(A) Temporal gut microbiome trajectories across lifespan. The human gut microbiome establishes a more adult-like composition at approx. the age of 3, followed by a long period of relative stability, ending with temporal changes with advanced age [188]. Starting in mid-to-late adulthood, gut microbiomes exhibit a depletion in core abundant taxa, complemented by an increase in rare taxa. This trajectory may originate early in the 40s and continue to develop in the later decades of human life (>65 years) [89]. A highly developed compositional uniqueness of the gut microbiome is a component of healthy ageing, which is amplified in centenarians [89] and supercentenarians [83]. (B) Gut microbiome uniqueness, metabolites and ageing. The degree of uniqueness of gut microbiome in the elderly with decline of the core taxa (e.g. Bacteroidetes and Firmicutes) and increased representation of rare taxa (e.g. Proteobacteria, Archaea, Actinobacteria, Verrucomicrobia and others) is critical in human ageing. The high abundance of microbiome uniqueness in normative ageing is characterised by a distinct change in microbial metabolites, including high activation phenylalanine/tyrosine and tryptophan metabolic pathways, and an increased output in secondary bile acids and SCFAs; low abundance of microbiome uniqueness in the elderlies is reflected in microbial metabolite profile with decreased secondary bile acids and SCFAs, as well as increased phenylalanine/tyrosine and tryptophan metabolic pathways [71,89]. The highly activated phenylalanine/tyrosine and tryptophan pathways, with toxic microbial end products, indicates an increasing burden of gut xenobiotic metabolites in an ageing host. Studies have produced inconsistent results regarding the association between these gut-derived toxins and ageing phenotypes in the elderly [89,189,190]. High plasma concentrations of metabolites like PAG, pCG, pCS, IS and IAA observed in healthy older adults and centenarians suggest that these resilient individuals adapt to, or neutralise the toxicity of microbial compounds. In contrast, those vulnerable to the negative effects of these toxins are predisposed to accelerated ageing and diseases. Notably, owing to high variability and discrepancies in the gut microbiota composition pattern reported between studies, the ratio between microbiome core taxa (e.g. Bacteroidetes and Firmicutes) and rare taxa (e.g. Proteobacteria, Archaea, Actinobacteria, Verrucomicrobia and others) and its changing pattern are only conceptual and are not settled to provide a precise representation at an individual level. Abbreviations: IAA, indole-3-acetic acid; IS, indoxyl sulphate; pCG, p-cresol glucuronide; pCS, p-cresol sulphate.