Genetically predicted causal links between gut microbiota and biological aging phenotypes in age-related macular...

Current knowledge regarding the role of gut microbiota (GM) dysbiosis and biological aging in the pathogenesis of age-related macular degeneration (AMD) remains limited. This study aims to explore the causal relationships among these factors in AMD development. Utilizing two-sample bidirectional mendelian randomization (MR), we analyzed genome-wide association study (GWAS) data from 105,248 individuals, including 14,034 early AMD cases, to assess causality between AMD, GM taxa, and biological aging phenotypes such as epigenetic clocks, telomere length, mitochondrial DNA copy number, immune cell traits, and inflammatory proteins. Multivariable MR (MVMR) was employed to evaluate mediation pathways, complemented by sensitivity analyses to ensure robustness. We identified 8 causal GM taxa (including one phylum, one class, one order, one family, and four species) along with 8 GM functional pathways. Additionally, 78 immune cell traits, 3 circulating inflammatory proteins, and DNA methylation PhenoAge acceleration were identified as causal biological aging phenotypes linked to AMD. Mediation analysis revealed three pathways connecting GM functional pathways, immune cell traits, and AMD. Reverse MR analysis highlighted the modifying effects of AMD on GM and other aging phenotypes. This study represents a pioneering effort to identify causal GM taxa associated with the onset of AMD and to unravel potential mechanisms from the perspective of biological aging, providing genetic insights into the connections among gut microbiota, immune cell traits, and AMD.