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Could the vagus nerve be key to reversing age-related memory loss? VILevi/Getty Images
  • A study in mice concludes that age-related loss in memory function may be driven by changes in the gut microbiome.
  • This effect is mediated by sensory neurons in the gut that contact the brain via the vagus nerve.
  • The scientists identified a mechanism by which gut-brain signals can impair memory formation in the hippocampus.
  • Importantly, the researchers also identified ways to reverse the decline in cognitive ability.

On average, human memory declines with age. However, there is substantial variation among individuals: some experience a rapid decline, whereas others barely notice a change.

With our rapidly aging population, understanding why some people are affected while others are not is important work.

A new animal study, published in Nature, concludes that memory problems associated with age may be driven by our gut and the bacteria that live within it.

In particular, the effect appears to depend on how the body perceives and responds to its internal environment, which is called interoception.

Their results may inform novel approaches to mitigating age-related memory deficits. Although the study is in animals, the results are likely to spark much more research.

Exteroception is our ability to sense the outside world: Sights, smells, sounds, and so on. Interoception, on the other hand, is the body’s ability to monitor its internal state.

The vagus nerve, which travels between the brain and all the major organs, is a superhighway for interoreception. It sends messages from the body to the brain, where it can make any necessary adjustments based on the new information.

Neuronal engrams, or memory traces, are the fundamental unit of memory storage. These clusters of neurons form during learning and store a memory. When we experience a relevant cue, the engram is activated, and we access the memory.

Our ability to form these engrams declines as we age. The researchers hypothesize that communication between the body and brain may be disrupted during aging, which might help explain memory decline.

According to the authors, existing evidence suggests that the gut microbiome “may contribute to age-associated memory loss,” so they started there.

Their research unravelled a relationship among microbes, the chemicals they produce (metabolites), and the immune system, the vagus nerve, and the hippocampus — a part of the brain pivotal for memory formation.

Reading more like a detective novel than a scientific paper, the team slowly unravels this complex web of interactions in minute detail.

Like many systems in the body, the gut microbiome slowly changes with age. The same is true in mice. For the first leg of the experiment, the scientists used various methods to alter a young mouse’s microbiome to more closely resemble that of an older mouse.

They did this, for instance, by using poop transplants or simply by housing a young mouse with an older mouse.

When a young mouse had an old microbiome, it exhibited cognitive decline similar to that observed in an older mouse. If it was then treated with antibiotics, which wiped out the microbiome, their cognitive abilities returned.

This evidence indicates that the microbiome contributes to memory decline with age. Next, they set out to identify which particular bacterial strains might be responsible. They concluded that the most likely candidate was Parabacteroides goldsteinii.

Then, they showed that harbouring an old microbiome, and specifically P. goldsteinii, was associated with altered neuronal responses in the hippocampus. They also noted concurrent changes in other brain regions that process sensory information. This, they theorized, might indicate that cognitive decline is related to disrupted interoception.

Using various techniques, the scientists eventually showed that the vagus nerve was the culprit. Specifically, it was a subtype of neurons called CCKAR+, which pass information from the gut to the hippocampus. These neurons respond to a gut peptide called cholecystokinin (CCK).

When the researchers treated old mice and young mice with old microbiomes with CCK, they recovered their cognitive abilities, becoming indistinguishable from control mice. The same effect was observed when they stimulated the vagus nerve with a GLP-1 receptor agonist, which is another gut peptide.

This was the next question to answer. Taken together, the researchers had established that increased levels of P. goldsteinii were associated with age-related memory decline and that this decline was due to reduced functioning of vagal neurons that run from the gut to the hippocampus.

Using a painstaking process of elimination, the scientists trawled through metabolites produced by P. goldsteinii. Eventually, they honed in on a medium-chain fatty acid (MCFA) called 3-hydroxyoctanoic acid (3-HOA). They found that oral supplementation with 3-HOA could induce age-related changes in the hippocampus.

They also tested two additional MCFAs, decanoic and dodecanoic acids. Both are increased in the presence of P. goldsteinii, and both had a similar effect to 3-HOA on the hippocampus of the mice.

In subsequent tests, the scientists found that MCFA levels did indeed slowly increase with age. Once again, co-housing a young mouse with an old one increased levels of both P. goldsteinii and 3-HOA.

This incredible Columbo-esque detective story is now in full flow: They have established that MCFAs associated with P. goldsteinii drive age-related memory decline by reducing the functionality of vagal neurons running between the gut and the hippocampus.

The next leg of the investigation focused on how MCFAs hinder memory formation, and the key appears to be inflammation.

MCFAs activate a receptor called GPR84. They noted that mice lacking GPR84 or treated with a GPR84-blocking compound were resistant to the cognitive decline induced by 3-HOA.

GPR84 is predominantly expressed on immune cells, and its activation promotes inflammation by triggering cytokine release. In line with this, the scientists noted that age-related cognitive decline was also associated with increased levels of inflammatory cytokines, particularly in the gut and fat tissue.

With this finding, the complex picture was complete. The authors write:

“Altogether, our findings suggest a model whereby aging leads to changes in the gastrointestinal milieu, including the outgrowth of P. goldsteinii and accumulation of MCFAs. These metabolites, in turn, drive pro-inflammatory [immune] cell responses through GPR84 signalling, thereby impairing vagal activity, hippocampal responses, and memory function.”

While this study was conducted in an animal model, the researchers’ thorough approach means we can be fairly confident that this is how it works in mice. That does not mean it is the same in humans, but it certainly opens the door to the possibility.

Medical News Today contacted Momo Vuyisich, PhD., founder and chief science officer of Viome and an adjunct professor at the University of New Mexico in Albuquerque, who was not involved in the study.

“Since intestinal biopsies and stool collections are commonly collected for medical and research purposes,” he told us, “these associations could easily be established in humans.”

He added that “a non-randomized control trial in humans has already shown cognitive improvements with fecal microbiota transplants,” so finding a similar relationship is certainly not in the realm of fantasy. However, he explained that replicating some parts of this study in humans would be “very challenging.”

We asked Vuyisich whether these findings could eventually lead to new approaches to slowing cognitive decline. He was hopeful and believed that food might hold some of the answers:

“To me, the most promising therapeutic avenues will be nutritional, since the microbes producing MCFAs likely require specific nutritional ingredients to produce them. Once we identify those ingredients, susceptible people, based on their gut microbiome test, will be given specific diets that minimize the production of MCFAs and minimize cognitive decline.”

Scientists have already shown that the gut microbiome can have wide-ranging impacts on overall health, including brain health, so this at least provides a new avenue for exploring cognitive decline with age.

“Pharmacological activators of interoceptive pathways — which we refer to as interoceptomimetics may thus have the potential to stimulate sensory input into the brain to boost the formation of memory engrams in the hippocampus,” conclude the authors.

“Our findings call for the systematic exploration of possible interoceptomimetics and their impact on the aging brain,” they add.