Exercise in a Pill? Could Muscle Protect Memory and Fight Alzheimer’s with Professor Constanza J Cortes

Speaker A: 00:00:00

Welcome to Beyond Longevity, the podcast that.

Speaker B: 00:00:08

Explores not just how we age, but how we can build a longer, healthier future for ourselves.

Could your body get some of the benefits of a workout without you doing the exercise?

And could a drug like that help prevent memory loss or treat Alzheimer's?

My guest today is Professor Constanza Cortes, a neuroscientist at the University of Southern California.

She investigates how exercise could help preserve our memory as we age.

Her goal is to develop treatments for people who cannot exercise enough because of pain, illness, or limited mobility.

Her research starts with our muscles.

When we exercise, our muscles send chemical messages around the body, including the brain.

Professor Constanza is testing whether a drug could deliver those messages without the need to exercise.

Her team has already improved memory in mice used to study Alzheimer's by changing what happens in their muscles.

Could that eventually help someone whose memory has already started to deteriorate?

We discussed how much of exercise a drug could really reproduce, whether healthy people could benefit, too, and what still needs testing in humans.

Professor Constanza also explains her ambition to have a treatment in the clinic within 10 years.

Please enjoy my conversation with Professor Constanza Cortes.

Speaker A: 00:01:37

Hi, Professor Constanza, thank you so much for joining me today on Beyond Longevity.

I recently heard you speak at a conference, and you were talking about exercise in a pill.

The moment I heard that, I knew I wanted to have you on Beyond Longevity because what a topic.

I want to know more about it, and I'm sure so does everyone else listening to it.

So is it true?

Could we just take a pill and get stronger without going to the gym?

And I'm very much hoping the answer is yes.

But before we get to that and explore all that properly, I thought we'd start with you.

And I'd love to hear a bit more about you.

You're an assistant professor at the University of Southern California, studying how exercising affects the brain.

What first drew you to studying the brain?

Speaker C: 00:02:30

So it all began when I was a graduate student back, I'm not going to tell you how long ago, but I became very interested in what happens to our brain as we start to age.

And I began to realize that a lot of things begin to work not super well.

And what that meant is that there's not necessarily a disorder or a disease that's occurring.

It's just a slow, progressive, natural breakdown of a lot of processes.

And then that took me right into this idea of what can we do to slow down that breakdown?

And I realized that one of the most powerful interventions we have that we know works is exercise.

And so this took me into this journey of trying to figure out, what does exercise do, how does it work, and how can we begin to develop, as you mentioned, potential exercise and a pill therapies for folks that can't necessarily exercise to the level required to get those benefits.

Speaker A: 00:03:25

Wow, that's super interesting and exciting.

And I'm not surprised that you're now studying all this because it's.

Wow, it's mind blowing.

Your training took you from chile to a PhD in Chicago.

And I also read while you were doing your postdoc, you were competing in salsa dancing.

Speaker C: 00:03:44

I was.

Speaker A: 00:03:45

So there was quite a lot happening outside the lab, too.

But when you started with your own lab, what was the problem you were ultimately trying to solve?

Speaker C: 00:03:58

So it was this kind of intersection of questions, right?

It's.

We knew exercise is protective for the brain and it can protect against not just age, cognitive decline that we all will experience to some degree, but also the cognitive diseases of aging, including things like Alzheimer's disease and stroke and other kinds of dementia.

And the problem, the challenge that we were facing is that everything we knew about exercise until very recently was based on young systems.

So usually very young people, young athletes, are the ones that volunteer for a lot of these exercise studies.

And so we knew a lot about what the young brain does when exposed to an exercise intervention.

But what we were finding when we're repeating these experiments back in the lab is that the aging systems, in my case, I use mice as my model in the lab, and we translate a lot of that into human systems as well.

The aging systems were just responding slightly differently or not at all.

And so this created this barrier where this exercise prescription was, you know, making the rounds in social media and through the clinical population.

And yet it might not be enough or we might have to tweak it a little bit.

And so to help push that research forward is where my lab is hoping to contribute and figure out what do we need to do, when do we need to do it, and for how long.

Speaker A: 00:05:19

Your lab studies how the brain ages, including what happens in diseases such Alzheimer's.

When we talk about memory loss or Alzheimer's, we tend to go straight to the brain.

Your work brings muscle into the picture.

What led you to investigate whether muscle could influence memory?

Speaker C: 00:05:39

Yes, and this is another point where I'll take you back to when I was a grad student, when I was training as a neuroscientist.

The neuroscience field, we like to say it stopped at the neck.

So we studied the brain almost in isolation as this, you know, entity that existed behind what we call the blood brain barrier.

And it was mostly isolated from anything happening in the periphery.

And since then, we've come to realize that it's not existing in isolation.

It's part of our body, it's part of our physiological system, and all of our tissues are communicating with each other.

And what these communications entail are things like, where are we, what are we doing?

Are we currently eating, Are we currently on a treadmill, Are we currently experiencing some sort of disease or state that's taking us away from what we call the baseline or the healthy state?

And this is where, when I started my lab, I was very interested in the specific conversation between muscle and brain.

Because for an adult, lean human, we are about 40% skeletal muscle, which means if our muscle is not happy, usually the rest of the body is going with it because there's so much of it.

And this is also where exercise comes in.

