Senescent+Cell+Transcript+11-30-11

I'm going to talk about a paper that was fairly exciting that was just published this month November 2011. And it was published by several departments of the Mayo clinic in Rochester Minnesota as well as between a collaboration with Groningen University in the Netherlands. I might have pronounced Groningen wrong. Yeah and just a little bit about the Mayo clinic. .they're quite a good clinic and hospital. They have several different facilities. Their headquarters are in Rochester Minnesota, but they also have a clinic in the Phoenix Scottsdale Arizona area and also in Jacksonville Florida. And the Mayo clinic has been rated one of the best healthcare places in the world and they also do a lot of combination between treating patients but then also core research too. They try to put 40% of their effort about into research. So in this paper. . it's about the aging effects of senescent cells, and they were able to remove the senescent cells from mice and show that this reduced age related phenotypes. The mice were much healthier. Before I go too much further I just ant to talk about one sentence they have here in the abstract. They say cellular senescence which halts the proliferation of damaged or disfunctional cells is an important mechanism to constrain the malignant progression of tumor cells. So I mean yeah they claim as well as many people claim the purpose of senescent cells is to prevent cancer. I'm sure many of you know cells will become senescent after it's telomeres get too short. So cells can keep on dividing and every time they divide their telomeres get shorter and shorter and once the telomeres reach a critically short length those cells will either no longer divide and become senescent or it could escape this stopping of division and they can become senescent (*supposed to be "cancerous"). So but I just wanted to say that I don't know if this necessarily has to be the case. Another theory that some people have proposed about the purpose of senescence is that maybe it's not so much to stop cancer. . another possibility could be that cells just become senescent because there was never really any reason in the past for evolution to uh design an organism like ourselves that had cells that didn't become senescent. So the organism just had to live long enough to reproduce in it's environment and if it reached that goal then there's no really pressure to escape this senescence mechanism. So rather than having a purpose to stop cancer, it may have just been. . the avoidance of senescence may have just been left out because there wasn't evolutionary pressure for it. Anyway, enough of that. I'll go on and start talking about the paper a little bit more here. The mice they were working with were a BubR1 progeroid mouse background. And um some of you may know about the disease progeria. There's some humans with progeria as well and when they have progeria they age extremely quickly. So when they're teenagers or in their early twenties, they look much much older and they die at a young age. And uh so in this particular mouse they have something similar and they have a mutation which causes the chromosomes to not separate during cell division. And uh some of the cell types that are most affected by this process are the adipose tissue and skeletal muscle and eye tissue. But some of the things that won't be affected by this process of reaching senescence are things like heart cells which divide very rarely if at all so that's something to keep in mind as they go into some of the results later in the paper. So right now I'll just show you the schematic of this construct they put into these progeria mice. This is the Ink attack construct. So they genetically engineered the mice so that when they administered the drug it they could kill just the senescent cells. So kind of the way it worked here is they had uh they had this p16 promoter. . so p16 is a biomarker in some senescent cells. . so it's a gene in some senescent cells. So this gene would normally turn on and produce p16 but they also added these other genes that would be transcribed or created with it. So one of the genes is caspase, and then the other one was green fluorescent protein this EGFP. So the green fluorescent protein would allow them to detect which cells had this genetically engineered construct. And then uh with the caspase what that's all about is uh actually caspase is turned on when a cell undergoes apoptosis and kind of kills itself. In fact when a T cell of the immune system finds a cell that it needs to kill what it will do is actually activate some pathways that will activate caspase and then caspase will tell the cell to undergo apoptosis and kill itself. So here with the way this system works that they created the caspase will be created and then it won't have any effect until they add this drug AP20187 so this AP drug. Once this AP drug binds it turns this inactive caspase into an active caspase and the cell will undergo apoptosis. So all of these other figures here I'm not going to spend time talking about. All they're doing is that they're showing that their construct does work the way they expect it to work. And uh yeah here's a sentence summarizing all of these figures. Taken together these results indicate that INK attack which is that genetic construct is selectively expressed in p16 positive senescent cells. So senescent cells will produce that p16. Okay so so now let's get to the results with the mice and see what happens there. So um first here they show that uh when they do add the drug it does truly kill the cells that have been genetically engineered to respond to this AP drug. So this drug rosglitazone. What it will do is it will cause cells to become senescent and it will cause cells to produce senescent cell biomarkers such as p16. And then here in this figure they do not add the minus AP. And here, this is a little bit of a fuzzy image but uh here they do add the AP and you can see there's much fewer cells here. So it is true that the AP does kill the cells. Now now for these mice they different groups of mice which received the AP drug during their lifetime so the senescent cells were being killed and removed and some didn't. And the ones that received the drug fared better. So here what they have on this curve is they have the percent of the mice which have lordokyphosis which is just like a curvature of the spine associated more with old age and uh damaged skeletal muscle tissue. And uh with these dotted lines, you can see that um they had a much lower incidence of lordokyphosis. And the dotted lines up here are the ones that received the AP drug. So plus AP and plus AP. You'll see that this is ATTAC-3 and this is ATTAC-5 um that's there just two different cell lines that both have this genetically engineered construct. And this minus AP hre are those dark lines and this didn't even have the genetically engineered construct and you can see these lines here. . they have a much higher rate of lordokyphosis. They also measured cataract. . yeah cataract