The Role Of Nutrient Sensing Pathways In Delaying Ageing

Abstract

Caloric restriction (CR) without malnutrition is a robust dietary intervention that extends lifespan and improves health in virtually every species studied. Recently, some of the mechanisms for the effects of CR on ageing have been elucidated, including several cellular master switches collectively called “nutrient sensing pathways”. CR is not sustainable in humans, therefore research has begun to focus on developing ad libitum-fed diets that maximise lifespan and healthspan. This thesis presents research on the effects of diets with differing ratios of macronutrients on nutrient sensing pathways, and their impact on ageing and age-related end points. This is achieved using the paradigm of the Geometric Framework (GF), an analytical tool used to disentangle the effects of various nutritional components such as macronutrient ratios and energy intakes on outcomes. Using the GF, a large-scale nutritional study is used to examine the aging process through genotypic and phenotypic changes in nutrient sensing pathways, and their relationship with parameters of health and lifespan. Taken together, the results presented here form a case that manipulation of the nutrient sensing pathways are a mechanism for the beneficial effects of dietary interventions on ageing and health. Further investigation of these growth pathways could help to develop guidelines for optimal nutritional intake, or form the basis for pharmacological interventions targeted at prolonging lifespan, healthspan, and promoting health in old age, without the use of long-term dietary manipulation. The algorithmic tools developed here, also have the potential to be applied to a wider array of experimental fields, supporting the overarching experimental model of comparing multi-dimensional inputs on responses, as opposed to the more commonly used control versus treatment model that is largely seen in scientific research.