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Animals That Don't Age at All — What It Means for Us · The LIVING Room Podcast | Inside The WNDR Lab

• 0:00
  SPEAKER_03: Evolution never works in a single gene.
• 0:01
  SPEAKER_03: Evolution works in a whole genome.
• 0:03
  SPEAKER_00: I think we can bypass 120.
• 0:05
  SPEAKER_00: We studied Bohe and Whale, which is the longest living mammal, they live over 200 years.
• 0:13
  SPEAKER_00: We wanted to understand the molecular mechanism behind the cancer resistance of naked morons because they almost never get cancer.
• 0:21
  SPEAKER_00: There is a new drug.
• 0:23
  SPEAKER_00: Most diseases of modern society are related to age, and the incidence increases exponentially as people get older.
• 0:31
  SPEAKER_00: I'm very optimistic about that we can improve human lifespan and health fund.
• 0:36
  SPEAKER_00: Right now I would focus on lifestyle changes, but the more you know, the more power it gives you.
• 0:42
  SPEAKER_00: 20-year-olds get very few diseases, not those chronic diseases, those start to become as we get into 50, 60, 70.
• 0:50
  SPEAKER_03: Be very careful not to overdo it.
• 0:52
  SPEAKER_03: There is a huge need that people want to kill some kind of silver bullet.
• 0:56
  SPEAKER_03: And unfortunately we don't have it.
• 0:57
  SPEAKER_00: Now we are happy with 10%, but what about 100% hi, welcome.
• 1:15
  SPEAKER_04: So you spent your career studying animals that live an exceptionally long time and are typically, and correct me if I'm wrong, free from disease and illness, as well as so they're living a long and healthy life.
• 1:29
  SPEAKER_04: And I think when we think about this term longevity, really that's what we all want, right?
• 1:34
  SPEAKER_04: And so we want to not only live longer, but we want those extra years to be full of health.
• 1:40
  SPEAKER_04: And that's not happening right now, right?
• 1:43
  SPEAKER_04: And I think we're spending I think around a fifth of our lives suffering from some form of comorbidities, right?
• 1:52
  SPEAKER_04: And so I think what's what's really frightening for most people with when they think about getting older is this concept that they will gradually, if not quite quickly, decline cognitively, physically, and their capacity to live a good life will diminish.
• 2:08
  SPEAKER_04: And so, what is it about these animal models that is allowing them to not only live long but live healthy?
• 2:15
  SPEAKER_00: Well, there is a very strong selection for it because if imagine you are a bat and it needs to catch insects, yeah.
• 2:24
  SPEAKER_00: Um, so the moment it cannot fly, it will not survive any longer.
• 2:29
  SPEAKER_00: So it has to stay really fit to survive.
• 2:32
  SPEAKER_00: Um, humans, well, we are free from these pressures of selection, so we start to accumulate maybe some undesirable genetic mutations.
• 2:42
  SPEAKER_00: So this is one part of it.
• 2:43
  SPEAKER_00: But the second part, uh, we are living maybe way past the age that prehistoric humans would live.
• 2:51
  SPEAKER_00: So if you also take an old bat and start hand feeding it, you can probably keep it alive even longer.
• 2:58
  SPEAKER_00: Um, so I think it's a combination of these two factors.
• 3:02
  SPEAKER_00: So, first of all, we um yeah, we don't um live the healthiest lifestyle, um, and then we live way longer.
• 3:11
  SPEAKER_00: And what we can learn from these animals that, yeah, if like there are bats that live more than 40 years for the tiny creature, it's amazing.
• 3:21
  SPEAKER_00: Um, so whatever adaptations we find with them, so these are adaptations for healthy life because they are under such a strong pressure from you know the environment where they need to survive.
• 3:33
  SPEAKER_04: But is that not the case for all animals other than humans?
• 3:37
  SPEAKER_04: You know, why would one naked mole rat live longer than a mouse?
• 3:43
  SPEAKER_00: Uh well, I think what's true for all animals is that they live in fairly harsh um realities, so they need to survive, they need to stay fit.
• 3:54
  SPEAKER_00: Um, but uh some of them were selected to kind of lose their capacities very quickly, like a mouse would be in the wild, mice rarely live past one year of age, and that's because they're being taken by predators, not because they you know fall apart.
• 4:14
  SPEAKER_00: Um, so they evolve to maintain their bodies just long enough to reproduce, they don't need to uh invest into maintaining their bodies for 20 years because they have no chance surviving 20 years.
• 4:28
  SPEAKER_04: Is that right?
• 4:29
  SPEAKER_04: Is that why?
• 4:30
  SPEAKER_00: Yes, but naked morat lives underground, there are very few predators that can get to it.
• 4:36
  SPEAKER_00: So it is beneficial for naked morat to take their time.
• 4:40
  SPEAKER_00: Yeah, to take their time, exactly.
• 4:42
  SPEAKER_00: And during this time they can reproduce successfully, and that's why genetically evolutionary, it makes sense for them to invest more into maintenance.
• 4:52
  SPEAKER_00: Huh.
• 4:52
  SPEAKER_03: I just would like to add because if you look even human society or human population, we have a relatively small group of human individuals who is living long life but also healthy.
• 5:03
  SPEAKER_03: Yeah, we are talking about centenarians.
• 5:05
  SPEAKER_03: The superior and super centenarians, yeah.
• 5:07
  SPEAKER_03: It means we still have even for humans when we have like some kind of right genome, we don't know what it is, some combination of genes, I guess, um, which allow them and stay healthy uh up to 90 years of age and live up to 100 years of age or beyond the hundred as well.
• 5:24
  SPEAKER_03: It means all that super centenarians and scenarios, they're they're going to work until 90s.
• 5:30
  SPEAKER_03: It means they are they're quite happy, you know.
• 5:33
  SPEAKER_03: That's it's possible to be done, but how to can achieve for the general population?
• 5:37
  SPEAKER_03: Yeah, that's a bigger question.
• 5:39
  SPEAKER_04: Do you see that in these um exceptionally long-lived mammals as well?
• 5:43
  SPEAKER_04: Are there some that live a long time, but is that an ex- are they an exception to the rule, or is there is that for all of them?
• 5:49
  SPEAKER_00: Well, mostly when we study long-lived species, especially wild species, uh, we don't have a lot of data on a lot of individuals.
• 5:59
  SPEAKER_00: So we treat species as kind of long-lived.
• 6:02
  SPEAKER_00: For example, naked mole rats have capacity to survive to 40 years, but like it's not like we followed uh millions of naked morats.
• 6:14
  SPEAKER_00: Right.
• 6:14
  SPEAKER_00: So we treat them more from genetic perspective.
• 6:18
  SPEAKER_00: What as a species makes them separate, but not like individual morats?
• 6:22
  SPEAKER_04: Let's talk about this naked mole rat because this was a really very well-known study of yours.
• 6:29
  SPEAKER_04: Um for the for the listeners, could you maybe give us a high-level overview of of what you found there?
• 6:36
  SPEAKER_04: Because it was pretty striking to me when I when I first read about this research.
• 6:42
  SPEAKER_04: And that you know, correct me if I'm wrong, they're the same size as a regular mouse, but yet are living around 10 times longer.
• 6:50
  SPEAKER_04: More than 10.
• 6:51
  SPEAKER_04: More than 10 times longer.
• 6:52
  SPEAKER_00: A mouse can survive up to three years.
• 6:56
  SPEAKER_00: Still, not every mouse.
• 6:57
  SPEAKER_00: I mean, if you put it in the best conditions, some of them will die at two, some can make it to three.
• 7:03
  SPEAKER_00: Um, moras can survive to 40 years, so it's more than beyond the 40 years, 41.
• 7:12
  SPEAKER_03: The record is growing.
• 7:13
  SPEAKER_03: We have to keep it.
• 7:14
  SPEAKER_03: Well, what's the record right now?
• 7:16
  SPEAKER_00: I think it's 41.
• 7:18
  SPEAKER_00: Yeah, yeah.
• 7:18
  SPEAKER_03: Wow.
• 7:20
  SPEAKER_00: Yeah, so it's absolutely amazing.
• 7:22
  SPEAKER_00: And uh, when we started studying them, um we found many adaptations to longevity that we don't see find in short-lived rodents like mice and rats that are much better studied.
• 7:37
  SPEAKER_00: Um, the most uh and yeah, I can talk for an hour about different studies, uh, but probably the most uh interesting one for the audience would be uh it started from we wanted to understand the um molecular mechanism behind the cancer resistance of naked morons because they almost never get cancer.
• 8:01
  SPEAKER_00: In the literature, there are maybe five or six cases described of naked morats developing cancer.
• 8:08
  SPEAKER_00: So we were very interested because for for comparison in mice, uh some of them, like 90% of for some laboratory strains develop cancer.
• 8:17
  SPEAKER_00: For others, it may be closer to 50%.
• 8:20
  SPEAKER_00: So if you keep uh hundred of mice, imagine 50 of them will have tumors, and but naked morads, I mean, you're less than one.
• 8:28
  SPEAKER_00: Less than one.
• 8:29
  SPEAKER_00: Yes.
• 8:30
  SPEAKER_00: Um, so we started culturing cells from naked morats, and we wanted to find some clues what's going on.
• 8:37
  SPEAKER_00: And then we noticed that the media in the Petri dish becomes viscous after naked morats cells were sitting in this media for maybe a week.
• 8:48
  SPEAKER_00: Um, and we're like, what is this viscous gooey stuff that cells are secreting something?
• 8:54
  SPEAKER_00: And we figured out that that was actually Andre was the first who noticed the gooey stuff.
• 9:00
  SPEAKER_00: He's like, What is this?
• 9:02
  SPEAKER_03: Because when you change the media in a plate, you are using the vacuum to aspirate it.
• 9:06
  SPEAKER_03: Right.
• 9:07
  SPEAKER_03: And it's got a small tubes, and it's quite easy to clog it when you have the some gooey substance in a naked mole rat.
• 9:13
  SPEAKER_03: It means usually you can change human or mouse cells like hundreds of maybe before the tubes get clogged.
• 9:19
  SPEAKER_03: In naked mole, if you grow in the cells, five, ten uh plates will give you already problems with the tubes and your vacuum is not working anymore.
• 9:27
  SPEAKER_00: What is this goo?
• 9:28
  SPEAKER_00: Um, and we had a very talented graduate student, Chris Hein, at the time.
• 9:33
  SPEAKER_00: Now he has his own lab.
• 9:34
  SPEAKER_00: Um, so Andre told Chris, Chris, figure out what is the goo.
• 9:39
  SPEAKER_00: And Chris spent some time, he tried various things, and then he thought maybe it's protein, no, it was not protein, then he said, What is it?
• 9:48
  SPEAKER_00: So he googled the gooey substances.
• 9:52
  SPEAKER_00: And uh one possibility was hyaluronic acid.
• 9:56
  SPEAKER_00: Uh, he tested for that, and that was right, that it was hyaluronic acid, but very unique hyaluronic acid, because hyaluronic acid is like a polysaccharide, a long linear chain of sugar.
• 10:09
  SPEAKER_00: Yeah, and it can be of different lengths.
• 10:12
  SPEAKER_00: Um, our bodies also produce hyaluronic acid, but much shorter.
• 10:17
  SPEAKER_00: In the naked morat, it may be six times, six to ten times longer than in human.
• 10:23
  SPEAKER_00: So it gives their tissues very different um uh viscoelastic property, like biophysically, they're different.
• 10:33
  SPEAKER_00: Um, their skin is more stretchy, um, it maybe holds water better, and then I mean, for this first study, we found that if we try to intentionally make a tumor out of naked moron cells, like in a Petri dish, uh, we couldn't do it, but if we prevented cells from making hyaluronic acid, then we could make a tumor out of these cells.
• 10:59
  SPEAKER_00: So that was helping them not to get cancer.
• 11:02
  SPEAKER_00: So that was one study kind of a breakthrough in understanding what protects them from cancer.
• 11:08
  SPEAKER_00: Uh, but we we also thought it might have something to do with longevity, but we didn't have a proof.
• 11:15
  SPEAKER_02: Yeah.
• 11:16
  SPEAKER_00: So then we engineered the transgenic mouse.
• 11:19
  SPEAKER_00: We took it the gene for making hyaluronic acid from the naked morat and introduced it into the mouse.
• 11:28
  SPEAKER_00: So these mice had less cancer.
• 11:31
  SPEAKER_00: I mean, they were not completely free from cancer, but they got maybe 50% less tumors.
• 11:37
  SPEAKER_04: Wow.
• 11:38
  SPEAKER_00: Uh, and they also lived longer by about um 15%, 10 to 15.
