165: Improving Cellular Cleanup to Extend Healthspan with Dr. Ana Maria Cuervo
Aging begins when cellular quality-control systems lose their precision.
In this episode, Professor Ana Maria Cuervo outlines how chaperone-mediated autophagy (CMA)—a selective lysosomal degradation pathway essential for proteostasis—progressively declines with age, triggering downstream failures across neuronal and metabolic tissues.
Reduced LAMP2A availability, impaired lysosomal docking, and disrupted protein triage lead to toxic proteotoxic burden, mitochondrial dysfunction, and metabolic inflexibility.
Emerging evidence shows that preserving CMA activity can improve healthspan, attenuate neurodegenerative pathology, and restore metabolic homeostasis.
Learn more about Dr. Ana Maria Cuervo:
https://einsteinmed.edu/faculty/8784/ana-maria-cuervo
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Transcript
Disclaimer: This transcript was generated by AI and may not be 100% accurate. If you notice any errors or corrections, please email us at phil@longevityroadmap.com.
You hear about sort of like the garbage cells and the dead cells and all that stuff that, that need to get recycled? Well, that's what autophagy is, right? Um, it's not necessarily just eating it up, but it's spitting it out the raw parts that you can reuse. And what we're realizing is autophagy is an enormous role in any number of disease processes and in aging as well.
Welcome everybody. This is Buck Joffey here with the Longevity Roadmap today. Um, talking to another really fantastic, uh, scientist. Her name is, uh, professor Ana Maria Cuervo. She's, um, really well known in the field of, uh, of autophagy, which you will learn all about, but basically. The idea with autophagy in general.
So autophagy, you might remember maybe from biology 1 0 1, or you know, if you went to medical school or whatever. It's the way that cells essentially recycle, uh, recycle stuff. It's kind of, you know, you, you hear about sort of like the garbage cells and the dead cells and all that stuff that, that need to get.
Recycled. Well, that's what autophagy is, right? Um, it's not necessarily just eating it up, but it's spitting it out, the raw parts that you can reuse. And what we're realizing is autophagy is an enormous role in any number of disease processes and in aging as well. So this particular discussion focuses on autophagy.
How exactly it works. What happens when things are not going well, why things do not work as well when we age or when there's early onset disease? And then finally, some of the things that you can do to help yourself, uh, to maximize your own levels of autophagy in your body, even as you age. Um, vis-a-vis various lifestyle behaviors.
Anyway, great conversation, uh, really smart scientist and physician. Um, and we'll have that interview for you right after these messages. Hey, longevity enthusiast. It's time to take you to the next level. I've been fine tuning my longevity regimen for years, and I look better and feel better than I did a decade ago.
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That's longevityroadmap.com. Welcome back to the show, everyone. Today my guest. Professor Ana Maria Cuervo, who is a world renowned cell biologist and a true pioneer in the study of cellular aging. She is the Robert and Renee Belford chair for the study of neurodegenerative diseases at Albert Einstein College of Medicine, where she co-directs the Einstein Institute for Aging.
Dr. Cuervo, thanks for joining us.
Thank you for having me.
Well, I want to kind of get into sort of one of the things that you're. I think one of the things you're most known for, which is the discovery, um, for those unfamiliar perhaps, could you talk a little bit about this concept of chaperone mediated autophagy and what exactly that is?
Just so that people have a big picture, uh, uh, that they can use as a framework.
Yes. So autophagy is something that happens every day in every single cell in your body, and it's mostly a process of recycling. So in a way it's cleaning. So you know, like in every. Other structures. So the same way that you clean your house every day, you need to clean your cells for any damage, anything that has accumulated that you don't want anymore.
But the beauty is that this process happen inside an organelle that is called, is kind of a, it's normally described as garbage container. Mm-hmm. But I would like to give them a little of glamor because I think more than garbage containers, they are really the most. Perfect recycling system in the world because what they do is they take these garbage, these things that the cell doesn't need anymore.
They chop it in pieces, but then they take those pieces for the cell to utilize them again. So it's the same thing that when you have an old car and you gave it to this place that they are gonna take the pieces and use it to. Create new cars or do other things. So this happened, as I say, every day, um, in your body.
