Drosophila Undigested Metabolite Profiling reveals age related loss of intestinal amino acid transport regulates longevity

Abstract

Age-related intestinal decline is marked by altered epithelial architecture, loss of barrier function, elevated stress and immune signalling and changes to the intestinal microbiota. Despite this we do not yet know whether age-related intestinal decline impacts nutrient management, a key function of the intestinal epithelium. In this study we have developed Drosophila Undigested Metabolite Profiling (D.U.M.P.) to assess the impact of intestinal ageing on nutrient absorption/excretion balance. We demonstrate that ageing results in a significant increase in amino acid load in the faecal matter that is largely driven by the microbiota and shortens lifespan. Increased amino acid load is associated with reduced expression of a subset of amino acid transporters. Knockdown of the amino acid transporter slimfast in the intestinal epithelium extends lifespan and confers improved microbial control in aged flies, suggesting reduced transporter expression is protective, preventing cellular uptake of excess amino acids. We conclude that age-related changes to the microbiota are an important determinant of the local nutritional environment, with consequences for health. In addition, age-related decline of the intestinal epithelium may impact its capacity for nutrient absorption. These findings have significant implications for the rational design of anti-ageing nutritional therapies.