Mining the microbiome: Can microbial interventions influence the pace of aging?

At this year’s Nutra Healthspan Summit, held in London from Nov. 12 to 13, industry experts highlighted that because the microbiome underpins health, biotics could drive a new wave of healthspan-enhancing solutions.

Kickstarting the conversation on day two of the conference, Synbiotic Health’s commercial and scientific advisor Dr. Gregory Leyer noted that the microbiome is a vital aspect of healthy aging due to its role in immune system maturation and development, disease risk and metabolic and neurological function.

In fact, gut microbes may influence certain hallmarks of aging. For example, autophagy and mitochondrial function are modulated by microbiome metabolites, and inflammation is altered by proportions of pro- and anti-inflammatory gut taxa.

And while the population does not experience age-related decline uniformly, gut microbiome composition can shape the pace of aging, according to Dr. Leyer. This has been shown in cohort data, illustrating that unhealthy aging is characterized by an increase in pathobionts (bacteria that can cause disease under certain conditions) and a rapid decline in protective taxa.

Some studies have gone as far to attempt to classify different taxonomic groups with different health statuses. One paper by Ghosh et al. (2020) found that three groups of microbial taxa were consistent across cohorts and were associated with either healthy or unhealthy aging.

Pointing to the available evidence, Dr. Leyer highlighted that Bifidobacterium crops up time and time again in healthy aging studies and reviews, pointing to three recent studies in centenarians.

For example, one study of Italian centenarians found that healthy aging was associated with the enrichment of Bifidobacterium and Akkermansia. In supercentenarians in India, Bifidobacterium was one of the most common genera, with B. longum among the most prominent species. In another study of Sardinian centenarians, an enrichment of Bifidobacterium was observed again, with B. adolescentis particularly dominant.

In addition, a recent study of an 117-year-old woman—the sixth oldest person recorded in human history— discovered a vast amount of Bifidobacterium in her gut. Her levels were three to four times higher than normal, countering the age-related decline typically seen with this genus of bacteria.

Dr. Leyer said these findings suggest that Bifidobacteria is likely to play an important role in healthy aging.

“I’m not here to say there is a direct link and point A goes to point B, but there is enough evidence out there to suggest that the Bifidobacteria genus, and maybe more specifically particular species, is really important in healthy aging,” he said.

During a subsequent panel discussion, Dr. Sean Gibbons, PhD, associate professor at the Institute for Systems Biology, said it is important to be wary of single-person studies.

“If I saw a microbiome that was that old and was essentially 60% Bifidobacterium, I would be concerned—it would be weird,” he said. “People who are centenarians have achieved a long life, but they are also going to die at some point. [It is important to consider] how close they are to that precipitous decline in health.”

Identifying microbiome-mediated drivers of healthy aging

In his presentation, Dr. Gibbons discussed the mechanistic drivers of microbiome-mediated healthy aging. Looking at the available literature, he determined there are predominantly two schools of thought. One suggests that changes associated with aging are essentially bad and forestalling these changes could be of benefit, and the other suggests that changes to the microbiome over time could be protective in older age.

Using data from two cohorts—one comprised of around 3,600 relatively healthy and affluent Americans (Arivale) and the other of roughly 1,000 older American men (MrOS)—Dr. Gibbons and his team determined that ‘uniqueness’ shows the strongest association with healthy aging. This signature reflects the extent to which an individual’s gut microbiome differs from that of their peers.

“No matter how you slice it or dice it, people who reported being healthier showed this signature of increasing uniqueness with chronological age, and those who had less good health did not,” he said. “We’ve now replicated this across several different cohorts. It has also been replicated in other parts of the world like China and Europe.”

This finding suggests that clinging on to a more youthful microbiota composition may negatively impact health, supporting the hypothesis that microbial diversity in older age is positive for overall health and well-being.

The research also found that dominance of certain types of bacteria may also affect healthy aging. For example, in the MrOS cohort, people aged 85 and above who had a high level of Bacteroides in the gut were more likely to die over a four-year window.