I think if any of our listeners have, you know, engaged in some sort of exercise bout, you feel a little sore the next day, that's your skeletal muscle responding to the exercise intervention you just performed.

Speaker A: 00:07:00

And.

Speaker C: 00:07:00

And it's actually communicating to all your other tissues.

I think we lifted weight yesterday.

We should change our baseline state.

And so this conversation is essentially where we've spent the last six years that my lab has been open, trying to figure out what the signals are, what they're saying, and can we change these communications via exercise and other geroprotective interventions.

Speaker A: 00:07:22

So I just want to pick up on something you just said, because I think it's a really important point, and I just want to really make it very clear, because we're used to thinking about the brain telling our muscles to move and what to do.

But you're studying communication in the other direction because muscles can release molecules into the blood that act as chemical messengers elsewhere in the body.

So just to put it very basic, if I go for a run one, what might my muscles be telling my brain?

Speaker C: 00:07:54

So as you begin to run, your muscle fibers are contracting, right as your legs go up and down and your arms swing up and down.

And so all of this contraction and release of the fibers is releasing factors into your circulatory system.

And these factors are communicating to multiple tissues.

But to the brain, what they're telling it is, hey, we're burning a lot of our caloric intake right now, a lot of our energy.

So I need you to start thinking about what are you gonna do to respond to this energy Usage.

And one of the things that the brain does in response to running, for example, is essentially it makes more brain food as a response of we're losing some of the food, I'm going to make some more.

And this brain food is called brain derived neurotrophic factor, and it's essentially food for neurons.

It makes neurons happy, it makes neurons healthier, it strengthens the connection between the neurons.

And we think this is one of the ways on why exercise is protecting the aging brain, because it's supporting these aging neurons as, again, some of their cellular processes begin to fail over time.

It's like watering your plants.

You're watering your neurons with this bdnf.

Speaker A: 00:09:01

So does this change as we get older?

Speaker C: 00:09:03

It does.

So the production and the availability of BDNF decreases over time.

And this happens specifically in an area of the brain called the hippocampus, which is where we make memories and store memories, which is one of the reasons that cognitive decline begins with memory loss and recall problems.

And so the hippocampus itself is also one of the first sections of the brain to respond to exercise.

It sits right on top of our ventricles in the brain, which is where all of these signals are coming in into the brain and then diffusing to the rest of the cortex.

Speaker A: 00:09:35

So researchers use the word exokins for signaling those molecules associated with exercise.

And these are chemical messages were talking about.

But finding one in the blood after a workout by itself doesn't really show that it's improving someone's memory.

Speaker B: 00:09:55

Right.

Speaker A: 00:09:55

How would you test whether one of those chemicals actually improves memory?

Speaker C: 00:10:00

So that's one of the hardest things in the field of exercise.

Many of these chemicals are changing in the blood after an exercise bout.

And so one of the ways we've approached this is in my lab, we've developed an exercise mimetic, which is a mouse that we've tricked it into thinking it's running, but it's actually not.

And so, by looking at the things that change in the blood of running mice and the blood of our exercise mimetic mouse, we're hoping to help prioritize what are the factors that are driving some of the brain benefits of exercise.

And then once we find those, we usually can create them artificially in the lab.

If it's a protein or a lipid or like you mentioned, an exer kind, it's usually a biological factor that we can create in the lab.

And then what I do is we go back and we inject that factor directly into the blood.

Just like you would get an injection into mice that are also not running.

And then I look at to see whether the brain is responding or not.

And so in science we call that sufficiency.

Is this factor sufficient to create the exercise response in the brain in the absence of exercise?

Speaker A: 00:11:09

Just to break it down a little bit and to make it clearer to myself, were you talking about PS18 which you were injecting under the skin of the mice and PS18?

Can you just tell us a little bit more about it?

It's a protein, I understand, but explain that a little bit further.

Speaker C: 00:11:28

One of the factors that we've discovered in my lab using this approach that I just mentioned is a factor called PS18.

And this is a protein, or actually a fragment of a protein that comes out of skeletal muscle and other tissues, but mainly skeletal muscle during exercise.

And so we proceeded to do this approach where we isolated this protein fragment, we injected it under the skin of our mice, and then we let them sit there for about a week.

And then we looked at their brains.

And what we saw was that the brain of these injected mice looked like they had been running.

So we were activating all of these neuronal pathways that we mentioned, all this neuronal food, the levels of brain derived neurotrophic factor were increased, they had better synapses.

And so we think that essentially the brain is responding to this injection because as the levels of PS18 spike, even in the absence of exercise, the brain thinks it's exercising and begins to protect itself.

Speaker A: 00:12:25

So you've done this study with old mice or an older group of mice and a control group.

I think you measured memory, frailty and metabolic health, probably some other markers.

What exactly were the results you've gotten from that study?

Speaker C: 00:12:46

So that study is actually ongoing right now.

So the study that I'm mentioning that launched this study in aging mice was actually done in young mice.

In science we usually do that to kind of test is this even going to work?

Because aging mice are a very precious resource.

And so we want to make sure we're really scientifically, our foundation is solid before we jump into that.

And so maybe if you're bringing me back next year, I can tell you what the results are, but I can give you a little peek.

Another reason we decided to do this is because we did the same experiment in a animal model of Alzheimer's disease.

So these are mice that develop a lot of the cognitive problems and neurodegeneration that you see in Alzheimer's patients.

