Identification of gut microbiota causally associated with aging and longevity and mediation roles of the cerebrospinal fluid proteins: proteomic genetic evidence from Mendelian randomization.

Gut microbiota (GM) is implicated in aging biology, yet its dual regulatory role in the distinct yet interconnected processes of lifespan extension and aging remains poorly understood. This study employed genetic approaches to identify GM taxa exerting causal effects on longevity and aging and assess the mediation role of cerebrospinal fluid (CSF) proteins. We leveraged summary statistics of the GM taxa (207 taxa, 7738 participants from the Dutch Microbiome Project), the CSF proteins (7008 aptamers, 3506 participants), and the longevity and aging phenotypes (UK Biobank, Longevity Genomics, and Edinburgh DataShare) from the largest genome-wide association studies so far. We performed bidirectional Mendelian randomization (MR) to explore causal relationships between GM and longevity and aging and two mediation analyses, the two-step MR and the multivariable MR (MVMR), to discover potential mediating proteins. Nine taxa exhibited causal associations with longevity-related phenotypes, such as the Bacteroides vulgatus and Blautia. Three taxa demonstrated causal associations with aging-related phenotypes, such as Streptococcus. Among them, Streptococcus was causally associated with aging (β = 0.3310, P = 0.0019) and lifespan-shortening (β =  - 0.0247, P = 0.0184), while Bacteroides vulgatus associated with aging (β = 0.3884, P = 0.0204) and lifespan-promoting (β = 0.0354, P = 0.0198). Mediation MR analysis found that CSF protein CD28 mediated the causal effects of Streptococcus on longevity (mediation proportion 11.7%, P = 0.0394). These findings establish genetic links between GM, CSF proteins, and longevity and aging-related outcomes, advancing gut-brain axis understanding while offering insights for future mechanistic exploration and clinical investigation.