And for a long time it was believed as this cleaning process, this process of autophagy. So autophagy means auto is yourself, fgy is eating so you can picture mm-hmm. How it's like, okay, because you are eating your garbage. It's not cannibals, you're just eating the garbage. So it was called out of this.
For a long time it was believed that it was this random process, right? Like the cell kind of put these bulldozers to take out anything that is around so you will get the good and the bad, because there was not way to differentiate what has to be degraded. So I think our contribution has been to show that this can be.
Very selective and it makes sense, right? Where are you gonna sacrifice things that are, is still functioning just because you have to clean others. So what we have identified with this chapar mediated autophagy is that this autophagy, this cleaning has a way to discriminate good from bad and the.
Protein or the, the main player here that does this is a chaperone. So the chaperone is really very similar to what within in normal life, right? Like chaperone is somebody that is there to make sure that you know, boyfriend and girlfriend be. Behave or, so the chaperones that behaving in the cell is a protein that makes sure that the other proteins, the other things in the cell behave.
So if they don't behave, you have to eliminate them. So the chaperone take it to this recycling compartment, and that's very selective because the chaperone can. Tell who is doing things that shouldn't from things that are properly behaving. And that was our main contribution to show that this cleaning and recycling is very selective.
Interesting. So, um, one of the things that you've shown is that this, we'll just call it CMA, chaperone mediated autophagy for the audience. So, uh, one, one of the things that you've shown is that CMA activity declines with age. Um, what's driving the decline? Is it, you know, genetic? Programs winding down or environmental or metabolic factors.
Yeah, so, so it's really a, a combination of all the above. And it's not only chaperone mete. So we have described that almost every kind of autophagy your, your cell, the same way that when you le you clean at home, you have the mop, the broom, the vacuum. So the cell has very different waste to do autophagy.
And we have shown that unfortunately, almost all of them decline as you get old. So in the case of chaperone mediated pha, CMA. We have seen, imagine like, you know, we were talking about these recycling compartments. So there is kind of like some hook, so it's a protein that is called lamby, but imagine that it's basically kind of a docking, a station in the surface of this compartment.
So when the chaperone brings the garbage it, it has to identify how to enter it inside this recycling compartment. So you have kind of like these proteins that stick out and that's where. Dogs and basically the, the garbage now can enter. So what we found is that as you get all the number of docking places, the number of entries into your.
Recycling compartment decrease. And we have shown that if genetically we increase or we prevent this decline in mouse models, they live longer, they are healthier, so, so we think that this decrease on these receptors is very important and the cause. And here is where all the above that you mentioned. So depending on the cell type.
In some cell types, it's really transcription. It's like you are producing less of these receptors as you get old. Meanwhile, in many other organs, you produce the same amount of these, uh, docking receptors in this compartment. But what happen is that they last less. So normally they are programmed that every three days you get a new one.
Right? Everything in yourself gets renewed. Periodically. So in 30 every three days you should get a new one. And that's how the old one lasts. But what we found is that as you get old state of being there for three days, there are only for 10 hours. So that means that you have almost two days and half that you don't have enough of these receptors.
So, so it's kind of a combination. And of course, even this happens as we get old, uh, you have point very interestingly that there are many factors. Of our way of living that can really affect, and we can go more in detail how many of these receptors you have. So for example, the diet affect the number of receptors, the exercise, we have a study that was just accepted, is gonna, came out, publish soon, showing how ex not lack of exercise, decrease the receptors.
If you exercise, you have more. Um, you know, there, there are many interventions that you can do to preserve your receptors.
So one of the things that obviously this becomes an issue for is, um, when you have proteins that are not folded properly or errors, um, that normally the, uh, autophagy would clean up, you would get an accumulation of those proteins that you don't want.
So. I guess, uh, it would probably be, um, a good time to maybe draw that connection between this impaired activity and, and neurodegenerative diseases such as Alzheimer's disease. Can you talk about, um, uh, how that would work?
Yeah, that's a a great question. So when I was talking about the chaperone, how make sure that proteins behave, the behaving for a protein is, as you mentioned, being properly fault and being functional or not, not having post translational modifications that you don't want.
So in this neurodegenerative conditions, and we are mostly talking about the what's more related to aging, Alzheimer's disease, frontotemporal, dementia, Parkinson's disease, so in all of those diseases. The protein is different, but in all of them there is a protein that misbehave and it's gonna need to be cleaned up.
