Mathematical modelling of hypoxia and temperature signalling pathways in lifespan

Abstract

A crucial step towards our understanding of ageing is the identification and characterisation of lifespan modifiers. Currently, investigations into lifespan modifiers use the non-parametric Kaplan-Meier estimator and the log-rank statistical test. Few studies employ parametric modelling to investigate lifespan modifiers and those that do use models which demonstrate monophasic lifespan. Recent studies have identified two phases of lifespan in C. elegans which cannot currently be modelled by monophasic parametric models. The aim of this research was to develop a biphasic parametric model (Bilogistic model) capable of modelling biphasic lifespan in C. elegans. The Bilogistic model has 5 parameters: the f parameter defines the proportion of lifespan in the early phase and late phase, and two death rates (k1 & k2) and two time phases (t1 & t2) for the early and late phases. The Bilogistic model was applied to lifespan data from flies, bees and mice to identify and quantify parameters. Two predictive models (chronological and biological) which used the Bilogistic model were developed and applied to temperature interventions in both wild type and trpa-1(ok999) mutants. Critical time points of interventions were identified, and indicated times at which the effects of intervention were lost. Also observed was that early lifespan conditions are important in determining the overall lifespan. The relationship between the HIF-1 (hypoxia) and TRPA-1 (temperature) signalling pathways were investigated in C. elegans mutants at different temperatures and oxygen concentrations. A relationship whereby TRPA-1 signals to HIF-1 was identified in mammalian cells but was not found to be applicable to C. elegans. In conclusion, a novel Bilogistic model has been developed and used to investigate the role of the TRPA-1 and HIF-1 pathways in C. elegans lifespan. However further work is required to fully understand the interaction between these pathways and how they act to regulate lifespan.