• 11:45
  SPEAKER_04: Which is not nothing.
• 11:46
  SPEAKER_04: Two things I want to unpack here.
• 11:48
  SPEAKER_04: One, I love the the this story that you found this discovery because some tubes got clogged up and then someone googled what the GUI clog was.
• 11:58
  SPEAKER_04: That's incredible.
• 11:59
  SPEAKER_04: But the second thing is I think as an audience member, I would want to know then if the transferring those cells to the mice helped prevent cancer in 50%-ish of them, which is huge.
• 12:14
  SPEAKER_04: Why can't we just do that with humans?
• 12:16
  SPEAKER_04: Um I'm mindful that we're not big mice, um, and that so much of this um translation is very difficult.
• 12:23
  SPEAKER_04: But as a as a listener, can you maybe unpack why it's not that simple?
• 12:28
  SPEAKER_03: Because for human treatment, we don't have to do the gene therapy.
• 12:32
  SPEAKER_03: You know, it's it's a very difficult procedure because you need to introduce the gene to every cell in our body.
• 12:37
  SPEAKER_03: Right.
• 12:38
  SPEAKER_03: And we are talking about billions of cells.
• 12:40
  SPEAKER_03: This it's not efficient.
• 12:42
  SPEAKER_03: Uh, what we did in mice is just a proof of principle because we uh introduced the gene into the ocytes, fertilized zygos, actually, and there it's easy to manipulate because when you have single cells, you can manipulate the genome and the whole mice is growing.
• 12:55
  SPEAKER_03: Of course, for human practice, you cannot do it because you can't do genetic editing and the human individuals and babies.
• 13:03
  SPEAKER_03: Um uh, but in human, what we can do, uh we can use the small molecules.
• 13:09
  SPEAKER_03: Uh, because what we achieved in the mice, we by introducing a gene from naked molar, they start to produce more and longer form of hyaluronic acid.
• 13:18
  SPEAKER_03: Uh now we have the same gene, which produced shorter form very similar to naked molar.
• 13:24
  SPEAKER_03: But now, how we can make it similar to naked molar red?
• 13:27
  SPEAKER_03: We can just block the degradation.
• 13:29
  SPEAKER_03: And now actually, we have the small molecules, not the ideal, but one of the as a proof of principle, which blocks the degradation of hyaluronic acid, and that prevents the formation of metastasis in mice.
• 13:44
  SPEAKER_03: It means this will be more clinical application because, again, for human gene therapy and development, it's not the right way to do it.
• 13:52
  SPEAKER_03: We don't make a transgenic human, probably.
• 13:54
  SPEAKER_03: Uh, maybe in the future.
• 13:56
  SPEAKER_00: Well, people are taking hyaluronic acid orally as a supplement.
• 14:00
  SPEAKER_04: Is this the same hyaluronic acid that you would people use as a skincare?
• 14:03
  SPEAKER_00: Yeah, in skincare, there is a lot of hyaluronic acid, uh, but it mostly stays uh uh on the surface of the skin, it doesn't penetrate.
• 14:13
  SPEAKER_00: Um, so it's an excellent moisturizer, but like we cannot really talk about these systemic effects.
• 14:20
  SPEAKER_00: People take it orally, uh, the evidence is mixed on oral hyaluronic acid, like because it's a large molecule, how does it get absorbed?
• 14:29
  SPEAKER_00: It's most likely it is broken down.
• 14:32
  SPEAKER_00: Um, people argue that maybe those shorter fragments can still boost production of hyaluronic acid uh internally.
• 14:41
  SPEAKER_00: So people, some people really report that it benefits, but it it's a bit mixed.
• 14:46
  SPEAKER_00: We don't really know.
• 14:48
  SPEAKER_00: Uh, and we cannot expect um just oral administration to bring like huge changes to the systemic levels of hyaluronic acid.
• 14:59
  SPEAKER_00: Um, gene therapy is considered um, but in a more localized way.
• 15:05
  SPEAKER_00: For example, um in arthritis treatment, people were injecting hyaluronic acid in knees, and some people were helped by that.
• 15:14
  SPEAKER_00: Um, it you know, there are also mixed reports on that, and we believe that the reason is that when people were injecting hyaluronic acid, they were not yet aware of our research.
• 15:26
  SPEAKER_00: So the size of hyaluronic acid that was injected was actually rather short.
• 15:31
  SPEAKER_02: Right.
• 15:31
  SPEAKER_00: It was not as long as what we find in the naked morat, and maybe in some people, these shorter versions can trigger inflammation instead of uh prevent inflammation because hyaluronic acid is a very interesting uh molecule.
• 15:46
  SPEAKER_00: Depending on the size, it has different effects on the cell.
• 15:51
  SPEAKER_00: Uh, long molecules are anti-inflammatory and anti-proliferative, well, short molecules are the opposite.
• 15:58
  SPEAKER_03: That's annoying.
• 15:58
  SPEAKER_00: Yeah.
• 15:59
  SPEAKER_03: So what's and what we can buy from the uh from the cosmetics usually short molecules.
• 16:04
  SPEAKER_03: Oh, is that right?
• 16:05
  SPEAKER_03: Because they can easily penetrate a little bit in the skin layer, the long molecules will not penetrate at all.
• 16:11
  SPEAKER_03: We can't just make these long molecules.
• 16:13
  SPEAKER_03: You can, but you need to inject them, you need to deliver, the delivery becomes the problem.
• 16:17
  SPEAKER_00: Well, injections is also a mixed bag because people now, you know, to fight wrinkles would inject it, it's probably better than Botox.
• 16:27
  SPEAKER_00: Uh, but the problem is that the um what is being injected is cross-linked hyaluronic acid.
• 16:34
  SPEAKER_00: So it makes it high molecular weight, but the structure is way different from the natural molecule, so it also can trigger inflammation because it's not exactly the same.
• 16:44
  SPEAKER_00: Um so that's why, again, injection it may have local effects, but not systemic.
• 16:52
  SPEAKER_04: Do you think, I mean, is there any sort of roadmap for translating that into something that we can take?
• 16:59
  SPEAKER_00: Yes.
• 17:00
  SPEAKER_00: So we are now working on uh developing these small molecule inhibitors of degradation of hyaluronic acid.
• 17:07
  SPEAKER_04: To stop it breaking down.
• 17:08
  SPEAKER_00: Right.
• 17:09
  SPEAKER_00: So this way, because it is our cells can produce high molecular weight hyaluronic acid, uh, but then it's quickly being broken down.
• 17:17
  SPEAKER_00: So if we we don't want to block this process completely, but if we just slow it down, uh we can increase overall size.
• 17:25
  SPEAKER_00: So I I think this is really the way to go.
• 17:27
  SPEAKER_00: And this way we can also have systemic effect, not just local.
• 17:31
  SPEAKER_04: So, how does that then, you know, what is that roadmap?
• 17:34
  SPEAKER_04: Is that now being tested?
• 17:36
  SPEAKER_04: You know, I think what I'm trying to figure out is we found the first molecule, what I already mentioned before.
• 17:42
  SPEAKER_03: Yeah, now we need to draw the bigger screen, probably to find a better molecule.
• 17:46
  SPEAKER_00: Yeah, because that was a I mean, that was a natural compound.
• 17:49
  SPEAKER_00: We were quite happy, it just popped up from the chemical screen.
• 17:52
  SPEAKER_00: We were not particularly looking for natural compound, but it did.
• 17:56
  SPEAKER_00: Um, we could administer it to mice with tumors and see that it slows down the metastatic process, which was very nice.
• 18:04
  SPEAKER_00: But um the molecule could be made more potent, so we still need to do more medicinal chemistry on it.
• 18:12
  SPEAKER_04: Sounds complicated.
• 18:14
  SPEAKER_04: Are you hopeful that that will translate into something that can help impact lifespan?
• 18:19
  SPEAKER_00: Yes, yes.
• 18:20
  SPEAKER_00: I'm very hopeful that we can uh um, you know, at least reduce inflammation systemically, because that was the not the effect that we observed in these mice with Nikid Mora gene.
• 18:31
  SPEAKER_00: Their overall level of inflammation was lower.
• 18:34
  SPEAKER_04: Hey, I'm super mindful that it's not always that simple.
• 18:37
  SPEAKER_04: It's never that simple, right?
• 18:38
  SPEAKER_04: When you look at the naked mole rat, was that the sort of standout one thing that you think contributed to them a not getting cancer, but also living longer, or was it a combination of a there must be a combination.
• 18:51
  SPEAKER_00: Yes.
• 18:52
  SPEAKER_00: Um, I don't know, to ex let's say if we compare mouse to naked mole rat, um, to make this creature live 10 times longer, like make mouse like naked mole rat, I mean, one thing would not do it.
• 19:06
  SPEAKER_00: So it's really a combination of things.
• 19:08
  SPEAKER_00: Um, hyaluronic acid was just the most striking effect that we absorb.
• 19:14
  SPEAKER_00: You you just really look at the tissues, they're different, and they're different from most other mammals that we know.
• 19:22
  SPEAKER_04: I think when everyone like when we hear about these incredible research projects and the findings that are most striking, like this, you know, the the idea that there is two there are two mammals, one lives ten times longer and doesn't get cancer, and I'm assuming retains cognitive function as well.
• 19:40
  SPEAKER_04: And so that is really the goal for all of us, is that's how we want to age.
• 19:45
  SPEAKER_04: And we spoke earlier about this.
• 19:46
  SPEAKER_04: I think everyone's ambition, if we were being completely honest, isn't necessarily to live forever, but it's that the the years that we have are as high quality as possible.
• 19:57
  SPEAKER_04: You know, and we use this example, you know, of a 90-year-old running around a football pitch with their grandchildren on their shoulders.
• 20:02
  SPEAKER_04: That's really what we want, right?
• 20:04
  SPEAKER_04: And Andre, you you gave the example that we're already seeing that happening.
• 20:08
  SPEAKER_04: There are humans that are doing that already.
• 20:11
  SPEAKER_04: Then we see evidence that there are mammals doing this, but but relatively a lot longer than we would be.
• 20:19
  SPEAKER_04: I think for us as consumers of this information, you just want to know when will I be able to use that or get my hands on that?
• 20:26
  SPEAKER_04: And I think in the media in general, we're led to believe that's happening very soon.
• 20:34
  SPEAKER_04: What's your perspective on that as a timeline?
• 20:36
  SPEAKER_04: Because it sounds like you're bullish on it happening, but we don't have these silver bullets yet.
• 20:42
  SPEAKER_03: I think, yeah, probably five, ten years.
• 20:45
  SPEAKER_03: It could be I don't think it will be a silver bullet, but it will be some kind of the chemical drug which can significantly improve our health span in the lifespan possibly as well.
• 20:56
  SPEAKER_03: Um and you're absolutely right when you are talking about wild animals, because we have this huge difference, only a hundredfold difference in a lifespan.
• 21:04
  SPEAKER_03: And evolution never works in a single gene.
• 21:07
  SPEAKER_03: Evolution works in the whole genome.
• 21:09
  SPEAKER_03: That's why we can find hyaluronic acid, we can find the other mechanisms as well.
• 21:13
  SPEAKER_03: And I think our tasks as a what we are doing is comparative biology of aging.
• 21:18
  SPEAKER_03: We are studying the aging in many different species to find how different species find a different way to live longer.
• 21:26
  SPEAKER_03: For example, Nikonora live underground.
• 21:28
  SPEAKER_03: We as a human never live underground.
• 21:30
  SPEAKER_03: Yeah.
• 21:30
  SPEAKER_03: In cave maybe, but it doesn't consider.
• 21:33
  SPEAKER_03: Um uh bats, they're flying, we never fly, actually, like butts, not on airplanes.
• 21:37
  SPEAKER_03: Uh whales, they dive in the ocean in very uh deep water, they also have very cold water and Arctic water.
• 21:44
  SPEAKER_03: Uh, we never live in that environment.
• 21:46
  SPEAKER_03: It means those species they have unique adaptations for this environment, which allow them as well to live longer time and healthy as well.
• 21:54
  SPEAKER_03: Because um, you know, these species they have this protected environment like bats are able to fly.
• 22:00
  SPEAKER_03: Whales are huge, you know, not that many predators could kill whale, maybe killer whale, but it's another big guy as well.
• 22:07
  SPEAKER_03: Um, naked morat, they escape predators underground.
• 22:10
  SPEAKER_03: It means when the species get in protected environments, they have a chance now to evolve long lifespan and healthy lifespan as well.
• 22:17
  SPEAKER_03: Yeah, now it's asked to find those mechanisms, and then in the end, okay, how we can apply some of them can be easily transferred to humans, like in case of uh naked morthy acid.