So for example, when you are young, you don't see even some of these patients are born with this mutation. Not all the neurogenetic patients are genetic, but imagine just the ones that are genetic. So they are born with a mutation, but they don't accumulate these proteins. And the reason why they don't accumulate when they are.
10 years old or 20 years old is because you have this very good cleaning systems that say, okay, this protein is mutant. We have to take it out. And that's why you don't see 10 years old with Alzheimer. But then as you get old is the decrease of disability. So you are producing the same amount of mutant protein that when you were young and that has been demonstrated, but because you are not eliminating it is when it start accumulating.
And the accu the accumulation of these proteins. The problem is that it creates these aggregates that at the end, you know, they don't kill the cell like the neurons in your brain auto like immediately, but with the time having all this is altering function and eventually they kill those cells and that's why you have neurodegeneration.
So is that the, um, is that the mechanism that we know that that is likely for early onset? Alzheimer's, for example, yes. Is not necessarily, you know, that something that is, uh, central to the brain itself, but rather, uh, the inability to, you know, to clear, I don't know, the amyloid plaques or whatever, uh, in this situation.
Yeah. So, so that's, that's a good point. So, so we think that in the case of the disease, some mutations are. More damaging to the protein, right? So the more damaging the area they start accumulating. Because something interesting is that I mentioned as you get all this cleaning decrease, so then they start accumulating.
But what we and our lab has contributed to that have found is that many of these mutant proteins. They go to this cleaning recycling system. So in theory, because the cell wants to eliminate them, but they just remain outside, it's like, you know, they, they start entering and they just get stuck there. And that's the big problem because that means that not only they are not being.
Eliminated, but any other protein that normally should be eliminated, cannot be eliminated anymore. Because you have clocked your cleaning system. Yeah, yeah. And within the early onset, the mutation is such that makes these proteins kind of like imagine somebody trained to go through a door and opening their arms, so then you cannot go inside the lysosome and then you prevent anybody else from entering.
So I know you focus on the brain, but you've also linked um, uh, CMA dysfunction. To various metabolic disorders like diabetes and, and, uh, fatty liver disease. So, um, can, can you talk a little bit about that and, and what you see in those conditions?
Yeah, so the autophagy, of course, as I mentioned, in all the cells in your body.
So of course when you have a misbehaving protein and an aggregate, the neurons are very sensitive to that. But the other function of autophagy, I mean in part, is cleaning, right? That is what we were talking in the brain. But if you remember, mention recycling. So recycling means. Utilizing energy in a very good way, right?
Because it's like, if you need, for example, if, if you are not eating and you need energy, what you do is like, okay, let's see what I have around that is not necessary and then let's chop it so I can get this as a, you know, full like amino acid. So, uh, lipid. So whatever you need, it's like let's get our cholesterol and our three gides, all everything chop up so then we can utilize.
So what we have seen that is as you get old. You're still able to do synthesis of lipids, right? But then you don't degrade them when you need it. So in a way, the, the body is energetically deficient because you cannot utilize, but your body is full of this fat because you cannot mobilize them. So that was the linkage with the fatty liver.
So for example, just in, even in a animal with a normal diet, if we take out autophagy, you start seeing a fatty liver. You could do for a graph with it. So, so that's kind of the stream, right? Everything happened gradually. We just do it in the lab very dramatically to see what is the phenotype. But that's kind of the connection and with.
And, uh, diabetes is a bit the same. It's like we have seen that, um, you know, this process of autophagy is very control related by insulin glucagon, right? Like if you are eating, autophagy goes down. So that's when your glucose is up. And if you are not eating, your insulin will go down and then autophagy gets activated.
So as you become insulin resistant, uh, you know your autophagy is gonna get compromised, and that's gonna give you more insulin resistant. So you create this vicious circle that perpetuates the process. So for us, it's like, you know, some people are entering. For therapeutics from the glucose insulin point of view, we would like to enter from the autophagy because we think if we restore autophagy, at least experimentally, we restore glucose and lipid metabolism.
Yeah.
