In their publication in eLife Sciences, researchers at Newcastle University in the UK have illustrated how radiation-induced damage can be somewhat ameliorated with senolytics. These researchers focused on navitoclax along with the well-known combination of dasatinib and quercetin.
A focus on cancer survivors
The researchers begin this paper with a discussion of cancer treatments. They point out that, while modern medicine has made many cancers much easier to cure, cancer survivors often suffer from premature aging. Part of this stems from the fact that successful methods of defeating cancer often involve sending the cancerous cells into a senescent state [1].
Turning these cells senescent usually puts a stop to their deadly, uncontrolled growth, but it opens the door to other dangers, and leaving these senescent cells as they are can even lead to the recurrence of cancer [2]. This makes senolytics an attractive proposition as an additional treatment [1].
Senolytics, delivered early and late
The researchers irradiated 5-month-old male mice with sublethal doses. As in previous experiments [3], this caused the mice to suffer from premature aging, including such symptoms as frailty, decreased coordination, memory problems, and increased mortality.
Administering senolytics soon after this irradiation aided the mice in multiple respects, decreasing whisker loss, body weight, and body condition. Navitoclax also decreased the numbers of tumors formed and improved fur color.
After three months, mice on early senolytics had reduced alanine transaminase, a measurement of liver damage. They were able to hang from their forelimbs for longer and stay on a rotating rod at greater speeds. They behaved smarter in a maze test and remained tumor-free for longer.
Early senolytics did not reverse the frailty caused by irridation, but they slowed its progression compared to other irradiated mice. While dasatinib and quercetin aided the mice in statistically significant ways, navitoclax was found to be more potent than that combination in nearly all the tests conducted in this part of the study. Hanging grip, frailty accumulation, and liver damage were also ameliorated by metformin, which reduces the accumulation of senescent cells.
However, later senolytics, delivered at the age of 11 months and tested at 14 months, did not help nearly as much. Navitoclax did protect against tumors in this cohort of mice. Dasatinib and quercetin improveed forelimb strength more than navitoclax in this cohort, and the rate of frailty decrease was similar. Memory was somewhat improved, but liver damage was largely unaffected, as was the mice’s performance on the rod rotation test.
Conclusion
While this study’s findings were significant, its results were limited and possibly disappointing to anyone who expected serious rejuvenative effects. While removing senescent cells does ameliorate radiation-induced damage, senolytic treatment does not reverse such damage, nor does it restore the frailty of radiation-affected mice to that of their unaffected counterparts.
However, this study does show that senolytics may be an effective treatment for slowing the accelerated aging of cancer patients, either shortly after such therapies or during them; early treatment is obviously a significant factor here. As always, human studies are required to know if this will truly be effective in people.
Literature
[1] Short, S., Fielder, E., Miwa, S., & von Zglinicki, T. (2019). Senolytics and senostatics as adjuvant tumour therapy. EBioMedicine 41: 683–692.
[2] Saleh, T., Tyutyunyk-Massey, L., & Gewirtz, D. A. (2019). Tumor cell escape from therapy-induced senescence as a model of disease recurrence after dormancy. Cancer research, 79(6), 1044-1046.