• 22:26
  SPEAKER_03: I think this small molecule inhibitor will work as well.
• 22:29
  SPEAKER_03: But for example, they have also better protein synthesis, they have very unique structure of ribosome, uh, which is well will be very difficult to transfer to human.
• 22:39
  SPEAKER_03: Uh, it means like our task is to search for this list of the different adaptations to find which one they can easily transfer as a small molecule, which one, okay, it's curious finding, and that's it.
• 22:50
  SPEAKER_04: So you think that across, and this is called comparative biology, right?
• 22:55
  SPEAKER_04: Exactly.
• 22:55
  SPEAKER_04: Where you're comparing different species and why some might live longer than others.
• 23:00
  SPEAKER_04: And you think, you know, if we continue to do that with more species, and I'm sure there is more to find out about the naked mole rat.
• 23:07
  SPEAKER_04: So within these um different studies, that eventually we might find more things that we can actually then translate to bedside that we could all use potentially.
• 23:16
  SPEAKER_03: You're absolutely right.
• 23:17
  SPEAKER_03: Uh right now we almost randomly picked six different mammalian species, long-lived mammalian species.
• 23:25
  SPEAKER_03: Uh whales, elephants was not our work, but somebody else picked elephants, uh, naked morad, blind morads, uh, squirrels, gray squirrels that we have on the ground, uh lives 25 years, and butts.
• 23:38
  SPEAKER_03: And they all have six different mechanisms.
• 23:40
  SPEAKER_03: Like my question as a biologist, I was thinking, okay, how many of these mechanism exist in nature?
• 23:45
  SPEAKER_03: Are we talking about 10, 100?
• 23:47
  SPEAKER_03: I don't know.
• 23:48
  SPEAKER_03: So far, we picked six, they're all different.
• 23:50
  SPEAKER_04: Wait, of the six species that you're studying, they each had different protective mechanisms that we think help.
• 23:57
  SPEAKER_03: Actually, we are studying around 50 species.
• 24:00
  SPEAKER_03: Six out of the three.
• 24:01
  SPEAKER_00: No, six were more in depth.
• 24:03
  SPEAKER_03: In depth, yeah.
• 24:04
  SPEAKER_03: Yeah.
• 24:05
  SPEAKER_00: I I think like there are unique mechanisms, what Andre has mentioned.
• 24:09
  SPEAKER_00: There are also some common mechanisms.
• 24:12
  SPEAKER_00: Uh, for example, when we compare 50 different species of different lifespans, and we uh do like multi-omic studies and we see uh to look, okay, what correlates with longer lifespans.
• 24:27
  SPEAKER_00: Um, something that we find repeatedly in multiple species that longer-lived species have better genome maintenance, they they they know how to repair their DNA better.
• 24:39
  SPEAKER_00: Uh, the exact mechanisms, how they achieve it, can differ.
• 24:43
  SPEAKER_00: For example, here we studied bowhead whale, which is the longest living mammal.
• 24:49
  SPEAKER_00: They live over 200 years.
• 24:51
  SPEAKER_04: The bowhead whale.
• 24:52
  SPEAKER_00: Bowhead whale twice human lifetime.
• 24:54
  SPEAKER_00: It's gangster.
• 24:55
  SPEAKER_00: Yeah.
• 24:56
  SPEAKER_00: And we found that they have very good DNA repair, very accurate, uh fewer mutations um than, for example, human cells.
• 25:07
  SPEAKER_00: Um, and they have unique mechanisms to do it.
• 25:09
  SPEAKER_00: So they have a protein uh that we also have, but they have hundred times more of this protein.
• 25:16
  SPEAKER_00: It's called the name is cold-induced RNA binding protein.
• 25:20
  SPEAKER_00: So when you do the cold plunge, you actually induce it.
• 25:24
  SPEAKER_03: That's what we did half an hour ago.
• 25:26
  SPEAKER_03: Yeah.
• 25:28
  SPEAKER_00: And um, this protein helps uh maintain DNA.
• 25:32
  SPEAKER_00: Well, again, to be precise, we don't know like what type of cold plunge you need to do to properly induce it.
• 25:41
  SPEAKER_00: But in cell culture, we know that if we take human cells and we expose them to colder temperature, we see that the level of this protein goes up.
• 25:51
  SPEAKER_00: It doesn't reach the same level as in the bowhead whale, but we can stimulate it.
• 25:55
  SPEAKER_04: Huh.
• 25:57
  SPEAKER_04: Fascinating.
• 26:00
  SPEAKER_04: With the bowhead whale, how did you two questions?
• 26:05
  SPEAKER_04: One, how did you like find that how do you pick the species that you're then gonna study?
• 26:10
  SPEAKER_04: Is that just observational?
• 26:11
  SPEAKER_04: You know over time that you know these mammals tend to live live longer.
• 26:15
  SPEAKER_04: Are there other examples of huge mammals that have longer lifespans than us?
• 26:22
  SPEAKER_00: Well, bowhead whale is really exceptional.
• 26:25
  SPEAKER_00: Um because we humans are very long-lived.
• 26:28
  SPEAKER_00: We humans are also exceptional, uh, which is what makes it difficult to extend human lifespan.
• 26:35
  SPEAKER_00: Um as you probably noticed, many interventions work in mice.
• 26:40
  SPEAKER_00: Uh, because mice are very short-lived by by design, evolutionarily.
• 26:47
  SPEAKER_00: Yeah, they're short-lived, they they're very fast reproducing, um, they're metabolically very fast.
• 26:54
  SPEAKER_00: So if we just slow them down a bit, we get significant lifespan extensions.
• 27:00
  SPEAKER_00: Uh, but humans, we are slow reproducing, slow developing.
• 27:05
  SPEAKER_00: So the same interventions that work in mice, in humans, they may have like small effects.
• 27:11
  SPEAKER_04: Yeah.
• 27:12
  SPEAKER_04: I think that's what's so confusing to us in general, is that there are lots of promising studies on improving health span and lifespan in mice.
• 27:21
  SPEAKER_04: And that is, you know, that is human nature to take that headline and be like, that sounds really exciting.
• 27:27
  SPEAKER_04: What what what are the biggest restrictions for translating that into humans?
• 27:32
  SPEAKER_04: Because am I right in saying that over 90% of those promising interventions in mice do not translate to humans?
• 27:39
  SPEAKER_00: Well, I don't know if the number maybe I I would be a little more optimistic than 90%.
• 27:44
  SPEAKER_00: Oh, if I made that number up.
• 27:45
  SPEAKER_00: Yeah.
• 27:45
  SPEAKER_04: We should fact check that.
• 27:47
  SPEAKER_00: Yeah, I think it it's true for um sea elegants and uh flies and worms.
• 27:52
  SPEAKER_00: So, yeah, there I would say over 90% doesn't translate.
• 27:56
  SPEAKER_00: Uh, with mice, I don't have an accurate number, but I would say maybe it's closer to 50%.
• 28:03
  SPEAKER_00: So it means maybe half of those things that work in mice will work in humans.
• 28:08
  SPEAKER_04: I think I got that number.
• 28:09
  SPEAKER_04: Half, I think less than 10% ever make it into some kind of approved interventional therapeutic.
• 28:16
  SPEAKER_04: That's I think where the number is.
• 28:17
  SPEAKER_04: Right.
• 28:18
  SPEAKER_04: I'm gonna fact check that as well then.
• 28:19
  SPEAKER_03: Yeah, because mice is a very convenient uh organism to study because it's very short-lived and fast reproduction.
• 28:28
  SPEAKER_03: Uh, but it's also very flimsy because we already mentioned it, you know, mice lives usually six months, maximum a year in a while.
• 28:36
  SPEAKER_03: Yeah, it means this uh body, even if they have any kind of mechanism, allow them to live longer or fight cancer, uh, this mutate uh this mechanism will be mutated.
• 28:46
  SPEAKER_03: Yeah, because they don't need it, they never live to that long lifespan.
• 28:49
  SPEAKER_03: And that creates the problem for us because we already, as humans, we already optimize the majority of our processes.
• 28:57
  SPEAKER_03: Yeah, and because we're so long-lived, quite cancer resistant compared to mice as well.
• 29:02
  SPEAKER_03: Yeah, and that's why we'll better compare something to something shortly to longer lifespan.
• 29:10
  SPEAKER_03: You know, it's always easy to shorten, but to extend the lifespan or improve the health span, it's always difficult.
• 29:16
  SPEAKER_00: No, I would say mice, uh, you know, they're useful in research because we can test interventions.
• 29:22
  SPEAKER_02: Yeah.
• 29:22
  SPEAKER_00: Uh, but to discover new interventions, um we la our philosophy is that we have to look at long-lived species.
• 29:31
  SPEAKER_00: Because if we just use mice for discovery, um, you know, they may not have those mechanisms for to extend the.
• 29:40
  SPEAKER_04: And I guess your research has already proven that, in that there are so many different mechanisms for the different species.
• 29:46
  SPEAKER_04: Can I ask you a question on health span within those species?
• 29:50
  SPEAKER_04: Do you ever see exceptionally long-lived animal models that that lose health span but live a long time?
• 29:59
  SPEAKER_04: Like a comparison to humans.
• 30:00
  SPEAKER_04: We've done a great job of increasing life span over the last century, but we haven't improved our health span linearly.
• 30:10
  SPEAKER_00: They stay very healthy.
• 30:13
  SPEAKER_00: Uh, we see very few alien naked morads in our colony.
• 30:18
  SPEAKER_00: We have about 300 of them, and they're all very healthy, very fit.
• 30:23
  SPEAKER_00: Um, you can kind of notice uh they slow down slightly with age and when they get to their twenties, but they don't develop diseases.
• 30:34
  SPEAKER_00: Um we see in contrast with mice, they always develop some kind of conditions, they always need treatment, attention from veterinarians.
• 30:44
  SPEAKER_00: Nikki Moras, no, they stay very fit and healthy.
• 30:47
  SPEAKER_04: Can we talk about some of these other known geroprotectors?
• 30:52
  SPEAKER_04: So molecules that have shown promise in animal models, but we don't yet know are safe and efficacious for humans.
• 30:59
  SPEAKER_04: Of those, are there a handful or any that you are that you think are more promising that we're a bit closer to being able to prove useful for humans?
• 31:10
  SPEAKER_00: It's very difficult to say.
• 31:13
  SPEAKER_00: Uh I think we will know a lot very soon because now with development of all the modern biomarkers, yeah, it became possible to test um those geroprotectors and test them in a fairly short period of time, maybe one-year trial.
• 31:33
  SPEAKER_00: Um so far, you know, the results are just coming in.
• 31:38
  SPEAKER_01: Yeah.
• 31:38
  SPEAKER_00: Uh, for example, people had very high hopes for rapamycin, but once the clinical trial, the first small trial was promising, but the larger trial didn't detect any signal.
• 31:49
  SPEAKER_04: This was rapamycin.
• 31:51
  SPEAKER_00: Rapamycin.
• 31:51
  SPEAKER_00: Oh, it was a rapologue.
• 31:53
  SPEAKER_04: Yeah, yeah, yeah.
• 31:54
  SPEAKER_00: Um, well, people are still optimistic, and there are additional trials ongoing, but we don't know the results.
• 32:00
  SPEAKER_04: You studied rapamycin, right?
• 32:02
  SPEAKER_00: Well, we used it uh a little bit in our research.
• 32:06
  SPEAKER_04: Do you take it?
• 32:07
  SPEAKER_00: No.
• 32:09
  SPEAKER_03: No.
• 32:09
  SPEAKER_03: But I think you know, when you're talking about these bioprotectors, the people think, oh, this is a silver bullet, you already mentioned it before.
• 32:16
  SPEAKER_03: It will work for the entire population.
• 32:19
  SPEAKER_03: And I think that's probably a wrong assumption.
• 32:21
  SPEAKER_03: I agree.
• 32:22
  SPEAKER_03: Because uh we'll need uh for different groups of people, maybe different genotypes, to have different bioprotectors.
• 32:30
  SPEAKER_03: Maybe somebody needs the repromycin.
• 32:32
  SPEAKER_03: That's why the population, uh, when it was the first study was done in the smaller group, they see the beneficial effect and try to make it for a bigger group.
• 32:38
  SPEAKER_03: Now they they lost it because now they dilute it uh by general populations.
• 32:43
  SPEAKER_03: Yeah.
• 32:44
  SPEAKER_03: And I really believe that probably if we are going to develop silver bullet, it will be individual for each subgroup, maybe.