And we did the same experiment where we injected them with this PS18, and then we also saw neuroprotection in that system.

So we reduce their plaques, we reduce their inflammation, we increase their synapses, which these mice lose very rapidly.

And so we think this should also work in an aging system.

But this is exactly what the meeting we met at was for, for me to introduce that project to that group.

Speaker A: 00:13:50

Let's talk about something else that you've been working on.

You have also heard a study with tfib, and in that study, if I understand it correctly, you made the muscle produce extra T fib and then measured changes in the memory and the brain.

This was to move towards a drug for possible chemical messengers that might explain the connection.

And one candidate was a protein called prosaficin.

Hope I said that.

Right.

Which is, you know, psap, I think.

Is that the short form?

Speaker C: 00:14:25

Yep.

Speaker A: 00:14:25

What is psap and what does it normally do in the body?

Speaker C: 00:14:29

So that's interesting because that's exactly the exercise mimetic model I mentioned earlier.

And so pro supposin is, or psap is a protein that we all produce.

It exists normally in all of our cells, and the cells use it.

It's a protein that exists in what we call the garbage chute of the cell.

It's a structure called the lysosome that the cell uses like a recycling system.

And so this lysosome sits there and cargo is delivered.

And cargo can be things that the cell no longer needs or things that are not functioning really well.

A mitochondria that may be burned a little bit too hot.

And so these materials are delivered to the lysosome.

And among other things, pros supposin comes in and helps degrade all of that material and essentially recycle the components back into their individual building blocks.

And so all of our cells have this, including our skeletal muscle fibers.

And so we think that when skeletal muscle is exercising, the system essentially senses the exercise situation, and the production of this protein spikes.

And the lysosome has another really cool feature where under certain conditions of where the cell needs to communicate with the rest of the neighboring cells.

These lysosomes move like little Amazon pickup trucks, and they go to a different location and secrete all of their components into circulation.

And we think that is how pros supposin, which is the large protein that we isolated PS18 from, is essentially leaving the skeletal muscle and moving through the circulation and eventually communicating to the brain.

Speaker A: 00:16:03

But how do you establish whether the PSAP in the blood actually came from muscles?

Speaker C: 00:16:08

That's a great question.

And I have a grant to try and develop that right now.

So we have kind of pieces of the puzzle right now.

We know that all our tissues have psap.

We know that PSAP in muscle goes up after exercise, and we know PSAP in blood goes up after exercise.

So the step we're missing is, like you asked, is it actually coming from muscle?

We have a lot of evidence that suggests it does, but we're probably gonna spend about, you know, the next six to nine months proving it.

And I think it should, based on all this evidence we have.

But we're almost there.

Speaker A: 00:16:43

Oh, I can't wait to hear about that study.

It's really exciting.

What results would make you think, oh, this is worth taking this further.

Speaker C: 00:16:52

So when we complete this ongoing aging study that we talked about, and we examine the brain and actually the muscle and other, like you mentioned, metabolic and frailty markers in these aging mice, and we see any of them being rescued, you can move the needle for any of them.

I think that creates this opportunity for intervention, because, as you may know, and I hope our listeners probably have experienced this too, exercise is good for everything, really.

And that's also one of the reasons it's very complicated to mimic it from a pharmaceutical standpoint.

But we think it could work on the brain, or it could work on muscle, or it could work on frailty, or it could work on locomotion, or it could work on all of these.

We don't know.

But that's one of the things that this project will help us figure out.

And again, based on the evidence that we have and the scientific literature and everything that kind of launched us into this project, I believe it will work for at least one of them.

And the hope would be multiple, but.

Speaker A: 00:17:51

We'll see what actually changes inside the body when we train.

Speaker C: 00:17:56

Oh, my goodness.

So the answer is pretty much everything but at.

At baseline.

And this again, may be something that if our listeners are chronic exercisers, as we call them, folks that have been physically active for a long period of time.

So I'm a neuroscientist, so I'll start from the top here.

Exercise can promote well being, right?

It's very effective against anxiety, very effective against depression.

It has a lot of mood targeting effects, so we feel good.

And folks that are listening may know that it releases endorphins as well.

So there's actually a chemical reaction happening in our brain, especially right after a very intense workout where we're flooded with endorphins, and that can Change the signals between the neurons to help with things like anxiety and depression and other mood disorders.

If we start moving down below the neck, the benefits of exercise on our strength are very obvious.

So this is where a lot of folks that may be doing weightlifting or resistance exercise can feel the benefits and can see the benefits where you start to create more muscle and your muscles get bigger.

And so that's an important thing that I want to highlight, too, Daphna, is that in this intersection of exercise and aging, which is where I'm at, we think about exercise very differently than in exercise and young systems, where exercise is usually used for muscle building.

In aging, we think about exercise as muscle retaining.

Right.

So we're not trying to build, you know, our grandparents to have gigantic muscles and go compete, but rather to maintain their muscle so they don't lose it as they move through their different decades of life.

And so the benefits of exercise on muscle, it improves also diabetes, regulation, and glucose control.

So for all of us that are, you know, aging trajectories, our doctors always look at our glucose levels, and if they're not where they should be, they usually recommend some sort of exercise intervention, because our muscle is actually the one that's responsible for pulling that glucose out of our blood after we eat.

And exercise makes muscle do that a lot better than if we're sedentary.

And then all the other metabolic benefits, it improves hormonal cycles as well.

