Non-causal association between α-klotho and human lifespan: evidence from multi-omics insights

While genetic evidence robustly associates longevity in non-human primates with Klotho protein, such a direct correlation in humans remains elusive. To scrutinize the potential causal link between genetically predicted Klotho levels and human lifespan, we devised a meticulous two-sample Mendelian randomization (MR) analysis, just leveraging single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) and protein quantitative trait loci (pQTLs) as instrumental variables, meticulously analyzing the relationship between serum -klotho and human longevity. By integrating MR estimates across diverse data sources using the fixed-effects inverse-variance weighted (IVW) approach, we consolidated our findings with a fixed-effects meta-analysis, fortified by sensitivity analyses embracing the simple median, weighted median, MR-Egger regression, and MR-pleiotropy residual sum and outlier assessments. Surprisingly, our genome-wide association MR analyses failed to uncover a causal association between Klotho and human lifespan, holding for both experimental and validation cohorts. Furthermore, the analysis grounded in protein quantitative trait loci also yielded no evidence of a causal link, with the sensitivity analyses consistently reinforcing the robustness of our findings. Hence, while animal models suggest a correlation between circulating Klotho and lifespan, this study demonstrates that genetically predicted levels of circulating klotho do not exhibit a direct causal effect on human longevity.