The power of microbes: C. elegans as a model to identify microbiome effects on age-related muscle function

Improvements in healthcare and nutrition mean that we now live longer than ever before, but with ageing comes frailty and deterioration of physiological functions, leading to large burdens for societies and healthcare systems globally. The current pandemic highlights the importance of health and resilience during ageing and the urgency of improving late-life health.

DO GUT MICROBES AFFECT THE WAY WE AGE?
One very promising but largely unexplored avenue to promote healthy ageing is the gut microbiome, the community of microbes in our guts. A series of studies link the microbiome to host ageing. Healthy gut microbiomes are characterised by bacterial taxonomic diversity, but during ageing the composition of the microbiome changes, resulting in decreased diversity, expansion of pathogenic bacterial species and alterations in microbial functions. Human age and frailty are associated with certain species/genera while the microbiomes of centenarians are more similar to those of young adults. Work in model organisms (C. elegans, Drosophila, killifish, mice), including the use of faecal transplants and genetic manipulation of bacteria, show that the microbiome is a direct cause of host ageing. Considering the evolutionary distance between these species, these studies suggest the microbiome also affects human ageing. Recently, exciting studies have shown that the microbiome affects muscle function and physical performance, but the underlying mechanisms are largely unknown. The aim of our study is to determine the molecular interactions between the host and its microbiome underlying the microbiome effects on muscle ageing, with the long term goal of finding ways to improve physical function in the elderly.

C. ELEGANS - AN IDEAL MODEL ORGANISM
To study host-microbiome interactions during ageing we are using a simple and tractable model system, C. elegans. C. elegans offers many advantages; it is cheap to grow, genetically amenable, shares many of its genes with humans, is short-lived and enables high-throughput research. Importantly, it is easy to sterilise these animals and colonise their guts with microbes of choice.

C. elegans has been crucial in the discovery of conserved ageing mechanisms, revolutionising our understanding of ageing. Recent high-profile studies show that host-microbiome interactions in C. elegans also act through conserved pathways, and we anticipate that many major discoveries of the fundamentals of host-microbiome interactions in the coming years will come from simple models. There is now an opportunity to expand the use of C. elegans to improve our understanding of host-microbiome interactions.

UNDERSTANDING THE HOST-MICROBIOME INTERACTIONS AFFECTING AGEING
Recently, the natural microbiome of wild C. elegans was isolated and cultivated in the lab, enabling the study of interactions between a tractable model and its natural commensals. My group has established a simplified natural microbiome consisting of 11 representative bacterial species from the natural microbiome of C. elegans, allowing us to study natural host-microbiome interactions. Using this system, we find that the microbiome suppresses age-related decline in motility in C. elegans relative to animals grown in standard laboratory conditions. We find that the microbiome alters the mitochondria, the cells' powerhouses, in muscle and affects age-related motility through the immune system. These results suggest that the microbiome affects muscle function through the mitochondria and immune signalling.

The goal of this project is to understand the molecular mechanisms underlying microbiome effects on age-related motility, and to work towards innovative ways to use the microbiome to improve health and quality of life for ageing people.

Age-related decline is a major global challenge, and interventions that result in healthy ageing are in urgent need. New findings show that the gut microbiome affects ageing, and that the microbiome could be used to develop interventions to improve ageing, but the underlying mechanisms however are not understood. Our aim is to use a tractable model system to define molecular host-microbiome interactions underlying age-related health.

I have established a model consisting of C. elegans and a simplified microbiome based on the natural C. elegans microbiota, offering an opportunity to study how microbial species and molecules affect host ageing. This simplified microbiome has dramatic effects on motility and suppresses age-related motility decline. It also affects immunity and muscular mitochondrial network dynamics, suggesting routes of communication whereby gut microbes communicate through immunity and mitochondria to alter muscle function and metabolism. Moreover, extracellular molecules from the simplified microbiome suppress age-related amyloid aggregation toxicity in C. elegans muscle, and suppress amyloid aggregation in vitro, suggesting that molecules produced by the bacteria affect muscle proteostasis.

Our aim is to gain mechanistic understanding of host-microbiome interactions. We will address the following questions:

1. What are the effects of the microbiome on muscle function and muscle ageing?
2. What are the effects of the microbiome on mitochondrial function and mitochondrial signalling?
3. Which are the chemical signals by which the microbes alter host ageing?

We will advance the understanding of how molecular host-microbiome interactions affect healthspan, and work with collaborators to establish evolutionary conservation of our findings in other models and evaluate their translational potential.