For anybody that's experienced that, there's a lot of studies right now at the intersection of exercise and menopause, because we think it might help regulate a lot of that as well.

So overall, exercise works for many, many things, and none of us do it as much as we should.

Speaker A: 00:20:22

Very true.

You've mentioned so many benefits, and obviously I'm not a scientist, but I find it hard to understand or believe that sort of one drug can target all of these issues.

So which benefit of exercise would you most want to turn into a treatment?

Speaker C: 00:20:42

Yes, and so this is just a personal preference because it's my topic of interest, but my goal is to find exercise and a pill for your brain.

And to your point, yes, this is a conversation we have a lot in the field of exercise medicine of we will never create one pill that mimics all of these benefits.

Pharmacological, you know, research is not there yet, but we will definitely be able to target very specific benefits of exercise.

And this is where the field of personalized medicine comes in, where we want to think about, what do you need?

You know, Connie, what is your Aging trajectory.

And what are you most at risk for?

Is it going to be something like diabetes?

Is it going to be Alzheimer's?

Is it going to be cardiovascular disease?

Is it going to be kidney disease?

And once we know that, then we can say, okay, this exercise and a pill for your brain will be for you.

But, say my brother, his trajectory might be different, and for him, it might be exercising a pill for your heart.

And so over time, I think we'll have a list of pharmaceuticals that we could use for that, both from a.

Speaker A: 00:21:51

Medical perspective and from a personal perspective.

What would be your first priority in who you'd want to help?

Is it someone with cognitive decline or someone whose brain is still healthy?

Speaker C: 00:22:04

Yeah.

So in the field, we think about these two stages, right, as prevention versus intervention, and the goal would be both.

So just because of the way scientific experiments and scientific experimental design work, we always start with prevention.

However, one of the things we have found is that even a brain that is already on this trajectory to, towards cognitive impairment or towards dementia, we can move that needle back.

It's harder, but we can do it.

And this is one of the fantastic things about the brain and why I, I think I will be a neuroscientist until I can't do it anymore is the brain is incredibly plastic.

So if you think about all the changes we experience from the moment we're born all the way through to the moment we're not here anymore, our brain is always responding and always changing and always adapting.

And that gives us, as, you know, scientists trying to intervene, a lot of opportunity to tweak that needle and to move that needle back and forth.

And so I think we're going to start with prevention.

But the ultimate goal is to help folks that are already, you know, somewhere in that trajectory of, of dementia and Alzheimer's disease.

So intervention is definitely on the top of my list as well.

Speaker A: 00:23:19

So let's go back to this exciting, you know, exercise in a pill headline.

Someone listening to this may think, I don't have a disease, but could this do anything for me?

So could someone who's already healthy benefits from a treatment like that?

And not only in preventing something that may happen or may not happen, you know, in 20, 30, 40, 50 years time, can it help someone who's healthy right now?

Speaker C: 00:23:54

Sorry about that.

So, yes and no.

What do I mean by that?

So, for example, I've been spending a lot of time mentioning the cognitive benefits of exercise, and yet, if you think about it, we never hear about, you know, people that are extremely high Exercisers say, Olympians, they're not necessarily smarter than anybody else.

Right.

And so what we've come to find is that exercise is really good at maintaining a baseline.

So if you're already at baseline, exercise will just help you stay there, but it will not take you higher up.

However, if you are aging or if you have some sort of disease or situation that's happening that's taking you below baseline, exercise can bring you back up.

Speaker A: 00:24:41

So back to the testing a little bit.

Your lab also tested the muscle brain connection in an Alzheimer's mouse model that is separate from giving PS18 or whatever to healthy mice.

And I think you used female mice that were genetically altered to develop these amyloid plaques, the clumps of protein associated with Alzheimer's.

Speaker B: 00:25:05

Yeah.

Speaker A: 00:25:06

Was the model called 5x Fad?

Speaker C: 00:25:08

5X fat is what we call them, yes.

Speaker A: 00:25:10

Tell us about that study.

Speaker C: 00:25:11

Now, that we had originally found that this overexpression of TFAB in muscle protected against just what we call healthy aging animals that just were allowed to reach kind of their maximum lifespan.

And we were seeing that at that point, that's where our two groups were separating our old animals.

Our control animals looked old.

Our TFIB animals looked younger.

We questioned if it can protect against cognitive aging, can it protect against Alzheimer's disease?

And so we created this new group of mice.

They're called the 5x Fad model because they have five different genetic modifications that mimic a lot of the same mutations that we see in Alzheimer's patients.

And so we studied those animals as well, and we wondered, can this T fab overexpression protect their brain as well?

And the answer was yes.

And we did this actually in two different Alzheimer's disease models, because, as you mentioned, in the brains of Alzheimer's patients, we have this amyloid beta plaques, but they also have something called tangles of tau protein.

And so we tested both.

And TFAB expression in muscle protects against both, which is really interesting because it protects against both, but it protects them in different ways.

And so now we're really interested to see to your point earlier of whether we can intervene once disease has already set in and the brain is already starting to accumulate these things.

Different patients of Alzheimer's disease and different stages of Alzheimer's disease means you will have more plaques or more tangles.

And we think that means the brain is calling for help in different ways.

And so, going back to this idea of personalized medicine, we think we can titrate it even more.

Not just do you need exercise and A pill for your brain.

