| 1 | Modern Healthspan | Single Gene Reverses 13+ Years of Aging - Safer Than Yamanaka Factors | 11355 | 592 | 84 | 87.1 | positive | 6:05 | [Music] What if one gene was able to provide the same or better rejuvenation with epigenetic reprogramming than the Yamanaka factors and without the risk of cancer? A new preprint just released documents a gene sp0000 that turns back the clock of cells without the danger of pluropotency and the loss of cell identity that are inherent when using the ammonaka factors. This addresses one of the main concerns with reprogramming as a therapy and is a great step forward. Let's look at what they found and why it's so important. Epigenetics is the layer of control that exists on top of the DNA. It uses activities such as methylation to control which genes are turned on and which are turned off. The epigenetics of cells changes in a predictable way as we age, which is what the epigenetic clocks use as a basis to measure biological age. Changing the epigenetic profile of a cell so that it is younger has been shown to make the cell behave as a more youthful cell. This has been possible with the yamanaka factors. These are four genes 2, zox 2, kf4 and cmix abbreviated tokm which when expressed in a cell can turn it back into a pluropotent stem cell. So a pluropotent stem cell is a cell that can become any type of cell in the body like a master cell that hasn't decided what to become yet. On the way to becoming pluropotent, the cell also becomes younger leading to the process to be called partial reprogramming. The problem with this is that it can lead to loss of cell identity which is necessary for a cell to become puropotent. So for example, a skin cell no longer remembers that it's a skin cell and may become a liver cell instead. This means that the cell no longer functions correctly in its place and may become cancerous. When delivering Yamanaka factors in vivo, that is to living tissue, it's very difficult to control how much reprogramming each cell gets. And so to be sure no cell changes identity. This is a major roadblock for partial reprogramming with the Yamanaka factors. But what if we could separate the rejuvenation effect from the pluropotency problem? The original Yamanaka factors were chosen because of their ability to induce puropotent stem cells. Rejuvenation was almost a side effect. So the team at Shift Biosciences took a different approach. They built a high throughput screening system that could test thousands of genes simultaneously using a rejuvenation first strategy to measure success. They developed AC3, a precise aging clock that determines a cell's biological age by analyzing gene activity patterns. This allowed them to quickly identify genes that reversed aging without the dangerous side effects leading them to discover SP0000. Now, the name does have three zeros, but from now on, I'm going to call it SP0. Initially, they tested on human skin cells. They use cells from donors aged between 1 and 87 from both sexes and various ethnic backgrounds. as well as AC3. They also tested against standard clocks such as hva, grim age and dunadin pace in aged human skin and lung cells when the genes were applied for 2 weeks. SP0 reduced the transcripttoic age by 4.52 years compared to 5.46 for six years for OSKM where transcripttoic age is the age of a cell based on which genes are active measured by analyzing the gene expression patterns. SP0 reduced scinessence markers by 28% more consistently than OSKM in skin cells for 6 weeks. SP0 reduced the Horvath clock by 7.42 years. The authors also tested the degree to which the cells moved towards pluropotency which was of course much high in OSKM. Meanwhile, the SP0 cells firmly retained their identity as skin cells. SP0 reversed epigenetic age by 13.6 years in caratinosytes even stronger than its effect in fibroblasts that is the skin cells. Delivering one gene is also much simpler than delivering a cocktail of them as building the AAV is less complex. Doing is more straightforward and figuring out the mechanism of action is also easier. In summary, using SP0 brings the same or better rejuvenation as the Yamanaka factors across multiple cell types with greater safety and ease of delivery and in particular gets around one of the biggest concerns of OSKM which is the risk of cancer. So far the paper is only a preprint and if shift biosciences has not released the nature of SP0 this may make getting it peer review tricky but it is certainly interesting and I will be keeping an eye on it in the future. Thank you for your attention and I wish you all well. [Music] | ↗ |
| 2 | Modern Healthspan | Surviving Lifespan Extended By 109% With Partial Reprogramming | 6831 | 383 | 42 | 83.6 | positive | 7:33 | [Music] foreign this is Richard from Modern healthspan partial programming is one of the most exciting Rejuvenation Technologies although it has been shown to rejuvenate tissues one outstanding question is whether it can extend the lifespan of an organism this is what the team looked at in this paper gene therapy mediated partial reprogramming extends lifespan and reverses age-related changes in aged mice please note that this is a preprint so it has not been peer-reviewed yet and one of the main authors is Dr Noah Davidson who has recently been on our Channel where we discuss some of the background to this paper the aim of the study was to see if cellular reprogramming impacts Health span and lifespan recent Studies have shown