Fig. 3 shows the logarithm of odds ratios of reaching old ages for men and women carrying the Gln27Glu (Fig. 3A) and Glu27Glu (Fig. 3B) genotypes and the Glu27 allele (Fig. 3C). These analyses include a limited subset of the genotyped sample. This subset is maximal for cut-offs at young-old ages (e.g., N = 773 for cut- off = 68 years). The number of SL individuals is, however, the smallest for these cut-offs due to a small number of deaths at those ages (e.g., 33 deaths occurred on or before the cut-off age = 68 years). When the cut-off age increases, the number of SL individuals gradually increases. However, the number of LL subjects (or, equivalently, the total number of individuals in the

4.1. Systemic role of the ADRB2 gene in healthy aging

Our results show that the ADRB2 Gln27Glu polymorphism might be involved in regulation of a broad range of complex aging- associated phenotypes including cancer, MI, IC, and longevity (but not survival). This finding suggests that the role of this polymor- phism in healthy aging can be of a systemic origin that might

4.2. Mechanisms linking systemic genetic health effects with longevity in evolutionary context

provide a genetic rationale for accumulated epidemiological evidence on favorable healthy aging phenotypes of long-lived individuals who have smaller prevalence of cancer, CVD, and better physiological phenotypes (Barzilai et al., 2003; Willcox et al., 2008a,b). Importantly, the effect of the Gln27Glu polymorphism on the risk of cancer might be sex and cancer-site insensitive (see discussion of Fig. 1)—which provides further support for its systemic role. Further evidence follows from the facts that: (i) the effect of the Gln27Glu polymorphism on these aging-associated diseases (Fig. 1) and longevity (Fig. 3) was not altered by common physiological and behavioral risk factors including blood pressure, total and high-density lipoprotein cholesterol, diabetes, BMI, and smoking and (ii) the effect of the Gln27Glu polymorphism holds for overall and healthy longevity (Fig. 3).

The association patterns of the Gln27Glu polymorphism with longevity (Fig. 3) exhibit consistent inverse relationships at younger and older ages supporting antagonistic pleiotropy theory on a change of the functional role of genetic variants with aging (Williams and Day, 2003). The effect of the Glu27 allele tends to be of dominant nature in these associations. This allele, which is protective against the aging-associated diseases, appears to be unfavorable early in life but becomes favorable for longevity at older ages. Fig. 4 helps understand why this role changes with aging.

Fig. 4A shows that the Gln27 allele is significantly more frequent than the Glu27 allele in the young-old population (e.g., who reached ages 65 years, about 40% of the sample, at the end of follow up in 2007)resemblingthepatternfortheentiresample.Thisimpliesthat evolutionary selection likely worked against ancestral Glu27 allele and favored derived Gln27 allele because mortality selection at young ages could not explain the observed proportions given small death rates of adults (e.g., http://www.cdc.gov/nchs/deaths.htm) and infants (Singh and Yu, 1995) in the contemporary U.S.

The systemic role of the polymorphism is further augmented by the consistently unfavorable role of the derived Gln27 allele in etiology of cancer, MI and IC. The ancestral Glu27 allele seems to be playing the protective role for these phenotypes. The mode of inheritance for these alleles is different for cancer, MI, and IC. Specifically, Fig. 1A–C shows the recessive effect of the Glu27 allele on cancer phenotype whereas Fig. 1E and F shows its dominant effect on MI and on compound phenotype of MI and IC.

Fig. 4B shows that frequencies of the Gln27 and Glu27 alleles are thesameinthesampleofindividualswhodiedrelativelyearlyinlife (LS   72 years) whereas the Gln27 allele is significantly more frequent than the Glu27 allele in the LL group (who are predominantly survivors; LS > 72 years) resembling patterns in Fig. 1A. Furthermore, the frequency of the Gln27 allele in the sample of individuals who died later in life (Fig. 4D, LS   83 years) becomes significantlylargerthanthatoftheGlu27allele,whereasfrequencies of these alleles become the same in the LL group (Fig. 4D, LS > 83 years).ThisimpliesthatthefrequencyoftheGln27alleleincreasesin the group of deceased individuals and declines in the LL group who are predominantly survivors (equivalently, the frequency of the Glu27 allele exhibits opposite behavior). This dynamics is explained bysurvivaldisadvantageofcarriersoftheGln27alleleattributableto increasedrisksofcancer,MI,andICasshowninFig.4Cforthecaseof cancer(similarpatternsholdwhendeathsamongMIandICpatients are added). Note that because of the recessive effect of the Glu27 allele on cancer phenotype (Fig. 1A) this protective role is more pronounced for the Glu27Glu homozygote.

immune, vascular, pulmonary, 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).