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

Ben Niu, Jia-Xin Wu, Xiao-Li Huang, Shu-Feng Lei, Fei-Yan Deng
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Abstract

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.

端粒长度是衰老相关生化标志的驱动标志:来自共同遗传效应和因果推论的证据。
端粒缩短是衰老的一个重要标志和驱动因素,但它与其他衰老相关生化标志的关联机制和因果效应在很大程度上还不为人所知。本研究首先进行了全面的遗传分析(如共享遗传分析、多效应分析、基因富集分析),以检测端粒缩短与衰老相关生化标志物之间关联的潜在分子机制。然后,进一步的双向磁共振分析研究了 TL 与其他生化特征之间的因果效应。TL与GDF15 (P = 0.024)、CRP (P = 0.007)、HbA1c (P = 0.007)和RBC (P = 0.022)之间呈负相关,但TL与IGF-1 (P = 0.002)和WBC (P = 0.007)之间呈正相关。TL的增加对低水平的GDF15(P = 3.73E-06)、SHBG(P = 6.30E-06)、睾酮(P = 5.56E-07)、FI(P = 2.67E-05)和RBC(P = 1.54E-05)有因果效应,但对较高水平的IGF-1(P = 3.24E-07)有因果效应。总之,观察到的 TL 与衰老相关生化标志物之间的表型相关性可能是由共同的遗传成分和因果效应共同作用的结果。TL被认为是衰老相关生化标志的驱动标志。
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