 Let's talk about the Yamanaka factors. All right, it's my favorite topic. First of all, what are they? Well, Yamanaka factors are like the transcription factors of this guy, Yamanaka. Shania Yamanaka discovered back in 2006. He was basically looking at things that can rewind a cell back into embryonic state. And he was looking at a panel of 24 different genetic factors. Like a transcription factor is just like a genetic mechanism that goes inside the nucleus and changes gene expression, changes what genes are turned on and off, and can do like a massive remodeling of a cell. And it turned out that those four, if you use them together, they do not just massive remodeling. They can actually bring it back to embryonic state where that cell can now, again, become anything you want in a body. Because what is so special about an embryonic stem cell? That it can turn into pretty much any cell in your body. It's a naive cell. They thought, yeah, before that, before Yamanaka, they thought that this is like a one-way street that you cannot come back. Your skin cell cannot be turned back into an embryo, right? They thought it's like the waterfall that they wanted to let the model where it just kind of rolls down and it can't get back up. And Yamanaka turned it all on its head and said, no, you actually can. Any cell that has a nucleus can turn back into an embryonic cell. And again, you can create an embryo. Like you can create your own clones from your skin cells or whatever and you have that kind of cell, which is a scary prospect, but that's beyond. So this is kind of like, so this would be kind of similar to like stem cells where? Yeah, it's even like a more, even more potent stem cell. It's an embryonic stem cell. So theoretically, I can draw my blood, theoretically. Apply through the therapy of stimulating the Yamanaka factors into my drawn blood. Let those cells then go back to a younger version of it and then re-inject it into me. Well, that's one of the ways. Yeah, you can create stem cells out of those or you can take your own stem cells and kind of rejuvenate them using Yamanaka factors, but how we stimulate the Yamanaka factors? Well, you have to kind of get them into the cell. You have to either get the genes for these factors into the cell and get the cell to start creating proteins from those genes, the actual transcription factors, or you can get the actual proteins, the Yamanaka factors into the cell. Of course, usually the easier ways to do the gene thing because we have a lot of instruments that can insert needed genes. So CRISPR tech would be used on this? CRISPR is, yeah, it's one of the ways, but I mean, they have kind of AAVs that then associate viruses that do, like, are you specialized for this, for gene delivery? I mean, CRISPR is more used for cutting stuff and you still need- They're good to RNA, cut it out, yeah. Yeah, pretty much, yeah. And so, yeah, once you get those genes into the cell and if you activate them, they can roll back the cell back to this kind of pluripotent state and not only do they do that, they rejuvenate it in the process. So if it was like a 100 year old skin cell that he had all these kind of problems that a 100 year old cell exhibits, like kind of misfolded proteins or reduced mitochondrial efficiency, mitochondrial function, if you induce them in aquifactors, roll it back to the pluripotent state and then create another, again, make it induce it to become a skin cell again, that new skin cell will be completely rejuvenated. It have normal, young levels of mitochondrial function, all the misfolded proteins. So where we are today with the research for this, this seems to be like... It's happening. Yeah, I mean, of course, on the cellular level that's creating pluripotent stem cells, they've been researching it as soon as in 2006, Yamunaka published this paper. But what just recently scientists in the aging field realized that you can use this in vivo, like in the animal, if you activate those factors just in the right dosage, then you can rejuvenate the animal itself, like systemically and make the animal live longer, which is, yeah, which is, I think, that's a groundbreaking thing because it's one thing to just, you know, take cells. So they've done this? Yeah, they have. Oh, rats? Mice. Yeah, it was a transgenic mouse line that was already like kind of predisposed to living much shorter periods. So they haven't been able to do this in normally aged mice, which is kind of right, that's where the field stands right now. This is like the next milestone we need to accomplish. We need to take these factors and make a normal aging mice that usually lives like two and a half years rather than like, I don't know, three months and make it live longer, as long as possible. And this milestone is still to be accomplished. But the proof of concept that was shown in 2016, this paper out of Salk Institute by Ocampo, it showed that you can use this kind of gene therapy in our bodies inducing Yamunaka factors to prolong lifespan. And this dovetails very well with the idea that aging is an epigenetically controlled process because Yamunaka factors, that's