• 32:52
  SPEAKER_03: I'm not sure what that will be, but uh yeah, it means we need to have uh sequencing of our genome, and first of all, to um group our human population on different subgroups and to say, okay, this will be uh this kind of pre-treatment more appropriate, the other will be completely different.
• 33:09
  SPEAKER_03: Yeah.
• 33:09
  SPEAKER_00: We can uh comment on uh one compound that we are now conducting clinical trial on, which is Fucoidin.
• 33:16
  SPEAKER_00: It's a component of brown seaweed, um which is very healthy.
• 33:23
  SPEAKER_00: People in Japan, South Korea eat a lot of brown seaweed.
• 33:28
  SPEAKER_04: And they live a long time.
• 33:29
  SPEAKER_00: And they live a long time, yes.
• 33:31
  SPEAKER_00: So that was a discovery uh we made um a couple of years ago, uh, because in addition to long-lived species, we are also very interested in genome stability, and we study um the protein called Sirtuin 6.
• 33:47
  SPEAKER_00: It's one of those Sirtuins, famous or infamous, but it's number six.
• 33:53
  SPEAKER_00: Um so we first demonstrated more than a decade ago that it's important for genome maintenance, and we've been studying it from this perspective and also epigenome.
• 34:04
  SPEAKER_00: Um, and then um in collaboration with people from Albert Einstein College, um, Yusin Sue, near Barzilla, uh, we uh studied um centenarians, and they look for various alleles that are uh you know overrepresented in centenarians, and one of those uh was a mutation in SIRTUIN6 uh that made it more active, but in a very particular way.
• 34:32
  SPEAKER_00: So, like one activity was enhanced.
• 34:35
  SPEAKER_00: Um, and we decided to find a molecule that would activate that particular activity of Cirtuin 6.
• 34:44
  SPEAKER_00: Um, and people before looked for activators of Cirtoin 6, but everybody focused on another activity which was actually not enhanced in the centenarians.
• 34:53
  SPEAKER_00: I mean, we need that activity, but for longevity it was not enhanced.
• 34:58
  SPEAKER_00: And we found that for coidon from brown seaweed was a very strong activator of actually both activities.
• 35:06
  SPEAKER_00: While what other people, all the compounds were discovered before, they would only activate the activity which we think is not important.
• 35:15
  SPEAKER_00: So we got very excited for coidon seaweed.
• 35:18
  SPEAKER_00: We started feeding it to mice, old mice, and we extended their lifespan by by about 15%.
• 35:26
  SPEAKER_04: Just from brown seaweed.
• 35:28
  SPEAKER_00: Yes, just we supplemented them with this.
• 35:31
  SPEAKER_04: Did they like eating it?
• 35:32
  SPEAKER_00: Doesn't sound like they didn't mind eating it.
• 35:35
  SPEAKER_04: Do you eat brown seaweed?
• 35:37
  SPEAKER_04: Yes.
• 35:37
  SPEAKER_00: Okay, yes, this is the one we eat because uh we are certain that it's safe.
• 35:43
  SPEAKER_00: It's been tested for centuries.
• 35:46
  SPEAKER_00: Uh and mice really benefited, and not only they lived 15% longer, but their uh frailty score improved dramatically.
• 35:56
  SPEAKER_04: Really?
• 35:57
  SPEAKER_04: Huh.
• 35:58
  SPEAKER_04: I think this is just such an important side note is that you know we have the pleasure and privilege of speaking to some the best uh researchers in the field of aging, and I think it's a really green flag when the researchers themselves are taking what they're um uh proposing is beneficial for health and lifespan.
• 36:24
  SPEAKER_04: And I think it's also a bit of a red flag when they're not, right?
• 36:28
  SPEAKER_04: And so I think that's just a good takeaway for the audience.
• 36:32
  SPEAKER_04: You know, we're being told that there are all these promising compounds and peptides and um supplements to take.
• 36:39
  SPEAKER_04: I I would generally just trust the people that are in the lab doing the research on them rather than spread betting and taking everything because it's such a great point that what works for one person does not necessarily work for another.
• 36:52
  SPEAKER_04: And I think we're still there's still so many unanswered questions that we should lean into the things that we have good evidence for first.
• 37:01
  SPEAKER_04: Can I ask you then um of those so rapamycin, I think, is is a is a good example of something that there's a lot of diff conflicting opinions on.
• 37:11
  SPEAKER_04: Why is there you know why are there so many people that are bullish on these compounds that that will recommend taking them when we don't really know not necessarily that there's a benefit, but we don't even know dosage or you know frequency or volume that we should be taking of these things.
• 37:29
  SPEAKER_04: Why do people still take them?
• 37:34
  SPEAKER_00: It's hard for me to judge.
• 37:36
  SPEAKER_00: Uh I think people really have the right to try themselves.
• 37:40
  SPEAKER_00: That's a good thing.
• 37:41
  SPEAKER_00: I and some people, biohackers, they feel like, well, I want to experiment on myself.
• 37:47
  SPEAKER_00: Um, but when recommending it to other people, that's a different story.
• 37:52
  SPEAKER_00: Then you have to be really confident that whatever you recommend will not do harm.
• 37:56
  SPEAKER_00: Yeah.
• 37:57
  SPEAKER_00: This is why for me it's very difficult to say which ones, because you know, I don't want people to then just go and start taking things which I'm not 100% confident that, well, again, maybe it helps some people, but uh it hurts other people, maybe there are different conditions.
• 38:15
  SPEAKER_04: I think that's the troubling problem in this field, though, in general, is that people who are and I think in large part they are good actors.
• 38:24
  SPEAKER_04: I don't think I'm not I'm I'm I'm optimistic that people are trying to do good, but to recommend and then to create a product line and sell a product that you don't know is going to be beneficial or even unharmful to people feels kind of reckless to me, right?
• 38:41
  SPEAKER_04: And but we see a lot of it.
• 38:43
  SPEAKER_04: How do you think in this field that do we stop that happening or reduce that?
• 38:47
  SPEAKER_04: Because I can understand why people want to, you know, people want to commercialize things and you know the addressable market of people that want to live a long and healthy and happy life is everyone.
• 38:59
  SPEAKER_04: And so we're always going to have this as a problem.
• 39:02
  SPEAKER_04: What do you think we could do it in as a field to to stop that happening?
• 39:06
  SPEAKER_00: Well, definitely doing more research, conducting proper clinical trials, randomized, placebo controlled, or even open label, but then it has to be communicated that that was an open label.
• 39:20
  SPEAKER_00: Um, because when there is more evidence, um then there will be, of course, more science-based decisions as to what to recommend.
• 39:30
  SPEAKER_00: Because now, if something is being broadly recommended just based on some warm study, you know, then yeah, well, it helped worms.
• 39:38
  SPEAKER_00: We really don't know if it helps.
• 39:40
  SPEAKER_04: And that happens.
• 39:41
  SPEAKER_04: Yeah.
• 39:42
  SPEAKER_04: I think it's tough.
• 39:43
  SPEAKER_04: That's a tough question that we don't yet have the answer for.
• 39:46
  SPEAKER_04: But I uh you would hope that the the evidence outpaces the the noise.
• 39:52
  SPEAKER_03: I think the problem because there is a huge need, so people want to take some kind of silver bullet, and unfortunately we don't have it.
• 40:01
  SPEAKER_03: Yeah, we have many different uh chemicals which may be useful for some people, but uh because of this hype, you know, people want to talk, you know, they take something and just uh no, but it's also for the lack of um alternative for the lack of evidence.
• 40:18
  SPEAKER_00: Uh and clinical trials are expensive, but um definitely we need more of them, and that would be the best solution once there is scientific evidence and the research was properly conducted, then everybody agrees.
• 40:34
  SPEAKER_04: Yeah, I mean I get it, right?
• 40:35
  SPEAKER_04: We we're all we we speak so often about the things that we do have evidence for, but they're so uh hard to do consistently and adhere to all the time, like it's a forever game.
• 40:46
  SPEAKER_04: We have to always continue to exercise and look after our stress levels and manage our sleep.
• 40:52
  SPEAKER_04: It's I can understand the appeal of a silver bullet or a selection of treatments that will help um slow down the process of aging.
• 41:01
  SPEAKER_04: It's difficult.
• 41:01
  SPEAKER_04: Do you think that with enough funding?
• 41:05
  SPEAKER_04: And I know that's a that's a separate episode to talk about the issues we have with funding this research right now, but do you think with enough funding we do solve for this?
• 41:15
  SPEAKER_04: Do you think that there is a world where we can meaningfully extend human lifespan?
• 41:20
  SPEAKER_00: Oh, absolutely.
• 41:21
  SPEAKER_00: We we're as you just said, we need more funding, we need more research.
• 41:27
  SPEAKER_00: Um, there are lots of promising interventions, but like most of them were not appropriately tested on humans.
• 41:34
  SPEAKER_00: Yeah uh but once we have this data, then we can also test combinations of them because we discussed today how well it's not one gene, it's a combination.
• 41:44
  SPEAKER_00: So ideally, we would want to, for example, combine different adaptations from Nikid Morat, maybe from the whale, maybe we bring them together and then again test properly to see if they benefit humans.
• 41:58
  SPEAKER_00: And uh, I'm very optimistic that we can find things that work.
• 42:02
  SPEAKER_04: Do you think we would ever get to a place where we cure aging?
• 42:08
  SPEAKER_04: I know you don't categorize it as a disease, but do you think there's a world where we can not only slow down the onset of aging but reverse it?
• 42:17
  SPEAKER_00: Um I think it's possible.
• 42:20
  SPEAKER_00: Um if we really learn to modulate the process of aging itself, then uh well, there is a lot of hype now about um epigenetic reprogramming, which is one potential way to reverse things, not just uh slow it down.
• 42:37
  SPEAKER_00: I think there are lots of safety issues that need to be overcome before this is this can be used by people.
• 42:45
  SPEAKER_00: Um, but as a proof of concept, yes, it exists.
• 42:49
  SPEAKER_00: Um and even um uh trying to be more conservative, because with reprogramming you change cell fates, that is very dangerous because cancer can arise, it's also you change cell fate.
• 43:03
  SPEAKER_00: Um but even without changing cell fate, it's possible to um rejuvenate the cell.
• 43:12
  SPEAKER_00: Um because, like, for example, uh um, you know, like an epithelial cell, supposed to be epithelial cell, it shouldn't turn into another type of cell.
• 43:23
  SPEAKER_00: Yeah.
• 43:23
  SPEAKER_00: Um, because then it can also type it.
• 43:26
  SPEAKER_00: Cell type.
• 43:27
  SPEAKER_00: Uh it can because if cells lose their identity, they become cancerous because then they don't know what they are, they just divide and make a tumor.
• 43:35
  SPEAKER_00: So we don't want that to happen, and that's the danger of all reprogramming approaches.
• 43:41
  SPEAKER_00: Um, but now people are developing more conservative, where you rejuvenate the cell but without changing its identity.
• 43:48
  SPEAKER_00: Uh, even um uh with these uh Cirtuin 6 activating treatments, what we see that we can um actually lower epigenetic age of cells because.
• 44:00
  SPEAKER_00: Because Cirtuin 6 doesn't change cell identity, but it can kind of rewire its epigenome, tighten it up so that it gets younger.
• 44:10
  SPEAKER_00: And and that's possible.
• 44:12
  SPEAKER_00: Yes, we see it on cellular level.
• 44:14
  SPEAKER_00: Um and um we are exploring it on the whole organism level.
• 44:19
  SPEAKER_04: Can we can we talk briefly about epigenetics and this concept of measuring biological age?
• 44:25
  SPEAKER_04: Um, you know, we are seeing dozens of companies that are now claiming to have a biological clo like being able to measure the ageotype, the age of different organs and so on.
• 44:38
  SPEAKER_04: You know, I as you know, you've been through this process where we're doing this very deep N of one phenotyping, testing across all these different systems of biology.
• 44:48
  SPEAKER_04: My reservation about using biological age tests, and I've used all of them, is that they can be easily manipulated to come out with different outcomes intradaily, right?
• 45:01
  SPEAKER_04: And so I I did a bunch of them in one day and had a 17-year variation in my biological age.
• 45:07
  SPEAKER_04: But yeah, I see lots of companies hanging their hat on that as a metric for the success of their intervention or their program or their supplement.
• 45:18
  SPEAKER_04: How do you feel being in the in the field and actually studying and potentially I suspect using some of these tools?
• 45:25
  SPEAKER_04: You know, we say that that this is successful at reducing or reversing or rejuvenating ACL age.
• 45:32
  SPEAKER_04: How do we actually know that?
