The causal relationship and metabolic mediation between telomere length and intervertebral disc degeneration: A...

Intervertebral disc degeneration (IVDD) is a common degenerative spinal disorder and a major contributor to low back pain. Although aging is a key risk factor, the causal role of biological aging markers, such as telomere length (TL), in IVDD remains unclear. Moreover, the metabolic pathways underlying this association are largely unexplored. This study employed a 2-sample Mendelian randomization (MR) framework based on genome-wide association study summary data to investigate the causal effect of TL on IVDD risk. Genetic correlation between TL and IVDD was further evaluated using linkage disequilibrium score regression (LDSC). Additionally, we performed a network MR mediation analysis to investigate whether circulating blood metabolites mediate the relationship between TL and IVDD. Univariate MR analysis showed that TL had a significant causal effect on IVDD. (odds ratio = 0.883, 95% CI: 0.835-0.934, P = 1.15 × 10-5). LDSC revealed a significant negative genetic correlation between TL and IVDD (rg = -0.1409, SE = 0.0274, P = 2.6 × 10-7). Mediation analysis identified 16 circulating metabolites as partial mediators, with tyrosine showing the most significant mediating effect. Specifically, genetically predicted TL was negatively associated with tyrosine levels (β = -0.124, 95% CI: -0.159 to-0.089), and elevated tyrosine levels were causally associated with increased IVDD risk (β = 0.113, 95% CI: 0.055-0.172). The indirect effect mediated by tyrosine accounted for 12.78% (95% CI: 7.42%-18.14%) of the total effect of TL on IVDD. This study provides robust genetic evidence supporting a protective effect of longer TL against IVDD, and highlights tyrosine as a potential metabolic mediator in this process. These findings provide new insights about the aging-metabolism-degeneration axis in spinal health and propose telomere maintenance and amino acid metabolism as promising targets for early intervention in intervertebral disc degeneration.