But do you need exercise and a pill for your brain for an Alzheimer's disease diagnosis where you have more plaques or do you have more tangles, you might also have two different options there for intervention.

And so we're really, really spending a lot of time in this idea of what does this particular brain need?

Because I think that's where the future of medicine actually lies.

Speaker A: 00:27:21

So in your September preprint, I think you gave the Alzheimer model mice access to a running wheel, and the exercise changed some of their biology, but I don't think it improved their performance in the memory test and in the maze test that you gave them.

What would an exercise drug need to do differently?

Speaker C: 00:27:45

So the reason we executed that study is because, as we were talking earlier, this idea of how much exercise should we do, and the prescription that many of us probably have heard in social media and things like that is three times a week, 90 minutes a day, usually some sort of endurance training like running or swimming or dancing.

We were really interested to see.

Well, that's a prescription for a young, healthy brain.

Is that the same for an Alzheimer's brain?

And so that's why we took these Alzheimer's mice and gave them this intervention.

That is kind of what a normal citizen of the world would do.

And it turns out that we were not able to rescue a lot of the things that we expected to.

And so this comes back to this idea of how long, how hard, and how much should we exercise?

And that's the next study that we're also executing right now, where we're doing exercise dosage.

Essentially, how.

How much do these mice need to run to actually get the benefits?

And then to your point of how do we translate that into our extra kind and exercise in a pill studies is once we know the levels of exercise that we need, then we can titrate back our PS18, for example, to match that level.

But since we don't know what that level is yet, we're also doing a lot of dose testing with the PS18 of how much do I need to give the mice to see the brain respond to the level that I want it to?

Speaker A: 00:29:07

So could it be that the diseased brain is receiving the signals but can no longer respond to it, as you would hope?

Speaker C: 00:29:15

Exactly.

So if you think about the brain as a house, right, and extra kinds and PS18 coming as a UPS or a FedEx person knocking on your door and ringing your doorbell, you will hear it.

But what if the Alzheimer's brain can't hear the doorbell?

Anymore.

And so the signal is there and it's waiting to come in, but it just can't translate properly.

And so we're hoping to be able to open that door by either increasing the dosage and making the doorbell louder or potentially figuring out how is PS18 getting into the brain.

So, keeping with this house analogy, can we get in through the window or the chimney instead?

Speaker A: 00:29:53

Does it make you more cautious about treating changes in the brain proteins as evidence of better brain function?

Speaker C: 00:30:01

Oh, absolutely.

So in the field of Alzheimer's, we've known for over a hundred years that one of the diagnosis of Alzheimer's disease is you have plaques and tangles in your brain.

However, about, I want to say, five to eight years ago now, this family in Colombia was found to have their brains full of amyloid beta plaques, and yet they had no cognitive problems.

And so does this mean that the amyloid beta is not necessarily the cause of the cognitive decline and it might be a consequence or the way that the brain is trying to save itself?

And that's a really interesting question that we still need a little bit more time to answer.

But it's going back to this idea of sufficiency that I mentioned earlier, where just because we see something that shouldn't or should be there doesn't mean it's the cause of the phenotype or the biological process that we're trying to find.

And so we don't know, but we'll find out.

Speaker A: 00:30:59

We'll find out and you'll come back on the podcast and tell us all about it.

So this is all super interesting, and you've really come a long way with all your research.

But there's still a long way between a result in mouse model and knowing whether it helps someone with Alzheimer's.

But I think that is a possibility people will want to understand.

So if a family asked you, could this ever help my mother or my father or me, what would you tell them right now?

Speaker C: 00:31:30

So my answer would be yes.

To put it into context, pretty much every drug that is currently on the market that many of us are probably taking, were originally discovered, tested and validated in mice.

For example, things like insulin for all of our diabetic patients, things like metformin, which are also is another medication for diabetic patients, and to be topical, something that's very popular today.

GLP1 agonists were also discovered, validated and tested in mice before they made it into our clinical population.

So we as scientists are always very careful on how and whether our findings in mice or other Animal models will translate to humans.

And there are very good ways in which we can test this.

And a lot of discoveries stop at the mouse level because we're like, oh, this was a mouse thing that happened, not a human thing.

But luckily, the fields of exercise, neuroscience and aging are actually very good at translating this.

So I would say, yes, we're, we're going to get there.

Speaker A: 00:32:30

What would you most want to test and have proven before moving towards a human study?

Speaker C: 00:32:36

So we always want to prove what we call efficacy, meaning does this work?

That's in animal models.

And the first step into humans is safety.

So does the human system respond well?

And this is why in clinical trials there's multiple steps.

And that's why it takes us a little bit long to get these things into the clinic.

We first have to test is this safe?

And we do this in a normal healthy population.

For example, if we were going to test PS18, we wouldn't do it in aging people, we wouldn't do it in folks with Alzheimer's disease.

We would do it in young, healthy people and see if there's are side effects, is there an immune response, is there inflammation, things like that.

If it makes it past that stage, then we go into efficacy, into the, what we call the target population.

So again, we would test this in aging folks.

So anywhere from 50 to 65 years of age, is it safe?

And once it's safe, then we test it in a population of patients with Alzheimer's disease.

So that's why sometimes you'll see a lot of these big splashes in the news that we have found something, and then you don't hear about it for about five to 10 years because it's about how that long it takes us to do a very rigorous clinical trial.

