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 is a complex stress response whereby cells irreversibly lose the capacity to proliferate, accompanied by numerous changes in gene expression. Many potentially oncogenic insults induce a senescence response, which is now recognized as a potent tumor suppressive mechanism. Other senescence-inducing stimuli include radiation, genotoxic drugs, tissue injury and remodeling, and metabolic perturbations. Moreover, senescent cells accumulate with age in several vertebrate organisms, and their elimination can delay the onset of several age-associated disorders in mice. Senescent cells most likely promote aging through the senescence-associated secretory phenotype (SASP): the increased expression and secretion of inflammatory cytokines, chemokines, growth factors and proteases.
Genotoxic and cytotoxic drugs are widely used as anti-cancer therapies. Most such agents target proliferating cells through distinct, cell cycle-dependent mechanisms. Their cytotoxicity for many types of dividing cells often leads to side effects, which include immunosuppression, fatigue, anemia, nausea, diarrhea and alopecia. Moreover, clinical studies of cancer survivors treated during childhood suggest that some chemotherapies causes a range of long-term side effects that resemble pathologies associated with aging, including organ dysfunction, cognitive impairment and secondary neoplasms. Many chemotherapeutic drugs alter cellular states, including the induction of senescence, in cancer cells and the tumor microenvironment. Therapy-induced senescence (TIS) can stimulate immunosurveillance to eliminate tumor cells, but can also be a source of chronic inflammation and drug resistance. Indeed, a recent study showed that treatment of breast cancer patients with anthracycline and alkylating agents durably induces cellular senescence and a SASP in a p16INK4a-dependent, telomere-independent fashion. Expression of the tumor suppressor p16INK4a increases with age and is a robust senescence marker in numerous mouse and human tissues.
To more precisely assess the physiological effects of TIS in vivo, we used a recently described mouse model (p16-3MR) in which p16INK4a-positive senescent cells can be detected in living animals, isolated from tissues, and eliminated upon treatment with an otherwise benign drug. Using this approach, we determined the contribution of senescent cells to a variety of common short and long-term chemotherapy toxicities. Additionally, we used a senescence marker to assess the relationship between senescent cells and chemotherapy toxicity in human patients. We show that TIS cells contribute to local and systemic inflammation, as determined by increased expression of pro-inflammatory SASP factors in tissue and increased levels of inflammatory cytokines in sera, which is reduced after removal of senescent cells in vivo using p16-3MR transgenic mice. Further, the elimination of senescent cells limited or prevented the development of multiple adverse reactions to chemotherapy.
In addition, weeks after chemotherapy treatment, TIS cells were important for bone marrow suppression and development of cardiac dysfunction, both limiting factors for the use of some chemotherapeutic agents, particularly the anthracyclines. The promotion of cardiac dysfunction might be due to either cardiac senescent cells, which we show are primarily endothelial cells, or senescence-induced inflammation. Senescent non-tumor cells were important for cancer relapse and spread to distal tissues after chemotherapy, at least in the breast cancer model we used. Moreover, clearing senescent cells increased overall spontaneous physical activity in the presence or absence of cancer. Importantly, these murine findings were validated in a human cohort, showing that p16INK4a expression in peripheral T-cells predicts chemotherapy-induced fatigue in human patients with breast cancer. We believe this latter finding is consistent with recent work showing that aging is the major risk factor for long term (more than 2 or more than 5 years) fatigue after chemotherapy treatment.
The data presented here show a direct role for TIS cells in mice, and a strong correlation between fatigue and senescent cells in humans. An alternative approach, then, is to develop therapies that can selectively target senescent cells (senolytics) and/or the SASP, an approach that recently showed promise. Indeed, the administration of a senolytic agent, ABT-263, efficiently eliminated senescent cells, improved physical activity, and reduced cancer relapse in mice treated with Doxorubicin. Such therapeutic approaches will, of course, need to carefully consider whether there are beneficial effects of TIS, such as promoting the repair of tissues damaged by the chemotherapy or the potential of senescent cells to activate the immune response to tumor cells. Nonetheless, the pharmacological removal of senescent cells from the tumor microenvironment might be an innovative strategy to limit toxicities of current chemotherapies with consequent improvements in the health span and possibly life span of cancer patients.