Common genetic variants of the β2-adrenergic receptor affect its translational efficiency and are associated with human longevity. Ling Zhao, Fan Yang, Ke Xu, Huiqing Cao, Gu-Yan Zheng, Yan Zhang, Jianxin Li, Hanbin Cui, Xiaomin Chen, Zhiming Zhu, Hongbo He, Xianming Mo, Brian K. Kennedy, Yousin Suh, Yi Zeng and Xiao-Li Tian conducted a 10-year follow-up study of the Chinese longitudinal healthy longevity survey to test whether genes encoding key components of the β-adrenergic signaling pathway are associated with human longevity. They selected and genotyped 16 SNPs from ADRB1, ADRB2, ADCY5, ADCY6, and MAPK1 genes. Two SNPs (rs1042718 and rs1042719) of ADRB2 in linkage disequilibrium (D = 1.0; r2 = 0.67) were found to be associated with enhanced longevity in men in two geographically isolated populations. Bonferroni-corrected P-values in a combined analysis were 0.0005-0.0010. Men with haplotype A-C showed an increased probability of becoming centenarians (the frequency of A-C in long-lived and young individuals is 0.332 and 0.250 respectively; OR = 1.49; CI 95% = 1.17-1.88; P = 0.0007), in contrast to those with haplotype C-G (the frequency of C-G in long-lived and young individuals is 0.523 and 0.635 respectively; OR = 0.63; CI 95% = 0.51-0.78). ADRB2 encodes the β2-adrenergic receptor. The haplotype A-C markedly reduces its translational efficiency compared with C-G (P = 0.002) in transfected HEK293 cells. Thus, the data indicate that enhanced production of β2-adrenergic receptors caused by genetic variants is inversely associated with human lifespan. The β-adrenergic signaling pathway is critical to the regulation of vascular tone, cell growth and apoptosis, lipid metabolism, and the immune response. Therefore, it is clinically one of the most common pharmacological targets for treating various cardiovascular diseases and asthma. Because of their protective effects from various types of cardiovascular stresses, beta-receptor blockage was hypothesized to increase longevity (Milne & Hong, 2004). In support, it was recently demonstrated that mice lacking ADCY5, encoding type 5-adenylyl cyclase (AC5), are stress-resistant and experience a 30% increase in median lifespan (Yan et al., 2007). AC5 is a member of the adenylyl cyclase (AC) family that is activated by β-adrenergic receptors (βARs) and is responsible for the production of cAMP in vivo (Roth et al., 2002). Null function of AC5 blocks the signaling transduction of βARs. On the other hand, transgenic mice engineered to overexpress a β2AR in cardiac tissue have reduced lifespan, with males displaying a more dramatic phenotype (Gao et al., 2003). These findings establish a role for βAR signaling in mammalian longevity regulation and also suggest that this pathway may underscore sexual dimorphic features of this complex phenotype. However, a role for βAR signaling in human longevity remains to be established, and it is important to address this question because β-adrenergic agonists and antagonists are widely used in treating various human diseases.incorrectly combined word "b-adrenergic" should be split into "beta-adrenergic". 

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