Biological Aging, Adiposity, and Inflammation in Degenerative Spine Disease: Mendelian Randomization and Longitudinal...

Telomere length (TL) is a marker of cumulative biological aging, but whether it causally contributes to degenerative spine disease or reflects upstream metabolic and inflammatory burden remains unclear.

We performed a population-based study integrating two-sample Mendelian randomization (MR) with longitudinal UK Biobank analyses. MR used genetic instruments for leukocyte TL, body mass index (BMI), and C-reactive protein (CRP) against five degenerative spine GWAS outcomes. We estimated direct TL effects after adjustment for BMI and CRP. Observational analyses included 265,805 UK Biobank participants of European ancestry with measured leukocyte TL and no baseline degenerative spine disease. Cox proportional hazards models adjusted for age, sex, BMI, smoking status, and Townsend deprivation index evaluated incident degenerative spine diagnoses, and spine surgery.

We found no evidence that genetically proxied TL was associated with spinal stenosis, spondylosis, disc degeneration, spondylolisthesis, or disc prolapse (all p>0.32). In contrast, genetically proxied BMI and CRP were both associated with spinal stenosis (BMI OR=1.55, p<0.001; CRP OR=1.49, p=0.002) and multiple other degenerative spine outcomes. Observationally, longer TL was associated with lower risk of any degenerative spine disease (HR=0.953, p<0.001), lumbar stenosis (HR=0.943, p<0.001), lumbar decompression (HR=0.962, p=0.005), and all-cause mortality (HR=0.923, p<0.001). Short TL was associated with higher risk of composite spine disease (HR=1.07, p<0.001).

Leukocyte TL was modestly associated with incident degenerative spine disease and lumbar decompression, but did not show a causal effect. TL appears to reflect cumulative biological aging rather than directly drive degenerative spine pathology.