that three of the four yamanaka factors opt-4 sox2 and klf4 with cmic being omitted have reversed age-related changes in vitro and in Vivo however whether the lifespan of wild-type mice can be extended has not been studied in the study they delivered these osk factors intermittently to the whole body using a viral Vector into 124 week old mice which is about equivalent to an 80 year old person this extended the remaining weeks of Life by 109 compared to the controls and also Health span as measured by a lower Frailty index they also saw a reversing of epigenetic age in human skin cells with the same set of three yamanaka factors I will not cover this in any more detail the results may have important implications for the development of partial reprogramming interventions before we jump into the paper let's hear Dr Davidson describe partial reprogramming with yamanaka factors yeah for our next generation of uh therapeutic targets um I mentioned epigenetics uh earlier and our goal is to re-regulate all of your genes back to an earlier State a very powerful tool for this is to use epigenetic modifying factors similar to the yamanaka factors where you do this partial reprogramming which has been a very hot topic of lately where you temporarily turn the cell toward a stem cell and then let it relax back into its normal cell function people have shown benefits from doing this partial reprogramming I did a had a collaboration with Sinclair lab where they were able to show um rejuvenating effects in the optic nerve from an aav that delivered osk these are three genes that are part of this um reprogramming set that uh that came from the pluripotent stem cell field and our next generation of therapies is taking advantage of this idea that you can re-regulate all the genes in a Cell back to an earlier State and make that entire cell younger and if you can infect enough cells in a tissue the entire organ and if you can infect enough organs in the body the entire person and so our goal is to start with a very specific tissue and show that we can have a large effect on a particular disease and then expand the different tissues and cells that we can get into throughout the body so that we can reverse aging systemically in each individual cell they made a couple of points in the paper which I think are worth highlighting the first is that some previous Studies have used transgenic mice which were designed to express the yamanaka factors in the presence of Doxycycline this has the benefit that it removes the problem of delivering the factors to the cell but is not translatable as we are not going to have transgenic humans so in this case they used aavs or adeno-associated viruses to deliver the genes the second is that it will not be young people who are going to be rejuvenated rather it will be the elderly so it makes sense to try the therapy on aged mice in this case the mice were c57 bl6 J mice 124 weeks old these mice have a median lifespan of 129 weeks in the study they used an aav an aav is a non-pathogenic virus for which the DNA can be changed when the virus is injected it will enter into the cell and produce the proteins based on the DNA that have been loaded into it in this case they use two separate payloads one was the three yamanaka factors opt for sox2 and klf4 the genes were not active all the time instead they were used on a Cadence of one week on one week off throughout the trial to control the expression of the genes they used a system which would Express them only in the presence of Doxycycline and antibiotic one of the viral vectors could detect the presence of Doxycycline which then released a promoter Tre that activated the amanaka factors in the other viral package here are some of the key results this graph shows the survival curves from the start of the experiment with the mice aged 124 weeks there were 20 in the treatment group and 20 in the control group the median lifespan is the time when 50 of the mice is still alive for the control group this was 133 weeks and for the treatment group 142.5 weeks this is an increase from 8.86 weeks of life remaining at 124 weeks to 18.5 weeks or 109 percent the total lifespan increase was about seven percent The Gray Line is for the historical data for this type of mouse from the Jax lab which supplied the mice using the Frailty index defined by Heinz Mill they assessed the health of the mice the treatment group was significantly less frail than the control where a lower Frailty score index is better it should be noted that the study was run by rejuvenate bio who is developing Therapies in this area the paper skipped some details with any yamanaka Factor based reprogramming there is concern over Cancer all they mention on this is that they did not observe any gross teratoma formation overall I thought this was a great first step to show that partial reprogramming could extend lifespan in older mice I like that they used old wild type rather than transgenic mice as discussed with Dr Davidson rejuvenate bio is currently trialing a more targeted gene therapy for specific proteins in the liver with the same aav technology which is closer to clinical trial this overall Rejuvenation is in development for their next generation thank you for your attention and I will speak to you again soon [Music] | ↗ |