Speaker A: 00:33:47

How much does AI help you in your research?

Speaker C: 00:33:51

Not a lot.

So I am one of those people that trained in the pre AI era and I am training junior scientists right now.

And it's very hard to teach them how to use it properly.

AI is only as smart as the literature it's consumed and only as smart as the programming it was given.

And I can tell you as a neuroscientist, it's actually not that smart.

And so it's very useful as a tool in the same way that Google is a tool.

But for scientific discovery, it will never replace a scientific human mind because the connections that we can make AI can never make.

And so we use it in the lab as a writing tool, mostly for editing, for grammar, sometimes for collating references.

If it's a really big search that we're doing.

But I train my grad students, my postdocs, my technicians to really train their brain first.

Because otherwise you get into this feedback loop where you're only doing what you already did and you're never doing anything new, which is the main problem with AI.

Speaker A: 00:34:56

Absolutely.

I mean, we've had many people on here who were praising the benefits of AI, and I'm sure there are loads of them.

But I'm very happy that, you know, you've mentioned the limitations of AI because I think that's sometimes overlooked with all the hype about it.

And it does deserve a lot of credit for what it's doing.

But there are still a lot of fields where the human mind and human thinking is still more advanced than AI.

Speaker C: 00:35:27

The power of discovery of the human brain is something that AI.

And actually, to be fair, artificial intelligence is a misnomer.

It is not intelligent.

It's just very quick.

So I think a lot of people need to remember that.

To give you an example, there was a major publication, one of the biggest journals in the field about two, three years ago now, where what they did is they took three of the biggest health concerns for the aging human population.

Alzheimer's disease, diabetes and cancer.

A lot of bioinformaticians and computer scientists and biologists kind of dove into the AI LLM platforms and asked it, look at all the literature that exists and tell me where we go next for these three disorders.

It was years of work.

It was a very intense research approach that they took at the computer, you know, algorithm level.

And the outcomes were things that we already knew it was.

In diabetes, you should study metabolism, and in Alzheimer's, you should study things like inflammation and brain function.

And in cancer, you should study chemotherapy.

And it's like, well, yes, and I'm oversimplifying a little bit, but this is a great example of.

It can only summarize it can't come up with anything new.

And this is where us as scientists need to, yes, use it.

It's a very good tool, but we need to remind ourselves that it's still just a tool.

Speaker A: 00:36:52

Very true.

So happy you said that, because I.

Speaker B: 00:36:55

Think, like I said, I think it's.

Speaker A: 00:36:56

A very important point to make.

We need to use all the tools in our toolbox, but we can't and shouldn't rely just on one thing helping to push us through.

Let's get back to the exciting bit.

Exercise in a pill, let's presume, which I'm sure it will, the work on delivery and safety.

All goes well.

And the first study in, people still has to really establish, I guess, what the treatment actually does.

What would we need to learn from that first human study?

Speaker C: 00:37:32

So the first basic question we have to answer is, does it work?

And so the way we would test that would be really simple.

So the challenge we have in the space of neuroscience research in humans is that I can't really ask the volunteers to give me a piece of their brain to look at.

So we have had to devise kind of alternative ways to indirectly test brain function and brain states without really getting in there and digging around.

And so one of the ways that we do that is we can take blood samples and look at these again, circulating proteins that the brain is secreting when it's working, and we can track brain function that way.

It's one of the recent findings as well, where we've created a new test for Alzheimer's disease.

It used to be that the only way you could get officially diagnosed with AD was to do a very expensive brain scan and or donate your brain to science after you passed away.

But now we can take a blood sample and measure levels of this particular protein that all Alzheimer's patients have increased levels of, and folks that don't have it have much lower levels.

And so we can do very similar things to track stable brain function as well.

And so the first thing we would do is inject PS18.

And ideally, our goal would be that this could be a pill, not an injection, but we'll see.

And then after that injection is delivered, we would give a little bit of time to get the system working, and then we would get a blood sample and examine are the markers of exercise increasing or not.

And luckily, we are at that stage where we have that ability.

We couldn't do it five years ago.

We.

We couldn't do it 10 years ago.

So I think, again, we're at this great moment where we're almost there, we're almost ready.

And importantly, we have the tools to test it.

Once we get to the clinic, it'll be quicker than it usually is, hopefully.

Speaker A: 00:39:19

You know, sometimes a biological marker does not reflect how a person feels or behaves.

So in your future human tests, if the biological measures improved but the person didn't, how would you interpret that?

Speaker C: 00:39:39

And.

And yeah, just to take a step back, we see that a lot in exercise studies.

So people are very interested in participating in exercise trials because they know how good it is for you.

And having that structure helps folks kind of stick with an exercise regime.

And the way we monitor their well being is usually by surveys.

So how do you feel?

Right.

On a scale of 1 to 5, you know, how's your anxiety, how's your mood, things like that.

And then we also take blood samples and look at these markers that I mentioned.

And very often the participants will have an improvement in these survey results before and after.

And yet we'll see that the biomarkers, as we call them, these markers that we measure in blood, are not necessarily changing in the same direction at all.

And so what does it mean?

I think this is where us basic scientists that spend a lot of time thinking about individual cells and I mentioned lysosomes and kind of circulating proteins, need to speak to the community a little bit more, right.

And say, how are you feeling?

Because sometimes that's what the patient or the participant wants.

They want to feel better.

