Cancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesise that therapy-induced senescence and senescence progression via bystander effects are significant causes 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 sublethally 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 1 year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p<0.05) and improved muscle (p<0.01) and liver (p<0.05) function as well as short-term memory (p<0.05) 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 (p<0.05) and short-term memory (p<0.05). 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 reactive oxygen species production via NADPH oxidase 4 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.
Keywords: ageing; cancer biology; cell biology; frailty; metformin; mouse; senescence; senolytic.
Cancer treatments save lives, but they can also be associated with long-term side effects which greatly reduce quality of life; former patients often face fatigue, memory loss, frailty, higher likelihood of developing other cancers, and overall accelerated aging. Senescence is a change in a cell’s state that follows damage and is associated with aging. When a cell becomes senescent it stops dividing, can promote inflammation and may damage other cells. Research has shown that cancer treatment increases the numbers of cells entering senescence, potentially explaining the associated long-term side effects. A new class of drugs known as senolytics can kill senescent cells, but whether they could help to counteract the damaging effects of cancer treatments remain unclear. To explore this question, Fielder et al. focused on mice having received radiation therapy, which also exhibit the long-term health defects observed in human patients. In these animals, a single, short senolytic treatment after irradiation nearly erased premature aging; frailty did not increase faster than normal, new cancers were less prevalent, and the rodents retained good memory and muscle function for at least one year after irradiation. Even mice treated later in life, after frailty was already established, showed some improvement. In addition, multiple tissues, including the brain and the liver, hosted fewer senescent cells in the animals treated with senolytics, even up to old age. Research should now explore whether these remarkable effects could also be true for humans.
© 2022, Fielder, Wan et al.