Yeah. And a massive problem in getting worse because as we start to not succumb to more, um, Uh, issues like infectious disease or even heart disease, we're going to see more and more of that. So we're talking about, uh, issues like, uh, uh, muscle loss. We're talking about, um, chronic inflammation. What are some other potential targets and potential therapeutics that are coming down the pipeline?
[00:36:40] Eric Morgen: Um, yeah, so, you know, at bio age, uh, you know, we're interested in, as I mentioned, muscle aging, um, you know, immune aging, um, you know, broadly speaking within the field. Um, it's a, it's a really wide open new field, um, where, you know, companies like Bio H are just starting to kind of, you know, Uh, aging therapeutics, um, in a, in a fo in a way that's focused on, on developing new therapies.
Um, and we're just starting to get them into the clinic. And, uh, so, you know, there's a lot of approaches that are being taken and, you know, some notable ones are, uh, you know, sy alytics. So these are therapies that are trying to, um, destroy selectively senescent cells. Uh, and senescent cells are, you know, have been called sort of zombie cells, that they're a small proportion of your cells that.
You know, they get, gets alar, get to be a larger proportion as you age. And they're these dysfunctional cells that essentially should have died but, but didn't. And they hang around secreting really kind of noxious toxic factors that, um, you know, negatively impact the health of all the cells and tissue around them.
And so, um, there's a strong promise here that, you know, if you could just kill the senescent cells in a specific tissue or across the body, you could, um, you know, Do really good things for aging. Um, another common, uh, or thing that people are interested in is stem cell function, which I mentioned before.
Um, it's really. Key that, you know, as you get older, your stem cells in different parts of your body are much less able to regenerate, um, their specific tissues, um, or organs in response to, you know, damage to those organs, whether that damage be, you know, really acute or chronic. Um, and so being able to revitalize those stem cells could do a lot for human.
Um, there's other companies interested in, um, sort of young versus old blood, um, which, um, you know, that's kind of entered the public eye in the media. Um, looking at sort of, you know, what's different between the circulating factors and old, uh, people's blood and young people's blood. And using that to find, um, you know, interesting drug targets, um, including for no generation.
That's, that's one approach. Um, another, uh, approach that's gotten a lot of press recently is partial, partial reprogramming, where you take the science behind, um, sort of being able to take terminally differentiated cells like regular everyday cells, um, and turn them back into stem cells, um, which have, you know, much more biological, um, you know, power or potential.
And you take that same technology and say, can we turn this into a therapeutic? Um, that, you know, it's not just gonna take a cell and a dish and, and, and revert it to. Primordial state, but it's gonna take your whole body and kind of revert it to a slightly, uh, more primordial state, which will rejuvenate all your tissues.
Very cool. But, um, but just in its infancy. Um, and I'll just say that, you know, at bio age we don't sort of pick any of these particular approaches. We take this data-driven approach where we, um, look at the cohorts and all of this molecular data coming outta the cohorts and let it tell. You know, which pathways are really important, and then afterwards we kind of look up and say, ah, that pathway is relevant for, um, you know, for this, for, for whatever biologic process.
So, um, and, and, and I guess there's, you know, this, this aging field is kind of wide open, so there's a lot of take, you know, companies taking different approaches and. , uh, we'd, you know, love to see, you know, any and all of them succeed because, uh, you know, there's, the field is wide open. The space is wide open, there's no therapies of this sort.
Um, and there's gonna be many of these once they begin to become successful. And, uh, and obviously the first company that is successful in really bringing one of these drugs to market that's based on a fundamental aging process, will really open the field, wide up for all of the other companies as well.
Um, in terms of validation of that really fundamental.
[00:40:32] Kevin Folta: No, I very much agree and, and just learning about your company and about this approach, it really has made me rethink how I think about research and health that mm-hmm. , certainly there's a lot of focus on cancer and a lot of focus on Alzheimer's.
Mm-hmm. , a lot of focus on heart disease, uh, you know, lung dysfunction, all the major killers. But really shouldn't we be focusing at least maybe a little bit more on how to slow the aging process, because that really may be the prerequisite. to all of these other degenerative disease.
[00:41:05] Eric Morgen: Absolutely. I mean, it's this fundamental maximum of, you know, don't treat the symptom, treat the cause.
And it's really becoming very clear that, um, it's the biology of aging, which, you know, deteriorates as you get older. That's the driving factor for all of these diseases. Um, and so, you know, focusing huge amounts of, you know, money and research efforts on, you know, specific diseases will only ever be relevant to those specific disease.
Um, and, uh, you know, it's quite clear that, you know, even completely curing specific diseases will actually have a lot less of an impact on overall, you know, human health, population health than you'd expect. Um, and it's. because there's all these different diseases developing kind of at the same time. So curing cancer, which has been this sort of moonshot goal for, you know, many decades, uh, there's been untold resources spent on it.
If we were actually to achieve that goal of completely curing cancer, you know, intuitively we'd feel, wow, that would be amazing for human health. Of course, it would be amazing for, you know, the specific people, um, who don't get cancer. But it turns out that the actual benefit at the population level to overall lifespan, um, is only a few years.
