AbstractGut microbiota associated with longevity plays an important role in the adaptation to damaging stimuli accumulated during the aging process. The mechanism by which the longevity‐associated microbiota protects the senescent host remains unclear, while the metabolites of the gut bacteria are of particular interest. Here, an integrated analysis of untargeted metabolomics and 16S rRNA gene sequencing was used to characterize the metabolite and microbiota profiles of long‐lived individuals (aged ≥90 years) in comparison to old‐elderly (aged 75–89 years), young‐elderly (aged 60–74 years), and young to middle‐aged (aged ≤59 years) individuals. This novel study constructed both metabolite and microbiota trajectories across aging in populations from Jiaoling county (the seventh longevity town of the world) in China. We found that the long‐lived group exhibited remarkably differential metabolomic signatures, highlighting the existence of metabolic heterogeneity with aging. Importantly, we also discovered that long‐lived individuals from the familial longevity cohort harbored a microbiome distinguished from that of the general population. Specifically, we identified that the levels of a candidate metabolite, pinane thromboxane A2 (PTA2), which is positively associated with aging, were consistently higher in individuals with familial longevity and their younger descendants than in those of the general population. Furtherly, functional analysis revealed that PTA2 potentiated the efficiency of microglial phagocytosis of β‐amyloid 40 and enhanced an anti‐inflammatory phenotype, indicating a protective role of PTA2 toward host health. Collectively, our results improve the understanding of the role of the gut microbiome in longevity and may facilitate the development of strategies for healthy aging.