The Relationship Between the Gut Microbiome and Declining Immune Function in Aging

The composition of the gut microbiome changes with age, becoming less helpful and more inflammatory as the proportion of actively harmful bacteria grows. There are many contributing causes with plausible supporting evidence in the scientific literature, including dietary changes characteristic of late life, immune aging, intestinal tissue dysfunction that is downstream of stem cell aging or senescent cell accumulation, and so forth. As is often the case in these matters, it remains unclear as to which of these causes are the most relevant targets for the development of therapies.

That said, it is possible to produce some reversal of aspects of microbiome aging in mice by innoculation with flagellin. This spurs the immune system to more aggressively destroy problematic gut microbes that manufacture flagellae in order to move into gut tissue. That this intervention is beneficial to a meaningful degree suggests that immune aging is an important cause of harmful shifts in gut microbiome populations. In fact, one can argue for a bidirectional relationship, in which the immune system falters in its gardening of the microbiome with advancing age, but a part of that faltering is caused by the activities of inflammatory microbes.

The aging gut microbiome and its impact on host immunity

The microbiome plays a fundamental role in the maturation, function, and regulation of the host immune system from birth to old age. In return, the immune system has co-evolved a mutualistic relationship with trillions of beneficial microbes residing our bodies while mounting efficient responses to fight invading pathogens. As we age, both the immune system and the gut microbiome undergo significant changes in composition and function that correlate with increased susceptibility to infectious diseases and reduced vaccination responses. Emerging studies suggest that targeting age-related dysbiosis can improve health- and lifespan, in part through reducing systemic low-grade inflammation and immunosenescence - two hallmarks of the aging process. However, a cause and effect relationship of age-related dysbiosis and associated functional declines in immune cell functioning have yet to be demonstrated in clinical settings.

Given the ever-growing impact of the gut microbiome on the host immune system, it is reasonable to speculate that restoring age-related declines in gut microbial richness and function - be it through personalized nutrition or supplements - may represent a prophylactic measure to fight functional declines in immune fitness. In this context, prebiotics, probiotics, and postbiotics or synbiotics with the ability to reinforce immunity through supporting intestinal barrier integrity or by regulating inflammatory processes have been tested in clinical settings. However, a lack of consistency between studies, strain specific differences or doses, prebiotic nature and quantity, or age and medical conditions of the subjects have made it difficult to validate the effectiveness of such approaches to reinforce age-associated declines in host-immune fitness.

None the less, mining the gut microbiome is a treasure trove waiting to be unlocked, and gerontology is no exception here. As exemplified by numerous preclinical studies, restoration of a youthful microbiome has rejuvenating potential for the aged host through sustaining immunity and health-span. Thus, a better understanding of the dynamic age-related changes in gut microbial community structures and associated metabolome, how such alterations affect cellular immune networks and how these pathways can be therapeutically targeted will have wide-reaching implications for future strategies to reinforce or even rejuvenate the aging immune system.