Intestinal interoceptive dysfunction drives age-associated cognitive decline [RNA-Seq]

Aging is accompanied by declining memory function, necessitating the development of effective countermeasures1. Brain- extrinsic factors influencing cognitive decline, including the intestinal microbiome, have emerged as attractive targets for peripheral interventions2-6, but the underlying mechanisms remain largely unclear. Here, by charting a high-resolution map of microbiome aging and its functional consequences throughout the lifespan of mice, we identify a mechanism whereby age- associated inhibition of gut-brain signalling results in impaired novelty-induced neuronal activation in the hippocampus and loss of memory encoding. Specifically, gut bacteria producing medium-chain fatty acids, such as Parabacteroides goldsteinii, accumulate over the lifespan and drive intestinal myeloid cell inflammation through GPR84 signalling. As a result, the function of afferent gut-innervating vagal neurons is impaired, the interoceptive signal received by the brain is weakened, and hippocampal function declines. We leverage this pathway to define interventions that restore memory in aged mice, such as phage targeting of Parabacteroides, GPR84 inhibition, and restoration of vagal activity. These findings indicate a key role for interoceptive signalling from the gastrointestinal tract in regulating brain aging and suggest that interoceptomimetics that stimulate gut-brain communication may counteract age-associated cognitive decline.