We become forgetful as we age. This is often seen as a universal truth, but in fact it is far from universal: some people remain incredibly sharp at 100 years old, while others experience memory loss starting in middle age.
While it seems logical that age-related cognitive decline would be blamed on brain aging and degeneration (which, like anything in the brain, is notoriously hard to treat), there's some evidence that processes elsewhere in the body influence the brain's ability to form memories. In particular, neuronal pathways that sense the status of other organs in the body can influence cognitive functions in the brain. Other studies have shown that our gut microbiome affects learning, memory, and behavior. But what we don't yet understand is how these connections work – the specific molecules, microbes, and gut-brain communication involved – and whether we can use that knowledge to prevent or reverse age-related memory loss.
In our new work published today in Nature , we discovered that the aging gastrointestinal tract produces specific molecules that blunt the activity of a key gut-brain neuronal pathway, leading to age-related cognitive decline in mice.
Interoception: how our brain senses what's going on in our body
Our five senses – sight, hearing, taste, smell, and touch – are known collectively as exteroception, and they decline with age. What's much less understood, and what our lab is particularly interested in, is interoception: how our brains subconsciously perceive the state of our peripheral organs to regulate physiological processes. The vagus nerve is a major source of interoceptive information, connecting many major organs like the heart, intestine, lungs, and liver to the brain.
In this study, we discovered that intestine-to-brain signaling through the vagus nerve protects mice against age-related cognitive decline. In fact, stimulating specific gut sensory neurons that feed into the vagus nerve was capable of restoring youthful cognitive function in old mice. A key finding of this work, then, is that our interoceptive senses also decline with age, similar to exteroceptive senses like sight and hearing. But what is causing this decline? And what is the equivalent of eyeglasses or hearing aids to restore interoceptive function?
What do bacteria have to do with it?
Our gut microbiome composition – the types of microbes, their relative abundance, and therefore the types of metabolic processes happening in our intestines – shifts as we age. To assess whether these changes might affect cognitive decline, we used several strategies to introduce the microbiome from old mice into young mice and measured their performance in cognitive and memory tasks. Young mice with old microbiomes did poorly on these tests, just like their old counterparts. But depleting their microbiomes using antibiotics reversed the effect, enabling the mice to regain youthful levels of cognitive function. What was really surprising to us was that germ-free mice that do not have a microbiome show slowed cognitive decline with age, compared to normal mice with typically aging microbiomes. All of this evidence supports the idea that some component or byproduct of the aged microbiome drives the process of memory loss.
We narrowed this down to a possible bacterial culprit called Parabacteroides goldsteinii, though we suspect that other age-associated microbes may contribute too. The key activity of this microbe that drives the cognitive decline process is its production of molecules called medium-chain fatty acids (MCFAs). High levels of MCFAs accumulate with age, due to the increasing abundance of producers like P. goldsteinii, and activate gut-resident myeloid immune cells to produce inflammatory signaling molecules. One of these signaling molecules in particular, IL-1β, impaired the function of vagal sensory neurons. Our experiments allowed us to trace the effects of MCFAs from the producing gut microbes, through intestinal immune cells and their secreted cytokines, into sensory neurons and up the vagus nerve, into the hippocampus of the brain where memories are formed.
So what can we do about this?
Encouragingly, several of our experiments suggest that mice already experiencing cognitive decline can be rescued to a more youthful cognitive state by various interventions. Microbiome depletion by antibiotic treatment reversed cognitive decline, though this is not a viable treatment strategy long-term. In a more targeted approach, we used a bacteriophage – a bacterial virus that affects the activity of P. goldsteinii – and showed that it lowered MCFA levels and improved memory.
A more realistic intervention might be to target the vagus nerve itself to prevent or reverse its functional decline in old age. We stimulated the vagus nerve by treating mice with the gut hormone CCK or with GLP-1 receptor agonists (drugs similar to Ozempic), both of which reversed the age-related memory deficits.
Importantly, these findings prove that what we have traditionally thought of as "brain aging" can actually be controlled and even reversed by processes happening elsewhere in the body – including those that are relatively straightforward to manipulate with drugs or other existing treatments.
Questions for future work
Our study was exclusively done in mice, which means that we don't yet know if this process happens in humans. We are working on new projects to address this question, and we hope that other scientists and clinicians will be inspired by this paper to explore its potential relevance to humans too.
There are, however, a few pieces of evidence out there that suggest we may be on the right track. In patients with severe epilepsy or those recovering from a stroke, one possible treatment is vagus nerve stimulation using implanted devices that deliver mild electrical pulses. Interestingly, people undergoing this procedure have reported cognitive improvements, hinting at the possibility that human vagus nerve activity can also counteract memory loss.
It is also possible that other biological processes, such as chronic inflammation or infection, could contribute to vagus nerve dysfunction through similar pathways. Future work will be necessary to figure out whether stimulating the vagus nerve could offer any improvement of the cognitive effects in those patients. We are also very interested to see whether this process is involved in more severe forms of age-related cognitive decline, such as neurodegeneration and dementia.
Cox, T.O., Devason, A.S., de Araujo, A., Mason, S., Subramanian, M., Salvador, A.F., Descamps, H.C., Kim, J., Zhu, Y., Litichevskiy, L., Jung, S., Song, W., Cortés-Martín, A., Henderson, N.T., Huang, K.-P., Nguyen, T., Sae-Lee, W., Umana, I.C., Sacta, M., Rahman, R.J., Wisser, S., Nelson, J.A.D., Golynker, I., McSween, A.M., Hohmann, E.F., Patel, S., Bub, A.L., Soekler, C., Blank, N., Hoxha, K., Boccia, L., Wong, A.C., Bahnsen, K., Kim, J., Biderman, N., Abbasian, D., Shoffler, C., Petucci, C., McAllister, F.E., Alhadeff, A.L., Fuccillo, M.V., Hill, C., Jang, C., Betley, J.N., de Lartigue, G., Lee, V.Y.-M., Levy, M., & Thaiss, C.A (2026). Intestinal interoceptive dysfunction drives age-associated cognitive decline. Nature. https://doi.org/10.1038/s41586-026-10191-6
Authors
- Christoph Thaiss (X: @ChristophThaiss ) is a Core Investigator at Arc Institute and an Assistant Professor of Pathology at Stanford University.
- Maayan Levy (X: @MaayanLevyPhD ) is an Assistant Professor of Pathology at Stanford University and an Arc Institute Innovation Investigator in Residence.
- Timothy Cox is a MD-PhD Student at the University of Pennsylvana