• 45:34
  SPEAKER_00: Well, yes, no, it it's a big problem, big discussion, but um I think developing development of these first methylation now multi-omics biomarkers is one of the greatest breakthroughs.
• 45:48
  SPEAKER_00: Yeah.
• 45:48
  SPEAKER_00: Um they, as you just pointed out, they they are not perfect for assessment of an individual age.
• 45:58
  SPEAKER_00: They're but people are constantly trying to improve them, and I think it will be possible to develop them so that they can be used for an individual.
• 46:07
  SPEAKER_02: Yeah.
• 46:07
  SPEAKER_00: And where science is going is combining these, for example, mutilation biomarkers with some of typical clinical chemistries and seeing that they point in the same direction.
• 46:21
  SPEAKER_00: Um, so it is possible, but right now um they work, but more on a uh cohort level.
• 46:28
  SPEAKER_00: Yeah.
• 46:28
  SPEAKER_00: So for a clinical trial, when looking at, let's say, 200 people, yes, you get meaningful signal from them.
• 46:35
  SPEAKER_00: But of course, individual people should not, you know, make their estate planning based on a mutilation biomarker.
• 46:43
  SPEAKER_00: But for a clinician conducting a clinical trial, that is still very useful data.
• 46:50
  SPEAKER_03: Yeah, I think pretty soon we can get probably more reliable biomarkers, like mutilation clock as well, or combination different clocks, yeah.
• 46:58
  SPEAKER_03: Because that's a future.
• 46:59
  SPEAKER_03: And uh, this is really uh, as we already mentioned, a breakthrough because right now we can measure it.
• 47:05
  SPEAKER_03: Like before, if you'll do any kind of clinical trials, are we going to wait 50 years?
• 47:09
  SPEAKER_03: I think a cockalist no way to do it.
• 47:11
  SPEAKER_03: Now we can do it.
• 47:12
  SPEAKER_00: Well, but some people are really trying to like poo-poo on these biomarkers and say, oh, like I did 10 of them and they all give me different.
• 47:21
  SPEAKER_00: But yes, because they're not really they are not they are not good enough for that.
• 47:26
  SPEAKER_00: Yeah, I mean, we have to understand it.
• 47:28
  SPEAKER_03: Yeah, if you uh got a biomarker and it tells you you are 17 years younger, I mean it makes you very happy, but you know, don't really you mentioned 17 years difference, it's not huge because we are talking like 55 something plus minus 17, you know, it's well, whoa, whoa, not 55, as a cannon, as a couple of years.
• 47:51
  SPEAKER_03: I'm 55 as a live life.
• 47:53
  SPEAKER_00: Well, but if you have 200 people and everybody's biological age, you know, went down by you know, maybe for some person it will show one year, but for another it will be 17 years, uh, then it tells you something about the intervention for the code.
• 48:11
  SPEAKER_04: Yeah, but I think as a consumer, um if I if if I can't rely on that number, but yet my whole program is based on it, or the the continuation of a product or a supplement or a I don't know, a course is based on you're doing well, it's working, you've you've lowered your biological age by 17 years.
• 48:32
  SPEAKER_04: If I can't rely on that as valid and reliable, then I'm not sure it's it's I think it's misleading.
• 48:38
  SPEAKER_03: You're probably right, but you're talking about different mutilation clocks.
• 48:42
  SPEAKER_04: If you're using the same two of the tests with the same clock on the same day, or the same day.
• 48:47
  SPEAKER_03: Oh, it's 17 years different.
• 48:49
  SPEAKER_04: No, it was seven years different for the two clocks I did on the same day with the same company, but across five different companies it was 17 years.
• 48:56
  SPEAKER_00: Um, yeah, that happens.
• 48:59
  SPEAKER_00: For us, we we also did uh the mutilation clock, and first time uh it showed well, we were maybe six years younger, made us super happy.
• 49:09
  SPEAKER_00: And then we repeated it in six months, and we were actually a couple years older.
• 49:14
  SPEAKER_00: But what happened just uh in between, uh, we both got COVID, yeah.
• 49:20
  SPEAKER_00: And I think there was probably a reason that our biological age on that day was not as great.
• 49:27
  SPEAKER_00: Um, so those uh markers can change depending on what happened in the person's life.
• 49:33
  SPEAKER_04: Yeah, playing devil's advocate with my own argument, maybe over time that does in the same way as you know there is some interference effect or learning effect for some of the tests we did today, maybe over time that does bounce out because you know, hydration or fatigue or stress can all impact your epigenome, right?
• 49:51
  SPEAKER_04: And so maybe I am wrong.
• 49:53
  SPEAKER_03: This is just just a very recent technology, yeah.
• 49:56
  SPEAKER_03: Just in the beginning, you know, it's very amazing.
• 49:59
  SPEAKER_03: I think that that it will improve significantly.
• 50:02
  SPEAKER_03: It is already improving.
• 50:03
  SPEAKER_04: Do you think that is a funding issue as well?
• 50:05
  SPEAKER_04: If we had more resources that we would solve for that too, definitely, yeah.
• 50:09
  SPEAKER_00: I think ideally if we could apply these biomarkers also on the broad population level, we could learn a lot more.
• 50:17
  SPEAKER_04: More resolution, yeah.
• 50:18
  SPEAKER_00: If let's say a few million people we would um genotype their methylome.
• 50:24
  SPEAKER_00: Um but that's a problem.
• 50:26
  SPEAKER_00: We're still working with a fairly small amount of data, and I think they add, like, because some clinicians would say, Well, I have uh sort of your typical blood chemistry, like I don't need to know all that.
• 50:38
  SPEAKER_00: Well, but I think it will add more information, we just need to learn how to properly explore it.
• 50:43
  SPEAKER_04: I I'm a big fan of just more data, and you know, we still do those tests, we don't always surface the results because we can't yet stand behind them.
• 50:51
  SPEAKER_04: But again, we were talking off camera about some of the uh multi-omics tests that the science hasn't quite yet caught up with the ability to capture the data.
• 50:59
  SPEAKER_04: Do you think there are there other examples where you know you're seeing big claims being made in the media specifically that you think it it's kind of promising, but the science isn't quite there?
• 51:12
  SPEAKER_00: Well, I think it mostly applies to these biomarkers because people get tested for a lot of things.
• 51:20
  SPEAKER_00: Um and then how to interpret it, well we don't know, but there may be things.
• 51:27
  SPEAKER_00: I think the more data we have, um the more we'll know.
• 51:31
  SPEAKER_00: But yeah, sometimes you see a lot like okay, we'll screen you on all these tests and we'll just tell you something.
• 51:38
  SPEAKER_00: Yeah.
• 51:38
  SPEAKER_00: Well, you have to understand that there are limitations to what you can learn, but maybe in five years from now that will that data will become much more valuable, I'm assuming.
• 51:49
  SPEAKER_03: But you're asking about the media hype.
• 51:51
  SPEAKER_03: Uh we are trying not to watch media about the science at all because uh it's not trustable.
• 51:57
  SPEAKER_03: Uh they're after hype, they're after sensation.
• 52:00
  SPEAKER_03: Yeah, and you I I know from my interactions with journalists and medias, they're trying to fish anything out of you and trying to present in the most ridiculous way.
• 52:10
  SPEAKER_03: Yeah, and you read it in the end, like, did I say that?
• 52:13
  SPEAKER_03: Really?
• 52:14
  SPEAKER_04: Well, you you mean like they will sensationalize to get more views?
• 52:18
  SPEAKER_04: Yeah, after the job, right?
• 52:21
  SPEAKER_03: Yeah, yeah, yeah.
• 52:22
  SPEAKER_04: Huh.
• 52:23
  SPEAKER_04: But where where then do we get as as general consumers that want act, you know, we want to know that what we're reading or consuming is something to rely on, right?
• 52:34
  SPEAKER_04: And I've spoken about this many times in the past.
• 52:37
  SPEAKER_04: We are made to feel like we are failing when we go online and look at what I should be doing to protect against these signatures of aging.
• 52:45
  SPEAKER_04: Because if I were to do everything I was being told on in the media, I wouldn't have any time to enjoy my life, right?
• 52:52
  SPEAKER_04: And so I just think it where do we how do we solve for that?
• 52:55
  SPEAKER_00: Well, it is a big problem.
• 52:57
  SPEAKER_00: Um, so those lifestyle interventions, we all know it exercise, good sleep, uh, good diet.
• 53:06
  SPEAKER_00: Well, yeah, and in even good diet, it's still always changing.
• 53:09
  SPEAKER_00: What the what is a good diet recommendation?
• 53:12
  SPEAKER_04: Nutrition's a real minefield still.
• 53:14
  SPEAKER_00: Yes, because there are lots of recommendations not based on science, and it's constantly improving again with more data uh from large cohorts of people, knowing what type of diet they followed and what happened to them.
• 53:28
  SPEAKER_00: Uh, so that is also improving.
• 53:30
  SPEAKER_00: Um, so these are safe things.
• 53:34
  SPEAKER_02: Yeah.
• 53:34
  SPEAKER_00: Um, in terms of like oh, lots of supplements, yeah, there are so many claims.
• 53:40
  SPEAKER_00: Um, and yeah, people have the right to try, but we have to also understand uh the limitations to the knowledge and to your question, where do people find uh the information?
• 53:52
  SPEAKER_00: No, that's very difficult.
• 53:54
  SPEAKER_00: Uh, even for scientists, it's sometimes very difficult to distinguish okay, what level of evidence is there?
• 54:00
  SPEAKER_03: We have to go to original publications to really understand that and sometimes even you go to original publication and you read it and you're not sure, you try to judge it.
• 54:12
  SPEAKER_03: Okay, is it trustable love?
• 54:13
  SPEAKER_03: Do you know these people?
• 54:15
  SPEAKER_04: Then you can try, you know, that that's that's a different level of yeah, not all research should be weighted the same, right?
• 54:21
  SPEAKER_04: Like some of the some of the sort of a meta-analysis on something that we've spent a long time studying is much more valuable than a very small random trial with like a very small cohort.
• 54:33
  SPEAKER_04: But as a consumer, when we read both, it they both look compelling.
• 54:36
  SPEAKER_04: And so it's it's it's a challenge.
• 54:39
  SPEAKER_04: And I also I think you you want to we and I think we're getting more agency now.
• 54:44
  SPEAKER_04: The more data we collect, the more the science evolves.
• 54:47
  SPEAKER_04: We're able to do these N of one studies on ourselves now with wearables and CGMs and monitoring our intake of food.
• 54:54
  SPEAKER_04: So we want we've got more agency and we want it to know what to do with the information, but it's actually knowing what to do.
• 55:00
  SPEAKER_04: And I think sometimes we're all we're all guilty of you know collecting that data and then not really knowing what to do with it.
• 55:08
  SPEAKER_04: Not guilty, but we're all susceptible to that.
• 55:10
  SPEAKER_04: Like I think about wearable data and you know, sleep specifically.
• 55:14
  SPEAKER_04: It's fine to be told you're not sleeping well, but then what?
• 55:18
  SPEAKER_04: You know, how do I improve it that's not actually helping all that much?
• 55:22
  SPEAKER_03: Maybe I I have this hope that EI can solve it, but it's just you know, because I don't know much about it.
• 55:27
  SPEAKER_03: Aggregating the data, yes.
• 55:29
  SPEAKER_04: That's what the that's what AI is, right?
• 55:31
  SPEAKER_04: It's it's trend pattern recognition.
• 55:33
  SPEAKER_04: Yeah, and that's kind of what we need more data, more pattern recognition, um, and then we could actually deduce what to do with it.
• 55:40
  SPEAKER_03: And probably the same is important for aging research because you know aging is is a is a big problem.
• 55:46
  SPEAKER_03: Many different pathways get affected, and now how we can tweak them independently.
• 55:51
  SPEAKER_03: You know, right now we are studying them one at a time, but maybe again, I don't know much about the eye.
• 55:58
  SPEAKER_03: Maybe you can some kind of generate the more global pathways which will affect different marketers and bring it all together and make all sense out of that.
• 56:06
  SPEAKER_03: I hope so.
• 56:07
  SPEAKER_04: I mean, it's so nuanced and layered that you kind of that that is the only way, I think, of being able to solve for this.
• 56:14
  SPEAKER_04: Um, can I ask you about the development of some of these technologies with regards specifically to your research?
• 56:22
  SPEAKER_04: You know, all you take this whole sum of these promising number of gyro protectors and you know, hyaluronic acid and and DNA repair, it feels like it costs a lot of money to do and takes a long time to prove.
• 56:38
  SPEAKER_04: Do you think that the development of AI and some of these new tools and technologies will help expedite that so that we don't have to wait so long asking for a friend?