But which mechanisms are driving this? Dr. Gibbons suggests one reason for this finding may be that Bacteroides are mucin degraders. They essentially ‘eat’ the mucin layer in the gut—a barrier that separates the gut microbiota from the immune system. Mucus production also declines with age, meaning older people with high Bacteroides abundance may be more prone to infections and inflammation.

Conversely, high levels of gram-positive anaerobes, such as Clostridia, were associated with healthy aging. Dr Gibbons suggests this may be because Clostridia produces butyrate, a potent molecule that can ‘turn down’ systemic inflammation in the body.

In another study using the Arivale cohort, Dr. Gibbons’ team paired microbiome data and blood clinical chemistries to assess butyrate production with health outcomes. They found that a higher level of butyrate was associated with lower LDL cholesterol, improved insulin sensitivity and lower levels of systemic inflammation.

“If we apply this to the context of uniqueness and aging, what we find is that this uniqueness score is very positively associated with predictive butyrate production,” he said. “This matches our intuition because we also saw that butyrate-producing Clostridia were rising in their relative abundance. So perhaps this is one of the effector molecules that’s mediating the healthy effect of this particular microbiota composition in these aging folks.”

Butyrate: The solution to the problem?

This mounting evidence has led scientists to hypothesize that butyrate may play a role in healthy aging. However, boosting butyrate production is no easy feat given that everyone produces different levels due to their gut microbiome composition and functional capacity of their gut microbes.

To test whether dietary changes could affect butyrate production, Dr. Gibbons’ lab conducted an in silico trial using data from 2,500 participants. Using computer modelling, the researchers simulated either a standard European diet (similar to the American diet) or a high-fiber vegan diet.

While they expected those on the high fiber diet to produce more butyrate, there were many non-responders and even some regressors—those who produced less butyrate on the high fiber diet as opposed to their normal diet.

The team then added pre- and probiotic supplements and found that there was no singular co-intervention that expressed in everybody, underscoring the problem with typical microbial intervention studies.

Precision prebiotic firm Myota is one company working to find a solution to this problem by creating optimized prebiotic blends that use a diverse array of fibers to increase the likelihood of a response.

“Butyrate is a really important, potent anti-inflammatory substance,” said Dr. Caitlin Hall, Myota’s head of research. “There’s huge potential there in terms of the cognitive and metabolic [benefits] and blood glucose control.”

However, inter-individual variability in butyrate production is a significant hurdle to consider, she said.

“If we were to give everyone in this room a banana, there’s going to be huge inter-individual variability,” she said. “So, there’s two approaches, we could give everyone a personalized prebiotic supplement where they’re guaranteed to produce butyrate. But in reality, from a manufacturing and health claim perspective, this is really difficult to do. The second option is to create an optimized blend of prebiotic fibers where everyone will produce a reliable amount of butyrate from that blend.”

Other companies have taken a different approach, selling butyrate capsules as a standalone supplement. However, there are several problems with this method, according to Dr. Hall and Dr. Gibbons.

“Bypassing the microbiome and going straight to the solution seems like a great approach, but there are several issues,” Dr. Hall said. “Firstly, butyrate tastes horrendous—it’s akin to a vomit smell—and secondly, you either need to administer butyrate directly to the colon or take around 20 capsules a day to see similar effects to what the microbiome can produce on its own.”

“There’s obviously a lot going on in the microbiome aside from the production of butyrate as well,” she added. “There’s cross feeding, there’s interactions between different microbes and dietary fiber and probiotics that is independent from butyrate. So, I think there’s a lot more to gain by feeding the system rather than just giving the end product.”

Dr. Gibbons added that colonic delivery is integral for efficacy, with some companies attempting to conjugate butyrate to fibers for a slower release. Even so, the most effective solutions are likely to be those which feed gut microbes, he said.

“We talk about butyrate almost like it’s a drug—it is very potent, but compared to a drug, it’s not that potent,” he said. “You need a really high amount of butyrate, and you need it to be produced all the time in situ, and this is technologically really difficult to do in a direct delivery model. I think having your endogenous microbiota make several millimoles per hour per gram of biomass is probably the best way to do it.”