The gut microbiome is influential on health over the long term, possible as much so as exercise. That said, research related to aging in this part of the field is comparatively recent, and consequently is far less developed than the long-standing evidence for the effects of exercise on mortality and risk of age-related disease. It seems fairly clear that the gut microbiome changes in characteristic ways with age, becoming less helpful and more harmful. Species that produce beneficial metabolites decline in number and activity, while inflammatory microbial populations grow in size, contributing the state of chronic inflammation found in older individuals. Equally, the immune system plays a role in gardening the gut microbiome, and as the immune system declines with age, this gardening fails, allowing detrimental changes to take place. This is a two-way relationship.

There is good evidence in short-lived animal models for fecal microbiota transplant from young individuals to old individuals to reverse age-related changes in the gut microbiome and consequently improve health and life span. It is unknown as to how well such a strategy would work in long-lived humans, meaning how long the beneficial changes last. That said, fecal microbiota transplant is a proven therapy in human medicine, used to cure conditions in which pathological bacteria have overtaken the gut. It is not a stretch to consider expanding on this approach to favorably readjust the aging gut microbiome as a preventative measure to improve health and extend health life expectancy across the population as a whole.

The microbiome: An emerging key player in aging and longevity

During the past two decades, studies have provided evidence that age-associated shifts in the gut microbiome contributes to increased predisposition of aged individuals to certain diseases, including cardiovascular diseases, cancer, obesity, cancers, diabetes, and neurodegenerative diseases. Aging is a complicated process that affects physiological, metabolic, and immunological functions of the organism and thus is accompanied by inflammation and metabolic dysfunctions. The overall age-related increase in chronic inflammation and deterioration of systemic immune system led to coining the term “inflammaging“. A direct causal role of the gut microbiome on host aging has been suggested by a number of studies using various experimental models.

The symbiotic co-existence between the host and microbiota is feasible due to the anatomical separation of microbial species from the host by a physical barrier. The intestinal barrier is responsible for adjusting metabolic homeostasis and systemic antimicrobial responses by detecting microbial-cell components and metabolites through its extensive repertoire of innate immune receptors. Relevant to aging, decline of the immune system in the aged intestinal epithelium have been suggested to contribute to age-onset dysbiosis. An important characteristic of age-onset dysbiosis is reduced microbiota diversity, which is suggested to lead to an expansion of distinct groups of bacteria. Concurrently, bacteria that is reported to be involved in maintenance of immune tolerance in the gut, such as Bifidobacteria and Lactobacilli, are found in reduced level in aged groups, whereas those that are found in increased levels, such as Enterobacteriaceae and Clostridium, are involved in infection and intestinal inflammation stimulation. Together, these studies suggest that the host immune system shapes not only the host’s immune response to microbiome changes, but also the structure of the microbiome itself.

Cumulative evidence has implicated a close functional relationship between the immune system of the host and the microbiome, to an extent that the gut microbiome is important for proper development and expansion of intestinal mucosal and systemic immune system. Supporting the notion that the microbiome can directly shape the immune states of the host, the transcriptomic profile of African turquoise killifish guts derived from animals that received young or old gut microbiota transplants showed clear differences, especially in expression of immune-related genes.

Increased permeability of the intestinal barrier with age has been described across animal species, including worms, flies, mice and rats. Age-related deterioration of intestinal barrier function has been proposed to result in leakage of gut microbes into the systemic circulation, and ultimately lead to increased antigenic load and systemic immune activation. For example, age-associated remodeling of the gut microbiome in mice was shown to result in increased production of pro-inflammatory cytokines and intestinal barrier failure. In Drosophila, the age-related increase in Gammaproteobacteria was suggested to lead to increased intestinal permeability, inflammation, and mortality. The study showed that regardless of chronological age, intestinal dysbiosis serves as an indicator of age-onset mortality in flies.

Microbiome-derived short-chain fatty acids (SCFAs), including butyrate, propionate, acetate, and valerate, are important energy source for the epithelium and ultimately affects hypoxia-inducible factor-mediated fortification of the epithelial barrier. Interestingly, a decline in SCFA levels, including that of butyrate, were observed in aged humans, whereas centenarians presented with a rearrangement in the population of specific butyrate-producing bacteria. Microbiota-derived metabolites has also been reported to play a role in intestinal epithelial stem cell proliferation. For example, butyrate and nicotinic acid, both by-products of the gut microbiota, are involved in suppression and promotion of stem cell proliferation in the colon, respectively. In addition, microbiota-derived neurostimulators, including serotonin, glutamate, gamma-aminobutyric acid, have been reported to regulate proliferation of intestinal epithelial stem cells through the enteric nervous system. Other microbiota-derived metabolites have been shown to directly affect numerous systems of the host, although their functions in relation to host aging is in need of further investigation.