Intestinal interoceptive dysfunction drives age-associated cognitive decline

Ageing is accompanied by declining memory function, with extremely heterogeneous manifestation in the human population<sup>1</sup>. Brain-extrinsic factors influencing cognitive decline, such as gastrointestinal signals, have emerged as attractive targets for peripheral interventions<sup>2-6</sup>, 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.

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Publication Details

Journal
Nature
Published
2026-03-11
DOI
https://doi.org/10.1038/s41586-026-10191-6
Citations
2
Primary Topic
Gut microbiota and health
Type
article
Field-Weighted Citation Impact
44.47
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article

Intestinal interoceptive dysfunction drives age-associated cognitive decline

Nathan T. Henderson, Jihee Kim, Cholsoon Jang, Thao Nguyen et al.
2 citations
Nature
Gut microbiota and health
44.47
article

Intestinal interoceptive dysfunction drives age-associated cognitive decline

Nathan T. Henderson, Jihee Kim, Cholsoon Jang, Thao Nguyen, Eric Hohmann, Maayan Levy, Ryan J. Rahman, Madhav Subramanian, Clarissa Shoffler, Hélène C. Descamps, Lev Litichevskiy, Alana M. McSween, Stephen Wisser, Kuei-Pin Huang, Julie Kim, Timothy Cox, Fiona E. McAllister, Niklas Blank, Wisath Sae-Lee, Christopher Petucci, Andrea C. Wong, C. Hill, Klaas Bahnsen, Ashwarya S. Devason, Yi Zhu, Shaan Patel, Lavinia Boccia, Won-Suk Song, Sydney Mason, Sunhee Jung, Dina Abbasian, Ilona Golynker, Marc V. Fuccillo, Natalie Biderman, Clara Soekler, Kevt’her Hoxha, Guillaume de Lartigue, Anna L. Bub, Alan de Araujo, Amber L. Alhadeff, J. Nicholas Betley, Virginia Y.-M. Lee, Christoph A. Thaiss, Andrea F. M. Salvador, Adrián Cortés-Martín, Maria Sacta, J. Andrew D. Nelson, Iboro C. Umana
article en
2 citations

Abstract

Ageing is accompanied by declining memory function, with extremely heterogeneous manifestation in the human population<sup>1</sup>. Brain-extrinsic factors influencing cognitive decline, such as gastrointestinal signals, have emerged as attractive targets for peripheral interventions<sup>2-6</sup>, 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.

Nature
Children's Hospital of Philadelphia (US), University of California, Irvine (US), Cardiovascular Institute of the South (US), University College Cork (IE), Monell Chemical Senses Center (US), Enzo Life Sciences (United States) (US), Institute for Neurodegenerative Disorders (US), Palo Alto Institute (US), Institute on Aging (US), Stanford Medicine (US), APC Microbiome Institute (IE), Activated Research Company (United States) (US), Arc Research Institute, University of Pennsylvania (US), Stanford University (US)
Openalex Percentile: Top 0%
Gut microbiota and health
44.47
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