They don't really care if they have more or less plaques necessarily.

It's do I feel better?

And that, you know, is really important then for quality of life as well.

And so the design of the clinical trials of exercise has been shifting a lot in the last couple of years to try and incorporate kind of this well being measurement so that we can really track that, like you say, Daphne, of how is the participant feeling?

In a way that we can quantify as well.

Speaker A: 00:41:11

And would you be happy with it just moving the biological marker without making the person actually feel better?

Because the truth is, if the biological markers move, it definitely has an improvement on their life, their health span, their lifespan.

Speaker C: 00:41:29

The reverse.

Right.

Where you would move the biomarker, but not the emotional state.

Yeah.

And so I think this is a bigger question than I can answer in the sense that in our society we think of aging as a problem.

Aging is not a disease.

There are diseases of aging, which is very different, but getting old is actually not the main problem.

And so we really need to change the way we think about these things and the contributions that those of us over 40 can continue to make to this field.

There's a reason that in science we say that we stand on the shoulders of giants.

None of these things that I'm mentioning today, I discovered by myself, right.

I used decades, sometimes centuries of research.

If we think about when were the first Olympics, right back in Greece, 2,000 years before Christ.

And so that's how far back we knew that exercise is good for you and people enjoy it.

And so this idea of what does it mean to age, what does it mean to get old and how can we use that to intervene not just at the biochemistry level, not just pharmaceutical medicine, but, you know, social medicine, if you want to think about it that way.

So I think that's something that we can all work towards together, which is why podcasts like yours are so important to get that message out there.

Speaker A: 00:42:48

You're right.

It's very important to, to spread the word and to share that with everyone.

Now back to the thing that excites me about this exercise pill.

You did say you did.

Human trials are still required and all that, but realistically, when could this exercise pill come to market?

Speaker C: 00:43:10

That's a great question.

So, like I mentioned earlier, we're getting faster and faster and quicker and quicker.

And one of the approaches we're taking to make that timeline even faster is there's another arm of my lab that I haven't discussed too much where we're looking at what's called drug repurposing.

So here in the United States, we have the fertile drug, Drug and Food Administration organization.

And what they do is they have already approved a lot of these drugs like metformin and GLP1 agonists and things like that.

And what we are doing at the bioinformatic level is we're taking these exercise profiles.

We discussed a lot about what exercise does to muscle, to blood, to brain, to all of these things.

And what we're doing is we're starting to build these maps of exercise.

And then once we have those maps, we can go to these FDA approved drug lists and start finding the maps that match.

And you'll be surprised that a lot of them do not all of them are perfect.

Which goes back to this idea of exercising a pill for your brain as opposed to exercising a pill for your heart.

But they match enough that we think we can repurpose these drugs to get them to the clinic faster since they're already FDA approved.

Speaker A: 00:44:22

So this exercise in a pill, I must have said it now ten times throughout the podcast.

What do you want people to understand when you use the word exercise in a pill?

Speaker C: 00:44:33

I want them to understand that it's never going to be a full replacement for it.

That the benefits of exercise go well beyond, like you said, reducing plaques on your brain or reducing inflammation or increasing your metabolism.

It's getting us out of the house.

It's something as simple as going around the block or walking your dog or playing with your grandchildren.

Again, thinking of aging populations, the benefits of exercise are also social, right?

Isolation in the elderly is a very big problem.

And exercise very often comes with a social component.

You're either going to A class, you're meeting a friend.

And so we're talking about this idea of it makes you feel better.

And we're trying to figure out both the biochemistry and the biology of it, but also the social and psychological aspects of it as well as.

And so I mentioned earlier that in the intersection of exercise and aging, we think about exercise slightly differently than in exercise and young systems because we think it more as a way to extend your health span, to keep you independent, to keep you active, to keep you cognitively intact for longer, not necessarily to make you stronger or bigger, for that matter.

And so for me, when I talk about exercise in a pill, I think of it as a supplement or as a jumping board to get you there so you can actually start exercising.

Because the thing we think about a lot as well is that aging populations sometimes can't exercise due to pain or in mobility or some other comorbidities like obesity or diabetes or something like that.

And so how can we help these patients that need a little bit of help to get there?

Is the way we consider it not necessarily a muscle gain or a thing like that.

Speaker A: 00:46:23

Are you worried or are you thinking about, I don't want to say the abuse of this pill, but the off labor use, let's call it sort of like the GLPs.

Obviously, again, it was meant for overweight people, originating in the use for, for diabetic people.

But a huge number of people are now using it off label to lose a little bit of weight or for all the other benefits that it certainly has.

Are you worried at all about the product you're developing is going to be used differently than you intended to do?

Speaker C: 00:47:03

I would say yes, mostly because in the field of exercise, this has already happened, right?

We already have discovered a lot of muscle activating exercise like drugs.

Think about steroids, right?

We all know about steroid abuse in sports competitions.

And why athletes feel the need to use it is because they do work, but they're not prescribed for that.

And so this is why we're always very careful about how we design our studies and why we don't prescribe these things until we're really sure that they will not have side effects or if they do, this is what you should know before you start.

In the end, it is a personal decision.

I can only provide information.

And that's why I come into podcasts like yours to get the information out there so folks can make an informed decision.

But as with anything, any supplement that you take, any drug that you, you know, are interested in, to talk to Your doctor talk to your provider before you make that decision so you can monitor things, because a lot of the things do work, but we really need some help figuring out how they work for you.

