Navitoclax is Better than Dasatinib and Quercetin at Clearing Senescent Cells Produced by Radiotherapy
It is now well known that many of the negative consequences resulting from chemotherapy and radiotherapy are mediated by a raised burden of senescent cells. One of the goals of cancer therapy is to drive cancerous cells into senescence: better to have senescent cells than cancerous cells! Nonetheless, gaining a greater burden of senescent cells is literally accelerated aging, as these additional senescent cells actively degrade tissue function and create chronic inflammation via their secretions. Thus senolytic therapies should be of great benefit to cancer survivors, removing this harmful side-effect of cancer therapy.
Are all senolytics the same? No, absolutely not. This has already been made quite clear from the work of the past few years. Some approaches are much better than others for differing cell types and origins of cellular senescence. Here, researchers show that navitoclax is a whole lot better than the dasatinib and quercetin combination when it comes to cells made senescent as a result of irradiation. One could make an argument that navitoclax is one of the better senolytics across the board, but its highly undesirable side-effects make it a poor choice despite its ability to kill a sizable fraction of senescent cells in animal studies. Recent efforts to produce a navitoclax prodrug that only activates in senescent cells, removing those unwanted side-effects, are thus quite exciting.
A surprise here is that metformin turns out to be pretty good at sabotaging the consequences of radiation-induced cellular senescence, presumably by reducing the inflammatory signaling of senescent cells, since it is not a senolytic drug. The researchers treated mice with metformin for 10 weeks, longer than the few doses of the shorter senolytic treatments, which perhaps allowed the immune system to catch up and remove more senescent cells than would otherwise have been the case. For practical outcomes in mouse health following irradiation, such as frailty and organ function, this longer metformin treatment turns out to be about as good as a short dosing period with navitoclax.
Cancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesize that therapy-induced senescence and senescence progression via bystander effects is a significant cause of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sub-lethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow up was for one year.
Treatments commencing within a month after irradiation effectively reduced frailty progression and improved muscle and liver function as well as short-term memory until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty and short-term memory. Metformin was similarly effective as senolytics. At therapeutically achievable concentrations metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial ROS production via NOX4 inhibition in senescent cells.
Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions.