Genetic association of the gut microbiota with epigenetic clocks mediated by inflammatory cytokines: a Mendelian randomization analysis.

Background: A new aging biomarker epigenetic clock has been developed. There exists a close link between aging and gut microbiota, which may be mediated by inflammatory cytokines. However, the relationship between the epigenetic clock, gut microbiota, and the mediating substances is unclear. Methods: Two large genome-wide association meta-analyses were analyzed by two-sample Mendelian randomization. The results between gut microbiota and epigenetic clock were investigated using the four methods (Inverse variance weighted, MR-Egger, weighted median, MR-PRESSO). Genetic correlation was measured by Linked disequilibrium score regression (LDSC). The correctness of the study direction was checked by the Steiger test. Cochran's Q statistic and MR-Egger intercept were used as sensitivity analyses of the study. The two-step method was used to examine the mediating role of inflammatory cytokines. We use the Benjamini-Hochberg correction method to correct the P value. Results: After FDR correction, multiple bacterial genera were significantly or suggestively associated with four epigenetic clocks (GrimAge, HannumAge, IEAA, PhenoAge). And we detected several inflammatory factors acting as mediators of gut microbiota and epigenetic clocks. Conclusion: This study provides genetic evidence for a positive and negative link between gut microbiota and aging risk. We hope that by elucidating the genetic relationship and potential mechanisms between aging and gut microbiota, we will provide new avenues for continuing aging-related research and treatment.