| 3 | Modern Healthspan | Cellular Reprogramming In Practice | Prof Vittorio Sebastiano Intervie... | 2019 | 104 | 16 | 81.8 | positive | 9:46 | [Music] foreign [Music] you've tried in Vivo with human uh no sorry in vitro with human cell types what cell types have you tried have you tried like neurons and heart cells and like all cell types uh we we have tried about variety of different cell types uh really a lot human cell types and human cell types that have been naturally aged in the sense that they have been isolated from from an elderly individuals uh this is very important because aging as we know is a very complex phenomenon uh and uh it cannot be simplified it needs to be study in its in its complexity in my opinion um yeah we have tried a variety of different cell types uh uh dermal fibroblasts that were derived from different parts of the body endothelial cells that were derived for example from harder is or or or veins chondrocytes muscle stem cells mesenchymal stem cells different cells of the of the eye blood cells um and so in all of these instances in all of these cell types era has worked successfully uh and so yeah so we we have been trying a lot of different cell types and I can say that you know the same cocktail seems to be working across uh all of them I I seen that you've you've talked about using the cocktail using era to reduce the age of stem cells rather than somatic cells is that like the correct term for yeah normal cells um so can you talk a little bit so how would that work would you take the stem cells out you make them younger and then you put them back in again or you you make them younger inside the body yeah but both both are are true in the sense that if we if we know how to obviously doing this outside of the body is simpler is easier uh provided that you know how to isolate the stem cells and keep them in culture expand them multiply them and so forth so for example in the case of muscles themselves we have been successful successful in doing so because we know thanks also to another to another um IP that's that turn owns exclusively and that was developed by one of the co-founders of turn Marco Cuarta we know how to isolate the muscles themselves from the from the muscle we know how to keep them in culture we know how to expand them and we know how to preserve their stemness which is their capacity of giving rise to all the cells of the muscle for others for other stem cell types you know this is not possible yet because we still need to understand and figure out how you know this process of isolation expansion proliferation happens because every every cell type every organ is in a way very unique in this in this regard um and so for those for those organs or for those tissues in which we know how to isolate the stem cells we know how to expand them we know how to uh to characterize them this process of X Vivo uh Rejuvenation is probably the the first the kind of the low-hanging fruit in a way because it allows us to Target those cells and put them back into into the organ they they came from but of course the vision is to bypass this this process and being able to to Target the stem cells where they are in the organ in the tissue in the body how do you do that by for example again once you know where they are and once you know their chemical you know the the chemical features of their membranes or their features in general you can you can develop solutions to specifically Target them in Vivo in the in the body this video is brought to you by buy optimizers magnesium is a crucial mineral for hundreds of reactions in the body it impacts everything including sleep and muscle and bone health it is difficult to get sufficient magnesium through our food in our efforts to remain fit and healthy my wife and I frequently exercise after which it's important to recover well and get restful sleep to help us with this we chose magnesium breakthrough from biooptimizer because it Blends all seven essential forms of magnesium into one effective supplement while also using all-natural ingredients and being gluten soy and lactose free it has improved our recovery and Sleep Quality since we've been taking it and we are happy to tell you that by optimizers are offering a 10 discount for magnesium breakthrough two Modern Health span audience just go to www.magnesianbreakfruit.com Modern or click on the link in the description to get a 10 discount with coupon code modern10 thank you for your support so how would that work or would that work in cases where you have long-lived cells like the brain right the brain does not build new cells generally so would you be able to do that or would you have to rejuvenate the existing somatic cells well uh era era has worked successfully in both the stem cells and in the so-called fully differentiated somatic cells um so uh I haven't tried yet we haven't tried yet in neurons right but um I I think actually probably the neurons are from a biological standpoint are probably even um kind of better to targets because since they are post mitotic what does that mean it means that they are not cycling it means that they are way more resistant to pass beyond the point of no return because the point of no return is also a function of the cell cycle the more the cells divide the higher is the chances that they can actually go beyond the point of no return neurons hard cells or any other cells which is uh by definition considered post mitotic which means they do not divide are more resistant to that process of of reprogramming and more it's more unlikely for them to go beyond the point of no return so that means that from a safety