Large-scale human metagenomic sequencing has identified associations between gut microbiome composition and host physiology, including immunity, nervous system function, and ageing. New findings in humans and model organisms suggest that the gut microbiome affects healthy ageing, and that the microbiome could be used to develop interventions to improve the way we age, but underlying mechanisms are not understood. To define host-microbiome interactions affecting ageing we have established a new model system consisting of the nematode C. elegans combined with an experimental microbiome of 11 bacterial isolates representing the most abundant genera of C. elegans in the wild. Cultivation with the experimental microbiome preserves age-related motility, an effect that requires components of the
p38 MAP kinase pathway, including
nsy-1 and
pmk-1. The experimental microbiome also induces mitochondrial fragmentation in body-wall muscle in a non-
pmk-1 dependent manner, suggesting multiple routes of communication by which the experimental microbiome may modulate age-related motility. In a transgenic proteotoxicity model expressing human AB42 in muscle, age-associated paralysis is suppressed by the experimental microbiome. Cell-free supernatant from the experimental microbiome suppresses paralysis and reduces AB42 aggregation in vitro, suggesting secretion of microbial bioactive compounds capable of abrogating AB42-associated toxicity. Together these findings show that molecular host-microbiome interactions modulate muscle function, mitochondrial dynamics and proteostasis during ageing to delay age-related decline in motility.