Association of lipidome with senility and the mediated effect of metabolites: A Mendelian randomization study.

The aim of this study was to assess the causal effects of lipidome on senility and the mediated effects of metabolites by Mendelian randomization (MR). Lipidome, metabolites, and senility datasets were acquired in genome-wide association study, and single nucleotide polymorphisms were screened according to the underlying assumptions of MR. Subsequently, inverse variance-weighted was used as the primary method to analyze the causal effect of lipidome on senility and the mediated effect of metabolites. Finally, MR-Egger intercept, Cochran Q, and leave-one-out sensitivity analysis were used to assess horizontal pleiotropy, heterogeneity, and robustness of the results, respectively. The MR analysis showed that phosphatidylcholine (PC) (18:2_0:0) increased genetic susceptibility to senility by reducing X-17690 levels (mediated proportion 7.36%, P = .033); PC (16:0_22:5) (mediated proportion 29.20%, P < .001) and PC (18:0_22:5) (mediated proportion 25.60%, P < .001) increased genetic susceptibility to senility by reducing dimethylglycine levels. Additionally, phosphatidylethanolamine (PE) (18:0_20:4) decreased genetic susceptibility to senility by increasing linoleoyl-arachidonoyl-glycerol (18:2/20:4) [1] levels (mediated proportion 11.30%, P < .001); PE (18:0_20:4) reduced genetic susceptibility to senility by reducing the glucose to N-palmitoyl-sphingosine (d18:1 to 16:0) ratio (mediated proportion 11.20%, P = .002). These results were free of horizontal pleiotropy and heterogeneity and were robust. Our findings revealed 5 pathways for lipidome regulating senility through metabolites. Lipidome components, including PC (18:2_0:0), PC (16:0_22:5), PC (18:0_22:5), and PE (18:0_20:4), as well as metabolites such as X-17690, linoleoyl-arachidonoyl-glycerol (18:2/20:4) [1], dimethylglycine, and glucose to N-palmitoyl-sphingosine (d18:1 to 16:0) ratio, may play an important role in the regulation of senility.