I mean it's conceptually that's, I, I would think that that's one of the reasons, uh. People see benefit in, in things like intermittent fasting, right? Where you're not eating for a period of time and allowing for autophagy to do its thing without, you know, constantly peppering the body with food and, and triggering the more anabolic effects.
Yeah, so, so in this, I mean, and that's why we were saying like, you know, our society has evolved to be eating every 30 minutes, right? Yeah. Like, it's like, and I'm from the generation that, you know, the endocrinologist were telling you, oh, eat many, many meals. But there is small, and, and that kills autophagy because autophagy is a motivation.
The motivation is like, okay, I don't have food. I have to start cleaning. Right? So if you are continuously eating, so that's why, you know, you don't have to go extreme fasting, like. A whole day or something, but just separating, even if you eat the same calories, if you just separate them to give time for autophagy to get activated, and it'll lunch and dinner, so don't snack in the middle, and then your autophagy will get activated.
I mean, autophagy can get activated like in one or two hours. Of course you want to go into the six to eight hours just to have maximal benefit. But you know, having this separation in between meals is very important. And also the time. When you eat, because autophagy is circadian, so it's gonna be favor if you do your meals during the day, is much better than during the night, because at night the chances of activating autophagy is, is different.
Yeah.
Yeah. Um, uh, takes us to, you know, what can you do about it? And so you've been able to restore CMA in, in aged animal models, um, and, and gotten impressive improvements. What's the, um, therapeutic measure? How do you, how do you do that?
Yeah, so, so we have done different things. So basically it's a kind of a three prone approach, right?
So you always have to do as, as you know, very well, um, genetic proof of concept because we want to convince ourselves that if you restore, if you maintain CMA. This is something good that happens. So we cannot convince pharma to start developing compounds for something that we don't have an evidence that this is good.
So what we did is genetically, we were talking about this docking protein, this receptor in the lysosomes going down with H. So what we have done is to create a mouse model. That whenever their endogenous copy of these receptors goes down, we just activate an extra copy. So basically those animals have not seen a decrease in CMA per life.
And then we compare them with the ones that are lit mates. They are born all at the same time, but they, we have an activated that copy. So then our readouts are longevity. And I have to say personally, don't care how long they live as far as they are healthy, but for what is worth, we get that. 10, uh, 20% increase in maximum lifespan, and we also get the mean lifespan to increase.
So that means they are healthy. So we have done the same thing that when you go to the clinic, that you do frailty tests in our elders. So we do the same with animals. So we look how the speak of walking their, their reflexes, the hair, the, you know, we cannot look at wrinkles, but we can look at white hair versus like balding and all those people.
And then we did metabolic studies. So the animals, they live longer, but they live longer because they are healthy till the last moment. So that's kind of a proof of concept. So if we are able to maintain CM activity, this has beneficial effects. The problem is that realistically, at least not in the very near future, I don't think we can say, okay, whenever people reach 50, we are gonna do gene therapy to restore CMA.
That's not realistic. So then the second approach that we have done in the lab. It's to design small molecules like drugs that can mimic or can increase the levels of this receptor. In this case, we do it transcriptionally. It's like, okay, if we activate transcription of this receptor, now we can restore the normal levels.
So we wait till the animals are mid age and then we start giving these compounds. And what kind of
compounds are those outta curiosity. Yeah. So what
we did is, is kind of interesting. So these are custom made. Like, you know, I, I collaborate with an amazing chemist. Dr. Evers, GABA is here at Einstein, and what we did is to look is like what are the physiological breaks of this pathway?
Because every pathway in your cell, as you know, has accelerator and breaks. So we look at one of those breaks and we were like, okay, what about if we do something to take out this break once you reach midlife, so this way you can keep going and you can keep producing this receptor. So in this case, they add through this N core pathway.
So it's a pathway that. You know, uh, when, when you stabilize this com, I mean the compounds stabilize, um, a transcription pathway, so then you end with most of these receptor. The nice thing is that even they are experimental drugs, so that's the side back. So is these are not FDA approved compounds, so anything that is given, but you know, at least we know how they're acting.
We know the me, we have published it many times. They have been licensed. So there are companies that are now. Tend to develop them farther. But the nice thing is that when we try them, we try them in. Physiological aging. So the animals do as well as the genetic models that I was telling you. But then we also start, uh, using them in age-related diseases, mouse models, right?
