Longevity Code: Lipidome Associations and Mediated Metabolite Effects

The effects of lipidome on longevity and the role of metabolites in between have not been fully elucidated. The purpose of this study was to assess the causal effects of lipidome on longevity and the mediated effects of metabolites using Mendelian randomization (MR).

Data on lipidome, metabolites, and longevity were acquired in the genome-wide association studies, and single-nucleotide polymorphisms meeting the basic assumptions of MR were selected. Subsequently, inverse variance weighted was employed as the primary method to analyze the causal effects of lipidome on longevity and the mediated effects of metabolites. Finally, MR-Egger intercept was used to assess horizontal pleiotropy in the results. Cochran's Q and leave-one-out sensitivity analysis were used to assess the heterogeneity and robustness of the results, respectively.

The MR analysis showed that sterol ester (27:1/18:3) decreased genetic susceptibility to longevity (90th) by reducing ethylenediaminetetraacetic acid (EDTA) levels (mediated proportion: 13.60%; mediated effect: -0.020, 95% confidence interval [CI] -0.039 to -0.002, p = 0.033); triacylglycerol (52:2) decreased genetic susceptibility to longevity (90th) by reducing EDTA levels (mediated proportion: 11.20%; mediated effect: -0.025, 95% CI -0.045 to -0.004, p = 0.020); triacylglycerol (54:5) decreased genetic susceptibility to longevity (90th) by increasing 1-arachidonoyl-gpc (20:4n6) levels (mediated proportion:8.37%; mediated effect: -0.010, 95% CI -0.021 to -9.44e-05, p = 0.048); phosphatidylcholine (O-16:0_18:2) increased genetic susceptibility to longevity (90th) by increasing EDTA levels (mediated proportion: 22.10%; mediated effect: 0.029, 95% CI 0.007-0.050, p = 0.008). MR-Egger intercept showed that these results lacked horizontal pleiotropy (p ≥ 0.05). Cochran's Q and sensitivity analysis showed that the MR results had no heterogeneity and were robust.

The MR analysis revealed four pathways through which lipidome regulates longevity via metabolites. Lipidome such as sterol ester (27:1/18:3), phosphatidylcholine (O-16:0_18:2), triacylglycerol (52:2), and triacylglycerol (54:5), as well as metabolites such as EDTA and 1-arachidonoyl-gpc (20:4n6), may play important roles in longevity.