• 56:48
  SPEAKER_00: Well, to some extent, yes.
• 56:50
  SPEAKER_00: I think, especially in uh processing large cohort data from humans, different interventions, lifestyles, genetics, aggregating all of it.
• 57:01
  SPEAKER_00: Uh now, as uh far as testing, some people would say, Oh, you just model a human, and I mean we are not there yet.
• 57:10
  SPEAKER_00: Now, you still need to run actual tests first on mice if things look good, then on humans.
• 57:17
  SPEAKER_04: What about this sort of middle ground, like pluripotent stem cell lines, for example, like uh creating an organoid of that specific person?
• 57:24
  SPEAKER_04: Do you think there's promise there for testing these gyroprotectors?
• 57:27
  SPEAKER_00: Well, there is promise, and uh um, you know, the government really wants us to move away from animal research and use organoid models, uh, but it requires a lot of development.
• 57:41
  SPEAKER_00: Organoid models are mostly used for some kind of toxicity studies where you just put you know toxins and see if your cells die.
• 57:50
  SPEAKER_00: Um, there is no model of aging in a Petri dish.
• 57:54
  SPEAKER_00: We don't know what aging in a Petri dish is because it doesn't recapitulate the whole organism.
• 58:00
  SPEAKER_00: There is no immune system, there is no endocrine system, so how things work together.
• 58:07
  SPEAKER_00: It will take a long time to develop this type of um in vitro um Petri dish assay that would replicate what happens in a body.
• 58:18
  SPEAKER_03: Yeah, I don't think it's possible to have the organoids as a model for aging, because we are aging not because of our liver or brain failure or not in a silo, yeah.
• 58:28
  SPEAKER_03: Everything together, yeah.
• 58:30
  SPEAKER_03: We can't model this single organ for liver disease, yes, of course.
• 58:33
  SPEAKER_03: Yeah, but because aging is complex, every organ is affected.
• 58:37
  SPEAKER_04: That's a good example of toxic.
• 58:39
  SPEAKER_04: We can we can test for uh models of disease and illness probably fairly well with them, but not for aging itself, right?
• 58:47
  SPEAKER_04: That's a complicated one.
• 58:50
  SPEAKER_04: Okay, what was then something that you know now that 10 years ago or 20 years ago you you had no idea, and that it was a surprise to you?
• 59:01
  SPEAKER_00: Well, you know, maybe it was more like 20 years ago there was huge excitement about telomeres and like when we extend telomeres and we live forever, then we understood well that they are short for a reason because it protects us from cancer.
• 59:16
  SPEAKER_00: We don't want to just extend our telomeres, and even if we do, it doesn't necessarily make us live longer.
• 59:23
  SPEAKER_04: I would say that's still a common misconception.
• 59:26
  SPEAKER_04: Yes, I I would Could you maybe explain that to someone who wouldn't, you know, who's heard this word telomere before, and people say, you know, this is the solution to aging.
• 59:38
  SPEAKER_00: Yeah, so telomeres are these ends of chromosomes.
• 59:42
  SPEAKER_00: Um, and in many organisms, we not we, but like mice, for example, or even some unicell organs like yeast, they can extend the ends of chromosomes.
• 59:54
  SPEAKER_00: They have the enzyme to do it.
• 59:56
  SPEAKER_00: Uh enzyme is called telomerase.
• 59:59
  SPEAKER_00: Uh, but in humans and some other large animals, this enzyme is restricted.
• 1:00:07
  SPEAKER_00: We only have it in stem cells in very limited amounts, and in our germ cells, in the eggs, in the sperm.
• 1:00:15
  SPEAKER_00: Um, and then what happens as a result that in many of our cells, like take skin cell or some other cell, um, as we get older, those ends start to get shorter.
• 1:00:26
  SPEAKER_00: And if they get critically short, it can trigger senescence, it can trigger cell death, um, can slow down regenerative processes.
• 1:00:37
  SPEAKER_00: So that's why when people discovered it for the first time, oh, telomerase is limited.
• 1:00:43
  SPEAKER_00: Um, well, let's just boost it and we live forever, but it it doesn't happen really.
• 1:00:50
  SPEAKER_00: Um, and uh one place where this threshold is being overcome is in tumors, because tumors they need to grow uncontrollably.
• 1:01:01
  SPEAKER_00: So if their ends of chromosomes were shortening like that, they would then stop very quickly and will die, and there will be no tumor.
• 1:01:10
  SPEAKER_00: So tumor finds some tricks to bypass it.
• 1:01:14
  SPEAKER_00: So they would tweak this gene or mutate it and activate so their telomeres is very active, so we don't want that to happen.
• 1:01:25
  SPEAKER_00: Um, and this is where you know the problem arises that first of all, it's not so easy, even if we try to lengthen the telomeres, we don't necessarily live forever, yeah, or even longer at all.
• 1:01:38
  SPEAKER_00: Um, and second, there may be unintended consequences, like making it easier for the tumors uh to grow.
• 1:01:47
  SPEAKER_04: It's annoying how complicated biology is, um, because I think we all want answers to these questions, and that I think that's sometimes why we we take we pull on that thread of evidence, you know.
• 1:02:00
  SPEAKER_04: The the concept that you know increasing telomer length would result in you living longer is nice to think about, right?
• 1:02:07
  SPEAKER_00: Like it's nice that it's very elegant, it's a very elegant policy.
• 1:02:11
  SPEAKER_04: So I can understand why it is exciting.
• 1:02:14
  SPEAKER_04: There's there's so much discord and discourse still in science, and rightly so.
• 1:02:19
  SPEAKER_04: That's the point, is which we should try and disprove a hypothesis.
• 1:02:23
  SPEAKER_04: Given that you are in the unusual position to run a lab together and be married.
• 1:02:31
  SPEAKER_04: Do you do you have a discord between you?
• 1:02:34
  SPEAKER_04: Do you disagree on things?
• 1:02:36
  SPEAKER_00: Well, occasionally, but it's more like scientific discussion.
• 1:02:40
  SPEAKER_00: We we love to discuss science.
• 1:02:42
  SPEAKER_02: Yeah.
• 1:02:43
  SPEAKER_00: Uh for the most part we agree, but sometimes we don't, and then we are trying to convince each other, and usually one of us succeeds.
• 1:02:52
  SPEAKER_03: Yeah, because usually quite frequently we have this discussion, and we come up with some kind of solution, uh, how to solve that problem, scientific problem.
• 1:03:01
  SPEAKER_03: And uh usually we could that that's that's it means we are always in a discussion mode that we always come up with the right, I hope it's the right solution.
• 1:03:10
  SPEAKER_03: We have some maybe differences, different views, because I uh there is more focus like on ideal uh lifestyle.
• 1:03:19
  SPEAKER_03: I was thinking more about more like hermetic effects, yeah.
• 1:03:23
  SPEAKER_03: You know, that's just a little bit of bad stuff is good for you as well.
• 1:03:28
  SPEAKER_00: No, we our brains work very different.
• 1:03:32
  SPEAKER_00: So we are in this example, like where our thought process is completely different, so that's very useful for us to discuss because we we don't anticipate what the other will say because our brains are just very different.
• 1:03:45
  SPEAKER_00: But it's healthy discord.
• 1:03:47
  SPEAKER_00: It's healthy discord.
• 1:03:49
  SPEAKER_03: It's really good arrangement because in this case we are getting really like honest critiques.
• 1:03:56
  SPEAKER_03: Yeah, you know, when you're going to the when you're publishing the paper, uh people don't say this bad critiques if they think something well.
• 1:04:03
  SPEAKER_03: Yeah, yeah.
• 1:04:03
  SPEAKER_03: When presenting the seminars, you know, usually it's not a problem.
• 1:04:06
  SPEAKER_03: Sometimes your reviewers can criticize your paper quite badly.
• 1:04:09
  SPEAKER_00: Anonymous reviewers can have.
• 1:04:13
  SPEAKER_03: Here you have the consistent reviewer present all of your life, yeah, and he's quite honestly, she's quite honestly to tell you, okay, this is not right, this is not true.
• 1:04:21
  SPEAKER_03: And I think it's good because we are constantly bouncing idea, and I really don't understand how people, if who doesn't have this person to bounce the idea, how they can manage the lab, because for us, this is a huge advantage.
• 1:04:35
  SPEAKER_00: No, it it it's dangerous because once you get to this level, like you are a professor somewhere, and you talk to your students and postdoc, and they I mean very few would try to contradict the professor.
• 1:04:48
  SPEAKER_00: So it's always like you're in this echo chamber, but uh, when your spouse is also in science, yeah, you can tell me what he well.
• 1:04:56
  SPEAKER_04: I think that's what had what made us so excited about this model with the big scientific council in the first place, is you want the appropriate level of discourse and discord.
• 1:05:06
  SPEAKER_04: You want people to disagree and challenge those things.
• 1:05:09
  SPEAKER_04: And I think actually that you know, at times, rightly or wrongly, if you've been studying the same thing for two, three decades, you kind of want it to be there's some confirmation bias there, right?
• 1:05:22
  SPEAKER_04: You want it to work out, and I think that is a problem in science as well, whether we like it or not.
• 1:05:28
  SPEAKER_04: Like we all want to be right about the thing we've devoted our time to studying.
• 1:05:32
  SPEAKER_04: So I bet that's a really good dynamic in that you can sort of check one another early on so that it doesn't end up getting out of hand.
• 1:05:42
  SPEAKER_00: Also, because we study long lived species, we study epigenetics, we like with species you never know where science takes you.
• 1:05:50
  SPEAKER_00: Um so if we see that something doesn't work, we abandon it and we pursue exciting things.
• 1:05:56
  SPEAKER_00: So we um I can't imagine just staying and studying the Same like process or the same pathway for all.
• 1:06:03
  SPEAKER_00: One protein.
• 1:06:05
  SPEAKER_03: Yeah, for us.
• 1:06:06
  SPEAKER_03: Maybe we are a little bit more unfocused in this stage because we are again right now we are studying like 15 mammalian species, and people always come to ask why you want to study like parrots, why not tortoises?
• 1:06:18
  SPEAKER_03: Greenland sharks is 500 years.
• 1:06:20
  SPEAKER_03: I said, Let's wait.
• 1:06:22
  SPEAKER_03: We still have enough mammals just to study.
• 1:06:25
  SPEAKER_03: Somebody else can 500 years?
• 1:06:27
  SPEAKER_03: Uh Greenland shark.
• 1:06:29
  SPEAKER_03: No way.
• 1:06:31
  SPEAKER_00: 400.
• 1:06:32
  SPEAKER_03: 400 something years, yeah.
• 1:06:34
  SPEAKER_03: But again, sexual maturity about 100 years.
• 1:06:38
  SPEAKER_00: Well, but it's a very slow life.
• 1:06:39
  SPEAKER_00: It's not something we would want for ourselves.
• 1:06:43
  SPEAKER_00: It it swims very slowly, eats maybe once every six months.
• 1:06:48
  SPEAKER_00: Boring.
• 1:06:49
  SPEAKER_03: It lives in the cold water, it's cold-blooded.
• 1:06:52
  SPEAKER_03: Yeah.
• 1:06:54
  SPEAKER_04: Hey, there's a jellyfish that that lives forever, right?
• 1:06:58
  SPEAKER_04: Or it rejuvenates.
• 1:07:00
  SPEAKER_04: Why don't you study that?
• 1:07:01
  SPEAKER_00: I mean, not every jellyfish.
• 1:07:02
  SPEAKER_00: Yeah, there are some jellyfish.
• 1:07:04
  SPEAKER_04: Is that true?
• 1:07:05
  SPEAKER_00: Yeah, there are different species.
• 1:07:07
  SPEAKER_00: Just some of them can do it.
• 1:07:09
  SPEAKER_00: No, I think regenerative process, because it's not really mortality, it's more this unlimited capacity to regenerate.
• 1:07:17
  SPEAKER_00: It's actually quite widespread in lower organisms.
• 1:07:21
  SPEAKER_00: There are flat worms.
• 1:07:23
  SPEAKER_00: You can chop them into several pieces, and each piece will grow into a worm.
• 1:07:28
  SPEAKER_04: Wait, wait.
• 1:07:29
  SPEAKER_04: You can chop a flat worm into several pieces, then you have several worms.
• 1:07:33
  SPEAKER_04: Yes.
• 1:07:34
  SPEAKER_04: But they grow their, they be all live independently.
• 1:07:37
  SPEAKER_04: Yes.
• 1:07:38
  SPEAKER_00: Yes.
• 1:07:38
  SPEAKER_04: Is that true?
