Rejuvenation of the Gut Microbiome as a Strategy to Improve Late Life Cognitive Function

The aging of the brain is driven by many factors. Animal studies have demonstrated that the composition of the gut microbiome is one such factor. With age, the balance of microbial populations shifts to favor harmful, inflammatory microbes at the expense of helpful microbial species that produce metabolites necessary for tissue function. Chronic inflammation is a feature of many age-related conditions, neurodegenerative conditions particularly, and the aging gut microbiome contributes to that inflammatory state. Further, the microbiome generates metabolites such as butyrate that support neurogenesis, the creation of new neurons necessary for learning and memory function. Butyrate production falls with advancing age as the microbiome changes.

Fecal microbiota transplant from a young animal to an old animal has been demonstrated to produce a lasting rejuvenation of the gut microbiome, restoring a more youthful balance of populations. In some studies this has resulted in extended life span, in others improved physical and cognitive function. It is a comparatively simple procedure that is already used in a limited way in human medicine, as a treatment for C. difficile infection. It can be carried out width considerably less expense and medical support than the use of the FDA approved procedure, of course. Services like Human Microbes sell screened stool samples from young donors. Further, the measurement of gut microbiome composition and function, a way to clearly and accurately assess outcomes following fecal microbiota transplant, is available via low cost commercial services.

The use of fecal microbiota transplants from young individuals is promising, cost-effective, easy to conduct, and easy to assess as a self-experimenter in the present environment. The procedure should undergo broad clinical testing as a treatment to improve late-life health, but both academia and industry tend to be very slow to undertake clinical trials for a low-cost existing treatment that cannot be effectively patented and monopolized. Given that, setting up one or more low cost clinical trials of fecal microbiota transplant in a few hundred individuals would be a good project for a philanthropic initiative, a way to accelerate the adoption of a way to improve health in a lasting way for hundreds of millions of older people.

The gut microbiota is an emerging target for improving brain health during ageing

While the impact of ageing on the mammalian and human gut microbiome is well established, the impact of the gut microbiota on brain ageing has only recently been investigated, and relies dominantly on preclinical evidence and association analysis derived from small clinical trials. Studies utilising fecal microbiota transplantation (FMT) have demonstrated that the gut microbiota from aged individuals has the capacity to hinder cognitive performance and neurobiological phenotypes when transferred to younger individuals. For instance, transplanting microbes from aged and diseased models to young mice has been shown to impair learning, memory, and neuroplasticity in recipient young mice. Furthermore, young mice who received gut microbiota from aged donors suffered increased rates of mortality following ischemic stroke, along with increased levels of pro-inflammatory plasma cytokines and impaired motor strength. Conversely, aged mice who were colonised with the microbiota from young donor mice had increased survival and improved recovery post-stroke, demonstrating the functional differences between microbiota derived from young or aged individuals in influencing brain recovery following trauma.

Fascinatingly, the gut microbiota from young mice appears to harness properties that enable it to rejuvenate aspects of brain ageing when transferred into aged mice. Two studies recently confirmed similar findings, wherein FMT from young mice to aged mice improved ageing-related deficits in memory and learning ability. Microbiota from young mice restored age-related changes in peripheral and hippocampal immune responses and reversed age-related alterations in hippocampal transcriptional profiles and metabolites suggesting potential mechanisms by which the gut microbiota from young mice improve cognitive performance by modulating immune and metabolic pathways. In this regard, the microbially-derived metabolite δ-valerobetaine, which is increased in aged mice and humans, was shown to directly impair learning and memory abilities, and was reduced in aged mice following FMT from young donor mice. Relatedly, other gut microbiota-derived metabolites which are linked to age-related shifts in the gut microbiota and are increased in aged humans indicate that specific microbially-derived metabolites can impair cognitive abilities during ageing.

As the causal relationships between the gut microbiota and host brain ageing become increasingly clear, it is critical to continue to investigate whether microbiota-targeted therapeutics hold the potential to ameliorate the effects of ageing onto the brain. Several approaches to altering the gut microbiota, including medical interventions such as FMT and antibiotics, as well as lifestyle choices such as diet including probiotics, prebiotics, Mediterranean diet, and intermittent fasting, and exercise, may hold the key to the fountain of brain youth.

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