<div dir="ltr"><br><div class="gmail_extra"><br><div class="gmail_quote">On Fri, Feb 5, 2016 at 4:51 PM, John Clark <span dir="ltr"><<a href="mailto:johnkclark@gmail.com" target="_blank">johnkclark@gmail.com</a>></span> wrote:<br><blockquote class="gmail_quote" style="margin:0px 0px 0px 0.8ex;border-left-width:1px;border-left-color:rgb(204,204,204);border-left-style:solid;padding-left:1ex"><div dir="ltr"><div style="font-family:arial,helvetica,sans-serif;display:inline">Researchers report in the </div>Feb. 3 <div style="font-family:arial,helvetica,sans-serif;display:inline">issue of </div> Nature<div style="font-family:arial,helvetica,sans-serif;display:inline"> that a drug called </div><font color="#212121" face="Arial, sans-serif"><span style="line-height:18px">AP20187</span></font><div style="display:inline"><font color="#212121" face="arial, helvetica, sans-serif"><span style="line-height:18px"> increased the lifetime of mice by 30% even if the treatment isn't started till middle age: </span></font></div><div><div style="display:inline"><font color="#212121" face="arial, helvetica, sans-serif"><span style="line-height:18px"><br></span></font></div></div><div><div style="display:inline"><font color="#212121" face="arial, helvetica, sans-serif"><span style="line-height:18px"><a href="http://www.sciencemag.org/news/2016/02/suicide-aging-cells-prolongs-life-span-mice" target="_blank">http://www.sciencemag.org/news/2016/02/suicide-aging-cells-prolongs-life-span-mice</a> </span></font></div></div><div><div style="display:inline"><font color="#212121" face="arial, helvetica, sans-serif"><span style="line-height:18px"><br></span></font></div></div><div><div style="display:inline"><font color="#212121" face="arial, helvetica, sans-serif"><span style="line-height:18px"> </span></font></div></div></div></blockquote><div><br></div><div>### It should be mentioned that AP20187 is not a likely life-extesion drug. It is a homodimerizer designed to induce interactions between two DmrB, or FKBPv domains. The compound is commercially available and by itself it doesn't have any biological relevance, since it specifically binds to a mutated version of FKBP (FKBPv), which is absent in normal mammals.</div><div><br></div><div>Here is what was shown in the article: First they introduced a genetic detector of senescence into mice by genetic engineering. The detector is an artificial gene that contains an ink4a promoter that controls FKBPv-cas8 expression. Ink4a is a protein found in senescent cells of normal mice. In the senescent cells of genetically engineered mice ink4a will bind to the ink4a promoter and produce FKBPv-cas8. FKBPv-cas8 is an artificial protein, not normally found in animals. It has two parts: cas8 and FKBPv. Cas8 is a caspase, which kills cells if activated. FKBPv is a protein domain which binds to AP20187. If you have FKBPv in cells and add AP20187, the FKBPv will be induced to form homodimers (two identical FKBPv molecules stuck together by the action of AP20187). If the FPBPv molecules are designed to have cas8, their homodimerization will bring the cas8 domains together, and activate them, causing cell death. In this way you can induce controlled killing of cells of your choice, in this case determined by the presence of ink4a - in other words, you can specifically, using genetically engineered detector and effector molecules (which here they call INK-ATTAC), kill senescent cells. </div><div><br></div><div>The article basically repeats the group's previous work, published in 2011 (<span style="color:rgb(0,0,0);font-family:arial,helvetica,clean,sans-serif;line-height:1.45em"><a href="http://www-ncbi-nlm-nih-gov.proxy.library.vcu.edu/pubmed/22048312?dopt=Abstract&holding=npg#" title="Nature." style="color:rgb(102,0,102);border-bottom-width:0px">Nature.</a></span><span style="color:rgb(0,0,0);font-family:arial,helvetica,clean,sans-serif;line-height:1.45em"> </span><span style="color:rgb(0,0,0);font-family:arial,helvetica,clean,sans-serif;line-height:1.45em">2011 Nov 2;479(7372):232-6. doi: 10.1038/nature10600.) but in different strains of genetically engineered mice, and shows that selective ablation of some senescent cells seems to make mice healthier. Not all senescent cells were removed, since the INK-ATTAC doesn't seem to work in colon and liver.<br></span></div><div><span style="color:rgb(0,0,0);font-family:arial,helvetica,clean,sans-serif;line-height:1.45em"><br></span></div><div><span style="color:rgb(0,0,0);font-family:arial,helvetica,clean,sans-serif;line-height:1.45em">This is very neat but it doesn't have a direct application in humans, unless you wanted to genetically modify babies to carry the INK-ATTAC killer gene. However, it does open interesting research directions. One can think about many ways of specifically killing senescent cells in adult humans and I would not be surprised if some of them were tried in the next 10 - 15 years.</span></div><div><span style="color:rgb(0,0,0);font-family:arial,helvetica,clean,sans-serif;line-height:1.45em"><br></span></div><div><span style="color:rgb(0,0,0);font-family:arial,helvetica,clean,sans-serif;line-height:1.45em">Rafał</span></div></div>
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