Because we do everything in mass. So for example, we have used them in models for frontotemporal dementia, a model of Alzheimer, models of Parkinson's disease. And when you gave them these drugs, you can see that the pathology is less, memory is preserved. You know, motor coordination. So they have a beneficial effect in the disease.
So the idea is that now we are looking for, you know, we have pass it to industry because that's what I stopped, right? Like somebody else have to bring them to the clinic. And now we are thinking, okay, what other breaks, what other things can we do? So we have another three different approaches, and maybe in the future we will go combinatorial, right?
Because maybe depending on the organ, but, but at the moment we have another three that we are developing. So, so we have a program of track development. The idea that we do the preclinical and then we just pass it to the people who knows about how to do this. But then the third approach, and this is I think is my MD part, kicks in from time to time.
So I always feel that. You know, if we could give one less pill to our elders, I would love that. It's like, I don't want to add more to the pharma, uh, copy that we are continuously exposing them. So we've been looking for lifestyle interventions that could also preserve C activity. And this goes a little of what we talk about, you know, separation of, uh, the meals.
Also the type of things. It's like, we know sugars fine, sugars are so bad for this receptor. So, you know, things like that. Reduce your sugar intake. We'll be looking at the sleep because sleep is also, you know, when you shorter your sleep, your time that your CMA has to be active is, is minimal. So the idea is that, you know, if you compare animals that you allow them to sleep and animals are not.
So you can do that. And then exercise has been the, the last one that we look at. So even, you know, at the moment, I think having this pill is gonna be important. I think if we can also do lifestyle interventions that will be. More universal. Right? More democratic. It doesn't cost money. Yeah. And I think it can have important applications for population in general.
Is it fair to say that the things that, the same things that can potentially inhibit mTOR, uh, would upregulate autophagy.
So this, yeah, this is a great question. So this goes into that comment that I made, like, oh, there are different types of pha, different ways to clean. So, um, rapamycin, for example, that I'm sure that's what you're thinking, right?
Yeah, that's what I, I was getting at. Yeah. Yeah.
So, so rapamycin is mostly. Um, inhibiting third one, as you know, you have third one and tor two. So third one is inhibitory in one type of autophagy that is called macro todi. So absolutely, I mean, we think that part of the beneficial effect that has been shown in aging for rapamycin is autophagy dependent, and there are some, uh, experiments based on that.
In the case of CMA Cmma is inhibited by to two, a state of. One. So in that case, for example, Torin has been utilized as a way to enhance CMA activity. So one of the nice things of autophagy is that many of those ERO therapeutics that people has identified metformin is permitting rapamycin, a carbos. All of those also activate autophagy.
They do many other things, but we think that kind of autophagy score for many of these RO therapeutics because it's such an essential process that for something to be successful in aging among many other things, it has to improve autophagy.
Yeah. Um, you mentioned some of the lifestyle things. You talked about caloric, uh, restriction or at least, you know, intermittent type.
Yeah.
Uh, eating, um, uh, not necessarily extreme, but just. You know, not eating all the time. Uh, the other one, uh, I I'm curious about in terms of its, its benefit on increasing autophagy is exercise and what kind of evidence we might have for that.
Yeah, so that's, that's a great question because, so it was shown the group of Bethle and showed that if you put animals in a treadmill, they were looking at this other type of autophagy, this macro tofa one modulated, and they showed that, uh, just exercise, uh, was activating this process, but they had to do.
Kind of a quite intense exercise, but it, it was beneficial and it was, um, you know, it was part of facilitating clearance in many conditions. In our case, we have seen that CMA, if you put the animals in a treadmill, for example, for like 90 minutes, that is what we were doing, uh, every two days. Doesn't not to active activate auto skeletal muscle.
And that's beneficial because as you know, uh, the muscle. Release among many other things, MI kines and other components that are going to have a very beneficial effect in other organs. So even if the primary target with exercise of CMA will be in the skeletal muscle, then the beneficial effect is really systemic because of the, you know, the then cell, non-cell autonomous regulation of these processes.
So that work, I mean, it was accepted two weeks ago, so I hope it will be coming next month, probably.
Great. And in, in terms of, uh, and there probably isn't, but I, I'm just curious if, you know, people want to get a sense of, you know, if the autophagy levels that they have in their body are good, is, is there any biomarkers that people can depend on?
