The gut-facial aging axis: A two-sample Mendelian randomization and mediation analysis of gut microbiota, gut microbiota metabolic pathways, and blood metabolites.

Background: Facial aging (FA) is a complex process influenced by both genetic and environmental factors. Gut microbiota (GM), gut microbiota metabolic pathways (GMMPs), and blood metabolites (BMs) have been implicated in the regulation of FA, but the causal and mediating effects of these factors remain unclear.

Methods: We used summary-level data from genome-wide association studies (GWAS) of 16S rRNA gene sequencing data for GM (n = 18 340), GWAS of GMMPs (n = 7738), BMs (n = 24 925), and GWAS of FA (n = 423 999). We applied Mendelian randomization (MR) methods to estimate the causal effects of GM, GMMPs, and BMs on FA. We performed mediation analysis to quantify the proportion of the effects mediated by blood metabolites.

Results: We identified nine genus, two phylum, two families of GM, nine GM metabolic pathways, and 73 BMs that showed potential causal effects on FA. After Bonferroni correction, three BMs remained causally associated with FA, including average number of methylene groups per double bond (β, -0.023; 95% CI, -0.032∼-0.014; p = 3.120×10^-7) and average number of methylene groups in a fatty acid chain (β, -0.031; 95% CI, -0.045∼-0.016; p = 2.062×10^-5), which had strong negative causal effects on FA, and ratio of bisallylic groups to total fatty acids (β, 0.023; 95% CI, 0.017∼-0.029; p = 8.441×10^-15), which had a strong positive causal effect on FA. Mediation analysis revealed that histidine, average number of methylene groups in a fatty acid chain, and triglycerides in chylomicrons and largest VLDL particles mediated the effects of anaerofilum and/ or superpathway of Laspartate and Lasparagine biosynthesis on FA.

Conclusion: Our study provides novel insights into the causal and mediating effects of GM, GMMPs, and BMs on FA. These findings may have implications for the development of new strategies for preventing or delaying FA.