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 (e.g., shared genetic analysis, pleiotropic analysis, gene enrichment analysis) to detect the underlying molecular mechanisms for the associations between TL and aging-related biochemical hallmarks. Then, further bidirectional MR analyses investigated the causal effects between TL and other biochemical hallmarks. The genetic correlations were negative between TL and GDF15 (P = 0.024), CRP (P = 0.007), HbA1c (P = 0.007) and RBC (P = 0.022), but positive between TL and IGF-1 (P = 0.002) and WBC (P = 0.007). The increased TL has causal effects on the low levels of GDF15 (P = 3.73E-06), SHBG (P = 6.30E-06), testosterone (P = 5.56E-07), FI (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. TL is regarded as a driving hallmark for aging-related biochemical hallmarks.