• 1:07:39
  SPEAKER_00: Yeah, so it is actually this capacity for unlimited regeneration is something that mammals have lost.
• 1:07:47
  SPEAKER_00: And probably there was an evolutionary reason for that.
• 1:07:51
  SPEAKER_02: Yeah.
• 1:07:51
  SPEAKER_00: But it's not that unusual because in these invertebrate worlds, especially, yeah, there are many species that does it's like thinking exercise.
• 1:08:00
  SPEAKER_03: You know, it's uh amazing to think about all that, you know, hydras and the water.
• 1:08:04
  SPEAKER_00: Or even fish, like your usual aquarium fish, they can tear each other's fins when they fight, and then those fins grow back.
• 1:08:13
  SPEAKER_00: I mean, we cannot grow our hands back.
• 1:08:15
  SPEAKER_04: No, but unless we wound heal and like there's there's some element of that.
• 1:08:18
  SPEAKER_04: But not to grow the limb.
• 1:08:20
  SPEAKER_04: Yeah.
• 1:08:20
  SPEAKER_04: No, that's not that's annoying.
• 1:08:23
  SPEAKER_04: Yeah, but maybe one day.
• 1:08:24
  SPEAKER_04: Do you think that is something that could ever I mean, I've given up on saying never ever on every aspect of what we do now because I think the science is moving so quickly, and you know, I think that is getting even quicker, right?
• 1:08:38
  SPEAKER_04: It's not linear anymore.
• 1:08:40
  SPEAKER_04: We're we're making crazy discoveries now that I like to be optimistic about.
• 1:08:44
  SPEAKER_00: No, I am optimistic if fish can do it.
• 1:08:47
  SPEAKER_00: There are some amphibians like axolotils, can regrow limbs.
• 1:08:51
  SPEAKER_00: Yeah.
• 1:08:51
  SPEAKER_00: If we really understand that process, and most likely because these are, I would say, kind of more primitive organisms than animals, so there is something in us that maybe shuts down those pathways.
• 1:09:04
  SPEAKER_00: If we really learn how they are regulated, maybe we can remove those blocks.
• 1:09:08
  SPEAKER_00: Yeah.
• 1:09:09
  SPEAKER_00: Maybe not forever, because maybe it's there is a reason we don't want to always have this capacity for unlimited growth.
• 1:09:16
  SPEAKER_00: Maybe it will cause cancer.
• 1:09:18
  SPEAKER_00: But if a person loses uh his or her limb, maybe we can then activate, you know, put some chemicals on it and then induce regeneration, like in the fish.
• 1:09:30
  SPEAKER_03: That'd be amazing.
• 1:09:31
  SPEAKER_03: But it would be life changing for so many people.
• 1:09:33
  SPEAKER_03: Even in mammals, you can do it.
• 1:09:34
  SPEAKER_03: African spiny mice can regenerate with 60-70%.
• 1:09:38
  SPEAKER_00: Yeah, so that's another creature that we study.
• 1:09:40
  SPEAKER_00: We actually have a colony of those mice.
• 1:09:43
  SPEAKER_04: What's the mouse called African spiny mice?
• 1:09:45
  SPEAKER_04: It looks like it's a spiny mouse.
• 1:09:47
  SPEAKER_00: It looks almost like a regular mouse, but but it has this a little bit kind of longer spikier hair.
• 1:09:55
  SPEAKER_00: Um, and the way it escapes predators, because predator, imagine a hawk, it would grab the mouse.
• 1:10:03
  SPEAKER_00: Yeah.
• 1:10:03
  SPEAKER_00: So these mice, then their skin is very um feeble, so it will just tear easily, and um the mouse would lose all its skin and run away, and the hawk is left with the piece of skin.
• 1:10:18
  SPEAKER_00: Um, and then these mice can regenerate up to 70% of the skin.
• 1:10:23
  SPEAKER_04: That's just a product of millennia of evolution, yes.
• 1:10:27
  SPEAKER_03: Isn't nature almost like a lizard losing the tail, yeah?
• 1:10:30
  SPEAKER_03: It's losing the skin.
• 1:10:31
  SPEAKER_00: But it's a mammal, and we are studying them.
• 1:10:34
  SPEAKER_00: Uh, we are still very far from understanding like what makes them different, but if we find it, you've got a really cool job, don't you think?
• 1:10:43
  SPEAKER_04: I think that's amazing.
• 1:10:44
  SPEAKER_04: I would love to study that.
• 1:10:45
  SPEAKER_04: Uh Andre, you mentioned um hormesis a little while back, and I kept thinking about in my head that there's some debate about you know the um inducing stress for benef for benefit, and you know, we touched on cold plunge, and there's been a whole trend of people cold plunging, and now not so much.
• 1:11:06
  SPEAKER_04: And what what's your position on that in general?
• 1:11:09
  SPEAKER_04: Because you know, some when I look at some of these long-lived species or long-lived humans, even they all live kind of a chilled life, right?
• 1:11:17
  SPEAKER_04: Yet we are really bullish on exercise as a stressor, and you know, even heat therapy and cold therapy.
• 1:11:24
  SPEAKER_04: How do you feel about that in general?
• 1:11:25
  SPEAKER_03: Oh, you're absolutely right.
• 1:11:27
  SPEAKER_03: But we as an organism, we have this stress response, and all the mammals, not mammals, everything from yeast to mammals, actually have the stress response uh system, which gets activated upon the stress, and it allows to give the better DNA repair, better protein degradation, turnover as well.
• 1:11:45
  SPEAKER_03: It means our body is evolved in order to fight all kinds of stresses.
• 1:11:50
  SPEAKER_03: It means if the stress provides too much, it can kill you or provides too much damage.
• 1:11:55
  SPEAKER_03: But a little bit of stress will give you activation of this response, the survival of response, it will be beneficial for you for longer lifespan.
• 1:12:02
  SPEAKER_03: And that will be a way maybe to extend health span and the lifespan as well.
• 1:12:07
  SPEAKER_03: But we need to be very careful not to overdo it because the question, okay, at which limit we will see the beneficial effect, at which limit we'll lose the beneficial effect and becomes dangerous.
• 1:12:18
  SPEAKER_04: My stress is my stress is definitely at a dangerous level, I'm sure.
• 1:12:22
  SPEAKER_04: What can I ask you about what your own personal um approach is to your own longevity, given that you've been studying this for so long?
• 1:12:33
  SPEAKER_04: Do you have a set of do you have a program that you follow or you have a set of tools that you are most ambitious that people use?
• 1:12:41
  SPEAKER_00: Well, I'm trying to just live healthy lifestyle, um, healthy diet, um, and um, you know, exercise.
• 1:12:51
  SPEAKER_00: I like to be in nature because that's where your stress levels go down.
• 1:12:55
  SPEAKER_00: Yeah.
• 1:12:56
  SPEAKER_00: When you're surrounded by nature.
• 1:12:58
  SPEAKER_00: Uh, we eat seaweed.
• 1:13:00
  SPEAKER_04: Brown seaweed.
• 1:13:01
  SPEAKER_00: Brown seaweed.
• 1:13:02
  SPEAKER_00: Yeah.
• 1:13:03
  SPEAKER_00: Um, but that's about it.
• 1:13:05
  SPEAKER_00: You know, just try staying healthy, you know, doing all your health checkups, things like we were doing today.
• 1:13:12
  SPEAKER_01: Today, yeah.
• 1:13:12
  SPEAKER_00: Uh, learning about your body and understanding it.
• 1:13:16
  SPEAKER_00: Um, but um the research that we do for us, it's more of an intellectual pursuit rather than oh, we just want to make ourselves live longer.
• 1:13:26
  SPEAKER_00: Yeah.
• 1:13:27
  SPEAKER_00: That wasn't really the primary motivation.
• 1:13:31
  SPEAKER_00: No, it's more just gaining knowledge, uh helping um humankind to benefit, but personally, well, I'm doing what I can, but yeah.
• 1:13:42
  SPEAKER_04: Okay, then let me ask you a follow-up question.
• 1:13:45
  SPEAKER_04: Having discovered what you have, has that made you more hopeful about the process of aging or more frightened?
• 1:13:53
  SPEAKER_00: More hopeful, yeah.
• 1:13:55
  SPEAKER_03: Love because there is a new drugs going to be developed, and uh I think we're because we we know the targets, we know what to do, we don't have the right drugs, and one of the problems is the aging drugs as well, the threshold or the standards for the uh how much side effect you can you can get is very high.
• 1:14:18
  SPEAKER_03: Yes, because for example, if you develop the cancer drug which kills 50% of people, of sick people, sorry, but otherwise they are going 100% and gets killed by cancer, but 50% survive, it's a good drug.
• 1:14:31
  SPEAKER_03: Yeah, if you are talking about uh same drug which kills 50% of healthy individuals, yeah, it's a horrible drug in order to do it.
• 1:14:38
  SPEAKER_03: Uh means yeah, means the threshold is uh very, very high, and that's one of the problems because you need to make absolutely sure that no side effect, and especially the majority of these drugs, if you anticipate, will be taken for years, probably you'll start somewhere in middle age, continue for another probably 50 years.
• 1:14:57
  SPEAKER_03: That's a very long time, and any very minor side effects will be amplified through the years.
• 1:15:03
  SPEAKER_04: Is that one of the reasons why it's so difficult to actually you know prove that something is safe and effective?
• 1:15:09
  SPEAKER_04: Because we're talking about lifespan, and we can't just we have to we can't just wait for 50 years for someone to either still be alive or not.
• 1:15:19
  SPEAKER_04: Is that right?
• 1:15:20
  SPEAKER_00: Yeah, that's yeah, but that's where biomarkers hopefully will help.
• 1:15:24
  SPEAKER_04: Do you think that you know no one in history has ever lived more than I don't know, 126 years?
• 1:15:30
  SPEAKER_04: I think that's right.
• 1:15:31
  SPEAKER_04: Do you think that the first person to live past that point is alive now?
• 1:15:35
  SPEAKER_00: It's possible.
• 1:15:37
  SPEAKER_03: I I think it's relatively tricky question.
• 1:15:39
  SPEAKER_03: Easy, easy to not easier.
• 1:15:41
  SPEAKER_03: It's it makes sense to extend the average medium lifespan to close to 100 years, close to 120, maybe.
• 1:15:48
  SPEAKER_03: Yeah, because it will be a distribution again.
• 1:15:50
  SPEAKER_03: Yeah, 120 is the maximum, it's it's uh it's our biological limit.
• 1:15:55
  SPEAKER_03: Right.
• 1:15:55
  SPEAKER_03: Um, but now if you want to live beyond 120, we need to do some more drastic interventions.
• 1:16:01
  SPEAKER_00: Well, because up to today, those people who reached that 120, maybe 115, they were not doing any kind of interventions.
• 1:16:11
  SPEAKER_00: And maybe they benefited from improved sanitations, improved nutrition, but not really intervention.
• 1:16:18
  SPEAKER_00: So yeah, now if we get those uh scientifically based interventions and people start applying them, then I think we can bypass 120.
• 1:16:27
  SPEAKER_04: You do.
• 1:16:29
  SPEAKER_04: Huh.
• 1:16:30
  SPEAKER_04: And certainly more people will reach that number.
• 1:16:32
  SPEAKER_00: Yeah, that's for sure.
• 1:16:36
  SPEAKER_04: If you had an unlimited amount of funding, no restriction, what would be one question that you would love to find the answer for that you don't yet know?
• 1:16:48
  SPEAKER_00: Well, we would like to analyze all of the long-lived animal species using multiple approaches, understand really what contributes to their longevity, and then engineer those mechanisms in one model species and see which ones we have to put together.
• 1:17:08
  SPEAKER_02: Yeah.
• 1:17:10
  SPEAKER_00: To really significantly extend lifespan, you know, like now we are happy with 10%, but what about you know 100%?
• 1:17:18
  SPEAKER_03: Yeah.
• 1:17:20
  SPEAKER_03: Combine different genes, different pathways, treatments, yeah.
• 1:17:23
  SPEAKER_04: It feels incredibly uh hopeful that there are mammals that live that long and that there are people like you that are doing that kind of research, and that feels like a funding problem.
• 1:17:35
  SPEAKER_04: I mean, I'm not gonna be a dead horse here, but like it's so important.
• 1:17:41
  SPEAKER_04: It's something that impacts all of us.
• 1:17:44
  SPEAKER_04: I find it difficult to reconcile why we aren't spending more money on this.
• 1:17:51
  SPEAKER_00: I think it it's I think this concept that diseases are the result of aging, that aging is the cause and disease is just manifestation of things you know wearing out.