So that's very interesting because, I mean, our lab has been traditionally a mouse lab. Uh, but again, again, as an md, I feel. Very strong about understanding autophagy people. So we have done a s lab, so we, we have done several things. So one thing is like, you know, postmortem, you get the tissues, you isolate, so, so we have an index that we have elaborated that it predicts what was the autophagy.
You can use transcriptomics, proteomics, all those things. But then how do you measure in people that are alive? So in collaboration with Fernando Math, and what we did is to take blood and then rather than using all the. Cells in your blood. Uh, he was very smart in thinking, let's take only T-cells that have been with you for your whole life.
I mean T-cell that are already right, because you want to make sure that you're still respond to that antigen that you got exposed when you were two years old. So they have been for your health and he did beautiful work showing that. The changes that we see now, tofa in many organs as you age, they reproducing your T-cell.
So something that he was doing for a long time and now we are taking that over is just by taking blood from people and we are doing, I can tell you a little about studies that we are doing in human. Just get there, you know, you get a little of blood, you get the T cells, and then we have two things. We have, um, markers that we can just sustain and we know how it's autophagy because this garbage recycling containers, we have antibodies that can detect, so you can count.
It's like, okay, how many do you have? Do you still have good recycling? How is that going? So that's relatively straightforward. But the other thing that we can do is just. Simply like, you know, to, to look at some of the components, for example, this receptor, it's like, okay, you get the T-cell of people and you can measure, there are very good assays to measure this receptor that I mentioned decrease with H.
So how is your receptor? Is it decreasing too fast? And then you can compare that. But then, and at the level, and I, I think it's very important to start thinking on measuring all these parameters in humans because, you know, there is so much diversity, right? So for example, we have done. Studies, um, with people in Spain because I'm from there originally with Mediterranean diet or not.
So then you can see how an intervention as simple as that, people who are more into McDonald's and people who are more into Mediterranean diet, how, like if you follow them for like one year is like, how is the apha for example, the, there are some studies that they've been doing about this intermittent fasting, like, you know, separating the food and how that affects, so, so we have evidence in people that.
This is beneficial, right? Like based on these studies, the only thing is that that's still a very small population. So the idea is that the more broad we can go into different ethnicities, different regions, we will understand a little better.
How far away do you think we are of getting some kind of commercial, uh, commercially available test?
I think it's, it's, uh, you know, it's, it's difficult to put years, right? But I, I think it's happening because something that in the aging field, we've been talking a lot is that it will be ideal. I mean, we know, we know, we, we have some ideas about who are the drivers of aging, right? Like the typical ones that you guys have been discussing, like ERs, mitochondria, and you know, pha proteostasis.
So the idea is that. Labs. All the labs, we have tests to measure each of them. So there is kind of this initiative that is like, okay, if we create kind of a kit, just as a lab matter, it's like that we, each of us has expertise in one. We start applying it. It's just a matter of time of some companies saying, oh, we can do that as a single kit and do it like customized for like, you know.
Clinic use because of course in the lab we have more sophisticated tools, but we've been all simplifying these assays in a way. For example, our studies in centenarians with varsi, they were all done in the lab, but the, the, the clinic was the one collecting the samples, preparing the T-cells, doing this thing, and then freeze them for us.
And then it's just a matter of 30 minutes and we can have the, the results. So I, I think it's not so difficult. And actually that's kind of my. Dream for the future. That is like once you hit 50, you will go to the doctor and they will have this panel. The same way that they have your analytical, they will have this panel of markers of aging and they can tell you if you have accelerated or if you are good in relation to your age.
So, and, and that. The main reason to know that is that you know this, then you can customize your interventions, right? You might say, okay, your mitochondria are fine, your lysosomal system not so good, so let's do something to improve that. So I think that personalized neurotherapeutics are gonna have more chances that just appeal, that fits everybody.
How do you think of your work, uh, in the context of all of the other things that are going on in the, the, the field of aging, the, the study on, as you were talking about mitochondrial dysfunction or senescence or genomic instability. Um, you know, do these processes, I mean, they, they all fit together. Um, how do you look at where your work fits in there?