incidence. And the same thing here there was a lower incidence of cataract with the mice that had the senescence cells killed by the administration of the AP. Here's actually a screenshot comparing the two mice. So here's the one's that received the drug and the senescent cells were killed. You can see they look alm kind of chunkier but their posture looks better they don't have that curvature of their spine. They look kind of healthy whereas the uh and these are 9 month old mice. . these particular progeria mice if I recall they live just a little over a year. . not too much longer than that. And then um these mice did not receive the drug and died sooner. So they also show the muscle fiber diameters are thicker. Here the light blue and the orange have thicker muscle fibers in both the muscle associated with the stomach area. . or the gastrointestinal area and also the abdominal muscle. .and uh they also compare treadmill exercise. So in this graph both there's the 3 and the 5 like lines of mice and this is the percent improvement over the untreated mice. So these mice could run on a treadmill for a longer period of time for a longer distance and they performed more work also. Like work as you would calculate in physics. So it's quite impressive. They also measured the cell diameter of uh fat cells and the thickness and the fat cells and thickness were higher were larger greater in the mice that received the drug and had the senescent cells killed. This here they just have a table of numbers kind of showing the same thing. And uh the mass of these cells was measured with a technique called DEXA. I'm not very familiar with that but DEXA is. . well here I made a note down here. DEXA is dual energy x-ray absorptiometry. Yeah so that's kind of interesting uh this figure over here I won't spend much time on that, but I do want to talk about the next figure because everything I talked about before they were treating the mice from a young age they kept giving them that AP drug, but they also wanted to see what kind of effect they could observe if they started a late treatment. So the mice were already kind of old and they started administering the drug. And basically what they found. . maybe I won't even go into too many of the details of the figure. I'll just summarize what they did find here. And they measured many of the same things they measured before for example muscle fiber diameter, how far and how well they could run on a treadmill, all those different things, as well as the relative expression of different genes associated with senescence. Yeah so the treatment reflected attenuated progression of age related decline rather than a reversal of aging. So oh right so basically they weren't able to reverse the aging as well. . on these figures they show 10 month old mice and they also show just compare that with the 5 month old mice the black bar. The black bar always has the best values. So the 5 month old mice always have the best values. So when they started the treatment at 10 months they weren't able to reverse the treatment back to the condition of a 5 month old mice, but it was better than the mice that received no treatment at all. So basically what they were able to achieve is attenuation of these age related phenotypes rather than reversal. So um let me think if there's anything else I want to point out here. Uh oh yeah importantly they didn't notice any overt side effects so that's very positive. And um yeah so I'd just like to spend a little bit of time talking about what we would need to do in order to transfer this treatment to humans. So basically in order to apply this treatment to humans you wouldn't be able to copy exactly what they did in this paper obviously because we haven't been genetically engineered to respond to this AP drug and have our cells be killed when that drug is administered. However, what scientists could try to do is uh identify specific biomarkers unique to senescent cells. For example even these two papers go into which I haven't read yet myself, but they go into uh more details about specific components that senescent cells secrete or possess. And you can make um try develop drugs or specific therapies that will target and kill cells that have those things. So I mean it would take quite a bit of work to figure out how to do that, but then you would also be able to delay age-related phenotypes in humans. So we could be much healthier in old age. And uh another question about these mice that many people would ask is whether or not they actually lived longer, and the answer was no. So these mice that received the AP drug and had the senescent cells killed did not live longer. And the reason was that these mice appeared to die of cardiac failure or heart failure. So all of the problems that you would have with a normal heart or in the control mice you also saw in those mice because those were tissues and cells that were not affected as much by this senescence process because there's not a lot of cell division in the heart anyway so they still had the hardening of the arteries and everything. So if you did want to treat a human and prolong the life you would also need to develop treatments that can help these tissues that don't have a lot of dividing cells such as the heart. I believe also the brain does not have a lot of cell division. Um there's one last comment I'd like to make and that's about a company named TA Sciences in New York. And uh TA Sciences (TA is for Telomerase Activation) this telomerase activation science company. . they're kind of a branch off from the Geron corporation which is a big biotech company and uh what they did is they just screened many different compounds from different areas of nature and they identified this one compound that came from a Chinese tree that was capable of activating telomerase. And so this telomerase enzyme, once it's activated in your cells it will lengthen telomeres and prevent those cells from reaching senescence. So this company is actually selling this compound today. I think it's kind of expensive, but they are selling it to people today and there's people taking the drug. And the company has also had 3rd parties publish academic papers testing their compound, and from what I've seen I think it looks legitamite. You can never be completely sure. I mean there's a lot of there can be a lot of fraud in the world and everything. But uh yeah after this paper that was about removing the senescent cells was publish TA Sciences also sent out an e-mail just describing how it's great that removing the senescent cells did show such benefits. However, their treatment is focused on making sure that the cells never reached senescence in the first place. And so that may, and they seem to have tested and shown, that that has a lot of great benefits as well. So possibly in a human if you could do both. If you could make sure that fewer cells even reach senescence and also that you could remove the cells that do become senescent, then that may be a pretty good treatment and increase the healthspan of people.