Now that much more attention and funding is turning to cellular senescence as a cause of aging, a fair number of new discoveries are being made regarding the specific links between age-related disease and the growing presence of senescent cells in old tissues. Some of them seem almost obvious in hindsight, connections that researchers should have long assumed to be likely, such as senescent foam cells accelerating the progression of atherosclerosis. Now that senescent cells can be cleared effectively in the laboratory, proof of these connections is comparatively simple to obtain, and so the evidence is piling up month after month. The open access paper I'll point out today provides evidence for another connection that has the look of something that should be self-evident in hindsight, between cellular senescence and the harmful side-effects of cancer chemotherapy. It is PDF only at the time of writing, I'm afraid.

Chemotherapy at the levels needed to suppress cancer is enormously unpleasant, sometimes even fatal, and no-one with any other option would ever undergo such a treatment. Worse, it has a large impact on future life expectancy, as the outcomes for cancer survivors having undergone chemotherapy look much the same as those of life-long smokers. But why is chemotherapy so harmful? We can point to numerous side-effects ranging from outright toxicity to dysregulation of important cellular activities in a number of organs. The one thing that all chemotherapies should achieve along the way is to create a lot of senescent cells, however. Cellular senescence is a defense against toxic environments and cellular damage, and in modest amounts it lowers the risk of cancer by shutting down replication in those cells most at risk. Beyond producing senescence in bystander cells by putting them under stress, chemotherapy should also make a lot of cancerous cells senescent. For many chemotherapy drugs that is the intended goal. As is always the case for senescent cells, many will be destroyed by the immune system or their own self-destruct programs, but a fraction will linger. Chemotherapy might be thought of as the equivalent of decades of normal creation and destruction of senescent cells, run through on fast forward.

The harm caused by senescent cells is a matter of signaling. They secrete a mix of molecules, the senescence-associated secretory phenotype (SASP), that spurs chronic inflammation, damages the surrounding extracellular matrix, changes the behavior of normal cells for the worse, and more. If 1% of the cells in a tissue are senescent, that is sufficient to cause measurable dysfunction and decline in most organs. Given this, it seems very logical that to the degree chemotherapy pushes cells into a senescent state, it will harm patients in the long term via these mechanisms. This is an opportunity as well as a realization, however: in the years in which chemotherapy is on the way out, to be replaced by immunotherapy and other approaches, it might be made less damaging to patients through the use of therapies to clear out the senescent cells created during cancer treatments.

Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse