The impact of changing intestinal amino acid transporter expression and luminal nutrient content on healthy ageing

Abstract

Thanks to improved sanitation and advances in healthcare, humans are living for longer than ever before, however, the number of years an individual remains healthy has not improved, putting a strain on health services. Improving the health of this elderly population is therefore of great importance.
Unintentional weight loss, along with metabolic and body-composition changes, are common characteristics of ageing and frailty, associated with significant adverse health outcomes, increased mortality and progressive disability. While these changes may be partially explained by dietary changes and the metabolic cost of immune activation and inflammation that occur with age, other factors must contribute.
The intestine has been shown to be a key organ in the progression of ageing, undergoing many changes which directly impact mortality and morbidity. Nutrient absorption is a key role of the intestine which has not been studied in the context of ageing. Given the age-related intestinal changes which may impact its function, from an increased bacterial load to dysplasia and loss of intestinal barrier integrity, it is likely that nutrient absorption is a contributing factor to this unintentional weight loss.
This thesis aims to uncover whether changes to intestinal nutrient dynamics impact ageing phenotypes, using Drosophila as a model. Here I developed an assay to understand changes in the intestinal nutrient profile with age, showing increased luminal/faecal concentrations of amino acids upon advancing age and microbial association. This assay has the potential to be more widely applied to answer other biological questions. My data also links changes in the expression of intestinal amino acid transporters to age-related decline, through interaction with several key age- related pathways. Knockdown of the cationic amino acid transporter Slimfast, which has been shown to act as a nutrient sensor through interaction with mTORC1, extended lifespan and was unexpectedly found to link the JNK and JAK-STAT pathways. Modulation of the glutamate transporter, Eaat1, was also shown to impact lifespan, and stem-cell expression of Eaat1 was found to be important for their division. This opens a new avenue for ageing research, to understand the biology of ageing, and gain a better understanding of how targeted dietary interventions may improve the outcomes of ageing.