A Multi-stage Carcinogenesis Model to Investigate Caloric Restriction as a Potential Tool for Post-irradiation Mitigation of Cancer Risk

Abstract

The risk of radiation-induced cancer adds to anxiety in low-dose exposed populations. Safe and effective lifestyle changes which can help mitigate excess cancer risk might provide exposed individuals the opportunity to pro-actively reduce their cancer risk, and improve mental health and well-being. Here, we applied a mathematical multi-stage carcinogenesis model to the mouse lifespan data using adult-onset caloric restriction following irradiation in early life. We re-evaluated autopsy records with a veterinary pathologist to determine which tumors were the probable causes of death in order to calculate age-specific mortality. The model revealed that in both irradiated and unirradiated mice, caloric restriction reduced the age-specific mortality of all solid tumors and hepatocellular carcinomas across most of the lifespan, with the mortality rate dependent more on age owing to an increase in the number of predicted rate-limiting steps. Conversely, irradiation did not significantly alter the number of steps, but did increase the overall transition rate between the steps. We show that the extent of the protective effect of caloric restriction is independent of the induction of cancer from radiation exposure, and discuss future avenues of research to explore the utility of caloric restriction as an example of a potential post-irradiation mitigation strategy.

Keywords: Caloric restriction; Mathematical model; Prevention; Radiation.

Figure 1.

Armitage-Doll model fits of age-specific mortality data taken from Shang et al., calculated from deaths from all solid cancers (except sarcoma). The data points are plotted as the log of age-specific mortality (tumor-deaths per mouse day) versus the log of age (days) for each incremental 200-day period. The lines show the fit used to calculate the model parameters k and a, and the k parameter derived from each fit is shown. Drop lines from each point show the deviations from the fit.