standpoint they're probably you know an even better cellular targets to to to rejuvenate with air um so more work will follow but you know it is very likely that actually the neurons and heart cells are gonna be are gonna be even a better Target for for air so my understanding would be that you would have like two different I guess arms ways of doing this so one would be to rejuvenate the stem cells and and this is like the end point where you're aiming for is there one would be to rejuvenate stem cells which which would then repopulate the organ and one would be to rejuvenate somatic cells kind of in situ exactly speaking of rejuvenating organs So within kind of the mouse model how what how far have you got in terms of rejuvenating have you rejuvenated an organ like made a liver a young liver or any if you looked at that uh not the liver but we have done we have done this for example in muscle by which we needing the stem cells of the of the muscle in mice we have shown that we can bring the entire muscle because again the muscles themselves regenerate the whole muscle because that's their function we have regenerated the whole muscle to the levels of a youthful muscle so we did this experiment where we took uh a um stem cells from a 24 months old mouse so 24 months old mouse is a very geriatric Mouse okay it's like a 90 plus years old uh human being okay so we took the stem cells from that muscle we treated them with era for just 48 hours so a very short period of of or a very short treatment and then we transplanted those stem cells into a 24 months old recipients so that you know the donor and the recipient were of the same age okay we could show that by doing so so by treating the age stem cells with error that was sufficient to bring the strength of that whole muscle after the Regeneration to the levels of a young by Young I mean six months old mouse so if you compare the two the two ages it's like bringing back the strength of a muscle of the 90 years old human being to the strength of probably 40 30 40 years old human being which is pretty significant and that was xvivo so bring it up bring it out there was an evil followed by the transplantation indivo into into the animal yeah [Music] foreign | ↗ |
| 4 | Modern Healthspan | Practical Aspects of Cellular Reprogramming | Prof Vittorio Sebastiano... | 1467 | 85 | 18 | 79.8 | positive | 10:37 | In a more general case, so like the topic all on the screen, on the skin or something like that. So how often would you need to do this therapy? Because you're resetting the age of the cell, which one would assume would then last for a while. Is it something you're going to have to do often or once every few years or how often? Well, we don't have yet a definitive answer to that question. It's going to depend on the cell type. It's going to depend on the tissue, first of all. It's going to depend on the feature, the aging features of that tissue. And it's also going to depend a lot on the targeting efficiency that we're going to get. So just to go back to what we said before about the stem cells, if we're able to target the stem cells and make them younger, the stem cells have the long term capacity of regenerating the tissue. So that means that if we can target specifically the stem cells, we have a very, very long duration potentially just with one with one single treatment of the effects of that of that treatment. If we cannot target the stem cells and we target only the somatic cells, then depending on how long the somatic cells survive in that tissue, you may have different timing outcomes. In the case of the brain, and right now I'm just speculating again, I don't have data in my hands. In the case of the brain, since a neurons theoretically is there for for lifetime, if you can rejuvenate the neurons by let's say 20, 30, 40 years, I don't know, you probably gain 20, 30, 40 years in terms of function of that of the neuron. So again, it depends on the cell type, it depends on the tissue, it depends on the disease. But there is there is potentially a very, a very long or there is a chance for for a long lasting effects. How deterministic is the point of no return? And if you deliver like the therapy to three times, I mean, there's a probability that one cell will get hit three times and one cell, some cells won't get hit at all. Right. And so is there a danger that one or two cells would go, would be would go beyond the point of no return? There is there is a chance, yes, there is a chance. And that's why we absolutely need to conduct very rigorous safety studies and develop the appropriate models to study this important question. For example, we have never done experiments as of yet of repeating the error treatment over or pulsing the error, the error treatment over the course of several weeks or several months, we have only done a specific intervention of a certain number of days, which changes depending on the cell type, but we've done it only once for for two or three or four days. We are now doing studies in that in that in that regard. So we're trying to pulse the error treatment. So those two, three or four days, multiple times over the course of weeks to see, you know, what what you if what you were saying is true. And the first one is that by really understanding by really knowing the biology and the physiology of the cell type you're dealing with in depth, we can actually figure out even different windows of intervention or different modalities