Recently, there has been a focus on the removal of senescent cells as a therapy to treat age-related diseases by directly addressing one of the hallmarks of aging: senescent cell accumulation.
These senolytic therapies are the first SENS therapies to be developed in order to directly address and repair the damage that aging does to the body. We see the potential for this new kind of therapy in the research data, and evidence that senescent cells contribute to atherosclerosis [1], osteoporosis [2, 3], and many more age-related diseases continues to mount up.
A new research paper hot off the press shows another connection that, in retrospect, should have been obvious: the connection between cellular senescence, cancer [4], and the side effects of chemotherapy [5].
Chemotherapy is extremely toxic and damages and deregulates a number of cellular functions in the body. Chemotherapy works by inducing cancer cells to become senescent, but this process also causes a great deal of collateral damage that stresses healthy cells and causes a significant number of them to become senescent as well.
The immune system then removes these senescent cells and the debris, but some senescent cells resist this process and remain in situ. These populations of senescent cells accumulate naturally as part of the aging process anyway, causing inflammation, deregulation of intracellular signalling, and decline of tissue regeneration. In a very real sense, a course of chemotherapy could be considered to accelerate this particular aspect of aging.
Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals, which encourage other nearby cells to also enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase levels of chronic inflammation, and can increase the risk of cancer, as this latest paper discusses.
Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse
AbstractCellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a pro-inflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells non-specifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation.
Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T-cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anti-cancer treatments.
Conclusion
Based on this research, it appears that chemotherapy causes the rapid accumulation of senescent cells, and, in the long run, is bad for the patient due to driving this aging process and its associated risks. However, until better alternatives such as immunotherapy arrive, senolytic therapies could help to reduce the negative impact of chemotherapy.
Literature
[1] Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., & van Deursen, J. M. (2016). Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science, 354(6311), 472-477.
[2] Farr, J. N., Fraser, D. G., Wang, H., Jaehn, K., Ogrodnik, M. B., Weivoda, M. M., … & Bonewald, L. F. (2016). Identification of senescent cells in the bone microenvironment. Journal of Bone and Mineral Research, 31(11), 1920-1929.
[3] Xu, M., Bradley, E. W., Weivoda, M. M., Hwang, S. M., Pirtskhalava, T., Decklever, T., … & Lowe, V. (2016). Transplanted senescent cells induce an osteoarthritis-like condition in mice. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glw154.
[4] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology, 5, 99.
[5] Demaria, M., O’Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., … & Alston, S. (2016). Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discovery, CD-16.a
