The role of cardiorespiratory fitness and physical behaviours in protecting against premature mortality

Although cardiorespiratory fitness and lifestyle factors have been associated with health outcomes, their interaction and direction of causality remains uncertain due to the lack of long-term trials. We aim to investigate the following questions: 1) are associations between lifestyle factors and health outcomes modified by cardiorespiratory fitness? 2) Are there genetic markers of cardiorespiratory fitness and do these differ to other lifestyle behaviours? 3) Can potentially identified SNPs be used in Mendelian randomisation to help establish causality between fitness, lifestyle and health outcomes? Cardiorespiratory fitness is one of the strongest predictors of health outcomes in UK Biobank. However, it is largely unknown whether fitness modifies the association between lifestyle behaviours and health (e.g. does physical inactivity remain a determinant of health in the presence of high cardiorespiratory fitness) and whether associations are causal. Addressing these questions will enable the more effective deployment and personalisation of lifestyle therapies in the future. We will use the full UK Biobank dataset to explore the association between physical behaviours (e.g. sleep, sedentary behaviours and physical activities) and health outcomes and to test whether associations are modified by markers of cardiorespiratory fitness. We will then test whether there are specific genes that are associated with fitness and whether these also modify associations between physical behaviours and health outcomes. Furthermore we will use genetic data to test whether there is evidence that fitness is a causal determinant of health, after accounting for common factors such as body weight and age, as opposed to health being the causal determinant of fitness. We will use both the full cohort with walking pace or handgrip strength (markers of physical fitness) and the subset who 1) undertook the graded exercise test or 2) wore an accelerometer