Intestinal interoceptive dysfunction drives age-associated cognitive decline

Mar 12, 2026Nature

Problems sensing gut signals may contribute to memory decline with aging

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Inhibition of gut-brain signaling during aging in mice is associated with impaired neuronal activation in the hippocampus and loss of memory encoding.

Accumulation of gut bacteria producing medium-chain fatty acids may drive inflammation in peripheral immune cells.
This inflammation is linked to impaired function of vagal afferent neurons, weakening the signals sent to the brain.
Diminished interoceptive signals are correlated with declines in hippocampal function.
Interventions such as targeting specific gut bacteria and inhibiting GPR84 may enhance memory in aged mice.
The findings highlight the potential importance of gut-brain communication in addressing cognitive decline associated with aging.

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Ageing is accompanied by declining memory function, with extremely heterogeneous manifestation in the human population. Brain-extrinsic factors influencing cognitive decline, such as gastrointestinal signals, have emerged as attractive targets for peripheral interventions, but the underlying mechanisms remain largely unclear. Here, by charting a high-resolution map of microbiome ageing and its functional consequences throughout the lifespan of mice, we identify a mechanism by which inhibition of gut-brain signalling during ageing results in impaired neuronal activation in the hippocampus and loss of memory encoding. Specifically, accumulation of gut bacteria that produce medium-chain fatty acids, such as Parabacteroides goldsteinii, can drive peripheral myeloid cell inflammation through GPR84 signalling. As a result, the function of vagal afferent neurons is impaired, the interoceptive signal received by the brain is weakened and hippocampal function declines. We leverage this pathway to define interventions that enhance 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 dysfunction in brain ageing and suggest that interoceptomimetics that stimulate gut-brain communication may counteract age-associated cognitive decline. 1 2-6