The composition of the gut microbiome, the species present and their relative proportions, varies between individuals. Further, the balance of populations shifts with age in ways that are harmful to health. A growing body of animal and human data suggests that the composition of the gut microbiome is just as influential on long-term health as lifestyle choices such as level of physical activity. Some inroads have been made into identifying distinct features of the gut microbiome that are characteristic of specific age-related conditions, or of long-lived individuals.
As is the case for gene variants, even very small effects on mortality risk will lead to sizable enrichment of a specific gut microbiome characteristic in long-lived people. Thus we might expect that most of what is discovered via this sort of research will be of little practical use as a basis for interventions to slow aging and extend healthy life span. Nonetheless, it is interesting to watch the research community move from identifying specific microbial species that are present in greater numbers in long-lived individuals to trying to figure out exactly what those microbes are doing to increase the odds of living longer.
Biosynthetic potential of the gut microbiome in longevous populations
The gut microbiome plays a pivotal role in combating diseases and facilitating healthy aging, and natural products derived from biosynthetic gene clusters (BGCs) of the human microbiome exhibit significant biological activities. However, the natural products of the gut microbiome in long-lived populations remain poorly understood. Here, we integrated six cohorts of long-lived populations, encompassing a total of 1,029 fecal metagenomic samples, and employed the metagenomic single sample assembled BGCs (MSSA-BGCs) analysis pipeline to investigate the natural products and their associated species.
Our findings reveal that the BGC composition of the extremely long-lived group differed significantly from that of younger elderly and young individuals across five cohorts. Terpene and Type I PKS BGCs were enriched in the extremely long-lived, whereas cyclic-lactone-autoinducer BGCs were more prevalent in the young. Association analysis indicated that terpene BGCs were strongly associated with the abundance of Akkermansia muciniphila, which was also more abundant in the long-lived elderly across at least three cohorts.
We assembled 18 A. muciniphila draft genomes using metagenomic data from the extremely long-lived group across six cohorts and discovered that they all harbor two classes of terpene BGCs, which aligns with the 97 complete genomes of A. muciniphila strains retrieved from the NCBI database. The core domains of these two BGC classes are squalene/phytoene synthases involved in the biosynthesis of triterpenes and tetraterpenes. Furthermore, the abundance of fecal A. muciniphila was significantly associated with eight types of triterpenoids. Targeted terpenoid metabolomic analysis revealed that two triterpenoids, Holstinone C and colubrinic acid, were enriched in the A. muciniphila culture solution compared to the medium, thereby confirming the production of triterpenoids by A. muciniphila. The natural products derived from the gut of long-lived populations provide intriguing indications of their potential beneficial roles in regulating health.
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