The composition of the gut microbiome is influential on health, perhaps to a similar degree as diet and exercise choices. This composition changes with age in ways that are detrimental to long-term health, reducing the supply of metabolites necessary for tissue function while increasing the number of microbes capable of provoking chronic inflammatory signaling. Altering the composition of the gut microbiome in lasting ways, such as via flagellin immunization or fecal microbiota transplantation, has been shown to produce benefits to health and longevity in animal studies. Bringing these or related techniques to wider human use remains to be achieved, however, and the presently available approaches of diet and probiotics to adjust the balance of populations in the gut microbiome are not as effective as desired.
The gut microbiome is a salient contributor to human health, with considerable evidence also supporting it as a marker and mediator of healthy aging. The gut microbiome undergoes compositional and functional changes throughout the human lifespan. Studies in model organisms have demonstrated that the gut microbiome affects aging and longevity through metabolic activities that modulate host immunity. This modulation is also present in the centenarian gut microbiomes, with unique characteristics that plausibly contribute to longevity, including increased microbial and metabolic diversity, enriched beneficial taxa like Akkermansia and Christensenellaceae, and enhanced gut homeostasis.
Mechanistically, the gut microbiome orchestrates the aging process through various pathways. These pathways change with age, with age-related gut dysbiosis reciprocally promoting inflammaging through the decreased production of anti-inflammatory short-chain fatty acids and declined gut barrier integrity. The worsened inflammation amplifies neuroinflammatory responses, triggering cognitive decline through the gut-brain axis. Furthermore, gut dysbiosis also negatively affect muscle mass and function, which in turn exacerbate frailty in the elderly.
Some intriguing questions remain open for investigation. First, the human aging process is composed of nonlinear waves in molecular changes, with approximately 44 and 60 years of age being the two critical periods characterized by the highest number of dysregulated molecules and microbes. These two chronological ages are therefore of research interest, warranting further investigation into strategies based on gut microbiome modulation that could mitigate dysregulation to slow down or, at the very least, alleviate the aging process and reduce disease risk in later life. Second, some microbially derived metabolites, such as phenylacetylglutamine, accelerate host cellular senescence. Identifying gut microbes driving these metabolic processes and targeting them through dietary interventions to reduce the substrates fueling these pathways could provide internal benefits to the aging process.
Link: https://doi.org/10.1186/s12929-025-01179-x
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