Host-Microbe-Diet Interactions in Ageing

Centenarians are the fastest growing age group in the UK. The major burden of disability and ill-health in developed countries falls on older people as medical advances are not sufficient to maintain people healthier for longer. This incurs important medical, economic and social costs to societies barely coping with an ageing demographic. Ageing is modulated by genetics and its constant evolving environment. It has been found that body health during ageing is strongly affected by the symbiotic microbes that inhabit the gut. However, the understanding of how microbes affect the functions of the host biology is still in its infancy. This is where the use of model organisms such as nematode worms come into play. These models allow us to tease apart the complex interactions between host genetics, gut microbes and nutrition in a way that no other models can. They also provide a platform to prove mechanistic causation between interventions, such as nutrients or drugs, and allow scientists to build mathematical and computational models that can be used for the translation of this information to application in humans. Ultimately, the findings of this programme will inform on how to harness gut microbes to improve late life health.

Animals rarely live in isolation, but rather exist in intimate association with other species, particularly microorganisms. The microbiota and its genes play key roles in human health and disease. Recently, several reports have linked the role of microbiota with organismal ageing. Not only the composition and function of the microbiota changes over time within an ageing organism but also the function of the microbiota can modulate organismal ageing. Yet, the causal mechanisms regulating this intertwined and complex communication remain widely unexplored and ill-defined. Despite great advances in our understanding of ageing biology from a genomic-centric approach, we do not fully comprehend why similar mutations or treatments lead to a wide-range of host phenotypes in a context-dependent manner. Nutrition and the microbiome are two key environmental factors regulating host physiology. Chemical elements originating from these exogenous sources are the cornerstone of life as they offer a source of energy, the building blocks for cellular construction and the micronutrients which are essential for the adequate functioning of cells. Importantly, the microbiome is significantly enriched for genes involved in the metabolism of dietary compounds to produce molecules of biological relevance. These metabolites may explain the present gaps in our knowledge coupling the gut microbiota to biological host mechanisms in health and disease throughout life. The overarching goal of this programme is to unravel the molecular basis of microbial and dietary-induced host metabolic-rewiring during ageing. Here, we integrate novel experimental designs to build mechanistic in silico models through systems biology approaches in order to predictively understand the contribution of diet in the regulation of host biology through or independently of the microbiome. The underlying mechanisms will be studied using the powerful genetic, microbiota and ageing model Caenorhabditis elegans, which mirrors many conserved human metabolic pathways and allows for a well-defined control of environmental cues. This interdisciplinary programme will combine state-of-the-art high-throughput screening host- microbe- diet approaches developed in the Cabreiro lab and combined omics approaches at the host and microbial level to identify and characterize: microbially-regulated host metabolic pathways regulating ageing (Aim 1); identify dietary and microbial metabolites critical for healthy ageing (Aim 2); and microbial-diet -interactions regulating metabolism and host ageing (Aim 3). Ultimately, we aim at demonstrating the power of interspecies predictive models and the possibility of creating precise genetic interventions in bacteria for discovering and harnessing new metabolites with important implications in regulating healthy ageing.