Microbiota and Aging

Aging is a process leading to a generalized decline of physiological functions. This process depends on individual characteristics such as ethnicity, is genetically determined, and is modulated by environmental factors, including lifestyle, diet, medication use, and changes in gut microbiota. With regards to microbiota variations, they are associated with enteric nervous system degeneration, intestinal motility alterations, and a reduction in the defense system against mucosal barrier dysfunction. There is an overall decrease in the microbiota’s capability to ferment carbohydrates, whereas its capability to ferment proteins increases. Changes can involve both the composition and the stability of gut microbiota.

Normally, Firmicutes and Bacteriodetes are the most represented bacterial phyla in human gut microbiota, with Firmicutes as the predominant microorganisms in adults. However, in the elderly, the ratio is inverted; Bacteriodetes predominate, and the relative proportion of Firmicutes subgroups changes. Moreover, microbiota diversity decreases along with the abundance of species producing butyrate, which modulates the immune response by regulating inflammation mediators such as tumor necrosis factor α (TNF-α), interleukin IL-6, nitric oxide (NO) and IL-10. Also, among butyrate-producing reduced species is Faecalibacterium prausnitzii, a microbe protective against gut inflammation.

Bifidobacteria decrease too, whereas levels of Akkermansia muciniphila, a mucin-degrading bacterium, increase. Finally, in centenarians it is possible to observe the enrichment in potential pathogens, particularly in Proteobacteria. All these changes are also associated with pro-inflammatory IL-6 and IL-8 blood concentrations. Some gut microbiota changes, including the decrease of some butyrateproducing microbes and the increase of inflammation-associated species such as Escherichia coli, are less influenced by external factors than others; such changes may represent the core features of elderly gut microbiota and may be at least in part linked to the chronic activation of the immune system due to immunosenescence. Nevertheless, gut microbiota composition is also influenced by lifestyle factors such as diet.

First, a less diverse diet is linked to reduced gut microbiota diversity, and reduced diversity correlates with increased frailty, inflammatory markers, and impaired health parameters. Second, drastic dietary changes often occur with aging, resulting in the increase of sugars and fat-rich foods, and in reduced intake of plant-origin foods. A decreased consumption of healthy foods is associated with gut microbiota composition. An altered immune response to foods that promote inflammation may exacerbate microbial changes, and dietary factors altering the microbiome may exacerbate inflammation and alter immunity, leading to a two-way link between immunosenescence and dysbiosis.

Other factors that modulate gut microbiota in the elderly are medications, particularly antibiotics. These drugs influence gut microbiota along with the individual’s residential location; beneficial microbes such as bifidobacteria and lactobacilli are more abundant, respectively, in communitydwelling and temporarily hospitalized individuals. Finally, intestinal permeability can increase with age. Physical alterations of the epithelial barrier are associated with increased IL-6 concentrations and may play a role in dysbiosis and inflammaging, the low-grade proinflammatory state that is characteristic of aging associated with the expression of pro-inflammatory cytokines such as IL-6 and TNF-α. During advanced age, the ability to resolve inflammation becomes impaired; this leads to the sustained presence of immunity cells (namely, leukocytes) in tissues, and to the chronic release of such pro-inflammatory molecules even in the absence of acute infection. Gut microbiota is thought to have a role both in the induction and the maintenance of inflammaging, which has been hypothesized to increase the susceptibility to the development of different age-related diseases, including cancer.

Its alterations can participate in this phenomenon in several ways. For example, the lack of Akkermansia and the increase of Proteobacteria is associated with the local and systemic inflammatory response, promoting small intestinal inflammation and systemic T cell activation. Conversely, it has been demonstrated that probiotics (live bacteria providing health benefits when consumed) exert beneficial effects on gut microflora composition and systemic immunity in the elderly. Other microbiome-targeted interventions potentially leading to beneficial effects on age-related inflammation include caloric restriction, a Mediterraneanstyle diet implementation, and the use of nutritional supplements containing polyphenols such as resveratrol. Besides diet, physical activity may be helpful, too. Few human studies have been published to date, but preliminary results on animal models suggest that aerobic exercise could enhance epithelial membrane integrity, increase microbial diversity, and attenuate intestinal inflammation.

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