Relationship of α-Klotho with Frailty Index and Sarcopenia: A Bidirectional Mendelian Randomization Study

Previous studies have established associations between alpha-Klotho and frailty or sarcopenia; however, the causal nature of these relationships remains unclear. This study investigates the causal effects of alpha-Klotho on frailty and sarcopenia-related traits using Mendelian randomization (MR). Genetic instruments for circulating alpha-Klotho concentrations, frailty index (FI), low grip strength (LGS), appendicular lean mass (ALM), and walking pace were developed based on data from large genome-wide association studies. Two-sample MR analyses were performed, supplemented by sensitivity analyses to ensure the robustness of the findings. Reverse MR analyses were also conducted to explore potential reverse causation. The findings demonstrated an inverse causal relationship of circulating alpha-Klotho levels with FI (beta = -0.020, 95% confidence interval [95% CI] = -0.036 to -0.004; p = 0.017) and LGS (beta = -0.033, 95% CI = -0.061 to -0.004; p = 0.023). However, no causal relationship was observed between circulating alpha-Klotho levels and ALM or walking pace. Additionally, no evidence of reverse causation was identified between FI or sarcopenia-related traits and circulating alpha-Klotho levels. In conclusion, this MR analysis establishes an inverse causal relationship of circulating alpha-Klotho levels with both FI and LGS.