TY - JOUR
T1 - Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice
AU - Fielder, Edward
AU - Wan, Tengfei
AU - Alimohammadiha, Ghazaleh
AU - Ishaq, Abbas
AU - Low, Evon
AU - Weigand, B. Melanie
AU - Kelly, George
AU - Parker, Craig
AU - Griffin, Brigid
AU - Jurk, Diana
AU - Korolchuk, Viktor I.
AU - von Zglinicki, Thomas
AU - Miwa, Satomi
N1 - Publisher Copyright:
© Fielder, Wan et al.
PY - 2022/5
Y1 - 2022/5
N2 - 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 + quer-cetin) for 10 days or with the senostatic metformin for 10 weeks. Follow-up was for 1 year. Treat-ments 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.
AB - 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 + quer-cetin) for 10 days or with the senostatic metformin for 10 weeks. Follow-up was for 1 year. Treat-ments 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.
UR - http://www.scopus.com/inward/record.url?scp=85130992126&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85130992126&partnerID=8YFLogxK
U2 - 10.7554/eLife.75492
DO - 10.7554/eLife.75492
M3 - Article
C2 - 35507395
AN - SCOPUS:85130992126
SN - 2050-084X
VL - 11
JO - eLife
JF - eLife
M1 - e75492
ER -