Speaker A: 00:48:08

Effy, what is the unanswered question you most want to solve now?

Speaker C: 00:48:13

Ooh.

Something that I think we tangentially touched upon.

It's sex differences in exercise.

So I think I mentioned that we know a lot about what happens with exercise in young systems.

And one thing I didn't mention is that it's actually young male systems.

So a lot of exercise participants in our trials tend to be young men, you know, between 20 and 25 years old.

They're usually college students.

So we know a lot about what happens in their muscle, in their brain, and their blood and other tissues, which is great.

But again, I'm a woman Latina, and so we really have no idea what's happening to my brain when I get on a treadmill.

And what we're finding in the lab is that when we compare our male and female mice, they are responding differently.

They are both protected against aging and protected against ad.

And we see all of these benefits and good things, but the way they arrive at that protection is very, very different as well.

And so we think we've been missing half of the picture for a very long time.

And so I'm really excited for some of the research my lab is doing and some of my colleagues are doing to try and profile the female system now and both young and old.

That also changes as we think about the menopausal transition being kind of the second biggest shift in a woman's lifetime and trying to understand what does that do to these responses to exercise.

And one tiny bit I'll leave you with is that in the exercise trials, like I mentioned, most participants are male, but when there are women and then there are enough of them that we can separate the two groups and analyze them independently from each other, we keep finding that women experience most of the benefits of exercise.

And so that means that here we have this population that is really responsive and receptive to the intervention that we really have not studied as much as we should.

So hopefully, in the next five years or so, we'll.

We'll be inundated by the research in this space and be able to give back to the community and say, this is what we need to do.

Again, personalized medicine, if you're a woman on a trajectory for ad, might be different than if you're a man on a trajectory for ad.

Speaker A: 00:50:20

So you've just said where you want to be in five years or where you want the research world to be in five years?

Looking into your crystal ball, where do you see your research in 10 years?

Speaker C: 00:50:32

Oh my goodness.

So at that point I would like to have one of these drugs that we're hoping to develop in the clinic.

So that's my goal.

So by what would be that?

2036 We'll have exercise in a pill in the market available for folks that need it.

And this is something that we'll continue to work on, obviously, because like I mentioned, if PS18 makes it, we have a list of at least 15 other targets that we want to look at.

And so yeah, in 10 years I should hope to have our first target in the market and many more in the pipeline.

Speaker A: 00:51:04

Thank you so much for sharing your research and your thoughts on this really, really exciting field.

And as often as I've called it exercise in a pill and made it sound like a hype, it really is such a fundamental issue that people just cannot train.

And it's like you said, not about growing more muscle or looking buffer in the gym.

It's literally life saving to older people who just can't move.

So in all seriousness, it's the most wonderful drug you are developing and I'm sure it'll help a lot of people physically and mentally, which I think is equally important.

I wouldn't even know which one to pick.

So before I let you go, I always ask my guests five rapid fire questions.

Speaker B: 00:51:58

What's the single best piece of advice.

Speaker A: 00:52:01

You would give your younger self?

Speaker C: 00:52:02

You can do it.

Speaker A: 00:52:03

That's a good one.

Name one habit everyone should adopt for a longer, healthier life.

Speaker C: 00:52:09

Any kind of physical activity.

Speaker A: 00:52:12

If you weren't in longevity science, what career would you have chosen?

Speaker C: 00:52:17

Astronaut.

Speaker A: 00:52:18

That's so cool.

What microdose habit.

5 Minute routine or small daily action yields outsized longevity benefits?

Speaker C: 00:52:27

I can only speak from personal experience,.

Speaker A: 00:52:29

But meditation and what's the craziest longevity myth you've encountered?

And is there any truth to it?

Speaker C: 00:52:38

One glass of red wine a day.

Speaker A: 00:52:41

Is there any truth to it other.

Speaker C: 00:52:42

Than that it tastes very good?

There is biochemistry behind it.

But the amount of red wine you would have to consume to get the levels that you need would give you liver poisoning.

Speaker A: 00:52:52

So definitely a true longevity myth.

Speaker C: 00:52:55

Correct.

Speaker A: 00:52:56

But you know, as humans we like to find any excuse to sort of do something that we shouldn't.

I guess it's just human nature.

Thank you so much, Professor Constanza.

What a joy to have had you on Beyond Longevity.

Speaker C: 00:53:10

Thank you so much for the invitation.

This was a lot of fun as well.

Speaker B: 00:53:16

If pain or illness makes exercise difficult, a drug that offers some of the same benefits could make a real difference.

That is what Professor Constanza is working towards.

The possibility that it could also help preserve memory makes this research especially exciting.

The findings we discussed are in mice.

We still need human trials to find out whether this approach is safe and.

Speaker A: 00:53:41

Whether it works in people.

Speaker B: 00:53:43

Could it help prevent memory loss?

Could it slow the decline once symptoms begin?

We don't have those answers yet, but if this works in people, it could give us a new way to treat memory loss by targeting muscle.

Many thanks to Professor Constanza Cortes for joining me today.

If you enjoyed this episode, please follow Beyond Longevity and share it with someone.

Speaker A: 00:54:06

Who would enjoy it too.

Speaker B: 00:54:08

Thank you for listening.

Speaker C: 00:54:23

Sam.