Yeah, so, so one of the nice things is that, you know, when you look at these colorful charts that they have of the drivers of aging or the hallmarks of aging, so you know, you have these 12 or 14 processes that we all agree that are important for aging. The cool thing is that if you modify a couple of them.
All the others also benefit. So for example, I was telling you we have this mouse model that we have only touched CMA, right? We haven't touched mitochondria. We have, but when you look at these ene animals, their mitochondria better, their DNA has less damage. Senescence is like, actually we have a study coming on senescence and CMA senescence.
Transient as you should. And that
makes sense. Yeah,
exactly. So, so, you know, I always say like my mom used to say in a clean house, everything works better. But also for any of the other markers, it's like, I, I mean, we have studies with Seno, like, you know, they are improving senescent, so then you're autophagy is better because you don't have all these secretory components that mess up with autophagy.
So that's why I think it's the positive message that even it looks as scary how many things contribute to aging. You get the right combination, you can have beneficial effect in all of them. I think we need for every individual know what is the combination? I mean, what are the things failing in your case, that we should attack to maintain the others' functional?
What's your view on, you know, a number of these things that are in the lab right now, that the aging field is looking at, that they become reality? Do you think that that's a decade out? Do you think it's. I'm curious on that. It just seems like there's so many exciting things going on and I, you know, there was even, uh, I saw something about some, uh, company doing some, uh, trials and epigenetic uh, changes and things like that.
So it seems like things are starting to come out, but I'm curious on your perspective.
Yeah, so, so if you would have asked me like 10 years ago, I would say, oh, okay. We still have a long way. I think things have moved so fast these last 10 years have been incredible and I think in part is because the aging field has benefit of expertise from other areas.
So that's very important. You know, neurodegeneration, people become interested in aging cancer, people become very interested in aging and they had very good methodologies. But also the other one. And I know I should be careful about this because many people is against, I think, using it right. AI has been a major, major push for the field because all of a sudden, I mean, we are doing screenings of like 50 million compounds in like, you know, two days before it was just like pipetting because you do it in Silco, right?
So, so I think that, you know, if we will have to have a screen all those things by hand, that will have been hell of our work, right? So, so I think it, it's really accelerating things. And the other thing is that also as a field, I, I think we, we have become just to be, I mean. In the very old days of aging, everybody has a theory and this was my way on away kind of thing.
Right now it's so clear that they all interact and of course it's not, mitochondria are better than life, so, so I think this cooperative work and everybody thinking more global is, has also helped because the same way that, you know, people develop things, for example, for epigenetic modifiers. Then we can, how to look.
Okay. How is the cleaning that, so, so you get a much more broad view and I think it's easier to know first what works and what doesn't and what is a real general therapeutic and what is just something that modify a particular thing and that's it. So I think that's accelerating. It's difficult to put years as, you know, but I, I, I think, I mean, and also considering for example.
The other major limitation and uh, I dunno how cautious is to talk about this, but as you know, part of the problem has been the regulatory agencies, because you cannot do clinical trials for aging. You have to have a disease because a clinical trial is linked to a disease. So having now the milestone that tam is gonna be the first.
Clinical trial that is not related to disease just with aging. That changed the game now because that means they could be now is metformin. But the next thing you know, all these things that we are using in the lab is not so futuristic to say, well, this metformin has been already passed through there.
Now we can put this one, we can put the other. So I think that will exponentially accelerate. Discovery and, and also will help select who is suitable for this intervention versus the other. So I think there are gonna be a lot of negatives, but we learn from the negatives. It's like, okay, if this group of population doesn't benefit from this intervention and this group does what is different, can, can we make it more universal?
So, so I think that's gonna help in the next five years. Yeah. Yeah.
Thank you so much for this interview, Dr. Cuervo. It's, uh, really, uh, an honor and, uh, appreciate all the work you're doing.
No, it's, it's a pleasure and it's so great that you guys are taking this so serious because I think something with aging sometimes is misinformation, so we need media like you guys that take it very seriously.
Yeah, yeah. There's
a, there's, there's, there's a lot of misinformation, but, uh, we're trying to focus on what's actually happening in the lab, so.
I truly appreciate it. Thank you for inviting me.
Thank you. Thanks for listening. A quick reminder that while I am in fact a surgeon, nothing I say should be construed as medical advice.
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