Intestinal interoceptive dysfunction drives age-associated cognitive decline PMID: 41813891

ADC Targets in Oncology

2026-04-10

Intestinal interoceptive dysfunction drives age-associated cognitive decline

Nature. 2026 Apr;652(8109):442-450. doi: 10.1038/s41586-026-10191-6.

Timothy O Cox ¹ ² , Ashwarya S Devason ¹ , Alan de Araujo ³ ⁴ , Sydney Mason ¹ , Madhav Subramanian ¹ , Andrea F M Salvador ⁵ ⁶ , Hélène C Descamps ¹ , Junwon Kim ¹ , Yixuan Zhu ¹ , Lev Litichevskiy ¹ , Sunhee Jung ⁷ , Won-Suk Song ⁷ , Adrián Cortés-Martín ⁸ , Nathan T Henderson ⁴ , Kuei-Pin Huang ³ ⁴ , Thao Nguyen ⁹ , Wisath Sae-Lee ⁹ , Iboro C Umana ¹ , Maria Sacta ¹ ¹⁰ , Ryan J Rahman ¹ , Stephen Wisser ¹ ⁴ , J Andrew D Nelson ¹ , Ilona Golynker ¹ , Alana M McSween ⁵ ⁶ , Eric F Hohmann ⁵ ⁶ , Shaan Patel ⁵ ⁶ , Anna L Bub ⁵ ⁶ , Clara Soekler ⁵ ⁶ , Niklas Blank ⁵ ⁶ , Kevt'her Hoxha ² , Lavinia Boccia ⁴ ¹¹ , Andrea C Wong ¹ , Klaas Bahnsen ¹ , Jihee Kim ¹ , Natalie Biderman ¹² , Dina Abbasian ¹³ , Clarissa Shoffler ¹³ , Christopher Petucci ¹³ , Fiona E McAllister ⁹ , Amber L Alhadeff ³ ⁴ , Marc V Fuccillo ⁴ , Colin Hill ⁸ , Cholsoon Jang ⁷ , J Nicholas Betley ⁴ ¹¹ , Guillaume de Lartigue ³ ⁴ , Virginia Y-M Lee ² , Maayan Levy ¹⁴ ¹⁵ , Christoph A Thaiss ¹⁶ ¹⁷

Affiliations

1. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2. Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
3. Monell Chemical Senses Center, Philadelphia, PA, USA.
4. Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5. Arc Institute, Palo Alto, CA, USA.
6. Department of Pathology, Stanford University, Stanford, CA, USA.
7. Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
8. School of Microbiology and APC Microbiome Ireland, University College Cork, Cork, Ireland.
9. Calico Life Sciences LLC, San Francisco, CA, USA.
10. Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
11. Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.
12. Department of Psychology and Stanford Center on Longevity, Stanford University, Stanford, CA, USA.
13. Metabolomics Core, Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
14. Arc Institute, Palo Alto, CA, USA. [email protected].
15. Department of Pathology, Stanford University, Stanford, CA, USA. [email protected].
16. Arc Institute, Palo Alto, CA, USA. [email protected].
17. Department of Pathology, Stanford University, Stanford, CA, USA. [email protected].

Abstract

Ageing is accompanied by declining memory function, with extremely heterogeneous manifestation in the human population¹. Brain-extrinsic factors influencing cognitive decline, such as gastrointestinal signals, have emerged as attractive targets for peripheral interventions^2-6, 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.