Associations of smoking, aging, and their interplay with the gut microbiome and chronic disease risk profiles.

INTRODUCTION: Smoking and aging are both linked to chronic disease and gut microbiome, but their joint relationship with microbiome composition remains uncharacterized. This study examined the overlap between smoking- and age-associated gut microbial signals and their associations with cardiovascular diseases. METHODS: We analyzed 6676 participants from a filtered project-specific metadata subset from the Guangdong Gut Microbiome Project together with the public GGMP OTU table. Associations of smoking phenotypes and aging with gut microbiota were examined using multivariable linear models. Additional sensitivity analyses were performed in males only, and robustness analyses were repeated at the family and genus levels. RESULTS: We identified 222 OTUs associated with first-hand smoking and 117 OTUs associated with second-hand smoke exposure. Among never smokers, age was associated with 330 OTUs. Eighty-five OTUs overlapped between smoking- and age-associated signals. Differences in the abundance of these OTU groups between never smokers and daily smokers were more pronounced in younger than older age strata. The smoking- and age-related OTU groups were associated with several cardiometabolic markers, and mediation analysis suggested that systolic blood pressure may partly account for the association between this overlapping microbial signal and ASCVD risk score. In a male-only sensitivity analysis, the central smoking-aging microbial signal remained directionally consistent. Family- and genus-level robustness analyses also supported persistence of selected associations. CONCLUSIONS: In this cross-sectional secondary analysis, smoking and aging were associated with overlapping gut microbiome patterns, with stronger smoking-related deviations in younger adults. These findings support future longitudinal studies of microbiome-linked cardiovascular risk in smoking-exposed populations.