Why study ageing?
Age is the main risk factor for common diseases like cancer, cardiovascular disease and neurodegenerative diseases. Over the last 100 years, the improvements in healthcare have resulted in increased life expectancy worldwide. The increased life expectancy is a fantastic achievement but also presents society with new challenges; as an increasing number of people get older, more people suffer from age-related diseases, affecting the quality of life of older people and their families, and causing increasing costs for society. The focus of our research is to understand the ageing process, with the aim to slow down ageing and prevent age-related diseases.
The role of the microbiome in ageing
An emerging player in health is the gut microbiota, the population of microbes living in our guts. Our gut microbiota contains at least 1000 different species of bacteria with more than 3 million genes – 150 times more than human genes. The gut microbiota has important physiological functions including digesting certain foods, producing important vitamins and helping us combat infections. The composition of the gut microbiota has been associated with health and disease, suggesting it plays an important role in human physiology. It has been suggested that differences in the composition of the gut microbiota of individuals could explain differences in disease susceptibility, and that targeting the gut microbiome could be an avenue to improve human health.
During ageing, the gut microbiota undergoes dramatic changes. The composition of microbiota of the elderly is different, less diverse, and more easily altered than the microbiota of young people. The gut microbiota is affected by diet, and elderly living in the community have a microbiota that is more similar to that of younger adults than that of elderly people in care facilities. Centenarians have a microbiota that is rich in some microbial species, suggesting that specific species play a role in maintenance of health in old age. Furthermore, the gut microbiota has been linked to metabolic syndrome, inflammation and neurodegenerative diseases. Thus, the composition of the gut microbiota is tightly linked with the ageing process, making it important to understand the link between the gut microbiota and disease.
The need of simple model systems to dissect host-microbiome interactions
Metagenomic approaches have generated a long list of diseases associated with changes in the microbiome, but the mechanisms underlying host-microbiome interactions remain largely unknown. The challenge comes partly from the enormous complexity of human host-microbiome interactions, where microbe-microbe interactions add additional layers complexity, and partly from the time and cost associated with using mammalian models. If the field is to make significant process in the mechanistic understanding of host-microbiome interactions and move beyond correlations, well-characterised, fully controlled and cost-effective models are needed.
My lab uses the nematode C. elegans to study the effect of the microbiome on ageing, with a particular focus on the gut-brain axis. C. elegans is ideally suited to perform mechanistic studies and establish causation of host-microbiome interactions. The presence of microorganisms can be easily controlled. C. elegans is highly amenable to genetic manipulation with thousands of mutants and RNAi constructs are available, and can be combined with genetically tractable bacterial models. Many phenotypes relevant for studying host-microbiome interactions are well established, including innate immunity, nervous system function and ageing. C. elegans has a generation time of 3 days and lifespan of 3 weeks, allowing quick and inexpensive high-throughput experiments. C. elegans has a simple, well-characterised and mapped nervous system, and hosts many behaviours and simple forms of learning and memory, allowing assessment of nervous system function.
Decreased microbiome diversity is likely caused by Westernisation and diet, and there is an urgency to understand the links between the microbiome, ageing and health. We use C. elegans combined with bacterial model systems, transcriptomic and metabolomic approaches to test hypotheses generated from metagenomics, and identify mechanisms by which host-microbiome interactions affect the ageing nervous system. We collaborate closely with researchers using other models (flies, zebrafish and mice) to establish evolutionary conservation of our findings, ensuring translational potential and promoting the development of rationally targeted microbiome maintenance for life-long health.