what they're doing. They're kind of rewinding the epigenetic clock backwards to the time zero where it's embryonic cell, which has by definition age zero, epigenetic age zero. And luckily this rewinding process is gradual. And we're just, it didn't have to be, it could be like a, could have been a binary thing where the cell is an old cell, skin cell and somehow it's rolled back into embryonic cell, but like not in a gradual way. But luckily it is a gradual process where if we kind of cut off this kind of re-programming process just in time, so the cell still remains a skin cell, we can gain the rejuvenation aspect without losing the kind of cell identity. And this is important because that's the kind of danger right now of this process that when cells are taking too far, they lose their identity as a skin cell. They become kind of this kind of lost in a no-man's land where they're not yet an embryonic cell, that this kind of in-between thing. Then you can get all kinds of problems and that's why animal dyes. They develop these teratomas, it's pretty much like cancerous tumors from this process. And this is what we need to iron out. We need to make this process safe so that there's no side effects. And then of course, efficacious so that it extends lifespan by significant amounts. But it's very exciting because all of the signs are pointing that if we learn to control these, the epigenetic process of aging, then we can periodically kind of rewind this epigenetic clock. And this is another thing, this is a revolutionized field of aging research, the discovery of the epigenetic clock that we have in our bodies. It was like in 2013 and even before that the famous, famous scientist was Steve Horvath. I'm pretty sure you've heard of him of developing this epigenetic clock of aging. It was discovered that everybody, a person of a certain age, has a very similar level of specific genes like their epigenetic levels of these genes are the same, which was kind of weird. I mean, why would our bodies develop in such a predictable way? Because initially we thought that aging is like a stochastic process. And by that definition, all these epigenetic settings should diverge, right? You shouldn't be able to take two random people of the same age and have the same levels of certain genes being expressed, right? And so it was discovered that there is actually a subset of genes that change in a very predictable way so that you could take a cell from anybody without knowing their age and just using these analysis of like epigenetic patterns, you're able to say kind of how old the person is. Yeah, the cellular age, yeah. Yeah, and so, and you know, not just one type of tissue, that there's a universal epigenetic clock that you could take like your blood and then its epigenetic clock will correlate with your neurons. And this is very, very odd because it's very different cells. Neuron is as old as your, you are, right? Because you had it from being an embryo, but blood cells renew all the time. But at the epigenetic clock level, the clock is showing the same time. And this is very strange because it's showing that there is some kind of coordinated program in an epigenetic program that hopefully will decipher one day and be able to hack. It doesn't come as a surprise. Like, you know, the famous fly studies, you look like B-Mole clock and all the circadian clocks. We know our body functions on clocks. Of course. And yeah, to people who are not like, deep into biology, it seems like common sense that of course there's some kind of program, right? Because we have life stages. We know that at a certain age, puberty starts. And everybody about the same age goes through it. And then at another age, like for women, there's menopause. And that's also pretty much predetermined at a certain age. So our body does keep some kind of clock. It does, you know, of course there's a circadian clock. We, you know, we get, you know, want to go to sleep at a certain time. And of course it seems like common sense that the same kind of clock could be used to, like internally it needs to be synchronized, could be used for aging as well. But for biologists, I think it was, for some reason it was a surprise that, you know, there could be some kind of coordinate process that is tied to aging and even after, say, like even after your reproductive age stops, even after that it's also synchronized. Which, you know, this kind of goes against the dogma that we only evolved up to the level of when reproduction stops. And after that it's just, you know, mutations go wild and things should diverge in our bodies because that won't be passed to our progeny because we won't have any more progeny. But no, even after, you know, reproduction stops, for some reason there's a lot of coordinated processes that occur at very similar rates in different people. And this is odd, it kind of points to there being some kind of, you know, synchronization between, you know, what happens to people during aging and I think it's a manifestation of an aging program that hopefully we're just around the corner of being able to decipher and do something about it.