Intestinal interoceptive dysfunction drives age-associated cognitive decline

Area of Science:

• Neuroscience
• Microbiology
• Gerontology

Background:

• Ageing is associated with cognitive decline, particularly memory impairment.
• The gut microbiome and its signaling pathways are increasingly recognized as modulators of brain function.
• Mechanisms linking gut-brain communication to age-related memory loss are not well understood.

Purpose of the Study:

• To map the ageing microbiome and its functional impact on cognitive decline.
• To identify specific gut-brain signaling pathways involved in age-related memory impairment.
• To explore potential interventions for enhancing memory in aged individuals.

Main Methods:

• High-resolution mapping of the mouse microbiome throughout its lifespan.
• Investigating the role of medium-chain fatty acid-producing bacteria (e.g., Parabacteroides goldsteinii) and GPR84 signaling.
• Assessing vagal afferent neuron function and hippocampal activation.
• Testing interventions including phage therapy, GPR84 inhibition, and vagal activity restoration.

Main Results:

• Accumulation of specific gut bacteria drives inflammation via GPR84 signaling, impairing vagal nerve function.
• This disruption weakens interoceptive signals to the brain, leading to hippocampal dysfunction and memory loss.
• Interventions such as targeting Parabacteroides with phages or inhibiting GPR84 successfully enhanced memory in aged mice.

Conclusions:

• Interoceptive dysfunction plays a critical role in age-related cognitive decline.
• Modulating gut-brain communication offers a promising therapeutic strategy to counteract memory loss.
• Interoceptomimetics stimulating gut-brain signaling may be beneficial for brain ageing.