Telomere Length Is a Driving Hallmark for Aging-Related Biochemical Hallmarks: Evidence From the Shared Genetic Effect and Causal Inference.

Telomere shortening is an important sign and driving factor of aging, but its association mechanisms and causal effects with other aging-related biochemical hallmarks are largely unknown. This study first performed comprehensive genetic analyses (eg, shared genetic analysis, pleiotropic analysis, and gene enrichment analysis) to detect the underlying molecular mechanisms for the associations between telomere length (TL) and aging-related biochemical hallmarks. Then, further bidirectional Mendelian randomization (MR) analyses investigated the causal effects between TL and other biochemical hallmarks. The genetic correlations were negative between TL and growth differentiation factor-15 (GDF15) (p = .024), C-reactive protein (p = .007), hemoglobin A1c (p = .007), and red blood cell (RBC) (p = .022), but positive between TL and insulin-like growth factor 1 (IGF-1) (p = .002) and white blood cell counts (p = .007). The increased TL has causal effects on the low levels of GDF15 (p = 3.73E-06), sex hormone binding globulin (p = 6.30E-06), testosterone (p = 5.56E-07), fasting insulin (p = 2.67E-05), and RBC (p = 1.54E-05), but the higher levels of IGF-1 (p = 3.24E-07). In conclusion, the observed phenotypic correlations between TL and aging-related biochemical hallmarks may arise from a combination of shared genetic components and causal effects. Telomere length is regarded as a driving hallmark for aging-related biochemical hallmarks.