The ADRB2 gene is implicated in several physiological systems such as immune, vascular, pulmonary, and nervous (Brodde, 2008a,b). Some studies suggest that a common ADRB2 signaling pathway (involving ADRB2-mediated catecholamine, e.g., epinephrine-induced activation of adenylate cyclase through the action of G proteins) interacts with multiple proteins from various cell molecular pathways (Benovic, 2002). This might provide a biological rationale for pleiotropic physiological effects of the ADRB2 gene (Brodde, 2008a; Leineweber et al., 2004). In vascular tissue, for instance, the ADBR2 receptor regulates vasodilation and in healthy myocardium it regulates chronotropic and inotropic responses to endogenous and exogenous adrenergic agents (Brodde and Michel, 1999). The Arg16Gly and Gln27Glu polymorphisms are both associated with vasodilator responsiveness (Brodde, 2008b) and thus can be connected with cardiovascular events. Prior studies, however, are not in agreement on which specific variants of these polymorphisms are associated with enhanced vasodilation (Brodde, 2008b). Our findings are in line with earlier epidemiologic studies that support the protective effect of the Glu27 allele on risks of MI, as documented both in longitudinal population-based studies (e.g., the Cardiovascular Health Study (Heckbert et al., 2003)) and in case-control studies (e.g., Sala et al., 2001). 

Thus, the derived Gln27 allele was selected during evolution because of its favorable role for certain (unknown) conditions beneficial for early life. However, this advantageous effect appears to be not relevant for the oldest-old ages, which follows from the change of the favorable role of the Gln27 allele to an unfavorable one (Fig. 3). This unfavorable role is the result of a survival disadvantage for carriers of the derived Gln27 allele and, respectively, a survival advantage for carriers of the ancestral Glu27 allele associated with late-life health conditions. Given unknown forces driving theAdverse environments, which are markedly different from modern conditions, especially in developed societies (Kuningas et al., 2008), can be responsible for entirely stochastic changes in allele frequencies due to evolutionary forces (e.g., genetic drift) (Zimmer, 2001). These arguments, along with others, suggest that even a truly positive effect may not necessarily be replicated in other populations due to the inherent complexity of the net of causation of aging-associated phenotypes, which is not a result of a global genetic program similar to, for instance, the program of development (Thomas and Clayton, 2004; Vijg and Suh, 2005). As a consequence, replication studies should be accompanied by strategies for revealing potential effect modulators. Our study provides arguments that the lack of replication can be evolutionarily driven. For instance, because evolution has worked differently in Whites, Blacks, and Asians, the frequency of the derived Gln27 allele appears to be markedly different in these ethnic groups, i.e., 0.54-0.65 in Whites, 0.73-0.80 in Blacks, and 0.80-0.90 in Asians (Brodde, 2008a). Therefore, an unfavorable role of this allele for late-life phenotypes (which implies the case of antagonistic pleiotropy) revealed in the FHSO sample of whites might not necessarily be replicated in a sample of Blacks or Asians because these late-life phenotypes may not have driven evolutionary selection of the Gln27 allele. Lack of replication, however, might reveal race-specific factors contributing to late-life phenotypes.

Our analyses and current knowledge about molecular-biological mechanisms of ADRB2 mediating health effects support a systemic role of the ADRB2 gene in healthy aging. We also show that the same allele of the Gln27Glu polymorphism of this gene could be detrimental early in life, but its role may change to a favorable one in late life, implying the phenomenon of antagonistic pleiotropy. These important findings warrant further exploration in other populations.