Clearing Cellular Dead Wood | In the Pipeline – Science Magazine
By daniellenierenberg
For many years now, the topic of senescent cells has been the subject of plenty of research work. Back in the 1960s the Hayflick limit was noticed in cell culture: there was an apparent limit to the number of cell divisions that could take place before the cells just sort of stalled out. For human fibroblasts, that kicks in at around fifty divisions. Over time it was worked out that a primary mechanism involved is the shortening of telomeres with each cell division, specialized nucleotide sequences out at the ends of the chromosomes, and this cellular clock phenomenon has been making its way into the public consciousness ever since.
Its strange to think, but before these experiments human cells were considered to be more or less immortal and capable of unlimited numbers of divisions. Now, there are cells like that, but that (outside of some stem cell populations and a few other special cases) is a very short working definition of cancer. Those cells do indeed seem to be able to carry on for as long as conditions permit which in the artificial world of cell culture labs, means apparently forever. Henrietta Lacks died in 1951, but HeLa cells are still with us, and can be all too vigorous when they contaminate other lines. Tumor cells can pile up mutations that will make them die off, but short of that the jams have indeed been kicked out.
Its gradually become apparent that many aging or damaged tissues have a (sometimes substantial) population of cells that have reached their limit. Theyre alive and metabolically active but not really contributing much, in a stage of permanent growth arrest. Cellular senescence is a complex phenomenon, but its importance in aging, cancer, and tissue damaged by other factors (radiation, oxygen stress, etc.) is by now undeniable. Many of these non-aging states can be traced back to early telomere damage by other mechanisms, emphasizing that as a key countdown mechanism. But its clear that senescent have a different secretory profile (cytokines, growth factors and more) from the more vigorous cells around them and a number of other protein expression differences that can be used the characterize them.
Naturally enough, thoughts have turned to targeting such cells for therapy. There are a couple of very easy-to-picture hypotheses: first, could you keep telomeres from shortening (or shortening so much) and therefore keep cells in a non-senescent state for longer, potentially delaying biological aging? And second, could you somehow target cells that have already become senescent, and would doing so improve the health of the surrounding tissue? Though pretty obvious ideas, both of these are still very much in play. For now, Im going to talk about the second one, in light of a new paper.
That ones on the kidney. Younger people can regain some kidney function after an injury, but that ability goes down with aging, as youd imagine. It also goes down in states of chronic kidney disease, or after radiation damage. This new paper shows that targeting and removing senescent cells actually starts to reverse this phenotype once youve done that, the kidney tissue after injury shows increased function, increased regenerative ability, and less development of fibrosis. This is demonstrated both in aged tissue and in younger tissue exposed to radiation damage, in human cell culture and in mouse animal models.
You may well ask: how exactly does one target senescent cells? That takes us to ABT-263 (navitoclax), shown at right. This rather hefty molecule is part of a series of AbbVie protein-protein inhibitors for the Bcl-2 (B-cell-lymphoma) family. There are several of those, and navitoclax inhibits the function of Bcl-2, Bcl-xL, and Bcl-w. All of these proteins are intimately tied up in the pathways of apoptosis, programmed cell death, which is another monstrously huge pathway all its own. But one of the questions about senescent cells is why they dont go down some apoptotic pathway and just fall on their on cellular swords, instead of hanging around forever gumming up the works.
This one, like the others in its class, was developed to cause this to happen to tumor cells as an adjunct to other types of chemotherapy, but these have also turned out to be useful against senescent cells (although not all types of them). Similar to the kidney results reported in the new paper linked above, there have been reports in lung, CNS, muscle and other tissues of broadly similar enhancements (many of these summarized in this paper). So at this point you might be wondering why we dont just go ahead and put these things into the water supply already.
Theres a problem, unfortunately. It was clear from the clinical studies of the AbbVie compounds that platelet effects were dose-limiting. Cells in that pathway are sensitive to messing with these apoptosis pathways, and while you might be able to deal with that side effect in a chemotherapy situation, it doesnt exactly make for a good-for-what-ails-you drug. Navitoclax has alsorecently been shown to have profoundly bad effects on bone density and deposition, which is the exact opposite of what youd want for an aging population.
AbbVies next generation of such compounds, though, includes venetoclax, at right, also a lunker of a molecule and now approved for several types of leukemia. It still has platelet effects, but they arent nearly as disastrous as with navitoclax, thanks to deliberately lower binding to Bcl-xL. That also makes it a bit less of a mighty sword across senescent cell types for example, it appears that you need that pathway for activity against glioblastoma cells. But it has been reported to show strong protective effects against the development of Type I diabetes through the elimination of senescent cells in the islets of Langerhans. Meanwhile, other groups are looking at turning these ligands into targeted protein degraders, which (at least in some cases) seems to decrease the platelet problems and increase senolytic activity.
And before leaving the topic, it has to be noted that there are plenty of other ways to target these cells other than the Bcl pathway (although that one seems to be one of the most developed so far). What can I say? Im 59, and I doubtless have more senescent cells than I want or need, so I (and plenty of others) are interested in the idea. The whole cellular senescence pathway presumably developed as a way to avoid slipping into a tumor phenotype the more cellular divisions, the greater the chance of something going wrong along the way. Its a tradeoff, and evolution seems more than willing to shortchange older members of the species who have generally passed on their genes to all the offspring that theyre going to. But humans have other goals. We are looking at a rather rapidly aging planet, if current demographic trends hold up, and it would be extremely desirable to have that associated with less of a disease burden. Can we split the difference?
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Clearing Cellular Dead Wood | In the Pipeline - Science Magazine
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