Broadly, evolutionary selection did not directly work against genetic variants which could be harmful for inherently non- Mendelian late-life phenotypes that was suggested in prior works (Medawar, 1952) and evidently seen in our study. The human genome was established to provide better robustness under an adverse environment, which is markedly different from modern conditions, especially in developed societies (Kuningas et al., 2008). Evolutionary forces (e.g., genetic drift) can be responsible for entirely stochastic change in allele frequencies (Zimmer, 2001). These arguments along with others suggest that even a truly positive effect can be not necessarily replicated in other popula- tions because of the inherent complexity of a net of causation of aging-associated phenotypes, which is not a result of a global genetic program similar to, for instance, the program of develop- ment (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 lack of replication can be evolutionary-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 0.80–0.9 in Asians (Brodde, 2008a). Therefore, an unfavorable role of this allele for the late-life phenotypes (that 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 evolu- tionary selection of the Gln27 allele. Lack of replication, however, might reveal race-specific factors contributing to the late-life

Our analyses and current knowledge about molecular-biologi- cal 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.

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