And that's because, you know, you don't die of your cancer, but then you die of the, you know, heart disease that was creeping up right behind the cancer or, um, you know, or the, uh, you know, chronic kidney disease or the chronic lung disease or, or whatever it is. So there really is, you know, tremendously more potential in you.
Directing, uh, money and research resources towards these, these fundamental processes of aging, where if you target them, um, you're gonna have far-reaching effects across organ systems and across these diseases. Uh,
[00:42:56] Kevin Folta: it's a, it's a really interesting concept, but let me be a devil's advocate for a second because mm-hmm.
you know, I studied developmental biology in, in certain organisms and plants anyway, and I know, and from whether you're a fruit fly or a plant or a human being, senescence is a normal program of human development. It's a normal, uh, PR part of the process. And is there potentially, Is aging really a way that could protect us from, uh, degeneration And that maybe that, uh, something like cancer, if it's happening in a, uh, older senescent background is less aggressive or maybe there's a ac, um, aspects of it that keep things.
Slow, you know, because they're breaking down all over. And am I thinking about that completely wrong in, in that maybe anti-aging drugs could be just pouring the gas on the fire of the diseases that come as we age. . Mm-hmm. .
[00:43:53] Eric Morgen: Yeah. Well, I mean, biology is complicated. You know, in essence, you gave that example is that, you know, it's involved in different processes and there's some ways in which it's very functional, you know, in wound healing or in development.
And there's other ways that become really prominent as you get older, um, where it's extremely dysfunctional. Um, and I guess I'll just say that, um, anytime you develop a new therapy, there's clearly a chance of unanticipated. Or, you know, side effects or adverse effects, which is I think basically what you're getting at.
Um, and there's a long history of, you know, drugging new diseases, you know, like, um, you know, cardiovascular disease, like, you know, eye diseases, et cetera. And, um, you know, in certain cases those therapies have, um, you know, poor side effects and they're scrapped. And, uh, ultimately we've gotten to, you know, successful therapies that really improve those diseases.
And this is really, you know, of course the reason we do clinical trials, the reason we have a regulatory environment that really cares a lot about safety, uh, and um, you know, so I guess I would say that, um, you know, really I think that's different I guess about aging in this respect versus other diseases is that, um, you know, when we at bio age select targets from these healthy aging cohorts, we're really.
Taking the biology of, you know, an average person, for example, and shifting it to exactly, you know, better resemble that of a person who we know is living a really long, healthy life in these trials, like on average across all things, um, they just live longer and are healthier. So we actually have a much lower risk of running into those problems.
Um, uh, if we, you know, if we are modifying biology in that way and we get this really. You know, it's the right kind of information that you'd wanna know for developing a drug that, you know, if you're activating this pathway, that people who have more active pathway, uh, a active versions of that pathway, live longer and are healthier, you know, across all causes.
Um, so yeah, a lot less risk that will have those issues, but it's always a concern in, uh, developing new therapies.
[00:45:57] Kevin Folta: No, this is really, really great stuff. Can you go faster, please? ? .
[00:46:02] Eric Morgen: We are absolutely going as fast as we can. Um, and, uh, we'll try to get, you know, new therapies on the market as, as soon as we can.
We'd love to, we'd love to be able to help people. You know, all of us have, uh, you know, loved ones who are, um, having a lot of problems with aging.
[00:46:18] Kevin Folta: Yeah, it's definitely the case. I just rolled over a birthday last week and, uh, you know, and I'm kind of getting to that point, and uh, and I'm gonna be a parent rather late in life.
And so what's really kind of strange is it's the first time I've thought. About this where I'm thinking when I'm 75, I gotta kind of have my act together. So, um, you know, it's, I've never had that kind of focus before, so I'll be keeping an eye on bio age and watching your website and looking forward to your products
But if, but if people wanted to learn more about bio age, where would they look? Online or potentially in social media?
[00:46:52] Eric Morgen: Yeah, for sure. So you can check out our website, you know, bio ohh labs.com, uh, which we recently redid that showcases, you know, the, the clinical programs we're working on the science.
They're based on, you know, the team that's working on it. Um, for kind of the most up-to-date news, you can look on social media. We're on, uh, LinkedIn and Twitter. Um, and we also have a podcast called, uh, translating. That, uh, features, uh, researchers and, uh, you know, the companies that are, are working in aging biotech and kind of bringing longevity science, uh, you know, from the lab into the clinic.
[00:47:30] Kevin Folta: Excellent. So after you're done listening to talking biotech, go listen to it, . Um, no, it, it sounds exciting. Actually. I'll, I'll definitely check out your podcast because I think this is a fascinating topic and, um, I think if I was somebody who was at the beginning of my career in molecular biology, genomics, that kind of thing, I would be thinking about studying aging.
Big way because this just seems like, uh, a pinata ready to pop. Okay. Uh, so Dr. Eric Morgan, thank you very much for joining me today on the podcast, and I really hope that as new developments come along, that you'll reach out again and we can follow up on this and maybe someday look back on when we first con connected, um, long before the really good therapies came along.
So looking forward to talking to you in the.
[00:48:17] Eric Morgen: Absolutely. Thanks so much Kevin,
[00:48:19] Kevin Folta: and like always thank you very much for listening to The Talking Biotech podcast, uh, by Collabora. Check out Collabrate suite of products and find some that can help your laboratory, um, but also fill out reviews on the podcast.
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