Abstract
There is an unmet need to develop and validate therapies that can treat or at least prevent premature therapy-induced frailty, multi-morbidity and mortality in long-term tumour survivors. In an approach to develop a first mouse model for therapy-induced long-term frailty, we irradiated male C57Bl/6 mice at 5–6 months of age sub-lethally with 3 × 3 Gy (whole body) and assessed subsequent frailty for up to 6 months using a Rockwood-type frailty index (FI). Frailty scorers were trained to obtain excellent inter- and intra-observer reproducibility. Irradiated mice developed progressive frailty approximately twice as fast as controls. This was premature frailty; it was phenotypically identical to that in non-irradiated mice at higher age. As expected, frailty was associated with decreased cognition and predicted mortality. In irradiated mice, frailty and neuromuscular performance, measured by Rotarod and Hanging Wire tests, were not associated with each other, probably because of long-term decreased body weights after irradiation. We conclude that progressive frailty following sub-lethal irradiation comprises a sensitive and easy to use test bed for interventions to stop premature ageing in long-term tumour survivors.
Highlights
Improvements in cancer treatment have rendered many common cancers curable in a high proportion of patients
Assessing frailty according to Whitehead (Whitehead et al, 2014) longitudinally, we show here that sub-lethal whole-body irradiation induces progressive premature frailty in mice
Over a course of six weeks, weekly frailty assessments were performed by the three scorers as a group, during which the operationalisation of the scoring was discussed and modified towards a agreed version
Summary
Improvements in cancer treatment have rendered many common cancers curable in a high proportion of patients. Cancer remains a common disease, affecting an estimated 18 million of the world population in 2018, cancer-specific mortality has dropped sharply in the last few decades in developed countries. There is greater awareness of health issues in long-term survivors, and in some fields the emphasis has started to shift towards efforts to improve the quality of survivorship after successful cancer treatment (Damlaj et al, 2019). Widely used adjuvant therapies precipitate onset of frailty by about two decades of life prematurely in long-term survivors of many different cancer types (Arora et al, 2016; Ness et al, 2015, 2013). To develop and validate those, mouse models of therapy-induced frailty are urgently needed
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