of intervention over the course of time. Again, just thinking out here, it could be that maybe the first time you have to treat you have to treat the tissue for five days and then maybe the second time just for a couple of days, why because the cells now are rejuvenated in the way, maybe they're more prone to the point of no return, but at that point, the effect that you can get with a much shorter treatment is much is much more effective. So there is a lot, there is a lot of potential interventions, but the bottom line is that we really need to rigorously understand the specific cell type, the specific physiology, the specific pathology and then base, base our base our findings on base, our decisions on on on data. This video is brought to you by bio optimizers. Magnesium is a crucial mineral for hundreds of reactions in the body, it impacts everything including sleep and muscle and bone health. It is difficult to get sufficient magnesium through our food, in our efforts to remain fit and healthy, by a wife and I frequently exercise, after which it's important to recover well and get rest for sleep. To help us with this, we chose magnesium breakthrough from bio optimizer, because it blends all seven essential forms of magnesium into one effective supplement, while also using all natural ingredients and being glued, soy and lactose free. It is improved our recovery and sleep quality since we've been taking it and we're happy to tell you that bio optimizers are offering a 10% discount for magnesium breakthrough to modern health fan audience. Just go to www.magnesiumbreakthrough.com slash modern or click on the link in the description to get a 10% discount with coupon code modern 10. Thank you for your support. The reprogramming sounds pretty wonderful, I mean being able to make that tissue younger again. So is there anything that it doesn't cover? I mean, if I can rejuvenate my tissues, my liver or whatever, so will there still be pieces of me that are going to be getting old? It's an interesting question. So, well, the rejuvenation process doesn't mean that now the cells are no longer capable of aging actually. So you're just bringing the cells back in time, but the aging process in a way that is going to is going to is going to take the clock is going to start ticking again after that rejuvenation process, right? So I think that's that's inevitable. That's really part of our of our biology and our our physiology. There is there is a lot of other things, of course, they need to take it to be taken into consideration. So, for example, we are still not entirely sure and probably wouldn't be a good idea for example to reprogram senescent cells or fully senescent cells because those cells are senescent for for for a good reason because they carry major genetic defects, chromosome operations, translocations, mutations and so on. So it would probably be a good idea, at least that's the way we think about it, it would probably be a good idea, a bad idea, sorry, to reprogram those cells and bring them back in time because they you you potentially would engage them again in some processes of development that would lead to unwanted outcomes. So in that case, for example, one potential solution would be to for example to first clear the senescent cells will kill them somehow in a in a specific fashion, and this is where, for example, the senolytics are are going to be very helpful. And then once you have clear them, then you can reprogram and regenerate the the remaining the existing the resilience cell types in the in the tissue. So that's that's one way of thinking about it about it. The other thing that we have shown, for example, not being changed by by by era is any genetic feature or any genetic mutation that has been accumulated by by the cells. Of course, you know, if a genetic mutation has has happened has occurred, there is nothing error can do in that in that regard. Telomira Tricin, for example, the shortening of the telomira is something that also era is not capable of of reversing unless it's it's a stem cell. Why? Because somatic cells are not capable the somatic fully differentiated cells are not capable of elongating the telomeres. They are kept they become capable of elongating the telomeres once they become stem cells once they go beyond the point of no return. And as we as we said, we do not want to go beyond the point of return. So a quintessential feature of fully differentiated somatic cells is not being able to elongate the telomeres right. And so that's what something that era doesn't do just because of the just because of the fact you know of how error works. Does so what about mitochondria does making the cell younger also help the meaty country. Yes, yes, absolutely. We have we have studied is in a couple of different ways. So we have looked, for example, at the the amount of energy that the mitochondria generate. With or without era. And we have seen that era leads the cells to having more functional mitochondria that are capable of generating more more energy for the cells. My to conjure generate energy also at the expenses of production of the so called reactive oxygen species. So these are oxidative molecules that are detrimental to the cells. We have shown that not only era can lead them to generate more energy, but they generate more energy generating less oxidative stress in the cells. So both of the things are actually very very good for the cells and are triggered by by error. | ↗ |