Reviewing the Aging of the Gut Microbiome

Researchers here take a high level tour of what is known of age-related changes in the gut microbiome and how they influence health. Accumulating evidence shows a loss of beneficial populations that generate useful metabolites such as butyrate, accompanied by an increase in harmful populations that can provoke chronic inflammation. This is a likely a meaningful contribution to the onset and development age-related conditions, making it a priority to develop ways to reset the balance of populations in the gut microbiome. The best of the available approaches, given the evidence to date, is fecal microbiota transplantation from a young donor. This has been shown to rejuvenation the aging microbiome, improve health, and even extend life span in short-lived laboratory species.

The trillions of microorganisms found in and on the human body (the microbiota) offer tremendous potential in understanding aging. The microbiome (the aggregate genetic content of the microbiota) exceeds the human genome by multiple orders of magnitude. Microorganisms colonize numerous sites in and on the body, with the greatest extent of colonization occurring within the gastrointestinal (GI) tract. Extensive and rigorous prior research has emphasized the key role that the gut microbiota has in host health and disease, including contributions to diseases associated with aging such as cancer, Parkinson's disease, obesity, and type 2 diabetes. Yet, despite remarkable progress in understanding the cellular and molecular mechanisms through which the microbiome contributes to individual diseases linked to aging, the net effects of the microbiome for the aging process or the potential for manipulating the microbiome to promote healthy aging remain unclear.

The overall association between the human microbiome and age is strong enough that it is possible to predict biological age with striking precision with the microbiome. An initial proof-of-concept was demonstrated in early life, in which a "microbiota maturity index" established in healthy individuals was delayed in the context of malnutrition. More recently, machine learning tools have enabled the accurate prediction of age in adults from distal gut metagenomic data with a mean absolute error of 6 to 8 years. The composition of the microbiota found in other body habitats, including the skin and oral cavity, is also linked to age.

In animal studies, the microbiome can decrease life span in older animals. In C. elegans, GI accumulation of Escherichia coli contributes to age-related death. Removal of germ-free D. melanogaster from sterile conditions reduces life span in adults. More recently, the detrimental effects of the microbiome in aging animals has been studied using the African turquoise killifish. Middle-aged (9.5-week-old) killifish treated with antibiotics outlived untreated fish, suggesting that the microbiota impairs life span in older killifish. Remarkably, inoculation with the GI microbiota of 6-week-old killifish significantly increased the life span of middle-aged killifish groups.

These findings are also relevant to mammals. Work in two mouse models of progeria (a human premature aging syndrome) supports the potential for microbiome-based interventions to extend life span. The gut microbiota was altered in prematurely aging mice, including a significant decrease in Akkermansia muciniphila in a model of the most common human progeria syndrome. As in killifish, fecal microbiota transplantation (FMT) from wild-type mice significantly increased the life span of transgenic prematurely aging recipient mice. Even more excitingly, the Verrucomicrobium A. muciniphila, a common member of the human gut microbiota, was sufficient to extend life span in the mice. These results provide a major step towards identifying the cellular and molecular mechanisms responsible for microbiota-dependent changes in life span as well as an important step towards the potential translation of these results to humans.