• 1:18:05
  SPEAKER_00: I think that's only now is becoming more generally accepted because a lot of uh resources or financial resources were put into treating individual diseases.
• 1:18:16
  SPEAKER_00: Uh and uh we are, you know, I think we achieved a lot of progress with that, but then still, like for example in cardiology, yeah, you can now you know put stance and uh kind of fix the plumbing, but then still the whole system declines, so then you you hit the threshold now.
• 1:18:37
  SPEAKER_00: How do we bypass that?
• 1:18:39
  SPEAKER_00: Then we really need to treat the cause.
• 1:18:41
  SPEAKER_00: And this realization came just recently, so I hope that then with this realization more resources will be put into studying aging.
• 1:18:51
  SPEAKER_04: Do you think we need to see more cross-collaboration between institutes?
• 1:18:56
  SPEAKER_00: Oh, yes, of course.
• 1:18:58
  SPEAKER_00: I think collaboration is super important, and something you know, maybe that is uh for us scientists, we are now really concerned about it because um, like uh two weeks ago, there was this another idea proposed by the government to limit the number of grants that one researcher can hold.
• 1:19:18
  SPEAKER_00: And to limit the limits were set, like we don't know what it will be at two or three.
• 1:19:22
  SPEAKER_00: Uh, but that's crazy because if you can only investigate like two problems, i you cannot collaborate because everyone will be investigating their own two problems, and there will be no opportunity for people to like do cross-discipline research and collaboration, so we don't know what will happen.
• 1:19:42
  SPEAKER_04: Yeah.
• 1:19:43
  SPEAKER_04: Well, hopefully we can solve for that soon enough.
• 1:19:47
  SPEAKER_04: Where do you see uh your study evolving over the next 10 years?
• 1:19:52
  SPEAKER_04: Right.
• 1:19:52
  SPEAKER_04: So in 10 years' time, if you could look back at today and say we did this, what would what would feel like a win for you?
• 1:20:01
  SPEAKER_03: I really think that um improving epigenome is probably the most promising way to go.
• 1:20:10
  SPEAKER_03: And recently we got that funding from RPH, actually, to um use NRTIs.
• 1:20:17
  SPEAKER_03: Actually, yeah, to that's too much terminology, probably.
• 1:20:22
  SPEAKER_03: Yeah, how to stabilize the epigenome in order to extend the lifespan.
• 1:20:25
  SPEAKER_03: And we can show that in mice uh by controlling our repeated sequences in a genome, which is not genes, um we can extend the health span and the lifespan of the mice.
• 1:20:37
  SPEAKER_03: Again, not huge increase, but probably like 10, 10, 15.
• 1:20:42
  SPEAKER_03: Um another interesting observation we can see uh actually extension of the reproductive lifespan.
• 1:20:50
  SPEAKER_03: It means usually mice they reproduce up to nine months of age, 10 months for female, for female mice.
• 1:20:58
  SPEAKER_03: Uh but with um better control of the epigenome, they can breed up to like 15 months of age.
• 1:21:06
  SPEAKER_03: It's almost double.
• 1:21:07
  SPEAKER_03: There's huge huge yeah for males, usually it's 12 months for males, and uh they stop breeding after 12 months, black six mice.
• 1:21:15
  SPEAKER_03: And um when they control the epigenome, they can breed up to one year, two years, sorry, 24 months.
• 1:21:21
  SPEAKER_03: And this you have the huge effect.
• 1:21:23
  SPEAKER_03: I think for us, it's for me.
• 1:21:24
  SPEAKER_00: Yeah, that was like doubling of reproductive.
• 1:21:27
  SPEAKER_03: And if we're trying to to translate it to human, that means we can probably delay the menopause.
• 1:21:32
  SPEAKER_03: Yeah, yeah, yeah.
• 1:21:32
  SPEAKER_04: And no, menopause is a huge hit on a women's body because the also especially if we are then increasing lifespan, if that that becomes relatively more urgent because you know you want to increase that.
• 1:21:45
  SPEAKER_00: Even though it's not comparable to biology, but this is one of the yeah, we studied so this is so-called dark genome because well, we everybody knows genes, but genes only make one percent of our genome.
• 1:21:57
  SPEAKER_00: And what's the other 90 percent?
• 1:21:59
  SPEAKER_00: A lot of it is made of these elements they're called transposons, which are formerly viruses, but in evolutionary past they just integrated in our genome, and there's a lot of them.
• 1:22:12
  SPEAKER_00: Uh, and you like when we are young, they don't really make a problem, but when we get old and our epigenome gets old, so they become active and they start to kind of be expressed, and the cell responds to them as if it's infected with viruses.
• 1:22:29
  SPEAKER_00: So it's like our endogenous internal parasites, and they trigger inflammation.
• 1:22:35
  SPEAKER_00: Um, so one big project in our lab is how to keep these parasites under control because they may be uh accelerating the aging process, which other parasites do when they infect the host.
• 1:22:51
  SPEAKER_04: That would make sense, right?
• 1:22:52
  SPEAKER_00: Yes, but these are parasites on the level of our DNA.
• 1:22:56
  SPEAKER_00: Uh so that was also a very important discovery.
• 1:23:00
  SPEAKER_00: Um, and we are very excited that now it we may even progress to a clinical trial um with our page support and to see whether controlling these parasites can uh improve health span and lifespan.
• 1:23:16
  SPEAKER_04: Love that.
• 1:23:17
  SPEAKER_04: It's a good 10 years.
• 1:23:19
  SPEAKER_04: What would you say this is a two-part, it's one question, but it's two parts.
• 1:23:24
  SPEAKER_04: What would you say is the most underrated tool for improving length and quality of life that we know now?
• 1:23:32
  SPEAKER_04: And what would you say is the most overrated?
• 1:23:36
  SPEAKER_00: It's difficult to say what's underrated.
• 1:23:38
  SPEAKER_00: I think for a while I think psychological aspect of it was underrated, but now people really start to realize that uh from studies of centenarians, that most centenarians they just have very positive outlook on life, and that makes a huge difference.
• 1:23:56
  SPEAKER_04: Yeah.
• 1:23:57
  SPEAKER_04: Optimism is a real deal when it comes to having a long and healthy life.
• 1:24:02
  SPEAKER_03: This is really something interesting because I'm teaching the course of uh uh biology of aging when I'm talking about different pathways, mechanisms, genes, and how they get regulating the agent, but I always get puzzled by the this phenomenon of will to leave.
• 1:24:18
  SPEAKER_03: You know, if the people lose that will to leave, they'll actually die.
• 1:24:22
  SPEAKER_04: Yeah.
• 1:24:23
  SPEAKER_03: And how how does it control our aging?
• 1:24:26
  SPEAKER_03: I don't know what is that a will to live.
• 1:24:30
  SPEAKER_00: Well, but very often, you know, that that's everybody familiar people are very active in their jobs, then they retire and they start aging.
• 1:24:39
  SPEAKER_00: The most dangerous year of your life, yeah, retirement, yeah, and then they lose this will to live because like they really don't like having purpose, purpose, yes.
• 1:24:50
  SPEAKER_04: Yeah.
• 1:24:51
  SPEAKER_04: I agree, and it and we don't quite know why, right?
• 1:24:54
  SPEAKER_00: Right, right.
• 1:24:55
  SPEAKER_00: So that's you know, we big just now beginning to look into that and kind of get into the molecular aspects of it, but like in just psychological level, it just recently became kind of uh common knowledge.
• 1:25:11
  SPEAKER_03: But the men will live shorter than women, but also men is quite easy to give up when they kind of succeed to perform like when they're young.
• 1:25:20
  SPEAKER_03: Yeah, you know, maybe that's one of the crazy explanations why we short live because we uh easily give up.
• 1:25:26
  SPEAKER_04: Yeah, women they also make a lot of stupid decisions as well, and then that contributes.
• 1:25:32
  SPEAKER_04: What about overrated?
• 1:25:33
  SPEAKER_04: Something you see a lot of the time in the media, and you're like, I wish people would stop supplements.
• 1:25:39
  SPEAKER_03: Oh, the supplement of the supplements, they're extending lifespan and all that all these claims.
• 1:25:45
  SPEAKER_03: They're just yeah, you look on the come on, guess it's yeah.
• 1:25:49
  SPEAKER_04: I think you could maybe list the ones worth taking on one hand, exactly.
• 1:25:52
  SPEAKER_03: Yeah, and again, I'm not sure what those how frequently.
• 1:25:57
  SPEAKER_00: No, but they would say maybe I I there there must be supplements that work, you just don't know which ones.
• 1:26:04
  SPEAKER_04: We we need more data.
• 1:26:05
  SPEAKER_04: Well, even the ones that we suspect or we have strong evidence that do work, then am I actually getting that when I buy it?
• 1:26:13
  SPEAKER_04: You know, that that's unregulated.
• 1:26:16
  SPEAKER_04: That's a huge problem.
• 1:26:17
  SPEAKER_00: Yes, because if it's unregulated, yeah, you can buy something that says you know, NMN, and there's no NMN.
• 1:26:26
  SPEAKER_03: Yeah, yeah.
• 1:26:27
  SPEAKER_03: I think there was a test like that for for melatonin for NMN and others.
• 1:26:32
  SPEAKER_00: Well, yeah, many melatonian supplements have like almost zero.
• 1:26:35
  SPEAKER_04: Zero, yeah.
• 1:26:36
  SPEAKER_04: Like there's lots of examples of that.
• 1:26:38
  SPEAKER_04: What are your thoughts on NMN?
• 1:26:42
  SPEAKER_00: I'm not I think that's really overhyped.
• 1:26:45
  SPEAKER_00: I agree.
• 1:26:45
  SPEAKER_00: Uh, there is really no evidence that it extends lifespan in humans or even anything in humans.
• 1:26:52
  SPEAKER_00: Um, but for some reason it's a it sells very well.
• 1:26:57
  SPEAKER_03: Yeah, for some reason it gets hyped by the media journalists.
• 1:27:01
  SPEAKER_00: I mean, maybe there is some evidence that it helps muscle function.
• 1:27:05
  SPEAKER_00: I believe that.
• 1:27:07
  SPEAKER_00: Uh, but like overall general health, yeah, I don't think there is evidence.
• 1:27:12
  SPEAKER_04: I think there's a few scientists that have gone out there and said that this is something you should absolutely take, and then that's what's led to the media for a robot.
• 1:27:20
  SPEAKER_04: It's interestingly most of the scientists that I've asked that question have agreed with you in implicitly.
• 1:27:27
  SPEAKER_04: I agree as well.
• 1:27:28
  SPEAKER_04: Okay, last question.
• 1:27:30
  SPEAKER_04: If one of the or a number of the listeners were to tune into this episode for the last 60 seconds, what would you want them to take away?
• 1:27:39
  SPEAKER_04: What would be the message?
• 1:27:42
  SPEAKER_00: Well, I would say I'm very optimistic about um that we can improve human lifespan and health span.
• 1:27:52
  SPEAKER_00: Um, we don't know everything yet.
• 1:27:55
  SPEAKER_00: Um, right now I would focus on lifestyle changes and uh just following your health.
• 1:28:03
  SPEAKER_00: Doing all these tests, maybe they don't always give you a very concrete answer, but the more you know, uh the more power it gives you.
• 1:28:14
  SPEAKER_00: Um and uh with supplements to be conservative, look for evidence, uh, check what level of evidence exists for certain things to work.
• 1:28:24
  SPEAKER_00: If necessary, even go to check the primary literature and to see okay, what exactly did they show this now?
• 1:28:30
  SPEAKER_04: It's great.
• 1:28:32
  SPEAKER_03: Yeah, I absolutely agree.
• 1:28:33
  SPEAKER_03: It's very easy to modify the lifestyle, and everyone know how to do it, it's just our will.
• 1:28:39
  SPEAKER_03: We need to be able to do it.
• 1:28:42
  SPEAKER_03: And um I also think a little bit of bad things is good.
• 1:28:47
  SPEAKER_04: My guy well, I think you I think to what end are we doing all of this if we don't then enjoy life as well?
• 1:28:55
  SPEAKER_04: We can't suck the fun out of it.
• 1:28:58
  SPEAKER_04: It's been a pleasure and a privilege, really.
• 1:29:00
  SPEAKER_04: Thank you so much for coming in and and for taking the time to do this.
• 1:29:04
  SPEAKER_00: No, you're most welcome.
• 1:29:06
  SPEAKER_00: It was fun.
• 1:29:07
  SPEAKER_04: We had a fun day, right?
• 1:29:09
  SPEAKER_04: I mean, I had more fun and that I didn't do the tests.
• 1:29:12
  SPEAKER_04: Thank you guys.